Biomarkers For The Diagnosis And Treatment Of Fibrotic Lung Disease

Abstract

The present disclosure provides a method of treating a fibrotic lung disease in a subject comprising administering to the subject an effective amount of a therapeutic agent, wherein the subject is asymptomatic and wherein the subject is at risk of developing the fibrotic lung disease.

Description

RELATED APPLICATIONS

[0001] This application claims the benefit of provisional application U.S. Ser. No. 62/525,087, filed Jun. 26, 2017, and U.S. Ser. No. 62/525,088, filed Jun. 26, 2017, the contents of each of which are herein incorporated by reference in their entirety.

INCORPORATION OF SEQUENCE LISTING

[0002] The contents of the text file named "UNCO-018_001WO_SeqList_ST25.txt," which was created on Jun. 21, 2018 and is 418 KB in size, are hereby incorporated by reference in their entirety.

FIELD OF THE DISCLOSURE

[0003] The disclosure is directed to molecular biology, genetics, and therapeutics for fibrotic lung disease.

BACKGROUND

[0004] Fibrotic pulmonary diseases are progressive and irreversible. Standard therapies are mere palliative as they cannot address the underlying disease mechanism once the subject has progressed to a point at which symptoms are present. Thus, there is a long-felt but unmet need in the field for a method of treating asymptomatic subjects as well as those who are at risk of developing fibrotic pulmonary diseases to prevent onset of the disease, delay onset of the disease, or reduce the severity of disease symptoms, The methods of the disclosure provide a preventative or efficacious treatment, as opposed to a merely palliative treatment, for asymptomatic subjects as well as those subjects at risk of developing the disease.

SUMMARY

[0005] The disclosure provides a method of treating a fibrotic lung disease in a subject comprising administering to the subject an effective amount of a therapeutic agent, wherein the subject is asymptomatic and wherein the subject is at risk of developing the fibrotic lung disease.

[0006] In some embodiments of the methods of the disclosure, the subject presents radiographic Usual Interstitial Pneumonia (UIP). In some embodiments, the subject has fibrotic interstitial lung disease (FILD). In some embodiments, the subject has a blood relative with familial interstitial pneumonia (FIP). In some embodiments, including those embodiments wherein the subject has a blood relative with familial interstitial pneumonia (FIP), the blood relative is a sibling. Alternatively, or in addition, in some embodiments, the subject has a mutation in a sequence encoding Mucin 5B (MUC5B), Telomerase RNA Component (TERC), Family with sequence similarity 13 member A (FAM13A), Telomerase Reverse Transcriptase (TERT), Desmoplakin (DSP), Zinc-alpha 2-Glycoprotein 1 (AZGP1), Oligonucleotide/oligosaccharide-binding Fold Containing 1 (OBFC1), ATPase Phospholipid Transporting 11A (ATP11A), Isovaleryl-CoA dehydrogenase (IVD)/Dispatched RND Transporter Family Member 2 (DISP2), Dipeptidyl Peptidase 9 (DPP9), Sialic Acid Binding Ig-Like Lectin 14 (SIGLEC14), Adrenomedullin 2 (ADM2), Tetraspanin 5 (TSPAN5), Calcium/Calmodulin-Dependent Protein Kinase 1 (CAMKK1), zinc figner with KRAB and SCAN domains 1 (ZKSCAN1), isovaleryl-CoA dehydrogenase (IVD), ATPase phospholipid transporting 11A (AK025511) or Matrix Metalloprotease-7 (MMP-7).

[0007] In some embodiments of the methods of the disclosure, the subject has a mutation in a sequence encoding MUC5B, TERC, FAM13A, TERT, DSP, AZGP1, OBFC1, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7.

[0008] In some embodiments of the methods of the disclosure, the subject has a mutation in a nucleic acid or amino acid sequence encoding a gene or gene product that is upregulated in a subject having a fibrotic pulmonary disease of the disclosure. In some embodiments of the methods of the disclosure, the subject has a mutation in a nucleic acid or amino acid sequence encoding Leukotriene A4 Hydrolase (LTA4H), Surfactant Protein B (SFTPB), Breast Cancer Anti-Estrogen Resistance 3 (BCAR3), C-X-C motif Chemokine Ligand 13 (CXCL13), EPH Receptor A2 (EPHA2), Serum Amyloid A1 (SAA1), Phospholipase A2 Group IIA (PLA2G2A), Insulin-Like Growth Factor Binding Protein 3 (IGFBP3), C-C Motif Chemokine Ligand 28 (CCL28), S100 Calcium Binding Protein A12 (S100A12), Thromboxane A Synthase 1 (TBXAS1), Leukocyte Cell Derived Chemotaxin 1 (LECT1), Complement C3 (C3), Gastrin Releasing Peptide (GRP), C-Reactive Protein (CRP), Vitrin (VIT), Insulin-Like Growth Factor Binding Protein 1 (IGFBP1), Family with Sequence Similarity 173 Member A (FAM173A), Natriuretic Peptide A (NPPA), Secreted Frizzled Related Protein 1 (SFRP1), Ezrin (EZR), Inter-Alpha-Trypsin Inhibitor Heavy Chain Family Member 5 (ITIH5), Pleckstrin and Sec7 Domain Containing 2 (PSD2), Galectin 3 Binding Protein (LGALS3BP), Catenin Beta 1 (CTNNB1), Chromodomain Y Like 2 (CDYL2), Matrix Metallopeptidase 7 (MMPI), Apolipoprotein B (APOB), Proline and Arginine Rich End Leucine Rich Repeat Protein (PRELP), Eukaryotic Translation Initiation Factor 1A, X-linked (EIF1AX), Mesencephalic Astrocyte Derived Neurotrophic Factor (MANF), TNF Receptor Superfamily Member 13C (TNFRSF13C), Deformed Epidermal Autoregulatory Factor 1 transcription factor (DEAF1), Tumor Protein Translationally-Controlled 1 (TPT1), Unc-5 Netrin Receptor B (UNC5B), Phosphatidylethanolamine Binding Protein 1 (PEBP1), Syntaxin 8 (STX8), Polymeric Immunoglobulin Receptor (PIGR), Adenine Phosphoribosyltransferase (APRT), Matrix Metallopeptidase 3 (MMP3), Galectin 7 (LGALS7), Bruton Tyrosine Kinase (BTK), NSFL1 Cofactor (NSFL1C), FER Tyrosine Kinase (FER), Regenerating Family Member 1 Beta (REG1B), SMAD Family Member 2 (SMAD2), Interleukin 1 Receptor Like 1 (IL1RL1), C-C Motif Chemokine Ligand 18 (CCL18), Acid Phosphatase 2 Lysosomal (ACP2), Eukaryotic Translation Initiation Factor 4E Family Member 2 (EIF4E2), Neurexin 3 (NRXN3), IGF Like Family Member 1 (IGFL1), NME/NM23 Nucleoside Diphosphate Kinase 1 (NME1), Potassium Voltage-Gated Channel Isk-Related Family Member 1-Like (KCNE1L) or Neurexophilin 2 (NXPH2).

[0009] In some embodiments of the methods of the disclosure, the subject has a mutation in a nucleic acid or amino acid sequence encoding a gene or gene product that is downregulated in a subject having a fibrotic pulmonary disease of the disclosure. In some embodiments of the methods of the disclosure, the subject has a mutation in a nucleic acid or amino acid sequence encoding Surfactant Protein D (SFTPD), Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH), Histone Cluster 1 H1 Family Member C (HIST1H1C), YTH Domain Containing 1 (YTHDC1), Plexin A1 (PLXNA1), Serine Peptidase Inhibitor Kazal Type 6 (SPINK6), LDL Receptor Related Protein Associated Protein 1 (LRPAP1), Secretoglobin Family 3A Member 1 (SCGB3A1), H2A Histone Family Member Z (H2AFZ) or Chromosome 1 Open Reading Frame 162 (Clorf162).

[0010] In some embodiments of the methods of the disclosure, the subject has a mutation in a sequence encoding MUC5B. In some embodiments, the mutation is a polymorphism in a sequence encoding a MUC5B promoter. In some embodiments, the polymorphism is rs35705950 comprising (SEQ ID NO: 7).

[0011] In some embodiments of the methods of the disclosure, the human subject has a mutation in a sequence encoding TERC. In some embodiments, the mutation is a polymorphism in a sequence encoding TERC or a regulatory sequence thereof. In some embodiments the polymorphism is rs6793295 comprising (SEQ ID NO: 1).

[0012] In some embodiments of the methods of the disclosure, the human subject has a mutation in a sequence encoding intronic FAM13A. In some embodiments, the mutation is a polymorphism in a sequence encoding intronic FAM13A or a regulatory sequence thereof. In some embodiments, the polymorphism is rs2609260.

[0013] In some embodiments of the methods of the disclosure, the human subject has a mutation in a sequence encoding intronic TERT. In some embodiments, the mutation is a polymorphism in a sequence encoding intronic TERT or a regulatory sequence thereof. In some embodiments, the polymorphism is rs4449583.

[0014] In some embodiments of the methods of the disclosure, the human subject has a mutation in a sequence encoding intronic DSP. In some embodiments, the mutation is a polymorphism in a sequence encoding intronic DSP or a regulatory sequence thereof. In some embodiments, the polymorphism is rs2076295.

[0015] In some embodiments of the methods of the disclosure, the human subject has a mutation in a sequence encoding intronic ZKSCAN1. In some embodiments, the mutation is a polymorphism in a sequence encoding intronic ZKSCAN1 or a regulatory sequence thereof. In some embodiments, the polymorphism is rs6963345.

[0016] In some embodiments of the methods of the disclosure, the human subject has a mutation in a sequence encoding intronic OBFC1. In some embodiments, the mutation is a polymorphism in a sequence encoding intronic OBFC1 or a regulatory sequence thereof. In some embodiments, the polymorphism is rs2488000.

[0017] In some embodiments of the methods of the disclosure, the human subject has a mutation in a sequence encoding an AK025511 3' UTR. In some embodiments, the mutation is a polymorphism in a sequence encoding an AK025511 3' UTR or a regulatory sequence thereof. In some embodiments, the polymorphism is rs1278769.

[0018] In some embodiments of the methods of the disclosure, the human subject has a mutation in a sequence encoding IVD. In some embodiments, the mutation is a polymorphism in a sequence encoding intronic IVD or a regulatory sequence thereof. In some embodiments, the polymorphism is rs35700143.

[0019] In some embodiments of the methods of the disclosure, the human subject has a mutation in a sequence encoding intronic DPP9. In some embodiments, the mutation is a polymorphism in a sequence encoding intronic DPP9 or a regulatory sequence thereof. In some embodiments, the polymorphism is rs12610495.

[0020] In some embodiments of the methods of the disclosure, the subject has a mutation in a sequence encoding FAM13A. In some embodiments, the mutation is a polymorphism in a sequence encoding FAM13A or a regulatory sequence thereof. In some embodiments the polymorphism is rs2609255 comprising (SEQ ID NO: 2).

[0021] In some embodiments of the methods of the disclosure, the subject has a mutation in a sequence encoding TERT. In some embodiments, the mutation is a polymorphism in a sequence encoding TERT or a regulatory sequence thereof. In some embodiments the polymorphism is rs2736100 comprising (SEQ ID NO: 3).

[0022] In some embodiments of the methods of the disclosure, the subject has a mutation in a sequence encoding DSP. In some embodiments, the mutation is a polymorphism in a sequence encoding DSP or a regulatory sequence thereof. In some embodiments the polymorphism is rs2076295 comprising (SEQ ID NO: 4).

[0023] In some embodiments of the methods of the disclosure, the subject has a mutation in a sequence encoding AZGP1. In some embodiments, the mutation is a polymorphism in a sequence encoding AZGP1 or a regulatory sequence thereof. In some embodiments the polymorphism is rs4727443 comprising (SEQ ID NO: 5).

[0024] In some embodiments of the methods of the disclosure, the subject has a mutation in a sequence encoding OBFC1. In some embodiments, the mutation is a polymorphism in a sequence encoding OBFC1 or a regulatory sequence thereof. In some embodiments the polymorphism is rs11191865 comprising (SEQ ID NO: 6).

[0025] In some embodiments of the methods of the disclosure, the subject has a mutation in a sequence encoding ATP11A. In some embodiments, the mutation is a polymorphism in a sequence encoding ATP11A or a regulatory sequence thereof. In some embodiments the polymorphism is rs12787690 comprising (SEQ ID NO: 8).

[0026] In some embodiments of the methods of the disclosure, the subject has a mutation in a sequence encoding IVD/DISP2. In some embodiments, the mutation is a polymorphism in a sequence encoding IVD/DISP2 or a regulatory sequence thereof. In some embodiments the polymorphism is rs2034650 comprising (SEQ ID NO: 9).

[0027] In some embodiments of the methods of the disclosure, the subject has a mutation in a sequence encoding DPP9. In some embodiments, the mutation is a polymorphism in a sequence encoding DPP9 or a regulatory sequence thereof. In some embodiments the polymorphism is rs12610495 comprising (SEQ ID NO: 10).

[0028] In some embodiments of the methods of the disclosure, the fibrotic lung disease is pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), an interstitial lung abnormality (ILA), or an asymptomatic ILA. In some embodiments, the fibrotic lung disease is pulmonary fibrosis or IPF. In some embodiments, the fibrotic lung disease is IPF.

[0029] In some embodiments of the methods of the disclosure, the therapeutic agent comprises a N-acetylcysteine, pirfenidone, and nintedanib.

[0030] In some embodiments of the methods of the disclosure, the therapeutic agent comprises pirfenidone. In some embodiments, the effective dosage is administered orally as a capsule or a tablet. In some embodiments, including those embodiments wherein the therapeutic agent comprises pirfenidone, the effective dosage is about 2400 mg/day. In some embodiments, the effective dosage is administered according to an escalating dosage regimen. In some embodiments, including those embodiments wherein the therapeutic agent comprises pirfenidone, the escalating dosage regimen comprises (a) administering to the subject about 800 mg of pirfenidone per day for a first week; (b) administering to the subject about 1600 mg of pirfenidone per day for a second week; and (c) administering to the subject about 2400 mg of pirfenidone per day for the remainder of the treatment. In some embodiments, including those embodiments wherein the therapeutic agent comprises pirfenidone, the escalating dosage regimen comprises (a) administering to the subject a capsule or tablet comprising about 250 mg of pirfenidone three times a day for a first week; (b) administering to the subject two capsules or tablets comprising about 250 mg of pirfenidone three times a day for a second week; and (c) administering to the subject three capsules or tablets comprising about 250 mg of pirfenidone three times a day for the remainder of the treatment. In some embodiments of the escalating dosage regimen, the capsule or tablet comprises 267 mg of pirfenidone.

[0031] In some embodiments of the methods of the disclosure, the therapeutic agent comprises nintedanib. In some embodiments, the effective dosage is administered orally as a capsule or a tablet. In some embodiments, including those embodiments wherein the therapeutic agent comprises nintedanib, the effective dosage is about 300 mg/day. In some embodiments, the effective dosage is about 150 mg administered twice per day, wherein the daily doses are administered about 12 hours apart from one another. In some embodiments, including those embodiments wherein the therapeutic agent comprises nintedanib, the effective dosage is about 200 mg/day. In some embodiments, the effective dosage is about 100 mg administered twice per day, wherein the daily doses are administered about 12 hours apart from one another. In some embodiments, including those embodiments wherein the therapeutic agent comprises nintedanib, the effective dosage is administered according to a modified or interrupted dosage regimen. In some embodiments, the modified or interrupted dosage regimen comprises (a) administering to the subject about 300 mg of nintedanib per day until the subject presents an elevated level of liver enzymes compared to a control level of liver enzymes; (b) administering to the subject about 200 mg of nintedanib per day until the subject presents the control level of liver enzymes; and (c) administering to the subject about 300 mg of nintedanib per day for the remainder of the treatment; wherein the control level of liver enzymes is a level detected in the subject prior to an initiation of the treatment. In some embodiments, including those embodiments wherein the therapeutic agent comprises nintedanib, the modified or interrupted regimen comprises (a) administering to the subject a capsule or tablet comprising about 150 mg of nintedanib twice per day until the subject presents an elevated level of liver enzymes compared to a control level of liver enzymes; (b) administering to the subject two capsules or tablets comprising about 100 mg twice per day until the subject presents an elevated level of liver enzymes compared to a control level of liver enzymes; and (c) administering to the subject a capsule or tablet comprising about 150 mg of nintedanib twice per day for the remainder of the treatment; wherein the control level of liver enzymes is a level detected in the subject prior to an initiation of the treatment.

[0032] In some embodiments of the methods of the disclosure, the therapeutic agent prevents the onset or development of a sign or symptom of the fibrotic lung disease.

[0033] In some embodiments of the methods of the disclosure, the therapeutic agent delays the onset or development of a sign or symptom of the fibrotic lung disease when compared to the expected onset of the sign or symptom in the absence of treatment with the therapeutic agent.

[0034] In some embodiments of the methods of the disclosure, the therapeutic agent reduces the severity of a sign or symptom of the fibrotic lung disease when compared to the expected severity of the sign or symptom in the absence of treatment with the therapeutic agent.

[0035] In some embodiments of the methods of the disclosure, the therapeutic agent reduces the severity of a sign or symptom of the fibrotic lung disease when compared to the expected severity of the sign or symptom in the absence of treatment with the therapeutic agent.

[0036] In some embodiments of the methods of the disclosure, the at least one sign of the fibrotic lung disease is detectable before the subject presents a symptom of the fibrotic lung disease. In some embodiments, the at least one sign comprises gradual or unintended weight loss, clubbing of the fingers or toes, rapid and shallow breathing, fibrotic lesions in one or both lungs detectable by radiography, or a cough. In some embodiments, the symptom comprises shortness of breath during exercise, shortness of breath at rest, a dry and hacking cough, repeated bouts of coughing, and uncontrollable bouts of coughing.

[0037] In some embodiments of the methods of the disclosure, the method prevents the onset of a secondary condition associated with a severe form of the fibrotic lung disease. In some embodiments, a secondary condition comprises a collapsed lung, an infected lung, a blood clot in a lung, lung cancer, respiratory failure, pulmonary hypertension, heart failure or death.

[0038] The disclosure provides a method of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease, comprising administering to a non-human subject a dose of a composition that modifies transcription or translation of a sequence encoding Mucin 5B (MUC5B), Telomerase RNA Component (TERC), Family with sequence similarity 13 member A (FAM13A), Telomerase Reverse Transcriptase (TERT), Desmoplakin (DSP), Zinc-alpha 2-Glycoprotein 1 (AZGP1), Oligonucleotide/oligosaccharide-binding Fold Containing 1 (OBFC1), ATPase Phospholipid Transporting 11A (ATP11A), Isovaleryl-CoA dehydrogenase (IVD)/Dispatched RND Transporter Family Member 2 (DISP2), Dipeptidyl Peptidase 9 (DPP9), Sialic Acid Binding Ig-Like Lectin 14 (SIGLEC14), Adrenomedullin 2 (ADM2), Tetraspanin 5 (TSPAN5), Calcium/Calmodulin-Dependent Protein Kinase Kinase 1 (CAMKK1) or Matrix Metalloprotease-7 (MMP-7), wherein the dose of the composition is tolerable to the non-human subject and wherein the dose of the composition is therapeutically effective.

[0039] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the method of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease, comprising administering to a non-human subject a composition that modifies an activity of a product of a sequence encoding MUC5B, TERC, FAM13A, TERT, DSP, AZGP1, OBFC1, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7, wherein the dose of the composition is tolerable to the non-human subject and wherein the dose of the composition is therapeutically effective.

[0040] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the composition that modifies transcription or translation decreases or inhibits transcription or translation.

[0041] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the composition decreases or inhibits transcription or translation of a sequence encoding a gene selected from the group consisting of Leukotriene A4 Hydrolase (LTA4H), Surfactant Protein B (SFTPB), Breast Cancer Anti-Estrogen Resistance 3 (BCAR3), C--X--C motif Chemokine Ligand 13 (CXCL13), EPH Receptor A2 (EPHA2), Serum Amyloid A1 (SAA1), Phospholipase A2 Group IIA (PLA2G2A), Insulin-Like Growth Factor Binding Protein 3 (IGFBP3), C-C Motif Chemokine Ligand 28 (CCL28), S100 Calcium Binding Protein A12 (S100A12), Thromboxane A Synthase 1 (TBXAS1), Leukocyte Cell Derived Chemotaxin 1 (LECT1), Complement C3 (C3), Gastrin Releasing Peptide (GRP), C-Reactive Protein (CRP), Vitrin (VIT), Insulin-Like Growth Factor Binding Protein 1 (IGFBP1), Family with Sequence Similarity 173 Member A (FAM173A), Natriuretic Peptide A (NPPA), Secreted Frizzled Related Protein 1 (SFRP1), Ezrin (EZR), Inter-Alpha-Trypsin Inhibitor Heavy Chain Family Member 5 (ITIH5), Pleckstrin and Sec7 Domain Containing 2 (PSD2), Galectin 3 Binding Protein (LGALS3BP), Catenin Beta 1 (CTNNB1), Chromodomain Y Like 2 (CDYL2), Matrix Metallopeptidase 7 (MMPI), Apolipoprotein B (APOB), Proline and Arginine Rich End Leucine Rich Repeat Protein (PRELP), Eukaryotic Translation Initiation Factor 1A, X-linked (EIF1AX), Mesencephalic Astrocyte Derived Neurotrophic Factor (MANF), TNF Receptor Superfamily Member 13C (TNFRSF13C), Deformed Epidermal Autoregulatory Factor 1 transcription factor (DEAF1), Tumor Protein Translationally-Controlled 1 (TPT1), Unc-5 Netrin Receptor B (UNCSB), Phosphatidylethanolamine Binding Protein 1 (PEBP1), Syntaxin 8 (STX8), Polymeric Immunoglobulin Receptor (PIGR), Adenine Phosphoribosyltransferase (APRT), Matrix Metallopeptidase 3 (MMP3), Galectin 7 (LGALS7), Bruton Tyrosine Kinase (BTK), NSFL1 Cofactor (NSFL1C), FER Tyrosine Kinase (FER), Regenerating Family Member 1 Beta (REG1B), SMAD Family Member 2 (SMAD2), Interleukin 1 Receptor Like 1 (IL1RL1), C-C Motif Chemokine Ligand 18 (CCL18), Acid Phosphatase 2 Lysosomal (ACP2), Eukaryotic Translation Initiation Factor 4E Family Member 2 (EIF4E2), Neurexin 3 (NRXN3), IGF Like Family Member 1 (IGFL1), NME/NM23 Nucleoside Diphosphate Kinase 1 (NME1), Potassium Voltage-Gated Channel Isk-Related Family Member 1-Like (KCNE1L) or Neurexophilin 2 (NXPH2).

[0042] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the composition that modifies transcription or translation increases or activates transcription or translation.

[0043] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the composition increases or activates transcription or translation of a sequence encoding a gene selected from the group consisting of Surfactant Protein D (SFTPD), Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH), Histone Cluster 1 H1 Family Member C (HIST1H1C), YTH Domain Containing 1 (YTHDC1), Plexin A1 (PLXNA1), Serine Peptidase Inhibitor Kazal Type 6 (SPINK6), LDL Receptor Related Protein Associated Protein 1 (LRPAP1), Secretoglobin Family 3A Member 1 (SCGB3A1), H2A Histone Family Member Z (H2AFZ) or Chromosome 1 Open Reading Frame 162 (Clorf162).

[0044] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the composition that modifies an activity decreases or inhibits the activity.

[0045] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the composition decreases or inhibits the activity of a sequence encoding a gene selected from Leukotriene A4 Hydrolase (LTA4H), Surfactant Protein B (SFTPB), Breast Cancer Anti-Estrogen Resistance 3 (BCAR3), C--X--C motif Chemokine Ligand 13 (CXCL13), EPH Receptor A2 (EPHA2), Serum Amyloid A1 (SAA1), Phospholipase A2 Group IIA (PLA2G2A), Insulin-Like Growth Factor Binding Protein 3 (IGFBP3), C-C Motif Chemokine Ligand 28 (CCL28), S100 Calcium Binding Protein A12 (S100A12), Thromboxane A Synthase 1 (TBXAS1), Leukocyte Cell Derived Chemotaxin 1 (LECT1), Complement C3 (C3), Gastrin Releasing Peptide (GRP), C-Reactive Protein (CRP), Vitrin (VIT), Insulin-Like Growth Factor Binding Protein 1 (IGFBP1), Family with Sequence Similarity 173 Member A (FAM173A), Natriuretic Peptide A (NPPA), Secreted Frizzled Related Protein 1 (SFRP1), Ezrin (EZR), Inter-Alpha-Trypsin Inhibitor Heavy Chain Family Member 5 (ITIH5), Pleckstrin and Sec7 Domain Containing 2 (PSD2), Galectin 3 Binding Protein (LGALS3BP), Catenin Beta 1 (CTNNB1), Chromodomain Y Like 2 (CDYL2), Matrix Metallopeptidase 7 (MMPI), Apolipoprotein B (APOB), Proline and Arginine Rich End Leucine Rich Repeat Protein (PRELP), Eukaryotic Translation Initiation Factor 1A, X-linked (EIF1AX), Mesencephalic Astrocyte Derived Neurotrophic Factor (MANF), TNF Receptor Superfamily Member 13C (TNFRSF13C), Deformed Epidermal Autoregulatory Factor 1 transcription factor (DEAF1), Tumor Protein Translationally-Controlled 1 (TPT1), Unc-5 Netrin Receptor B (UNC5B), Phosphatidylethanolamine Binding Protein 1 (PEBP1), Syntaxin 8 (STX8), Polymeric Immunoglobulin Receptor (PIGR), Adenine Phosphoribosyltransferase (APRT), Matrix Metallopeptidase 3 (MMP3), Galectin 7 (LGALS7), Bruton Tyrosine Kinase (BTK), NSFL1 Cofactor (NSFL1C), FER Tyrosine Kinase (FER), Regenerating Family Member 1 Beta (REG1B), SMAD Family Member 2 (SMAD2), Interleukin 1 Receptor Like 1 (IL1RL1), C-C Motif Chemokine Ligand 18 (CCL18), Acid Phosphatase 2 Lysosomal (ACP2), Eukaryotic Translation Initiation Factor 4E Family Member 2 (EIF4E2), Neurexin 3 (NRXN3), IGF Like Family Member 1 (IGFL1), NME/NM23 Nucleoside Diphosphate Kinase 1 (NME1), Potassium Voltage-Gated Channel Isk-Related Family Member 1-Like (KCNE1L) or Neurexophilin 2 (NXPH2).

[0046] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the composition that modifies an activity increases or activates the activity.

[0047] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the composition increases or activates the activity of a sequence encoding Surfactant Protein D (SFTPD), Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH), Histone Cluster 1 H1 Family Member C (HIST1H1C), YTH Domain Containing 1 (YTHDC1), Plexin A1 (PLXNA1), Serine Peptidase Inhibitor Kazal Type 6 (SPINK6), LDL Receptor Related Protein Associated Protein 1 (LRPAP1), Secretoglobin Family 3A Member 1 (SCGB3A1), H2A Histone Family Member Z (H2AFZ) or Chromosome 1 Open Reading Frame 162 (C1 orf162).

[0048] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the non-human subject is a mammal.

[0049] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the mammal is genetically-modified.

[0050] In some embodiments of the methods of the disclosure, the genetically-modified mammal is a model organism for the fibrotic lung disease.

[0051] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the fibrotic lung disease is pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), an interstitial lung abnormality (ILA), or an asymptomatic ILA.

[0052] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the fibrotic lung disease is pulmonary fibrosis or IPF.

[0053] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the fibrotic lung disease is IPF.

[0054] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the non-human subject carries a mutation in a sequence encoding MUC5B.

[0055] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the mutation comprises a polymorphism in a sequence encoding a MUC5B promoter.

[0056] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the polymorphism is rs35705950.

[0057] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the non-human subject carries a mutation in a sequence encoding TERC, FAM13A, TERT, DSP, ZKSCAN1, AZGP1, OBFC1, MUC5B, AK025511, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7.

[0058] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the composition prevents the onset or development of a sign or symptom of the fibrotic lung disease.

[0059] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the composition delays the onset or development of a sign or symptom of the fibrotic lung disease when compared to the expected onset of the a sign or symptom in the absence of treatment with the composition.

[0060] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the composition delays the onset or development of a sign or symptom of the fibrotic lung disease when compared to the expected onset of the sign or symptom when treated using a standard therapeutic intervention.

[0061] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the composition reduces the severity of a sign or symptom of the fibrotic lung disease when compared to the expected severity of the sign or symptom in the absence of treatment with the composition.

[0062] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the composition reduces the severity of a sign or symptom of the fibrotic lung disease when compared to the expected severity of the sign or symptom when treated using a standard therapeutic intervention.

[0063] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the standard therapeutic intervention comprises a N-acetylcysteine, pirfenidone, and nintedanib.

[0064] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the standard therapeutic intervention comprises pirfenidone.

[0065] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, an effective dosage of pirfenidone is about 2400 mg/day.

[0066] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the effective dosage is administered orally as a capsule or a tablet.

[0067] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the effective dosage is administered three times per day.

[0068] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the effective dosage is administered according to an escalating dosage regimen.

[0069] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the escalating dosage regimen comprises, administering to the non-human subject about 800 mg of pirfenidone per day for a first week; administering to the non-human subject about 1600 mg of pirfenidone per day for a second week; and administering to the non-human subject about 2400 mg of pirfenidone per day for the remainder of the treatment.

[0070] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the escalating dosage regimen comprises, administering to the non-human subject a capsule or tablet comprising about 250 mg of pirfenidone three times a day for a first week; administering to the non-human subject two capsules or tablets comprising about 250 mg of pirfenidone three times a day for a second week; and administering to the non-human subject three capsules or tablets comprising about 250 mg of pirfenidone three times a day for the remainder of the treatment.

[0071] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the capsule or tablet comprises 267 mg of pirfenidone.

[0072] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the standard therapeutic intervention comprises nintedanib.

[0073] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, an effective dosage of nintedanib is administered orally as a capsule or a tablet.

[0074] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the effective dosage is about 300 mg/day.

[0075] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the effective dosage is about 150 mg administered twice per day, wherein the daily doses are administered about 12 hours apart from one another.

[0076] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the effective dosage is about 200 mg/day.

[0077] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the effective dosage is about 100 mg administered twice per day, wherein the daily doses are administered about 12 hours apart from one another.

[0078] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the non-human subject presents at least one sign of the fibrotic lung disease.

[0079] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the at least one sign comprises gradual or unintended weight loss, clubbing of the fingers or toes, rapid and shallow breathing, fibrotic lesions in one or both lungs detectable by radiography, or a cough.

[0080] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the compound prevents the onset of a secondary condition associated with a severe form of the fibrotic lung disease.

[0081] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, the compound prevents the onset for at 1 year, 2 years, 3 years, 4 years, 5 years or any whole or fractional number of years in between.

[0082] In some embodiments of the methods of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure, secondary condition comprises a collapsed lung, an infected lung, a blood clot in a lung, lung cancer, respiratory failure, pulmonary hypertension, heart failure or death.

[0083] The disclosure provides a composition for the treatment of a fibrotic lung disease identified by a method of the disclosure, including, a method of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease of the disclosure.

[0084] The disclosure provides a method of treating fibrotic lung disease in a human subject of the disclosure comprising administering a therapeutically effective amount of a composition identified by a method of the disclosure, wherein the subject is asymptomatic and wherein the subject is at risk of developing the fibrotic lung disease. In some embodiments, the subject is wild type (e.g. does not comprises a mutation or a sequence variation) with respect to a nucleic acid or amino acid sequence encoding one or more of TERC, FAM13A, TERT, DSP, ZKSCAN1, AZGP1, OBFC1, MUC5B, AK025511, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7.

[0085] In some embodiments of the methods of treating fibrotic lung disease in a human subject of the disclosure by administering a composition identified by a method of the disclosure, the human subject presents radiographic Usual Interstitial Pneumonia (UIP).

[0086] In some embodiments of the methods of treating fibrotic lung disease in a human subject of the disclosure by administering a composition identified by a method of the disclosure, wherein the human subject has fibrotic interstitial lung disease (FILD).

[0087] In some embodiments of the methods of treating fibrotic lung disease in a human subject of the disclosure by administering a composition identified by a method of the disclosure, wherein the human subject has a blood relative with familial interstitial pneumonia (FIP).

[0088] In some embodiments of the methods of treating fibrotic lung disease in a human subject of the disclosure by administering a composition identified by a method of the disclosure, wherein the blood relative is a sibling.

[0089] In some embodiments of the methods of treating fibrotic lung disease in a human subject of the disclosure by administering a composition identified by a method of the disclosure, wherein the human subject has a mutation or a sequence variation in a nucleic acid or an amino acid sequence encoding TERC, FAM13A, TERT, DSP, ZKSCAN1, AZGP1, OBFC1, MUC5B, AK025511, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7.

[0090] In some embodiments of the methods of treating fibrotic lung disease in a human subject of the disclosure by administering a composition identified by a method of the disclosure, the mutation comprises a polymorphism in a sequence encoding a MUC5B promoter.

[0091] In some embodiments of the methods of treating fibrotic lung disease in a human subject of the disclosure by administering a composition identified by a method of the disclosure, the polymorphism is rs35705950.

[0092] In some embodiments of the methods of treating fibrotic lung disease in a human subject of the disclosure by administering a composition identified by a method of the disclosure, the fibrotic lung disease is pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), an interstitial lung abnormality (ILA), or an asymptomatic ILA.

[0093] In some embodiments of the methods of treating fibrotic lung disease in a human subject of the disclosure by administering a composition identified by a method of the disclosure, the fibrotic lung disease is pulmonary fibrosis or IPF.

[0094] In some embodiments of the methods of treating fibrotic lung disease in a human subject of the disclosure by administering a composition identified by a method of the disclosure, the fibrotic lung disease is IPF.

[0095] In some embodiments of the methods of treating fibrotic lung disease in a human subject of the disclosure by administering a composition identified by a method of the disclosure, the method prevents the onset of a secondary condition associated with a severe form of the fibrotic lung disease.

[0096] In some embodiments of the methods of treating fibrotic lung disease in a human subject of the disclosure by administering a composition identified by a method of the disclosure, a secondary condition comprises a collapsed lung, an infected lung, a blood clot in a lung, lung cancer, respiratory failure, pulmonary hypertension, heart failure or death.

BRIEF DESCRIPTION OF THE DRAWINGS

[0097] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0098] FIG. 1 is a map depicting an exemplary hierarchical clustering of differentially expressed genes for pre-pulmonary fibrosis subjects and normal subjects.

[0099] FIG. 2A-B is a pair of volcano plots showing serum sample quality control using Principal component analysis (PCA). FIG. 2A shows before outlier exclusion and FIG. 2B shows after outlier exclusion.

[0100] FIG. 3 is a volcano plot of 3315 plasma proteins, comparing results from 70 patients with established IPF and 70 controls. Solid red symbols represent 57 proteins that were significantly up-regulated and solid blue symbols 12 proteins that were significantly down-regulated in patients with IPF after controlling for multiple comparisons and age/gender/smoking.

[0101] FIG. 4 is a survival plot showing receiver operator curves of predictive model for PrePF in asymptomatic relatives from FIP families. Area Under Curve (AUC) values for each model are as follows: Gene Expression alone (red)=0.83, Clinical Predictors (blue)=0.87, Clinical Predictors+MUC5B genotype (green)=0.87, Clinical Predictors+Gene Expression Score (yellow)=0.95, Clinical Predictors+MUC5B genotype+Gene Expression Score (black)=0.95, indicating that a peripheral blood biomarker panel may improve the diagnostic power of a predictive model for PrePF in an at-risk population.

[0102] FIG. 5 is a graph showing MUC5B expression in IPF (N=203) and unaffected subjects (N=139) stratified by MUC5B promoter variant (rs35705950) genotype.

[0103] FIG. 6A is a microscopic image demonstrating that MUC5B is produced in bronchoalveolar epithelia of patients with IPF (brown staining in photomicrographs). Staining is increased in the airways of patients positive for rs35705950 (TT) compared to WT (GG).

[0104] FIG. 6B is a graph showing the percentage of MUC5B positive area of bronchiolar epithelium. Unbiased stereological assessment of staining demonstrates that the volume fraction of stained airways (% positive area) is significantly greater in both the GT heterozygotes and the TT homozygotes.

[0105] FIG. 7A-B is series of bar graphs showing that Scgb1a1- and SFPTC promoter show significant worsening of fibrosis (hydroxyproline) after bleomycin while Muc5b-/- mice are protected. FIG. 7A is a series of graphs and FIG. 7B is a series of confocal images showing that the concentration of Muc5b is directly related to the fibroproliferative response to bleomycin. Representative images from second harmonic generation (SHG) demonstrate increased lung collagen (red) in transgenic mice following bleomycin injury.

[0106] FIG. 8 is bar graph showing that the baseline expression of ER stress genes in lung tissue from WT and Scgb1a1 Muc5bTg mice. Muc5bTg mice have greater ER stress gene expression than their WT littermates (all genes in the ER stress pathway, with p<0.05). Bleomycin also induces ER stress (data not shown).

[0107] FIG. 9 is a pair of microscopic images showing enhanced CHOP (Ddit3) protein in wild type (WT, top photograph) and Scgb1a1-Muc5bTg mice (bottom photograph) after repeat bleomycin.

[0108] FIG. 10 is a pair of microscopic images and corresponding graphs showing the expanded mucus layer and decreased mucociliary transport in SFTPC-Muc5bTg mice compared to littermate wild-type mice. Statistical differences were assessed by Mann-Whitney U Test.

[0109] FIG. 11 is a series of schematic diagram showing that the MUC5B variant and other biomarkers can identify an at-risk population or those with PrePF, establishing the opportunity for primary and secondary prevention of IPF. The `at-risk` population and the population with PrePF is large (19% with the MUC5B promoter variant and 1.8% of individuals .gtoreq.50 years of age respectively), IPF is diagnosed in a small population with established, end-stage disease and PrePF can be identified using the MUC5B variant rs35705950. Results indicate that PrePF (detected via chest CT scan) is associated with a poor prognosis suggesting that PrePF may be a harbinger of IPF.

[0110] FIG. 12 is a schematic diagram showing a method of screening at-risk populations (family members of patients with IPF) to identify individuals with PrePF. Focus is placed on identifying the genetic variants and biomarkers that increase the yield of PrePF on HRCT scan, in addition to gender, age, and physiology scores.

[0111] FIG. 13 is a table describing the baseline characteristics of patients with rheumatoid arthritis.

[0112] FIG. 14 is a table describing the genotypic association of MUC5B rs35705950 single nucleotide polymorphism in patients with RA, with and without interstitial lung disease

[0113] FIG. 15 is a table describing the dominant genotypic association of MUC5B rs35705950 single nucleotide polymorphism in patients with RA-ILD and a usual interstitial pneumonia or possible usual interstitial pneumonia pattern (RA-UIP) and in patients with RA-ILD and a pattern inconsistent with usual interstitial pneumonia (RA non-UIP).

[0114] FIG. 16A is a forest plot of odds ratios {OR) and 95% confidence intervals {C1) depicting the lack of association of the MUC5B rs35705950 promoter variant with RA without 1LD {RA-nolLD). The boxes indicate OR, and the horizontal lines indicate 95% C1 for the best-fitting genetic model for each association test. The black dotted line represents a mean OR value of 1. The red boxes and red lines indicate the overall OR and 95% C1, respectively. For comparisons between RA cases and controls, the associations were adjusted for the country of origin and sex. For intra-RA cases comparisons, the associations were adjusted for the country of origin, sex, age at inclusion and smoking.

[0115] FIG. 16B is a forest plot of odds ratios (OR) and 95% confidence intervals {C1) depicting the additive genotypic association of the MUC5B rs 35705950 promoter variant with RA-ILD. The red dotted line represent the mean value of overall OR value. The boxes indicate OR, and the horizontal lines indicate 95% C1 for the best-fitting genetic model for each association test. The black dotted line represents a mean OR value of 1. The red boxes and red lines indicate the overall OR and 95% C1, respectively. For comparisons between RA cases and controls, the associations were adjusted for the country of origin and sex. For intra-RA cases comparisons, the associations were adjusted for the country of origin, sex, age at inclusion and smoking.

[0116] FIG. 16C is a forest plot of odds ratios {OR) and 95% confidence intervals {C1) depicting dominant genotypic association of the MUC5B re35705950 promoter variant with ILD among patients with RA and those with the usual interstitial pneumonia or possible usual interstitial pneumonia (UIP) pattern. The boxes indicate OR, and the horizontal lines indicate 95% C1 for the best-fitting genetic model for each association test. The red dotted line represent the mean value of overall OR value. The black dotted line represents a mean OR value of 1. The red boxes and red lines indicate the overall OR and 95% C1, respectively. For comparisons between RA cases and controls, the associations were adjusted for the country of origin and sex. For intra-RA cases comparisons, the associations were adjusted for the country of origin, sex, age at inclusion and smoking.

[0117] FIG. 17 is a series of photographs depicting MUC5B expression in explanted lung issue from rheumatoid arthritis associates interstitial lung disease. Representative lung tissue images from unaffected control (GG genotype, Panel A), RA-ILD case #1 (GG genotype, Panel B), and RA-ILD case #2 (GT genotype, Panel C). Low power views with high power view insets identified. Panel A--low power view of normal lung; top and middle insets with high power view of bronchiole with MUC5B staining; bottom inset with high power view of alveolar epithelia. Panel B and C--low power view of the usual interstitial pneumonia pattern in explanted lung tissue of RA-ILD; top inset with high power view of bronchiole with MUC5B staining; middle and bottom insets with high power view of MUC5B staining in metaplastic epithelia lining honeycomb cysts and MUC5B staining of mucous in honeycomb cysts.

[0118] FIG. 18 is a flow chart depicting the screening and enrollment process for study subjects.

[0119] FIG. 19A-D is a series of photographs depicting High-resolution CT (HRCT) images of: 19A) chest from a study subject whose scan was read as normal, without signs of interstitial lung disease or fibrosis. 19B) HRCT image from subject who was categorized as having "Probable Fibrotic ILD." 19C) Representative HRCT image from subject who was characterized as having "Definite Fibrotic ILD." 19D) HRCT image from a case of previously diagnosed, established Idiopathic Pulmonary Fibrosis (IPF) in one of the study families.

[0120] FIG. 20 is a table depicting a summary of characteristics of study subjects used in quantitative CT Analyses.

[0121] FIG. 21A-F is a series of photographs depicting representative axial HRCT images visually assessed as "No Fibrosis" (21A), "Probable Fibrotic ILD" (21C) and "Definite Fibrotic ILD" (E). Below each is the corresponding quantitative HRCT results for the above scan: (21B) "No Fibrosis" fibrosis extent 1.7% (fibrosis score=0.55), (21D) "Probable Fibrotic ILD" fibrosis extent 18.5% (fibrosis score 2.92), (F) "Definite Fibrotic ILD" fibrosis extent 35.5% (fibrosis score 3.60), Classification results color coded as follows: green=normal lung, blue=airway, yellow=reticular abnormality, magenta=ground glass opacity, red=honeycombing.

[0122] FIG. 22 is a table depicting Screening Cohort Subject Characteristics. * DNA available on a total of 489 subjects (404 No Fibrosis and 75 PrePF subjects). ** Odds ratios reported in this table were calculated from a mixed effects logistic regression model including age (as a continuous variable), male sex, ever smoker (yes/no), and MUC5B promoter variant (rs35705950) genotype. ***In the reported model, rs35705950 coded as a dominant allele; in log-additive genetic model, p=0.05, as well.

[0123] FIG. 23 is a table depicting patterns of CT abnormalities in scans with probable or definite fibrotic ILD. * Because a confident single diagnosis was relatively uncommon, most cases included consideration of several patterns. For this reason, the percentages add up to more than 100%.

[0124] FIG. 24 is a box plot depicting fibrosis score by visual diagnosis. Boxplots of fibrosis scores based on quantitative HRCT assessment for each visual diagnosis category. Fibrosis score means were significantly different (ANOVA, p<0.0001) across groups defined by visual diagnosis. Comparison of fibrosis score between groups showed significant differences for all comparisons (p<0.01 for all).

[0125] FIG. 25A-C is a series of graphs depicting Receiver Operating Characteristic (ROC) curves for quantitative imaging measures of Fibrosis and PrePF. FIG. 5A depicts ROC curves for visual diagnosis compared to log HAA scores. FIG. 5B depicts ROC Curves for visual diagnosis compared to fibrosis scores. ROC analysis showed that fibrosis score discriminates subjects with visual diagnosis of PrePF. Average area under the curve (AUC) in fivefold cross validation was 0.85 (range 0.83-0.87) and average accuracy, sensitivity, and specificity in the test partitions were 0.83 (range 0.74-0.86), 0.74 (range 0.56-0.92) and 0.84 (range 0.76-0.89) respectively. Optimal threshold for fibrosis score ranged from 1.40-1.42.

[0126] FIG. 5C depicts Density plots of fibrosis scores for visually diagnosed PrePF (pink) and No Fibrosis (blue) scans--the fibrosis score optimal threshold is indicated with the red line (1.40).

[0127] FIG. 26 is a series of tables depicting Dyspnea questionnaire data. FIG. 26A depicts breathlessness responses for the cohort. FIG. 26B depicts breathlessness responses by Visual CT diagnosis.

[0128] FIG. 27 is a graph that depicts the prevalence of PrePF in FIP Siblings Cohort by Age and MUC5B Genotype. PrePF prevalence in this FIP siblings cohort increases by age, as shown in this graph. By age >60 years, the prevalence of PrePF differed significantly based on MUC5B genotype (*p=0.02). Subjects with the variant are depicted by the red line, while those without it are depicted with the blue line.

[0129] FIG. 28 is a table depicting subject characteristics based on Quantitative Fibrosis Score. Clinical characteristics and genotype breakdown of subjects with quantitative HRCT analyses. The cutoff of 1.4 for the logarithm of fibrosis score is based on analyses presented in the text. * p-value compares characteristic between groups. Linear regression values regress fibrosis score on age, male sex, smoking history, and MUC5B promoter variant. **In the reported model, rs35705950 coded as a dominant allele given small number of TT subjects.

[0130] FIG. 29 is a table depicting an exploratory genetic association study of 13 pulmonary fibrosis susceptibility variants in RA-ILD.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0131] The present disclosure provides a method of treating a fibrotic lung disease in a subject comprising administering to the subject an effective amount of a therapeutic agent, wherein the subject is asymptomatic and wherein the subject is at risk of developing the fibrotic lung disease.

Methods of Identifying a Therapeutic Agent of the Disclosure or Target Thereof

[0132] The disclosure provides a method of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease, comprising administering to a non-human subject a dose of a composition that modifies transcription or translation of a sequence encoding Mucin 5B (MUC5B), Telomerase RNA Component (TERC), Family with sequence similarity 13 member A (FAM13A), Telomerase Reverse Transcriptase (TERT), Desmoplakin (DSP), Zinc-alpha 2-Glycoprotein 1 (AZGP1), Oligonucleotide/oligosaccharide-binding Fold Containing 1 (OBFC1), ATPase Phospholipid Transporting 11A (ATP11A), Isovaleryl-CoA dehydrogenase (IVD)/Dispatched RND Transporter Family Member 2 (DISP2), Dipeptidyl Peptidase 9 (DPP9), Sialic Acid Binding Ig-Like Lectin 14 (SIGLEC14), Adrenomedullin 2 (ADM2), Tetraspanin 5 (TSPAN5), Calcium/Calmodulin-Dependent Protein Kinase Kinase 1 (CAMKK1) or Matrix Metalloprotease-7 (MMP-7), wherein the dose of the composition is tolerable to the non-human subject and wherein the dose of the composition is therapeutically effective.

[0133] The disclosure provides method of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease, comprising administering to a non-human subject a composition that modifies an activity of a product of a sequence encoding MUC5B, TERC, FAM13A, TERT, DSP, AZGP1, OBFC1, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7, wherein the dose of the composition is tolerable to the non-human subject and wherein the dose of the composition is therapeutically effective.

[0134] In some embodiments of the methods of the disclosure, the composition that modifies transcription or translation decreases or inhibits transcription or translation. In some embodiments, the composition decreases or inhibits transcription or translation of a sequence encoding a gene selected from the group consisting of Leukotriene A4 Hydrolase (LTA4H), Surfactant Protein B (SFTPB), Breast Cancer Anti-Estrogen Resistance 3 (BCAR3), C--X--C motif Chemokine Ligand 13 (CXCL13), EPH Receptor A2 (EPHA2), Serum Amyloid A1 (SAA1), Phospholipase A2 Group IIA (PLA2G2A), Insulin-Like Growth Factor Binding Protein 3 (IGFBP3), C-C Motif Chemokine Ligand 28 (CCL28), S100 Calcium Binding Protein A12 (S100A12), Thromboxane A Synthase 1 (TBXAS1), Leukocyte Cell Derived Chemotaxin 1 (LECT1), Complement C3 (C3), Gastrin Releasing Peptide (GRP), C-Reactive Protein (CRP), Vitrin (VIT), Insulin-Like Growth Factor Binding Protein 1 (IGFBP1), Family with Sequence Similarity 173 Member A (FAM173A), Natriuretic Peptide A (NPPA), Secreted Frizzled Related Protein 1 (SFRP1), Ezrin (EZR), Inter-Alpha-Trypsin Inhibitor Heavy Chain Family Member 5 (ITIH5), Pleckstrin and Sec7 Domain Containing 2 (PSD2), Galectin 3 Binding Protein (LGALS3BP), Catenin Beta 1 (CTNNB1), Chromodomain Y Like 2 (CDYL2), Matrix Metallopeptidase 7 (MMPI), Apolipoprotein B (APOB), Proline and Arginine Rich End Leucine Rich Repeat Protein (PRELP), Eukaryotic Translation Initiation Factor 1A, X-linked (EIF1AX), Mesencephalic Astrocyte Derived Neurotrophic Factor (MANF), TNF Receptor Superfamily Member 13C (TNFRSF13C), Deformed Epidermal Autoregulatory Factor 1 transcription factor (DEAF1), Tumor Protein Translationally-Controlled 1 (TPT1), Unc-5 Netrin Receptor B (UNC5B), Phosphatidylethanolamine Binding Protein 1 (PEBP1), Syntaxin 8 (STX8), Polymeric Immunoglobulin Receptor (PIGR), Adenine Phosphoribosyltransferase (APRT), Matrix Metallopeptidase 3 (MMP3), Galectin 7 (LGALS7), Bruton Tyrosine Kinase (BTK), NSFL1 Cofactor (NSFL1C), FER Tyrosine Kinase (FER), Regenerating Family Member 1 Beta (REG1B), SMAD Family Member 2 (SMAD2), Interleukin 1 Receptor Like 1 (IL1RL1), C-C Motif Chemokine Ligand 18 (CCL18), Acid Phosphatase 2 Lysosomal (ACP2), Eukaryotic Translation Initiation Factor 4E Family Member 2 (EIF4E2), Neurexin 3 (NRXN3), IGF Like Family Member 1 (IGFL1), NME/NM23 Nucleoside Diphosphate Kinase 1 (NME1), Potassium Voltage-Gated Channel Isk-Related Family Member 1-Like (KCNE1L) or Neurexophilin 2 (NXPH2).

[0135] In some embodiments of the methods of the disclosure, the composition that modifies transcription or translation increases or activates transcription or translation. In some embodiments, the composition increases or activates transcription or translation of a sequence encoding a gene selected from the group consisting of Surfactant Protein D (SFTPD), Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH), Histone Cluster 1 H1 Family Member C (HIST1H1C), YTH Domain Containing 1 (YTHDC1), Plexin A1 (PLXNA1), Serine Peptidase Inhibitor Kazal Type 6 (SPINK6), LDL Receptor Related Protein Associated Protein 1 (LRPAP1), Secretoglobin Family 3A Member 1 (SCGB3A1), H2A Histone Family Member Z (H2AFZ) or Chromosome 1 Open Reading Frame 162 (C1 orf162).

[0136] In some embodiments of the methods of the disclosure, the composition that modifies an activity decreases or inhibits the activity. In some embodiments, the composition decreases or inhibits the activity of a sequence encoding a gene selected from Leukotriene A4 Hydrolase (LTA4H), Surfactant Protein B (SFTPB), Breast Cancer Anti-Estrogen Resistance 3 (BCAR3), C-X-C motif Chemokine Ligand 13 (CXCL13), EPH Receptor A2 (EPHA2), Serum Amyloid A1 (SAA1), Phospholipase A2 Group IIA (PLA2G2A), Insulin-Like Growth Factor Binding Protein 3 (IGFBP3), C-C Motif Chemokine Ligand 28 (CCL28), 5100 Calcium Binding Protein A12 (S100A12), Thromboxane A Synthase 1 (TBXAS1), Leukocyte Cell Derived Chemotaxin 1 (LECT1), Complement C3 (C3), Gastrin Releasing Peptide (GRP), C-Reactive Protein (CRP), Vitrin (VIT), Insulin-Like Growth Factor Binding Protein 1 (IGFBP1), Family with Sequence Similarity 173 Member A (FAM173A), Natriuretic Peptide A (NPPA), Secreted Frizzled Related Protein 1 (SFRP1), Ezrin (EZR), Inter-Alpha-Trypsin Inhibitor Heavy Chain Family Member 5 (ITIH5), Pleckstrin and Sec7 Domain Containing 2 (PSD2), Galectin 3 Binding Protein (LGALS3BP), Catenin Beta 1 (CTNNB1), Chromodomain Y Like 2 (CDYL2), Matrix Metallopeptidase 7 (MMPI), Apolipoprotein B (APOB), Proline and Arginine Rich End Leucine Rich Repeat Protein (PRELP), Eukaryotic Translation Initiation Factor 1A, X-linked (EIF1AX), Mesencephalic Astrocyte Derived Neurotrophic Factor (MANF), TNF Receptor Superfamily Member 13C (TNFRSF13C), Deformed Epidermal Autoregulatory Factor 1 transcription factor (DEAF1), Tumor Protein Translationally-Controlled 1 (TPT1), Unc-5 Netrin Receptor B (UNC5B), Phosphatidylethanolamine Binding Protein 1 (PEBP1), Syntaxin 8 (STX8), Polymeric Immunoglobulin Receptor (PIGR), Adenine Phosphoribosyltransferase (APRT), Matrix Metallopeptidase 3 (MMP3), Galectin 7 (LGALS7), Bruton Tyrosine Kinase (BTK), NSFL1 Cofactor (NSFL1C), FER Tyrosine Kinase (FER), Regenerating Family Member 1 Beta (REG1B), SMAD Family Member 2 (SMAD2), Interleukin 1 Receptor Like 1 (IL1RL1), C-C Motif Chemokine Ligand 18 (CCL18), Acid Phosphatase 2 Lysosomal (ACP2), Eukaryotic Translation Initiation Factor 4E Family Member 2 (EIF4E2), Neurexin 3 (NRXN3), IGF Like Family Member 1 (IGFL1), NME/NM23 Nucleoside Diphosphate Kinase 1 (NME1), Potassium Voltage-Gated Channel Isk-Related Family Member 1-Like (KCNE1L) or Neurexophilin 2 (NXPH2).

[0137] In some embodiments of the methods of the disclosure, the composition that modifies an activity increases or activates the activity. In some embodiments, the composition increases or activates the activity of a sequence encoding Surfactant Protein D (SFTPD), Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH), Histone Cluster 1 H1 Family Member C (HIST1H1C), YTH Domain Containing 1 (YTHDC1), Plexin A1 (PLXNA1), Serine Peptidase Inhibitor Kazal Type 6 (SPINK6), LDL Receptor Related Protein Associated Protein 1 (LRPAP1), Secretoglobin Family 3A Member 1 (SCGB3A1), H2A Histone Family Member Z (H2AFZ) or Chromosome 1 Open Reading Frame 162 (C1 orf162).

[0138] In some embodiments of the methods of the disclosure, the non-human subject is a mammal. In some embodiments, mammal is genetically-modified. In some embodiments, the genetically-modified mammal is a model organism for the fibrotic lung disease.

[0139] In some embodiments of the methods of the disclosure, the fibrotic lung disease is pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), an interstitial lung abnormality (ILA), or an asymptomatic ILA. In some embodiments, the fibrotic lung disease is pulmonary fibrosis or IPF. In some embodiments, the fibrotic lung disease is IPF.

[0140] In some embodiments of the methods of the disclosure, the non-human subject carries a mutation in a sequence encoding MUC5B. In some embodiments, the mutation comprises a polymorphism in a sequence encoding a MUC5B promoter. In some embodiments, the polymorphism is rs35705950. Alternatively, or in addition, in some embodiments, the non-human subject carries a mutation in a sequence encoding TERC, FAM13A, TERT, DSP, AZGP1, OBFC1, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7.

[0141] In some embodiments of the methods of the disclosure, the composition prevents the onset or development of a sign or symptom of the fibrotic lung disease.

[0142] In some embodiments of the methods of the disclosure, the composition delays the onset or development of a sign or symptom of the fibrotic lung disease when compared to the expected onset of the sign or symptom in the absence of treatment with the composition. In some embodiments, the composition delays the onset or development of a sign or symptom of the fibrotic lung disease when compared to the expected onset of the sign or symptom when treated using a standard therapeutic intervention.

[0143] In some embodiments of the methods of the disclosure, the composition reduces the severity of a sign or symptom of the fibrotic lung disease when compared to the expected severity of the sign or symptom in the absence of treatment with the composition. In some embodiments, the composition reduces the severity of a sign or symptom of the fibrotic lung disease when compared to the expected severity of the sign or symptom when treated using a standard therapeutic intervention.

[0144] In some embodiments of the methods of the disclosure, the standard therapeutic intervention comprises a N-acetylcysteine, pirfenidone, and nintedanib.

[0145] In some embodiments of the methods of the disclosure, the standard therapeutic intervention comprises pirfenidone. In some embodiments, an effective dosage of pirfenidone is about 2400 mg/day. In some embodiments, the effective dosage is administered orally as a capsule or a tablet. In some embodiments, the effective dosage is administered three times per day. In some embodiments, the effective dosage is administered according to an escalating dosage regimen. In some embodiments, the escalating dosage regimen comprises (a) administering to the non-human subject about 800 mg of pirfenidone per day for a first week; (b) administering to the non-human subject about 1600 mg of pirfenidone per day for a second week; and (c) administering to the non-human subject about 2400 mg of pirfenidone per day for the remainder of the treatment. In some embodiments, the escalating dosage regimen comprises (a) administering to the non-human subject a capsule or tablet comprising about 250 mg of pirfenidone three times a day for a first week; (b) administering to the non-human subject two capsules or tablets comprising about 250 mg of pirfenidone three times a day for a second week; and (c) administering to the non-human subject three capsules or tablets comprising about 250 mg of pirfenidone three times a day for the remainder of the treatment. In some embodiments, the capsule or tablet comprises 267 mg of pirfenidone.

[0146] In some embodiments of the methods of the disclosure, the standard therapeutic intervention comprises nintedanib. In some embodiments, an effective dosage of nintedanib is administered orally as a capsule or a tablet. In some embodiments, the effective dosage is about 300 mg/day. In some embodiments, the effective dosage is about 150 mg administered twice per day, wherein the daily doses are administered about 12 hours apart from one another. In some embodiments, the effective dosage is about 200 mg/day. In some embodiments, the effective dosage is about 100 mg administered twice per day, wherein the daily doses are administered about 12 hours apart from one another.

[0147] In some embodiments of the methods of the disclosure, the non-human subject presents at least one sign of the fibrotic lung disease. In some embodiments, the at least one sign comprises gradual or unintended weight loss, clubbing of the fingers or toes, rapid and shallow breathing, fibrotic lesions in one or both lungs detectable by radiography, or a cough.

[0148] In some embodiments of the methods of the disclosure, the compound prevents the onset of a secondary condition associated with a severe form of the fibrotic lung disease. In some embodiments, the compound prevents the onset for at 1 year, 2 years, 3 years, 4 years, 5 years or any whole or fractional number of years in between. In some embodiments, the secondary condition comprises a collapsed lung, an infected lung, a blood clot in a lung, lung cancer, respiratory failure, pulmonary hypertension, heart failure or death.

[0149] The disclosure provides a composition for the treatment of a fibrotic lung disease identified by a method of the disclosure for identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease.

Subjects of the Disclosure

[0150] The disclosure provides a method of treating a fibrotic lung disease in a human subject comprising administering to the subject the composition for the treatment of a fibrotic lung disease identified by a method of the disclosure for identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease, wherein the subject is asymptomatic and wherein the subject is at risk of developing the fibrotic lung disease.

[0151] In some embodiments of the methods of treating a fibrotic lung disease in a human subject of the disclosure, the human subject presents radiographic Usual Interstitial Pneumonia (UIP). In some embodiments, the human subject has fibrotic interstitial lung disease (FILD). In some embodiments, the human subject has a blood relative with familial interstitial pneumonia (FIP). In some embodiments, the blood relative is a sibling. Alternatively, or in addition, in some embodiments, the human subject has a mutation in a sequence encoding MUC5B, TERC, FAM13A, TERT, DSP, AZGP1, OBFC1, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7. In some embodiments, the mutation comprises a polymorphism in a sequence encoding a MUC5B promoter. In some embodiments, the polymorphism is rs35705950.

[0152] In some embodiments of the methods of treating a fibrotic lung disease in a human subject of the disclosure, the fibrotic lung disease is pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), an interstitial lung abnormality (ILA), or an asymptomatic ILA. In some embodiments, the fibrotic lung disease is pulmonary fibrosis or IPF. In some embodiments, the fibrotic lung disease is IPF.

[0153] In some embodiments of the methods of treating a fibrotic lung disease in a human subject of the disclosure, the method prevents the onset of a secondary condition associated with a severe form of the fibrotic lung disease. In some embodiments, the secondary condition comprises a collapsed lung, an infected lung, a blood clot in a lung, lung cancer, respiratory failure, pulmonary hypertension, heart failure or death.

Idiopathic Pulmonary Fibrosis (IPF)

[0154] IPF is localized to the lung and is characterized by a pattern of heterogeneous, subpleural patches of fibrotic, remodeled lung, and often results in death within 3-5 years of diagnosis. IPF affects 5 million people worldwide, disproportionately affects men, is associated with cigarette smoking, increases with age, is inexplicably increasing in prevalence, and is likely underdiagnosed. Most patients with IPF are discovered in the advanced stage when little can be done to influence survival. There is a critical unmet need in idiopathic pulmonary fibrosis (IPF) for an early detection and prevention of IPF. Earlier diagnosis of IPF detects subjects with a lower burden of fibrotic lung disease providing an opportunity for secondary prevention of this progressive disease and changes the clinical approach to patients with IPF from palliative to preventive.

[0155] Early detection and prevention of idiopathic pulmonary fibrosis (IPF) is critical. As demonstrated herein, treatment of subjects at risk for developing PrePF is based on two central concepts of first, understanding that PrePF is essential for primary and secondary prevention of IPF and second, that similar to asymptomatic family members of familial IPF (FIP; .gtoreq.2 family members with IPF), asymptomatic family members of sporadic IPF represent an at-risk population for PrePF. These central concepts are supported by the observation that 1) IPF has a pre-symptomatic phase and PrePF appears to be a harbinger of IPF, 2) familial and sporadic IPF are similar etiologically, 3) MUC5B promoter variant is critical to early disease recognition and 4) identification of PrePF represents an opportunity to prevent extensive lung fibrosis. As shown herein, a common gain-of-function MUC5B promoter variant rs35705950 is a strong risk factor (genetic and otherwise), accounting for at least 30% of the total risk of developing IPF. The MUC5B promoter variant rs35705950 may be used to identify individuals with PrePF. MUC5B promoter variant rs35705950 is also predictive of radiographic progression of PrePF and is present in over 50% of non-Hispanic white patients with IPF and is also associated with unique clinical and biological IPF phenotypes. PrePF can be predicted using a combination of clinical risk factors, the MUC5B promoter variant rs35705950, and a panel of biomarkers. This disclosure provides methods of treating subjects with Preclinical Pulmonary Fibrosis (PrePF) and who may also be at risk for developing IPF. The methods of the disclosure fundmentally change the clinical approach to treating subjects with IPF, shifting the focus from a merely palliative to a proactive and preventive therapy.

Rheumatoid Arthritis-Associated Interstitial Lung Disease (RA-ILD)

[0156] Rheumatoid arthritis (RA) is a common inflammatory and autoimmune disease that is associated with progressive impairment, systemic complications and increased mortality. Interstitial lung disease (RA-ILD) is detected in up to 60% of patients with RA on high-resolution computed-tomography (HRCT), is clinically significant in 10%, and is a leading cause of morbidity and mortality in patients with RA.

[0157] RA-ILD shares several characteristics with idiopathic pulmonary fibrosis (IPF), including common environmental risk factors, the high prevalence of the usual interstitial pneumonia (UIP) pattern, the progressive nature of the disease, and poor survival. The hypothesis of a shared genetic background between IPF and RA-ILD was recently suggested by a whole-exome sequencing (WES) genetic association study in patients with RA-ILD, revealing an excess of mutations in genes in RA-ILD previously associated with familial interstitial pneumonia (FIP) including TERT, RTEL1, PARN and SFTPC.

[0158] The common gain-of-function promoter variant rs3570595013 of the gene encoding mucin5B (MUC5B) is the strongest genetic risk factor for IPF, observed in at least 50% of the cases of IPF and accounting for 30% of the risk of developing this disease. The MUC5B promoter variant is associated with increased expression of MUC5B in lung parenchyma of unaffected controls and cases of IPF. Consequently, it is hypothesized that the MUC5B promoter variant rs35705950 would also contribute to the occurrence of RA-ILD. To test this hypothesis, a multi-ethnic association study of the MUC5B promoter variantand RA-ILD in seven distinct case series was performed.

[0159] The MUC5B promoter variant rs35705950, the strongest genetic risk factor for IPF, is also a strong risk factor for RA-ILD, especially among those with radiographic evidence of UIP. Of note, the effect of the MUC5B promoter variant on the development of ILD associated with RA was similar in magnitude and direction to that observed in IPF.

[0160] The relationship between the MUC5B promoter variant and RA-ILD may be specific to UIP and may not generalizable to other autoimmune conditions of the lung. The MUC5B promoter variant has not been found to be associated with risk of ILDs linked to systemic sclerosis or autoimmune myositis. Unlike these other types of ILD, RA-ILD shares more characteristics with IPF, notably the increased frequency of the UIP pattern (both radiologic and histologic), an increased prevalence of male sex and older age, and genetic susceptibility as assessed by an excess of mutations in genes linked to FIP in a cohort of RA-ILD, and now the MUC5B promoter variant rs35705950.

[0161] The disclosure demonstrates that the MUC5B promoter variant is a risk factor for UIP, and not simply limited to IPF and RA-ILD. In fact, emerging studies have identified the MUC5B promoter variant as a risk factor for chronic hypersensitivity pneumonitis, another condition known to have a sub-phenotype of UIP. Further, since HRCT underestimates the presence of ILD and the UIP pattern of fibrosis, our point estimates for association with the MUC5B variant are likely conservative. Similar to IPF, early forms of RA-ILD can be identified using the MUC5B promoter variant as biomarker.

[0162] The disclosure demonstrates that Muc5b is overexpressed by the bronchoalveolar epithelia and MUC5B mRNA is co-expressed by cells expressing surfactant protein C, as has been shown in IPF. These findings suggest either type 2 alveolar epithelial cells can express MUC5B or that in patients with RA-ILD, the cells in the distal airspace de-differentiate. Importantly, the disclosure demonstrates for the first time that cells that overexpress MUC5B are undergoing ER stress, a recognized mechanism of cell injury and repair. In aggregate, these findings indicate that the gain-of-function MUC5B promoter variant rs35705950 injures alveolar epithelia by inducing ER stress.

[0163] RA-ILD is a complex genetic phenotype with the minor allele of the MUC5B promoter variant rs35705950 identified as a risk factor for the disease. The odds ratios for the association of MUC5B promoter variant with RA-ILD is equivalent to that observed with IPF and substantively higher than those for the most other common risk variants for RA-ILD, including cigarette smoking and the human leukocyte antigen locus for RA.

[0164] The MUC5B promoter variant is a risk factor for UIP in general and may prove relevant beyond RA-ILD and IPF.

[0165] Expression of MUC5B in the bronchoalveolar epithelia co-incident with markers of ER stress suggest that the MUC5B promoter variant may be causing pulmonary fibrosis by initiating microscopic foci of injury and repair.

[0166] The MUC5B promoter variant appears to predict ILD in the RA population, identifying potential opportunities for early ILD detection in patients with RA.

Preclinical Idiopathic Pulmonary Fibrosis

[0167] Better understanding and recognition of early pulmonary fibrosis is critical because medical therapies have been shown to slow progression, not to reverse or even stabilize established fibrosis--therefore, intervention before irreversible fibrosis has become extensive has the potential to improve quality of life and decrease morbidity. While IPF affects approximately 5 million people worldwide, between 1.8 and 14% of the general population .gtoreq.50 years of age have radiologic findings of undiagnosed pulmonary fibrosis. Large cohort studies indicate that interstitial lung abnormalities, postulated to represent early pulmonary fibrosis, are associated with increased mortality, and that most of these abnormalities progress over time. Members of families with 2 or more cases of pulmonary fibrosis (FIP, Familial Interstitial Pneumonia) have been identified as an "at-risk" population. In a previous study of FIP relatives, 14% had interstitial lung abnormalities on high resolution computed tomography (HRCT), and 35% had an abnormal transbronchial biopsy indicating interstitial lung disease.

[0168] HRCT provides visualization of the lung parenchyma and plays a key role in the diagnosis of the Idiopathic Interstitial Pneumonias (IIPs), including IPF. Currently, visual diagnosis by thoracic radiologists, in conjunction with multidisciplinary clinical conference, is the gold standard for diagnosing IIPs. However, visual assessment is imprecise and hampered by inter-observer variation. Quantitative HRCT (qHRCT) evaluation provides measures of fibrosis extent that, in subjects diagnosed with IPF, correlate with degree of physiologic impairment at baseline, and may be more sensitive to subtle changes in disease status than routinely used physiological metrics. The design and utility of quantitative methods in the context of early forms of fibrotic ILD requires further study. Deep learning methods have been increasingly used in imaging to identify and classify CT patterns, and may be particularly valuable in detection of early lung fibrosis.

[0169] PrePF is prevalent among FIP relatives, and a texture-based quantitative method of HRCT analyses is useful in identifying these abnormalities in this population, and key risk factors, including the MUC5B promoter variant, predict those at risk of this disease. PrePF subjects are older, more likely to be male, and more likely to have smoked than the unaffected subjects; additionally, the gain-of-function MUC5B promoter variant rs35705950, which has been shown in prior studies to be associated with pulmonary fibrosis, is more common in PrePF subjects when compared to their unaffected family members. Given the subtlety of the fibrotic change in many of these cases of PrePF, the high prevalence of potential UIP pattern on HRCT scan suggests that PrePF subjects may progress to IPF over time.

Methods for Detecting a Genetic Variant

[0170] The present disclosure also provides methods of detecting the biomarkers of the present disclosure. Methods of detecting a genetic variant are further described in US Application US 2016-0060701A1(the contents of which are incorporated herein by reference in their entirety). The practice of the present disclosure employs, unless otherwise indicated, conventional methods of analytical biochemistry, microbiology, molecular biology and recombinant DNA techniques within the skill of the art. Such techniques are explained fully in the literature. (See, e.g., Sambrook, J. et al. Molecular Cloning: A Laboratory Manual. 3rd, ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y., 2000; DNA Cloning: A Practical Approach, Vol. I & II (D. Glover, ed.); Oligonucleotide Synthesis (N. Gait, ed., Current Edition); Nucleic Acid Hybridization (B. Hames & S. Higgins, eds., Current Edition); Transcription and Translation (B. Hames & S. Higgins, eds., Current Edition); CRC Handbook of Parvoviruses, Vol. I & II (P. Tijessen, ed.); Fundamental Virology, 2nd Edition, Vol. I & II (B. N. Fields and D. M. Knipe, eds.)).

[0171] The methods of the invention are not limited to any particular way of detecting the presence or absence of a genetic variant (e.g. SNP) and can employ any suitable method to detect the presence or absence of a variant(s), of which numerous detection methods are known in the art. Dynamic allele-specific hybridization (DASH) can be used to detect a genetic variant. DASH genotyping takes advantage of the differences in the melting temperature in DNA that results from the instability of mismatched base pairs. The process can be vastly automated and encompasses a few simple principles. Thus, the aspects and embodiments described herein provide methods for assessing the presence or absence of SNPs in a sample (e.g. biological sample) from a subject suspected of having or developing an interstitial lung disease (e.g., because of family history). In certain embodiments, one or more SNPs are screened in one or more samples from a subject. The SNPs can be associated with one or more genes, e.g., one or more genes or other genes associated with mucous secretions as disclosed herein.

[0172] Typically, the target genomic segment is amplified and separated from non-target sequence, e.g., through use of a biotinylated primer and chromatography. A probe that is specific for the particular allele is added to the amplification product. The probe can be designed to hybridize specifically to a variant sequence or to the dominant allelic sequence. The probe can be either labeled with or added in the presence of a molecule that fluoresces when bound to double-stranded DNA. The signal intensity is then measured as temperature is increased until the Tm can be determined. A non-matching sequence (either genetic variant or dominant allelic sequence, depending on probe design), will result in a lower than expected Tm.

[0173] DASH genotyping relies on a quantifiable change in Tm, and is thus capable of measuring many types of mutations, not just SNPs. Other benefits of DASH include its ability to work with label free probes and its simple design and performance conditions.

[0174] Molecular beacons can also be used to detect a genetic variant. This method makes use of a specifically engineered single-stranded oligonucleotide probe. The oligonucleotide is designed such that there are complementary regions at each end and a probe sequence located in between. This design allows the probe to take on a hairpin, or stem-loop, structure in its natural, isolated state. Attached to one end of the probe is a fluorophore and to the other end a fluorescence quencher. Because of the stem-loop structure of the probe, the fluorophore is in close proximity to the quencher, thus preventing the molecule from emitting any fluorescence. The molecule is also engineered such that only the probe sequence is complementary to the targeted genomic DNA sequence.

[0175] If the probe sequence of the molecular beacon encounters its target genomic DNA sequence during the assay, it will anneal and hybridize. Because of the length of the probe sequence, the hairpin segment of the probe will be denatured in favor of forming a longer, more stable probe-target hybrid. This conformational change permits the fluorophore and quencher to be free of their tight proximity due to the hairpin association, allowing the molecule to fluoresce.

[0176] If on the other hand, the probe sequence encounters a target sequence with as little as one non-complementary nucleotide, the molecular beacon will preferentially stay in its natural hairpin state and no fluorescence will be observed, as the fluorophore remains quenched. The unique design of these molecular beacons allows for a simple diagnostic assay to identify SNPs at a given location. If a molecular beacon is designed to match a wild-type allele and another to match a mutant of the allele, the two can be used to identify the genotype of an individual. If only the first probe's fluorophore wavelength is detected during the assay then the individual is homozygous to the wild type. If only the second probe's wavelength is detected then the individual is homozygous to the mutant allele. Finally, if both wavelengths are detected, then both molecular beacons must be hybridizing to their complements and thus the individual must contain both alleles and be heterozygous.

[0177] A microarray can also be used to detect genetic variants. Hundreds of thousands of probes can be arrayed on a small chip, allowing for many genetic variants or SNPs to be interrogated simultaneously. Because SNP alleles only differ in one nucleotide and because it is difficult to achieve optimal hybridization conditions for all probes on the array, the target DNA has the potential to hybridize to mismatched probes. This can be addressed by using several redundant probes to interrogate each SNP. Probes can be designed to have the SNP site in several different locations as well as containing mismatches to the SNP allele. By comparing the differential amount of hybridization of the target DNA to each of these redundant probes, it is possible to determine specific homozygous and heterozygous alleles.

[0178] Restriction fragment length polymorphism (RFLP) can be used to detect genetic variants and SNPs. RFLP makes use of the many different restriction endonucleases and their high affinity to unique and specific restriction sites. By performing a digestion on a genomic sample and determining fragment lengths through a gel assay it is possible to ascertain whether or not the enzymes cut the expected restriction sites. A failure to cut the genomic sample results in an identifiably larger than expected fragment implying that there is a mutation at the point of the restriction site which is rendering it protected from nuclease activity.

[0179] PCR- and amplification-based methods can be used to detect genetic variants. For example, tetra-primer PCR employs two pairs of primers to amplify two alleles in one PCR reaction. The primers are designed such that the two primer pairs overlap at a SNP location but each matches perfectly to only one of the possible alleles. As a result, if a given allele is present in the PCR reaction, the primer pair specific to that allele will produce product but not the alternative allele with a different allelic sequence. The two primer pairs can be designed such that their PCR products are of a significantly different length allowing for easily distinguishable bands by gel electrophoresis, or such that they are differently labeled.

[0180] Primer extension can also be used to detect genetic variants. Primer extension first involves the hybridization of a probe to the bases immediately upstream of the SNP nucleotide followed by a `mini-sequencing` reaction, in which DNA polymerase extends the hybridized primer by adding a base that is complementary to the SNP nucleotide. The incorporated base that is detected determines the presence or absence of the SNP allele. Because primer extension is based on the highly accurate DNA polymerase enzyme, the method is generally very reliable. Primer extension is able to genotype most SNPs under very similar reaction conditions making it also highly flexible. The primer extension method is used in a number of assay formats, and can be detected using e.g., fluorescent labels or mass spectrometry.

[0181] Primer extension can involve incorporation of either fluorescently labeled ddNTP or fluorescently labeled deoxynucleotides (dNTP). With ddNTPs, probes hybridize to the target DNA immediately upstream of SNP nucleotide, and a single, ddNTP complementary to the SNP allele is added to the 3' end of the probe (the missing 3'-hydroxyl in didioxynucleotide prevents further nucleotides from being added). Each ddNTP is labeled with a different fluorescent signal allowing for the detection of all four alleles in the same reaction. With dNTPs, allele-specific probes have 3' bases which are complementary to each of the SNP alleles being interrogated. If the target DNA contains an allele complementary to the 3' base of the probe, the target DNA will completely hybridize to the probe, allowing DNA polymerase to extend from the 3' end of the probe. This is detected by the incorporation of the fluorescently labeled dNTPs onto the end of the probe. If the target DNA does not contain an allele complementary to the probe's 3' base, the target DNA will produce a mismatch at the 3' end of the probe and DNA polymerase will not be able to extend from the 3' end of the probe.

[0182] The iPLEX.RTM. SNP genotyping method takes a slightly different approach, and relies on detection by mass spectrometer. Extension probes are designed in such a way that many different SNP assays can be amplified and analyzed in a PCR cocktail. The extension reaction uses ddNTPs as above, but the detection of the SNP allele is dependent on the actual mass of the extension product and not on a fluorescent molecule. This method is for low to medium high throughput, and is not intended for whole genome scanning.

[0183] Primer extension methods are, however, amenable to high throughput analysis. Primer extension probes can be arrayed on slides allowing for many SNPs to be genotyped at once. Broadly referred to as arrayed primer extension (APEX), this technology has several benefits over methods based on differential hybridization of probes. Comparatively, APEX methods have greater discriminating power than methods using differential hybridization, as it is often impossible to obtain the optimal hybridization conditions for the thousands of probes on DNA microarrays (usually this is addressed by having highly redundant probes).

[0184] Oligonucleotide ligation assays can also be used to detect genetic variants. DNA ligase catalyzes the ligation of the 3' end of a DNA fragment to the 5' end of a directly adjacent DNA fragment. This mechanism can be used to interrogate a SNP by hybridizing two probes directly over the SNP polymorphic site, whereby ligation can occur if the probes are identical to the target DNA. For example, two probes can be designed; an allele-specific probe which hybridizes to the target DNA so that its 3' base is situated directly over the SNP nucleotide and a second probe that hybridizes the template upstream (downstream in the complementary strand) of the SNP polymorphic site providing a 5' end for the ligation reaction. If the allele-specific probe matches the target DNA, it will fully hybridize to the target DNA and ligation can occur. Ligation does not generally occur in the presence of a mismatched 3' base. Ligated or unligated products can be detected by gel electrophoresis, MALDI-TOF mass spectrometry or by capillary electrophoresis.

[0185] The 5'-nuclease activity of Taq DNA polymerase can be used for detecting genetic variants. The assay is performed concurrently with a PCR reaction and the results can be read in real-time. The assay requires forward and reverse PCR primers that will amplify a region that includes the SNP polymorphic site. Allele discrimination is achieved using FRET, and one or two allele-specific probes that hybridize to the SNP polymorphic site. The probes have a fluorophore linked to their 5' end and a quencher molecule linked to their 3' end. While the probe is intact, the quencher will remain in close proximity to the fluorophore, eliminating the fluorophore's signal. During the PCR amplification step, if the allele-specific probe is perfectly complementary to the SNP allele, it will bind to the target DNA strand and then get degraded by 5'-nuclease activity of the Taq polymerase as it extends the DNA from the PCR primers. The degradation of the probe results in the separation of the fluorophore from the quencher molecule, generating a detectable signal. If the allele-specific probe is not perfectly complementary, it will have lower melting temperature and not bind as efficiently. This prevents the nuclease from acting on the probe.

[0186] Forster resonance energy transfer (FRET) detection can be used for detection in primer extension and ligation reactions where the two labels are brought into close proximity to each other. It can also be used in the 5'-nuclease reaction, the molecular beacon reaction, and the invasive cleavage reactions where the neighboring donor/acceptor pair is separated by cleavage or disruption of the stem-loop structure that holds them together. FRET occurs when two conditions are met. First, the emission spectrum of the fluorescent donor dye must overlap with the excitation wavelength of the acceptor dye. Second, the two dyes must be in close proximity to each other because energy transfer drops off quickly with distance. The proximity requirement is what makes FRET a good detection method for a number of allelic discrimination mechanisms.

[0187] A variety of dyes can be used for FRET, and are known in the art. The most common ones are fluorescein, cyanine dyes (Cy3 to Cy7), rhodamine dyes (e.g. rhodamine 6G), the Alexa series of dyes (Alexa 405 to Alexa 730). Some of these dyes have been used in FRET networks (with multiple donors and acceptors). Optics for imaging all of these require detection from UV to near IR (e.g. Alex 405 to Cy7), and the Atto series of dyes (Atto-Tec GmbH). The Alexa series of dyes from Invitrogen cover the whole spectral range. They are very bright and photostable.

[0188] Example dye pairs for FRET labeling include Alexa-405/Alex-488, Alexa-488/Alexa-546, Alexa-532/Alexa-594, Alexa-594/Alexa-680, Alexa-594/Alexa-700, Alexa-700/Alexa-790, Cy3/Cy5, Cy3.5/Cy5.5, and Rhodamine-Green/Rhodamine-Red, etc. Fluorescent metal nanoparticles such as silver and gold nanoclusters can also be used (Richards et al. (2008) J Am Chem Soc 130:5038-39; Vosch et al. (2007) Proc Natl Acad Sci USA 104:12616-21; Petty and Dickson (2003) J Am Chem Soc 125:7780-81 Available filters, dichroics, multichroic mirrors and lasers can affect the choice of dye.

In Vitro Complexes

[0189] Provided herein are nucleic acid complexes, e.g., formed in in vitro assays to indicate the presence of a genetic variant sequence. One of skill will understand that a nucleic acid complex can also be formed to detect the presence of a dominant allelic sequence, depending on the design of the probe or primer, e.g., in assays to distinguish homozygous and heterozygous subjects.

[0190] In some embodiments, the complex comprises a first nucleic acid hybridized to a genetic variant nucleic acid, wherein the genetic variant nucleic acid is a genetic variant in a gene selected from MUC5B, TERC, FAM13A, TERT, DSP, AZGP1, OBFC1, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7. In some embodiments, the genetic variant nucleic acid is an amplification product. In some embodiments, the genetic variant nucleic acid is on genomic DNA, e.g., from a subject that has or is suspected of having an interstitial lung disease. In some embodiments, the first nucleic acid is an amplification product or a primer extension product. In some embodiments, the first nucleic acid is labeled. In some embodiments, the nucleic acid complex further comprises a second nucleic acid hybridized to the genetic variant nucleic acid. In some embodiments, the second nucleic acid is labeled e.g., with a FRET or other fluorescent label. In some embodiments, the first and second nucleic acids form a FRET pair when hybridized to a genetic variant sequence.

[0191] In some embodiments, the nucleic acid complex further comprises an enzyme, such as a DNA polymerase (e.g., standard DNA polymerase or thermostable polymerase such as Taq) or ligase.

[0192] The present disclosure includes but is not limited to the following embodiments:

[0193] A method for determining if an individual is predicted to develop and/or progress rapidly with an interstitial pneumonia comprising: detecting in a biological sample from the individual, at least one of: a) the presence of a marker polymorphism selected from the group consisting of: rs35705950; and/or, b) a level of gene expression of a marker gene or plurality of marker genes selected from the group consisting of: a marker gene having at least 95% sequence identity with at least one sequence selected from the group consisting of MUC5B, TERC, FAM13A, TERT, DSP, AZGP1, OBFC1, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7, or homologs or variants thereof c) polypeptides encoded by the marker genes of b) d) fragments of polypeptides of c); and e) a polynucleotide which is fully complementary to at least a portion of a marker gene of b); wherein the presence of the plurality of markers is indicative of whether an individual will develop a disease. In some embodiments, the genes detected share 100% sequence identity with the corresponding marker gene in b). In some embodiments, the presence or level of at least one of the plurality of markers is determined and compared to a standard level or reference set. In some embodiments, the standard level or reference set is determined according to a statistical procedure for risk prediction. In some embodiments, the statistical procedure for risk prediction comprises using the sum of the gene expression of the marker or markers or the presence or absence of a set of markers, weighted by a Proportional Hazards coefficient. In some embodiments, the presence of the at least one marker is determined by detecting the presence or absence or expression level of a polypeptide. In some embodiments, the method further comprises detecting the presence of the polypeptide using a reagent that specifically binds to the polypeptide or a fragment thereof. In some embodiments, the reagent is selected from the group consisting of an antibody, an antibody derivative, and an antibody fragment. In some embodiments, the presence of the marker is determined by obtaining the sequence of genomic DNA at the locus of the polymorphism. In some embodiments, the presence of the marker is determined by obtaining RNA from the biological sample; generating cDNA from the RNA; amplifying the cDNA with probes or primers for marker genes; obtaining from the amplified cDNA the expression levels of the genes or gene expression products in the sample. In some embodiments, the individual is a human.

[0194] In some embodiments, the method further comprises: a) comparing the expression level of the marker gene or plurality of marker genes in the biological sample to a control level of the marker gene(s) selected from the group consisting of: a control level of the marker gene that has been correlated with interstitial lung disease, the risk of developing interstitial lung disease, or having a interstitial lung disease; and a control level of the marker that has been correlated with slow or no progression of interstitial lung disease, or low risk of developing an interstitial lung disease; and b) selecting the individual as being predicted to progress rapidly in the development of interstitial pneumonia, if the expression level of the marker gene in the individual's biological sample is statistically similar to, or greater than, the control level of expression of the marker gene that has been correlated with interstitial lung disease, or c) selecting the individual as being predicted to not develop interstitial lung disease, or to progress slowly, if the level of the marker gene in the individual's biological sample is statistically less than the control level of the marker gene that has been correlated with interstitial lung disease.

[0195] In some embodiments, the method further comparing the presence of a polymorphism, in the biological sample to a set of genetic variants or polymorphic markers from an individual or control group having developed interstitial lung disease, and, selecting the individual as being predicted to develop or to progress with interstitial pneumonia if the polymorphic markers present in the biological sample are identical to or statistically similar to a set of polymorphic markers from the individual or control group or, selecting the individual as being predicted to develop or rapidly progress with interstitial pneumonia, if the polymorphic markers present in the biological sample are not identical to or statistically similar to the set of genetic variants or polymorphic markers from the individual or control group.

[0196] A method for monitoring the progression of interstitial lung disease in a subject, comprising: i) measuring expression levels of a plurality of gene markers in a first biological sample obtained from the subject, wherein the plurality of markers comprise a plurality of markers selected from the group consisting of: a marker gene having at least 95% sequence identity with a sequence selected from the group consisting of a) MUC5B, TERC, FAM13A, TERT, DSP, AZGP1, OBFC1, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7, or homologs or variants thereof; b) polypeptides encoded by the marker genes of a), c) fragments of polypeptides of d); and e) a polynucleotide which is fully complementary to at least a portion of a marker gene of b); ii) measuring expression levels of the plurality of markers in a second biological sample obtained from the subject; and iii) comparing the expression level of the marker measured in the first sample with the level of the marker measured in the second sample. In some embodiments, the marker genes detected share 100% sequence identity with the corresponding marker gene in a). In some embodiments, the method further comprises performing a follow-up step selected from the group consisting of CT scan of the chest and pathological examination of lung tissues from the subject. In some embodiments, the first biological sample from the subject is obtained at a time to, and the second biological sample from the subject is obtained at a later time t.sub.1. In some embodiments, the first biological sample and the second biological sample are obtained from the subject are obtained more than once over a range of times.

[0197] A method of assessing the efficacy of a treatment for interstitial lung disease or interstitial pneumonia in a subject, the method comprising comparing: i) the expression level of a marker measured in a first sample obtained from the subject at a time to, wherein the marker is selected from the group consisting of a) a marker gene having at least 95% sequence identity with a sequence selected from the group consisting of MUC5B, TERC, FAM13A, TERT, DSP, AZGP1, OBFC1, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7, or homologs or variants thereof; b) polypeptides encoded by the marker genes of a)

c) fragments of polypeptides of b); and d) a polynucleotide which is fully complementary to at least a portion of a marker gene of a); ii) the level of the marker in a second sample obtained from the subject at time t.sub.1; and, iii) performing a follow-up step selected from CT scan of the chest and pathological examination of lung tissues from the subject; wherein a decrease in the level of the marker in the second sample relative to the first sample is an indication that the treatment is efficacious for treating interstitial pneumonia in the subject. In some embodiments, the genes detected share 100% sequence identity with the corresponding marker gene in a). In some embodiments, the time t0 is before the treatment has been administered to the subject, and the time t1 is after the treatment has been administered to the subject. In some embodiments, the comparing is repeated over a range of times.

[0198] An assay system for predicting individual prognosis therapy for interstitial pneumonia comprising a means to detect at least one of: a) the presence of a marker polymorphism selected from the group consisting of: rs35705950; and/or, b) a level of gene expression of a marker gene or plurality of marker genes selected from the group consisting of: a marker gene having at least 95% sequence identity with a sequence selected from the group consisting of MUC5B, TERC, FAM13A, TERT, DSP, AZGP1, OBFC1, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7, or homologs or variants thereof c) polypeptides encoded by the marker genes of b) d) fragments of polypeptides of c); and e) a polynucleotide which is fully complementary to at least a portion of a marker gene of b). In some embodiments, the means to detect comprises nucleic acid probes comprising at least 10 to 50 contiguous nucleic acids of the marker polymorphisms or gene(s), or complementary nucleic acid sequences thereof. In some embodiments, the means to detect comprises binding ligands that specifically detect polypeptides encoded by the marker genes. In some embodiments, the genes detected share 100% sequence identity with the corresponding marker gene in b). In some embodiments, the means to detect comprises at least one of nucleic acid probe and binding ligands disposed on an assay surface. In some embodiments, the assay surface comprises a chip, array, or fluidity card. In some embodiments, the probes comprise complementary nucleic acid sequences to at least 10 to 50 nucleic acid sequences of the marker genes. In some embodiments, the binding ligands comprise antibodies or binding fragments thereof. In some embodiments, the assay system further comprises: a control selected from information containing a predetermined control level or set of genetic variants or polymorphic markers that has been correlated with diagnosis, development, progression, or life expectancy in interstitial lung disease patients.

[0199] A method of detecting a level of gene expression of one or more marker genes in a human subject with interstitial pneumonia, comprising, optionally, obtaining a biological sample from a human individual with interstitial pneumonia; detecting the level of expression of a gene selected from MUC5B, TERC, FAM13A, TERT, DSP, AZGP1, OBFC1, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7, or homologs or variants thereof, in one or more cells from the biological sample from the individual. In some embodiments, the method further comprises detecting the level of expression of a gene selected from MUC5B, TERC, FAM13A, TERT, DSP, AZGP1, OBFC1, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7, or homologs or variants thereof, in one or more cells from the biological sample from the individual. In some embodiments, the method further comprises detecting the level of expression of a gene selected from MUC5B, TERC, FAM13A, TERT, DSP, AZGP1, OBFC1, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7, or homologs or variants thereof in one or more cells from the biological sample from the individual.

[0200] A method of treating an interstitial lung disease in a subject in need of such treatment, comprising: detecting a level of one or more marker genes selected from MUC5B, TERC, FAM13A, TERT, DSP, AZGP1, OBFC1, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7, or homologs or variants thereof in a biological sample obtained from the human subject; and, administering an effective amount of an effective treatment. In some embodiments, the method further comprises detecting the level of expression of a gene selected from MUC5B, TERC, FAM13A, TERT, DSP, AZGP1, OBFC1, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7, or homologs or variants thereof, in one or more cells from the biological sample from the individual. In some embodiments, the method further comprises detecting the level of expression of a gene selected from MUC5B, TERC, FAM13A, TERT, DSP, AZGP1, OBFC1, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7, or homologs or variants thereof, in one or more cells from the biological sample from the individual.

Detection of Genetic Variants

[0201] Methods of detecting a genetic variant are further described, for example, in U.S. Pat. No. 8,673,565 (the contents of which are herein incorporated by reference in their entirety). Genetic variations in the mucin genes are associated with pulmonary diseases. These genetic variations can be found in any part of the gene, e.g., in the regulatory regions, introns, or exons. Relevant genetic variations may also be found the intergene regions, e.g., in sequences between mucin genes. Insertions, substitutions, and deletions are included in genetic variants. Single nucleotide polymorphisms (SNPs) are exemplary genetic variants.

[0202] In particular, 14 independent SNPs are associated with pulmonary disorders (e.g. FIP or IPF). The studies disclosed herein demonstrate that presence of one or more of these SNPs associated with MUC5B can lead to predisposition to a pulmonary disorder. In addition, in some embodiments, if present, some of these SNPs are related to a transcription factor binding site. The transcription factor binding site can effect modulation of MUC5B expression, for example E2F3 loss, and HOXA9 and PAX-2 generation.

[0203] The disclosure thus provides methods for assessing the presence or absence of SNPs in a sample from a subject suspected of having or developing a pulmonary disorder (e.g., because of family history). In certain embodiments, one or more SNPs are screened in one or more samples from a subject. The SNPs can be associated with one or more genes, e.g., one or more MUC genes or other genes associated with mucous secretion. In some embodiments, a MUC gene associated SNP is associated with MUC5B and/or another MUC gene, such as MUC5AC or MUC1. SNPs contemplated for diagnostic, treatment, or prognosis can include SNPs found within a MUC gene and/or within a regulatory or promoter region associated with a MUC gene. For example, one or more SNPs can include, but are not limited to, detection of the SNPs of MUC5B alone or in combination with other genetic variations or SNPs and/or other diagnostic or prognostic methods.

[0204] Methods for detecting genetic variants such as a SNP are known in the art, e.g., Southern or Northern blot, nucleotide array, amplification methods, etc. Primers or probes are designed to hybridize to a target sequence. For example, genomic DNA can be screened for the presence of an identified genetic element of using a probe based upon one or more sequences, e.g., using a probe with substantial identity to a subsequence of the MUC5B gene. Expressed RNA can also be screened, but may not include all relevant genetic variations. Various degrees of stringency of hybridization may be employed in the assay. As the conditions for hybridization become more stringent, there must be a greater degree of complementarity between the probe and the target for duplex formation to occur. Thus, high stringency conditions are typically used for detecting a SNP.

[0205] Thus, in some embodiments, a genetic variant MUC5B gene in a subject is detected by contacting a nucleic acid in a sample from the subject with a probe having substantial identity to a subsequence of the MUC5B gene, and determining whether the nucleic acid indicates that the subject has a genetic variant MUC5B gene. In some cases, the sample can be processed prior to amplification, e.g., to separate genomic DNA from other sample components. In some cases, the probe has at least 90, 92, 94, 95, 96, 98, 99, or 100% identity to the MUC5B gene subsequence. Typically, the probe is between 10-500 nucleotides in length, e.g., 10-100, 10-40, 10-20, 20-100, 100-400, etc. In the case of detecting a SNP, the probe can be even shorter, e.g., 8-20 nucleotides in length. In some cases, the MUC5B gene sequence to be detected includes at least 8 contiguous nucleotides, e.g., at least 10, 15, 20, 25, 30, 35 or more contiguous nucleotides. In some embodiments, the sequence to be detected includes 8 contiguous nucleotides, e.g., at least 10, 15, 20, 25, 30, 35 or more contiguous nucleotides.

[0206] The degree of stringency can be controlled by temperature, ionic strength, pH and/or the presence of a partially denaturing solvent such as formamide. For example, the stringency of hybridization is conveniently varied by changing the concentration of formamide within the range up to and about 50%. The degree of complementarity (sequence identity) required for detectable binding will vary in accordance with the stringency of the hybridization medium and/or wash medium. In certain embodiments, in particular for detection of a particular SNP, the degree of complementarity is about 100 percent. In other embodiments, sequence variations can result in <100% complementarity, <90% complimentarity probes, <80% complimentarity probes, etc., in particular, in a sequence that does not involve a SNP. In some examples, e.g., detection of species homologs, primers may be compensated for by reducing the stringency of the hybridization and/or wash medium.

[0207] High stringency conditions for nucleic acid hybridization are well known in the art. For example, conditions may comprise low salt and/or high temperature conditions, such as provided by about 0.02 M to about 0.15 M NaCl at temperatures of about 50.degree. C. to about 70.degree. C. Other exemplary conditions are disclosed in the following Examples. It is understood that the temperature and ionic strength of a desired stringency are determined in part by the length of the particular nucleic acid(s), the length and nucleotide content of the target sequence(s), the charge composition of the nucleic acid(s), and by the presence or concentration of formamide, tetramethylammonium chloride or other solvent(s) in a hybridization mixture. Nucleic acids can be completely complementary to a target sequence or exhibit one or more mismatches.

[0208] Nucleic acids of interest can also be amplified using a variety of known amplification techniques. For instance, polymerase chain reaction (PCR) technology may be used to amplify target sequences (e.g., genetic variants) directly from DNA, RNA, or cDNA. In some embodiments, a stretch of nucleic acids is amplified using primers on either side of a targeted genetic variation, and the amplification product is then sequenced to detect the targeted genetic variation (using, e.g., Sanger sequencing, Pyrosequencing, Nextgen.RTM. sequencing technologies). For example, the primers can be designed to hybridize to either side of the upstream regulatory region of the MUC5B gene, and the intervening sequence determined to detect a SNP in the promoter region. In some embodiments, one of the primers can be designed to hybridize to the targeted genetic variant. In some cases, a genetic variant nucleotide can be identified using RT-PCR, e.g., using labeled nucleotide monomers. In this way, the identity of the nucleotide at a given position can be detected as it is added to the polymerizing nucleic acid. The Scorpion.TM. system is a commercially available example of this technology.

[0209] Thus, in some embodiments, a genetic variant MUC5B gene in a subject is detected by amplifying a nucleic acid in a sample from the subject to form an amplification product, and determining whether the amplification product indicates a genetic variant MUC5B gene. In some cases, the sample can be processed prior to amplification, e.g., to separate genomic DNA from other sample components. In some cases, amplifying comprises contacting the sample with amplification primers having substantial identity to MUC5B genomic subsequences, e.g., at least 90, 92, 94, 95, 96, 98, 99, or 100% identity. Typically, the sequence to be amplified is between 30-1000 nucleotides in length, e.g., 50-500, 50-400, 100-400, 50-200, 100-300, etc. In some cases, the sequence to be amplified or detected includes at least 8 contiguous nucleotides, e.g., at least 10, 15, 20, 25, 30, 35 or more contiguous nucleotides. In some embodiments, the sequence to be amplified or detected includes 8 contiguous nucleotides, e.g., at least 10, 15, 20, 25, 30, 35 or more contiguous nucleotides. In some aspects, the contiguous nucleotides include nucleotide 28.

[0210] Amplification techniques can also be useful for cloning nucleic acid sequences, to make nucleic acids to use as probes for detecting the presence of a target nucleic acid in samples, for nucleic acid sequencing, for control samples, or for other purposes. Probes and primers are also readily available from commercial sources, e.g., from Invitrogen, Clonetech, etc.

Detection of Expression Levels

[0211] Expression of a given gene, e.g., MUC5B or another mucin, pulmonary disease marker, or standard (control), is typically detected by detecting the amount of RNA (e.g., mRNA) or protein. Sample levels can be compared to a control level.

[0212] Methods for detecting RNA are largely cumulative with the nucleic acid detection assays described above. RNA to be detected can include mRNA. In some embodiments, a reverse transcriptase reaction is carried out and the targeted sequence is then amplified using standard PCR. Quantitative PCR (qPCR) or real time PCR (RT-PCR) is useful for determining relative expression levels, when compared to a control. Quantitative PCR techniques and platforms are known in the art, and commercially available (see, e.g., the qPCR Symposium website, available at qpersymposium.com). Nucleic acid arrays are also useful for detecting nucleic acid expression. Customizable arrays are available from, e.g., Affimatrix. An exemplary human MUC5B mRNA sequence, e.g., for probe and primer design, can be found at GenBank Accession No. AF086604.1.

[0213] Protein levels can be detected using antibodies or antibody fragments specific for that protein, natural ligands, small molecules, aptamers, etc. An exemplary human MUC5B sequence, e.g., for screening a targeting agent, can be found at UniProt Accession No. 000446.

[0214] Antibody based techniques are known in the art, and described, e.g., in Harlow & Lane (1988) Antibodies: A Laboratory Manual and Harlow (1998) Using Antibodies: A Laboratory Manual; Wild, The Immunoassay Handbook, 3d edition (2005) and Law, Immunoassay: A Practical Guide (1996). The assay can be directed to detection of a molecular target (e.g., protein or antigen), or a cell, tissue, biological sample, liquid sample or surface suspected of carrying an antibody or antibody target.

[0215] A non-exhaustive list of immunoassays includes: competitive and non-competitive formats, enzyme linked immunosorption assays (ELISA), microspot assays, Western blots, gel filtration and chromatography, immunochromatography, immunohistochemistry, flow cytometry or fluorescence activated cell sorting (FACS), microarrays, and more. Such techniques can also be used in situ, ex vivo, or in vivo, e.g., for diagnostic imaging.

[0216] Aptamers are nucleic acids that are designed to bind to a wide variety of targets in a non-Watson Crick manner. An aptamer can thus be used to detect or otherwise target nearly any molecule of interest, including a pulmonary disease associated protein. Methods of constructing and determining the binding characteristics of aptamers are well known in the art. For example, such techniques are described in U.S. Pat. Nos. 5,582,981, 5,595,877 and 5,637,459. Aptamers are typically at least 5 nucleotides, 10, 20, 30 or 40 nucleotides in length, and can be composed of modified nucleic acids to improve stability. Flanking sequences can be added for structural stability, e.g., to form 3-dimensional structures in the aptamer.

[0217] Protein detection agents described herein can also be used as a treatment and/or diagnosis of pulmonary disease or predictor of disease progression, e.g., propensity for survival, in a subject having or suspected of developing a pulmonary disorder. In certain embodiments, MUC5B antibodies can be used to assess MUC5B protein levels in a subject having or suspected of developing a pulmonary disorder. It is contemplated herein that antibodies or antibody fragments may be used to modulate MUC5B production in a subject having or suspected of developing a pulmonary disease. In certain embodiments, one or more agents capable of modulating MUC5B may be used to treat a subject having or suspected of developing a pulmonary disorder. One or more antibodies or antibody fragments may be generated to detect one or more of the SNPs disclosed herein by any method known in the art.

[0218] In certain embodiments, MUC5B diagnostic tests may include, but are not limited to, alone or in combination, analysis of rs35705950 SNP in MUC5B gene, MUC5B mRNA levels, and/or MUC5B protein levels.

Additional Pulmonary Disease Markers

[0219] The above methods of detection can be applied to additional pulmonary disease markers. That is, the expression level or presence of genetic variants of at least one additional pulmonary disease marker gene can be determined, or the activity of the marker protein can be determined, and compared to a standard control for the pulmonary disease marker. The examination of additional pulmonary disease markers can be used to confirm a diagnosis of pulmonary disease, monitor disease progression, or determine the efficacy of a course of treatment in a subject.

[0220] In some cases, pulmonary disease is indicated by an increased number of lymphocytes, e.g., CD4+CD28- cells.

[0221] Genetic variations in the following genes are associated with pulmonary disease: Surfactant Protein A2, Surfactant Protein B, Surfactant Protein C, TERC, TERT, IL-1RN, IL-1.alpha., IL-1.beta., TNF, Lymphotoxin a, TNF-RII, IL-10, IL-6, IL-12, IFN.gamma., TGF.beta., CR1, ACE, IL-8, CXCR1, CXCR2, MUC1 (KL6), or MUC5AC. Thus, the invention further includes methods of determining whether the genome of a subject comprises a genetic variant of at least one gene selected from these genes. The presence of a genetic variant indicates that the subject has or is at risk of developing pulmonary disease. Said determining can optionally be combined with determining whether the genome of the subject comprises a genetic variant MUC5B gene, or determining whether the subject has an elevated level of MUC5B RNA or protein to confirm or strengthen the diagnosis or prognosis.

[0222] Abnormal expression in the following genes can also be indicative of pulmonary disease: Surfactant Protein A, Surfactant Protein D, KL-6/MUC1, CC16, CK-19, Ca 19-9, SLX, MCP-1, MIP-1a, ITAC, glutathione, type III procollagen peptide, sIL-2R, ACE, neopterin, beta-glucuronidase, LDH, CCL-18, CCL-2, CXCL12, MMPI, and osteopontin. Thus, the expression of one of these genes can be detected and compared to a control, wherein an abnormal expression level indicates that the subject has or is at risk of developing pulmonary disease. Said determining can optionally be combined with determining whether the genome of the subject comprises a genetic variant MUC5B gene, or determining whether the subject has an elevated level of MUC5B RNA or protein to confirm or strengthen the diagnosis or prognosis.

Biomarkers

[0223] The present disclosure provides a peripheral blood biomarker profile for IPF to demonstrate the use of a predictive biomarker profile in cases of preclinical pulmonary fibrosis (PrePF) derived from families with familial IPF. The present disclosure also provides biomarker identification for association between each genetic, epigenetic or protein (gene product) biomarker with PrePF and the predictive value of the combination of biomarkers associated with PrePF.

[0224] A large cohort of families with familial IPF for genetic research was established, including 937 families with .gtoreq.2 cases of IPF, and 2375 family members that have been previously phenotyped as unaffected. This study focuses on subjects with PrePF to elucidate the processes active in early disease pathogenesis and to predict or prevent the irreversible fibroproliferative process. Genetic risk factors, especially the MUC5B promoter variant, identifies individuals with preclinical interstitial changes on chest CT scan that progress and are associated with reduced survival. Biomarkers may be used to identify those subjects with PrePF among those at-risk for IPF. Given the irreversible nature of IPF, even approved treatments (pirfenidone and nintedanib) only modestly slow progression and have not been shown to alter the 3-5 year survival. Pirfenidone and nintedanib are effective in patients with mild disease, suggesting that patients with PrePF may be targeted for early intervention, before most of the lung has been irreversibly remodeled.

[0225] Table 1 below shows additional gene expression changes present in subjects with IPF compared to controls. Specifically, the expression of the genes listed in Table 1 are upregulated in IPF compared to the expression of these same genes in control subjects. Accordingly, the discovery of elevated expression levels of one or more genes listed in Table 1 compared to a control in an asymptomatic subject may indicate that the subject has PrePF and/or that the subject is at risk for developing IPF.

[0226] In some embodiments of the methods of the disclosure, the subject has a mutation in a nucleic acid or amino acid sequence encoding a gene or gene product that is upregulated in a subject having a fibrotic pulmonary disease of the disclosure. In some embodiments of the methods of the disclosure, the subject has a mutation in a nucleic acid or amino acid sequence encoding Leukotriene A4 Hydrolase (LTA4H), Surfactant Protein B (SFTPB), Breast Cancer Anti-Estrogen Resistance 3 (BCAR3), C-X-C motif Chemokine Ligand 13 (CXCL13), EPH Receptor A2 (EPHA2), Serum Amyloid A1 (SAA1), Phospholipase A2 Group IIA (PLA2G2A), Insulin-Like Growth Factor Binding Protein 3 (IGFBP3), C-C Motif Chemokine Ligand 28 (CCL28), 5100 Calcium Binding Protein A12 (S100A12), Thromboxane A Synthase 1 (TBXAS1), Leukocyte Cell Derived Chemotaxin 1 (LECT1), Complement C3 (C3), Gastrin Releasing Peptide (GRP), C-Reactive Protein (CRP), Vitrin (VIT), Insulin-Like Growth Factor Binding Protein 1 (IGFBP1), Family with Sequence Similarity 173 Member A (FAM173A), Natriuretic Peptide A (NPPA), Secreted Frizzled Related Protein 1 (SFRP1), Ezrin (EZR), Inter-Alpha-Trypsin Inhibitor Heavy Chain Family Member 5 (ITIH5), Pleckstrin and Sec7 Domain Containing 2 (PSD2), Galectin 3 Binding Protein (LGALS3BP), Catenin Beta 1 (CTNNB1), Chromodomain Y Like 2 (CDYL2), Matrix Metallopeptidase 7 (MMPI), Apolipoprotein B (APOB), Proline and Arginine Rich End Leucine Rich Repeat Protein (PRELP), Eukaryotic Translation Initiation Factor 1A, X-linked (EIF1AX), Mesencephalic Astrocyte Derived Neurotrophic Factor (MANF), TNF Receptor Superfamily Member 13C (TNFRSF13C), Deformed Epidermal Autoregulatory Factor 1 transcription factor (DEAF1), Tumor Protein Translationally-Controlled 1 (TPT1), Unc-5 Netrin Receptor B (UNCSB), Phosphatidylethanolamine Binding Protein 1 (PEBP1), Syntaxin 8 (STX8), Polymeric Immunoglobulin Receptor (PIGR), Adenine Phosphoribosyltransferase (APRT), Matrix Metallopeptidase 3 (MMP3), Galectin 7 (LGALS7), Bruton Tyrosine Kinase (BTK), NSFL1 Cofactor (NSFL1C), FER Tyrosine Kinase (FER), Regenerating Family Member 1 Beta (REG1B), SMAD Family Member 2 (SMAD2), Interleukin 1 Receptor Like 1 (IL1RL1), C-C Motif Chemokine Ligand 18 (CCL18), Acid Phosphatase 2 Lysosomal (ACP2), Eukaryotic Translation Initiation Factor 4E Family Member 2 (EIF4E2), Neurexin 3 (NRXN3), IGF Like Family Member 1 (IGFL1), NME/NM23 Nucleoside Diphosphate Kinase 1 (NME1), Potassium Voltage-Gated Channel Isk-Related Family Member 1-Like (KCNE1L) or Neurexophilin 2 (NXPH2).

TABLE-US-00001 TABLE 1 TARGET_GENE_SYM- ORGAN- B-H Fold BOL ISM p-value q-value Change LTA4H Human 8.70E-43 3.13E-39 3.912 SFTP8 Human 1.17E-37 2.10E-34 3.399 BCAR3 Human 4.28E-25 3.85E-22 2.906 CXCL13 Human 1.30E-29 1.56E-26 2.904 EPHA2 Human 9.62E-23 6.93E-20 2.651 SAA1 Human 6.01E-07 7.84E-06 2.631 PLA2GZA Human 8.19E-21 2.95E-18 2.171 Igfbp3 Mouse 1.18E-18 2.66E-16 2.149 CCL28 Human 1.22E-22 7.30E-20 2.135 S100A12 Human 1.06E-20 3.45E-18 2.125 TBXAS1 Human 1.60E-21 7.20E-19 2.11 LECT1 Human 4.17E-19 1.00E-16 2.082 C3 Human 7.08E-07 8.95E-06 2.062 GRP Human 8.35E-09 1.66E-07 1.988 CSP Human 1.36E-08 2.61E-07 1.957 VIT Human 2.47E-17 4.45E-15 1.929 IGFBP1 Human 4.32E-11 1.56E-09 1.914 FAM173A Human 2.19E-13 1.84E-11 1.904 NPPA Human 5.02E-12 2.58E-10 1.877 SFRP1 Human 1.74E-20 5.23E-18 1.866 EZR Human 6.41E-10 1.72E-08 1.809 ITIH5 Human 5.11E-21 2.04E-18 1.705 PSD2 Human 5.38E-18 1.08E-15 1.689 LGAL538P Human 8.06E-22 4.15E-19 1.678 1.18E-05 0.000102 1.668 CTNNB1 Human 5.66E-12 2.87E-10 1.625 CDVL2 Human 4.11E-07 5.59E-06 1.622 MMP7 Human 1.56E-19 4.02E-17 1.621 APOB Human 8.73E-13 6.42E-11 1.597 PRELP Human 1.13E-10 3.53E-09 1.595 EIF1AX Human 2.13E-06 2.31E-05 1.59 MANF Human 0.00458 0.015006 1.585 TNFRSF13C Human 1.77E-11 7.31E-10 1.573 C3 Human 2.40E-16 3.93E-14 1.566 DEAF1 Human 0.000221 0.001192 1.565 TPT1 Human 1.22E-12 7.82E-11 1.548 UNC5B Human 2.06E-34 2.18E-12 1.547 PEBP1 Human 4.92E-11 1.72E-09 1.544 STX8 Human 8.82E-12 4.13E-10 1.537 PIGR Human 1.29E-09 3.19E-08 1.532 APRT Human 1.51E-07 2.26E-06 1.525 MMP3 Human 9.50E-07 1.15E-05 1.524 LGAL57 Human 7.51E-05 0.000474 1.514 BTK Human 1.47E-09 3.52E-08 1.511 NSFL1C Human 7.33E-11 2.40E-09 1.506 FER Human 2.24E-07 3.24E-06 1.503 REG1B Human 6.68E-11 2.25E-09 1.502 SMAD2 Human 4.39E-10 1.25E-08 1.493 IL1RL1 Human 9.55E-07 1.15E-05 1.492 CCL18 Human 1.25E-13 1.07E-11 1.491 ACP2 Human 3.73E-08 6.33E-07 1.488 EIF4E2 Human 1.67E-12 1.02E-10 1.483 NRXN3 Human 2.33E-17 4.42E-15 1.48 IGFL1 Human 5.07E-10 1.40E-08 1.474 NME1 Human 1.43E-10 4.39E-09 1.463 KCNE1L Human 3.93E-20 1.09E-17 1.462 NXPH2 Human 9.66E-30 2.47E-08 1.451

[0227] Table 2 below shows additional gene expression changes present in subjects with IPF compared to controls. Specifically, the expression of the genes listed in Table 2 are downregulated in IPF compared to the expression of these same genes in control subjects. Accordingly, the discovery of decreased expression levels of one or more genes listed in Table 2 compared to a control in an asymptomatic subject may indicate that the subject has PrePF and/or that the subject is at risk for developing IPF.

[0228] In some embodiments of the methods of the disclosure, the subject has a mutation in a nucleic acid or amino acid sequence encoding a gene or gene product that is downregulated in a subject having a fibrotic pulmonary disease of the disclosure. In some embodiments of the methods of the disclosure, the subject has a mutation in a nucleic acid or amino acid sequence encoding Surfactant Protein D (SFTPD), Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH), Histone Cluster 1 H1 Family Member C (HIST1H1C), YTH Domain Containing 1 (YTHDC1), Plexin A1 (PLXNA1), Serine Peptidase Inhibitor Kazal Type 6 (SPINK6), LDL Receptor Related Protein Associated Protein 1 (LRPAP1), Secretoglobin Family 3A Member 1 (SCGB3A1), H2A Histone Family Member Z (H2AFZ) or Chromosome 1 Open Reading Frame 162 (Clorf162).

TABLE-US-00002 TABLE 2 TARGET_GENE_SYM- ORGAN- B-H Fold BOL ISM p-value q-value Change SFTPD Haman 8.19E-15 9.83E-13 -2.262 GAPDH Human 1.46E-09 3.52E-08 -2.096 HIST1H1C Human 3.68E-18 7.80E-16 -2.011 3.63E-16 5.69E-14 -1.964 YTHDC1 Human 1.19E-11 5.38E-10 -1.699 PLXNA1 Human 1.64E-12 1.02E-10 -1.64 SPINK6 Human 3.68E-07 5.04E-06 -1.635 LRPAP1 Human 2.65E-15 3.53E-13 -1.521 SCGB3A1 Human 3.35E-07 4.61E-06 -1.518 H2AFZ Human 3.91E-14 3.91E-12 -1.501 2.95E-11 1.16E-09 -1.493 C1orf162 Human 1.29E-84 7.52E-04 -1.458

[0229] In some embodiments of the methods of the disclosure, the subject having PrePF or at risk of developing IPF has a mutation in a sequence encoding MUC5B, TERC, FAM13A, TERT, DSP, AZGP1, OBFC1, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7.

[0230] In some embodiments of the methods of the disclosure, the subject having PrePF or at risk of developing IPF has a mutation in a sequence encoding Telomerase RNA Component (TERC). In some embodiments the polymorphism is rs6793295 comprising (SEQ ID NO: 1).

TABLE-US-00003 (SEQ ID NO: 1) AGAAAGAAGT CATGAAAGTA GGAACCACAT TTTTACTCAT CTTTCTGTCT CCAGCAAGCA GCTTACTGCT TTTCATACAC ATTTTGCTTT TATTACTCAT GATTTCAAAG GTGTAATGGT TCAGCCACAT CAATGTAACA AACAGTTCAC ACTGGGCTCT TATAGTCTGG CCTTTAAAAC CTTCACTATT TATGCTTTCA TCTTAACTAC TTTGACCCTC ACAGGTTTAC TCACTAAGAA CTTGAGTTTC AAGAGAAAAG ATGACATGTT TGCTGCTTAA ACAAGCAATA TCTAAAAGCA TATTTAGTTA TAAACGTCTT ACCAAGAATT GATATAATTT TCATTTAAAC ATTTTTATAA ATAGTAGTTT ACAAGATATA GTAAGTACAT CTCTAAAAAT ACAGTGTATT CATGTACCTT GACATAAACT TGTAGTAGTA CCTTAGTTTT ATTCATGTTG TTATATTAAC TACCATCACT TTGAATACAT ACCTGTTCAC B GTACAGTATA GGTCGGTTTA GGTTTATTGC CTTAATTGCT TGGTTTTGAG TTAGTACTGT AGCAAATGCT ATCACACTTT GCATTCCCTA AAAACAGGTA AATTCATTAA GGAAACAGAC AAAGTATATA ATAATCTCGC TACATAAATA TTTCAAGATC AGCTATCTGC ATTCTGATAA AATTGTTTTT AAAATTTAAG CATTCCTTGG ACTTTGAATT GTAAGTTGAT CAAATTCAAA AATGAATTGT TACTGTATTC TTCTCTCCTG GCCCTAAAAT CTATCTAAAA CATGGCATGG GGAGTTTCTT AATGTTTCAG TGTCCATTTC CTGGGTGTTT CCCTCTAGGT TTTTTTTCCT CACCCCTCAA GCTTCTATGT GGATCCCAGC TAGAGCTCAT ACTACTTATC CAACACACAT CATTGTGCAA GCACTCTTTT ATATTCATAC TAGTACTTTT AAGTGTGTGT GCGGTGGGAA AAGGTTACCA ATCACATTTT

[0231] In some embodiments of the methods of the disclosure, the subject having PrePF or at risk of developing IPF has a mutation in a sequence encoding Family with sequence similarity 13 member A (FAM13A). In some embodiments the polymorphism is rs2609255 comprising (SEQ ID NO: 2).

TABLE-US-00004 (SEQ ID NO: 2) GTATTCATCA ACTCCTATTT CATTCCCTCT TCCTGTGCTC ACTGGAAGAT GACATTTCCC AGACTTCCAA GAATGTTACT GAGTTCTGGA ATGTAAGTAG AAGGGATAAG TATCACTTCT GTGCTGTGGC GGTTATGGAC CTGTGAACTT TGCACACGCC TTCTATCTTC TTTTTCAGTG TCCATTTCAG AGGGCATGTT TTCAGATGAA ACCAGTAGAA GATGGAAGCA GCCTGTGACT AGAATCACTG CTTAGGGTCT TGCTGCCTAG GAATCCCACT CTACCTGCAA CAGACTGTGA AAGAACCGAG AAATACACTG ATTTTGAACA TAGCCCATAC TATAATGGGG ATGTTTGTTA CAGCAGTTAG CATTAAAAAC CTTGGCTAGG CATTGGTCAT AATTGTAGAA CACAGCAAAT GAAGGGAAAC TGGAACATAG AGGCCAGTGA GAACTTTAGG GTTAATGAAA AATGAGGGCA ACCAGGATAA TTTGGTTCTT K GCCAAATAGG AAGGTGAAAC CAAAGGTAGA CTGGAGGTCA GAAAATCAGT CCAGCACATG TGATGTTTTC ATTTAGTTGC CTGTATGTCT GTCTGGTCTC CAGCTCAGCC TGGCTCCTTG AGGTAAGAGG CAGTGGCTGT TCACCTTTGC ATCCCAGCAC CTGGCATACA ATAGATGGGA TGAAATGTTC AAACTGAGCC TAAGCTTCAG GGTGCTTATC AAAGCAGGGA AGATACACAA GAGGAGATGA TTCAGGTCCA GGGCAGGTCA GGTATCTAAA CCCAGTCTCT TAGGAAGCTG GATCCTCCGA ACCAGGGAGA ACAAGCTGGA TATGCACTGG ATTTCCCAGC AGTACTGATC TAGAGACTCT CATAGAGTCC CTTTTATTCC TTGGCCTAGG GTTACAACTG CTTATAGCAT CTGGAAAGAC TCAACACCTC AAAAGAGACT TTCAGTAGAT ACAGCAAATA CACTCATGGA ATTGATAATT AAGCTTCAAT

[0232] In some embodiments of the methods of the disclosure, the subject having PrePF or at risk of developing IPF has a mutation in a sequence encoding Telomerase Reverse Transcriptase (TERT). In some embodiments the polymorphism is rs2736100 comprising (SEQ ID NO: 3).

TABLE-US-00005 (SEQ ID NO: 3) ATTGTCGTTG TTTGCTTTTG TTTATTGAGA CAGTCTCACT CTGTCACCCA GGCTGGAGTG TAATGGCACA ATCTCGGCTC ACTGCAACCT CTGCCTCCTC GGTTCAAGCA GTTCTCATTC CTCAACCTCA TGAGTAGCTG GGATTACAGG CGCCCACCAC CACGCCTGGC TAATTTTTGT ATTTTTAGTA GAGATAGGCT TTCACCATGT TGGCCAGGCT GGTCTCAAAC TCCTGACCTC AAGTGATCTG CCCGCCTTGG CCTCCCACAG TGCTGGGATT ACAGGTGCAA GCCACCGTGC CCGGCATACC TTGATCTTTT AAAATGAAGT CTGAAACATT GCTACCCTTG TCCTGAGCAA TAAGACCCTT AGTGTATTTT AGCTCTGGCC ACCCCCCAGC CTGTGTGCTG TTTTCCCTGC TGACTTAGTT CTATCTCAGG CATCTTGACA CCCCCACAAG CTAAGCATTA TTAATATTGT TTTCCGTGTT GAGTGTTTCT K TAGCTTTGCC CCCGCCCTGC TTTTCCTCCT TTGTTCCCCG TCTGTCTTCT GTCTCAGGCC CGCCGTCTGG GGTCCCCTTC CTTGTCCTTT GCGTGGTTCT TCTGTCTTGT TATTGCTGGT AAACCCCAGC TTTACCTGTG CTGGCCTCCA TGGCATCTAG CGACGTCCGG GGACCTCTGC TTATGATGCA CAGATGAAGA TGTGGAGACT CACGAGGAGG GCGGTCATCT TGGCCCGTGA GTGTCTGGAG CACCACGTGG CCAGCGTTCC TTAGCCAGTG AGTGACAGCA ACGTCCGCTC GGCCTGGGTT CAGCCTGGAA AACCCCAGGC ATGTCGGGGT CTGGTGGCTC CGCGGTGTCG AGTTTGAAAT CGCGCAAACC TGCGGTGTGG CGCCAGCTCT GACGGTGCTG CCTGGCGGGG GAGTGTCTGC TTCCTCCCTT CTGCTTGGGA ACCAGGACAA AGGATGAGGC TCCGAGCCGT TGTCGCCCAA CAGGAGCATG

[0233] In some embodiments of the methods of the disclosure, the subject having PrePF or at risk of developing IPF has a mutation in a sequence encoding Desmoplakin (DSP). In some embodiments the polymorphism is rs2076295 comprising (SEQ ID NO: 4).

TABLE-US-00006 (SEQ ID NO: 4) ATTTGGGAAC CTTTAAAAAA TATTCTGGCT TCAAAAATAC TCCATATTTA CATCTTTGGT TCTATCTGAA GTAAAGCCGT GATGGTGTGC GTAAGTGAAA CAGGTGCAAA GGGGCAACAA CAAAGGGCGC CTCTCTTTGT CTTTGTGTCG CAGGCGGAGA TGGACATGGT GGCCTGGGGT GTGGACCTGG CCTCAGTGGA GCAGCACATT AACAGCCACC GGGGCATCCA CAACTCCATC GGCGACTATC GCTGGCAGCT GGACAAAATC AAAGCCGACC TGGTACTTGT CTGTGTTTCA TTTTAGAGTC TTCAAAATAT CTACCGAAGG ATCGTGTAAT TACTCAATCC CAGGGAGTTT CTTCTGAAAC ATTGCTATTA TTTCTTTCCC AGAAGACTGG AAATGTTTAG AAATCCCACT TCTTAAATGG GGAAGTGGAA TCAGTAGCCC TATTAGAGAT TATGTTAACA CTTGAAGAGG AGTTAAACCA GAGGCTGAGG K TGTGCAAACA CTCATTTGCA GTTTGTGAAT AAGTCTCTTT AGGGGTGGCA GTTTGTTTCT GCGGTAAGCA GAACATCTTT TTGAATAGGG GAAATGCAAC AGTCTTATAC AGTAGTTTGT GTCATTGGTG AATCCTTTCC TAGGTGGTAA TTAAAACATT ATTTCTACTG AGCAAAGCCA TATGTCATCC CGACACCCGC TCCCATGCTG AAAAAAGTCA GACTTGAAAC TGGGTTGAGA ATTACAGCAT AAAATCATAA CTGATCTTAA GTGCTTAGTT TCCCGCAGGT CTCTACACTT GTAAATCACT AAACTTTTTT TTTTTTTTTT TACCTGAGAC CATAGCTTCT CATCCTCATT TCTTCTTCTG GCTTTTTGGG GCTTACTTTT GTCCACCTGA GCCCCTGACC AACTTTCTCC TTCATTTCTC TAAGACCTAG GGAATCCTAA ATGATGTCTT TAAACTTTAA GACAATTTTC TAACACGTGA GTCTTTAAGT

[0234] In some embodiments of the methods of the disclosure, the subject having PrePF or at risk of developing IPF has a mutation in a sequence encoding Zinc-alpha 2-Glycoprotein 1 (AZGP1). In some embodiments the polymorphism is rs4727443 comprising (SEQ ID NO: 5).

TABLE-US-00007 (SEQ ID NO: 5) CCCAACCCAA ATAAGCACTA TAACCTCTTG TTATTCACTT CTCATGCAAC CAGTCTTCTG TTCTCTGTGA GTCTTTAGGA AATGAGGAGC ATGATCTTCT AGCAGTAAAA CACCTGTAGA GAATTGCCTT ATGTTTTTTG TTTGTTTATT TGTTTGTGTG CTTTGGTTTG GTTTGCTTTT TTTTTTTTTT TTTTTTTTTT TTTGAGATGG AGTCTCGCCC TGTTGCCCAG GCTGGAGTGT AGTGGCGAAA TCTCGGCTCA CTGCAACCTC CACCTCCCTG GTTCAAGCAA TTCCCCTGTC TCAGCCTCCC GAGTAGCTGA GATTACAGGT GCACACCACC ACGCCCGGCT AATTTTTTTG TATTTTTAGT AGAGATGGGG TTTCACCATG TTGGCCAGAC TGGTCTCGAA CTTCTGACCT CAGGCAATCC GCCTGCCTCA GCCTCCCAAA GCGCTGGGAT TACAGGCATG AGCCACTGCG CCCCGCCTCC ATGTTAATCA M TCTTTCTGAT TTCAAATAAC TCATTATCCC CATGACCTTA TGGATTTGTT TTTCCTCTTC ATCCACAAAA TTCTCCAGAG AAGTCTCCCT TGTTATCTCT TGGCTGTGCT TTCTATCTCA CCAGTTATCT TTCTCCAAAG AGCTTCCTCT GCAAAGAAGC TTTGTATATG AAGACCATGT GGGGGCTGAA TCAAGACCAA GTTTCACAAC CTAAAAGTAG TTCACAAAGC TTCCTTGCCT CTATTCTCTG CAAATCTGTA AACTCTTCAG CTGACCCAAT TTCTCTCTTT AGCCTTCAGA GATTATTTTA TTTTATTTTA TTTCATTTCA TTTCATTTCA TTTTGACAGA ATCTAGCTCT GTCGCCCAGG CTGGAGTGCA GTGGCACCAT CTTTGCTCAC TGCAACCTCC CCCTCACAGG TTCAAGCAAC TGTCCTGCCT CAGCCTCCCG AGTAGCTGGG ATTACAGGCG TGAGCCACCA CGCCCAGCTG ATTTTTTTTT

[0235] In some embodiments of the methods of the disclosure, the subject having PrePF or at risk of developing IPF has a mutation in a sequence encoding Oligonucleotide/oligosaccharide-binding Fold Containing 1 (OBFC1). In some embodiments the polymorphism is rs11191865 comprising (SEQ ID NO: 6).

TABLE-US-00008 (SEQ ID NO: 6) CCTCTACTGC CGTACACCCC ACCACTCAGC CTTGGAGTGC CTGTGTGCAG AGCAGGGCTG AGGCATGGTG CTGCTTTGGT GGTCTAGGTT TGCTGCAGGG CCAGGTGGCC TGAGCTCCAG GCAGGATCTC TGGCTGCACT CAGCCCTTTC TGCCTCCCCA AATGCTCTAT ATCACTATTT GTACACTGAG CAGAGTAAAG TTAGAGAGAA CTGTTTTATA GAATAGGGCT GGCCCCCGCT CCCCTGGCCT ACGTGATGGT CCTTCCTGGC TGCCAGGTAC TTGTTTGTAT TAGAGACAGA CACTCCACAG GGTCTGTTGT GGCCCACAGC ACATAGGCAA TCAGAGGCAG AAAGCAGAGC TGTTTGGACC CACAGAGGGC CGGCTGTCTG CCACTGAAAT GTCTTTCCAG TTGGTTGAGA AGCAGCAGGA TGCTCTGCTG GTGATGTCTG AAAGTCCCAG GATTCTTTGG GTCTCCAAGG AGATCCTAGC ATATACCACT R TCGTGGTTTT AATAAAGAGC AAAAACACTT TCAGATGGGG AGAAGAGTGG AACAAAAGGT ATTCTTCCTG GGTTGAAGTC TGGGGGAAAG GCATTGAGAA GACTGGGCTA ATGGCACAAA CCAATGAAGT ACTCAAGTCA CCTGTGATGG AGGCCAGTCA TCCAATGGTA TCAACTTTGT ATGTGGCAAC ACTTAATAAA AATCTGAACA GGTCTTCACT TGTGGACACA GTAGACTTTC TTGAAAAAGG ACAGAAAAGT GAGCCCTGTG AATTTTCATC TCACGGACTG ACAACAATGA CTTGCCTTTA AGGACAGTCA CTCAAGATGA AGATGCAACA AAACCCTTCC AGTTCCAAGT GGCTGATGAA AAAAAAAAAA TCTTAAAAGC ATCACAGAAC AACGGAGAAA GAGATCAGAA GACTATAACA GATAGTTTGA ATTTTAAAAC TCAGAGAAAA GCAACTGAGG AGGAAATACA CTGCTTAGAA AGAAGAAACT

[0236] In some embodiments of the methods of the disclosure, the subject having PrePF or at risk of developing IPF has a mutation in a sequence encoding Mucin 5B (MUC5B). In some embodiments the polymorphism is rs35705950 comprising (SEQ ID NO: 7).

TABLE-US-00009 SEQ ID NO: 7) TGGACGGCCT CTGAAGGGGT CTGTGGGGTC CTGGACGGGT CCCCATTCAT GGCAGGATTA ACCCCCCTCG GGTTCTGTGT GGTCCAGGCC GCCCCTTTGT CTCCACTGCC CCCTGGCCAG AATGAGGGAC AGTGACCCAC CCAGGGCTGG GCCTGGCTCA GACTCCGTCA GAGCCGCAGG GCAAGTTCCT GGCACGTCCG AGGTGGGAGG CTCCTCTGCG CTCCAGGAGG CTGTGCCTGG CCCCCCTTCC CGGCAGGAAC CGGCTGTGTC CCTTTCCTTC CTTTATCTTC TGTTTTCAGC D CCTTCAACTG TGAAGAGGTG AACTCTTCAA ACACGCTGAG CAAACAGGCC CGACTCCCAG GGCCGCATCC GGGATGTCTC AATAGCTGTG GCCTTGACGT CCACCTCGGA CCCCTGCCCC GGACCCAGCC CAGTTCCCAA TGGGCCCTCT GCCCGGGGAG GTGCCTAGTG GGAGGGACGA GGGCAAAGTC GGGGCCCCCA CTTGTTTGGT GTCACTGTGT GCCAGCGGCC ACTGGCGGGC GAGGCTGTTC CAGGGTGGAG GCGGGGAGGG TTGGACCACA GGCACTGAGC GGGGACAGAG

[0237] In some embodiments of the methods of the disclosure, the subject having PrePF or at risk of developing IPF has a mutation in a sequence encoding ATPase Phospholipid Transporting 11A (ATP11A). In some embodiments the polymorphism is rs12787690 comprising (SEQ ID NO: 8).

TABLE-US-00010 (SEQ ID NO: 8) GTCATTGGTC AAATGTGGCC TGTATCTAAA TTCCAACTGT TAGAATCATA GACATCTAGA GCTTACGTCA GTTTTAGATA TTTCTTATGA ATTCTCAGAA TTCATAGATT CTCATTTTTA TTCTTAGACT TCTCAGATAT TCCGTTTTTG ATAGTATACC CTTCTGAGTC TAATATGTCC TAAAGTGCGA ACTTGTACAA TTTttttttt tttttttttt tttttttttt t K tgataaggag ttttactctg tcacccaggc tggagtgcag tgacccgatc tcggctcact gcaacctctg cctcccgggt tcaagtgatt gtgatgtctc agtctcccaa gtagctggga ttacaggctc ctgccaccac atgcctagct aattgttata ctttagtaga aatggggctt cgccgtgtta gtcaggctgg tcttgtactc ctgacctcag ttgatctgcc taccttggcc cccaaggtgc tgggattaca ggcatgagcc accgcgcctg accCAGCTTC TTAAATTATT CTGGGCCACC AGTAATGTGA ATCATGtaaa ttaaaatata taattaaaCA AAATCATATA GCGATTAGAG ATAATAGTTG TGAAATGCTT GAAAAATCAT AGGCATTTAA TAAATAGAAG CCATTCCAAT TAGGATTCTT CTTGATTTTT TTTCAAGACC AAAAAAATAC TCttttaaat atttattata ataCTCCATG

[0238] In some embodiments of the methods of the disclosure, the subject having PrePF or at risk of developing IPF has a mutation in a sequence encoding Isovaleryl-CoA dehydrogenase (IVD)/Dispatched RND Transporter Family Member 2 (DISP2). In some embodiments the polymorphism is rs2034650 comprising (SEQ ID NO: 9).

TABLE-US-00011 (SEQ ID NO: 9) aggctgcagt tagtcatgac tgcgcgctgc actccagcct gggtgacaaa gtgaggccct gtctcaaaaa caataaaaaa TTTAAAAGAG CTGAGCATGG AGGCcacttt gggaggctga ggcaggcaga tctcttaagc ccaggagtct gagaccagcc tgggcgacat gatgaagccc catctctaca aaaaatacaa aaaaattagc tgagctttat ggcaaatccc tgtaatccca gttacctagg aggcccaggc aggaagatgg cttgagccca aaaggttgag gctgtagtga gctgtgatca tgaacagagt gagaccctgt ttcaaaacaa aatgaaaaac aaacaaacaa aaaaaCCAAG AAAACAAGAA AACAAAAACT ATACAATGAT GAGCCAAAAA GCAAGATATG GAAGAatata tatatatata tatatatata tataGTATGA GTCCAGCTAT AGAAAGTTTG AAATCAGGCA ACCTAAACAA TATTGTTCAG GGATCTATAC AGAGGCAGGA AGCCATTGAG AAAGGTAAGG GGAGGATTAT CACCAAATTC AGGATGGTGG CTCCCCTGGG GAGAATATGT CAAGGAGGGG CACATGGGCT TGGAATACTG TCTTCATTGA CCTGCGTGTT GGGTACACAG GAGTTTGTTA TTTTTCACAC TGCATATGTG CATGTATATA CTCTCCCATA TATACCATGC ATTTCACACA AGAACACAAA GGCTGTGTGG CTCTGCTCTG CCCCTTTCCC CTTCCAGCTC CCATTCTCGT C Y TCAGCTAGCA GAGGAGGGTC AGGGTCTTTT AGCACAGCTT CCTTCTGTCT CTGAGTGGGT CAGAGGAGTA CGGGGATGAG GGCCTCCCTT CTGCGGCTGG GCTCTGGCCA CTCCAGGGTG GGAAGGCCTG GAGAAAACAG GGCCAGGCAA AGCCGGCTGG CCCTGCTGTT TCTGCCAATG CTGGGATTAG GCCAGGGCTC TGGCCCACCT GTCATTTCAC TCATTCAGCA TGAACATAGC CACTGAGCAC TTACTGTGAG CCCCGGGTGC TATTGGGAGA GTTCAGATAA GTGAGAGAGG GTCTTTGACC TCAAAGATCT TACAGAGAGG ACCGTATACA CAAATAACAG TATACCAGCA AAATGTGAGC TAAGTGTCAT GTGACTACTC atctactctt tcaataaata tttgttgtgc acctattaca tgccaggaac tgtgctggat ggtgatcatg taaagacagt caaatcacag tcctagctct cagattcaca gcctgcctaa tgctggggaa acTGGAAT

[0239] In some embodiments of the methods of the disclosure, the subject having PrePF or at risk of developing IPF has a mutation in a sequence encoding Dipeptidyl Peptidase 9 (DPP9). In some embodiments the polymorphism is rs12610495 comprising (SEQ ID NO: 10).

TABLE-US-00012 (SEQ ID NO: 10) CCAGCCAGAA GGGGCGCAGT TTGTTAGTTC AGCTCCTCCT GAGACAGAAA TAAAGACACG AACCAAAGGA CATCAGCACT TACAGGGCTC TCAGGTCACA CACAGGATGT CCGCGCCCAC TGCAGAGCTG CAGGTCCCCT CCAGGGCAGT GGGGAGCCAC AAGCAGCGTT AGGCAGCGGC TGGGACCAGG ACCGCCTGAG CACTCAAGAA CCCCCACTGC CCCAAGCACT GCTGGCAGCA AGCCCAGAAA ACTGAGCCCG GGGAGCTCCT CTGAGCGGCC TAAGCACCCC TCTAAGCTGT GCTGCCCCAA TTCAAGCCTG GCTCACGGCA GCAAAGAAAA AATGTGACCT TCGGAGCTCC CAAAGGGGCC ACCCATAAGC TGAGAGCCTG CCCGGAAGCA CTTATAGACC CGCGTGGCTT GTTTTCATTG CAAAGAACAA TAAAAATTAT CTTGCCTCTG ATCACCACTG ATAGCCCAAG AAGCAAAAAT TCGATCCCGG D GATGAGAAAT GAAATGAAAC ATCGCGAGAA ACTTCCAGGA ATCTTCTGGA TGTGGCTAGA CTCTTTAGCT TGAGCTTCCA GACAGGCCGA GGCTTGGTGC TGGAGCCTGG CCCTCCGCTG ACCTCTCTTC TACCCGGGGG CACAGCCCGG ATTGCAGAGA GGCTGGCGCA AGAGTGAGGG AGCGAGGGCT AGCCTGTGAT GGGCTTTCTC CACCTAGCAC CACCCTATGC TGTGGCTCAG GGGAGTCAAG AGTTTACACA GCTGCAGAGA TGGATTCCAG GCCACTTACT CAAGTCTACC TACTCCTTCC TTCGGCCAAT CAGCTGGGTG CCTCTGCGGC CTGTGACACC ACCAGCAAAC AGCTCCAGAC CTCCTAGCAT GGTCTCTGTC AAGGCTGGGT GGCAGATCTG TGATCTCCTT TTTAAATTTT TCATTTTTTT TAAGAGATGG GGTCTTGCTA TATTGCCCAG GCTGGTCTCA AACTCCTGGG CTCCAGCGAT

[0240] In some embodiments of the methods of the disclosure, the wild type human MUC5B gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_002458.2):

TABLE-US-00013 (SEQ ID NO: 11) 1 cacccggccc ggctccctcc ctgcccgtcc ccgtcccccc acccgtgcca gcccccagga 61 tgggtgcccc gagcgcgtgc cggacgctgg tgttggctct ggcggccatg ctcgtggtgc 121 cgcaggcaga gacccagggc cctgtggagc cgagctggga gaatgcaggg cacaccatgg 181 atggcggtgc cccgacgtcc tcgcccaccc ggcgcgtgag ctttgttcca cccgtcactg 241 tcttccccag cctgagcccc ctgaacccgg cgcacaatgg gcgggtgtgc agcacctggg 301 gtgacttcca ctacaagacc ttcgacggcg acgtcttccg cttccctggc ctttgcaact 361 acgtgttctc tgagcactgc cgcgccgcct acgaggactt caacgtccag ctacgccgag 421 gcctagtggg ctccaggcct gtggtcaccc gtgttgtcat caaggcccag gggctggtgc 481 tggaggcgtc caacggctcc gtcctcatca atgggcagcg ggaggagctg ccttacagcc 541 gcactggcct cctggtggag cagagcgggg actacatcaa ggtcagcatc cggctggtgc 601 tgacattcct gtggaacgga gaggacagtg ccctgctgga gctggatccc aaatacgcca 661 accagacctg tggcctgtgt ggggacttca acggcctccc ggccttcaac gagttctatg 721 cccacaacgc caggctgacc ccgctccagt ttgggaacct gcagaagttg gatgggccca 781 cggagcagtg cccggacccg ctgcccttgc cggccggcaa ctgcacggac gaggagggca 841 tctgccaccg caccctgctg gggccggcct ttgcggagtg ccacgcactg gtggacagca 901 ctgcgtacct ggccgcctgc gcccaggacc tgtgccgctg ccccacctgc ccgtgtgcca 961 cctttgtgga atactcacgc cagtgcgccc acgcgggggg ccagccgcgg aactggaggt 1021 gccctgagct ctgcccccgg acctgccccc tcaacatgca gcaccaggag tgtggctcac 1081 cctgcacgga cacctgctcc aacccccagc gcgcgcagct ctgcgaggac cactgtgtgg 1141 acggctgctt ctgcccccca ggcacggtgc tggatgacat cacgcactct ggctgcctgc 1201 ccctcgggca gtgcccctgc acccacggcg gccgcaccta cagcccgggc acctccttca 1261 acaccacctg cagctcctgc acctgctccg gggggctatg gcagtgccag gacctgccgt 1321 gccctggcac ctgctctgtg cagggcgggg cccacatctc cacctatgat gagaaactct 1381 acgacctgca tggtgactgc agctacgttc tgtccaagaa atgtgccgac agcagcttca 1441 ccgtgctggc tgagctgcgg aagtgcggcc tgacggacaa cgagaactgc ctgaaagcgg 1501 tgacgctcag cctggacggc ggggacacgg ccatccgggt ccaagcggac ggcggcgtgt 1561 tcctcaactc catctacacg cagctgcccc tgtcggcagc caacatcacc ctgttcacac 1621 cctcgagctt cttcatcgtg gtgcagacag gcctggggct gcagctgctg gtgcagctgg 1681 tgccactcat gcaggtgttt gtcaggctgg accccgccca ccagggccag atgtgcggcc 1741 tgtgtgggaa cttcaaccag aaccaggctg acgacttcac ggccctcagc ggggtggtgg 1801 aggccacggg cgcagccttc gccaacacct ggaaggccca ggctgcctgt gccaatgcca 1861 ggaacagctt tgaggacccc tgctccctca gtgtggagaa tgagaactac gcccggcact 1921 ggtgctcgcg cctgaccgat cccaacagtg ccttctcgcg ctgccactcc atcatcaacc 1981 ccaagccctt ccactcgaac tgcatgtttg acacctgcaa ctgtgagcgg agcgaggact 2041 gcctgtgcgc cgcgctgtcc tcctatgtgc acgcctgtgc cgccaagggc gtacagctca 2101 gcgactggag ggacggcgtc tgcaccaagt acatgcagaa ctgccccaag tcccagcgct 2161 acgcctacgt ggtggatgcc tgccagccca cttgccgcgg cctgagtgag gccgacgtca 2221 cctgcagcgt ttccttcgtg cctgtggacg gctgcacctg ccccgcgggc accttcctca 2281 atgacgcggg cgcctgtgtg cccgcccagg agtgcccctg ctacgctcac ggcaccgtgc 2341 tggctcctgg agaggtggtg cacgacgagg gcgccgtgtg ttcatgtacg ggtgggaagc 2401 taagctgcct gggagcctct ctgcagaaaa gcacagggtg tgcagccccc atggtgtacc 2461 tggactgcag caacagctcg gcgggcaccc ctggggccga gtgcctccgg agctgccaca 2521 cgctggacgt gggctgtttc agcacacact gcgtgtccgg ctgtgtctgt cccccggggc 2581 tggtgtcgga tgggagtggg ggctgcattg ccgaggagga ctgcccctgt gtgcacaacg 2641 aggccaccta caagcctgga gagaccatca gggtcgactg caacacctgc acctgcagga 2701 accggaggtg ggagtgcagc caccggctct gcctgggcac ctgcgtggcc tacggggatg 2761 gccacttcat cacctttgat ggcgatcgct acagctttga aggcagctgc gagtacatct 2821 tggcccagga ctactgtggg gacaacacca cccacgggac cttccgcatc gtcaccgaga 2881 acatcccctg tgggaccacc ggcaccacct gctccaaggc catcaagctc ttcgtggaga 2941 gctacgagct gatcctccaa gaggggacct ttaaggcggt ggcgagaggg ccgggtgggg 3001 acccacccta caagatacgc tacatgggga tcttcctggt catcgagacc cacgggatgg 3061 ccgtgtcctg ggaccggaag accagcgtgt tcatccgact gcaccaggac tacaagggca 3121 gggtctgcgg cctgtgcggg aacttcgacg acaatgccat caatgacttt gccacgcgta 3181 gccggtccgt ggtgggggac gcactggagt ttgggaacag ctggaagctc tccccctcct 3241 gcccggacgc cctggcaccc aaggacccct gcacggccaa ccccttccgc aagtcctggg 3301 cccagaagca gtgcagcatc ctccacggcc ccaccttcgc cgcctgccgc tcccaggttg 3361 actccaccaa gtactacgag gcctgcgtga acgacgcgtg tgcctgcgac tcgggtggcg 3421 actgcgagtg tttctgcacg gctgtggctg cctacgccca ggcctgccac gacgcgggcc 3481 tgtgtgtgtc ctggcggact ccggacacct gccccttgtt ctgtgacttc tacaacccac 3541 atgggggctg tgagtggcac taccagccct gcggggcacc ctgcctaaaa acctgccgga 3601 accccagtgg gcactgcctg gtggacctgc ctggcctgga aggctgctac ccgaagtgcc 3661 cacccagcca gcccttcttc aatgaggacc agatgaagtg cgtggcccag tgtggctgct 3721 acgacaagga cggaaactac tatgacgtcg gtgcaagggt ccccacagcg gagaactgcc 3781 agagctgtaa ctgcacaccc agtggcatcc agtgcgctca cagccttgag gcctgcacct 3841 gcacctatga ggacaggacc tacagctacc aggacgtcat ctacaacacc accgatgggc 3901 ttggcgcctg cttgatcgcc atctgcggaa gcaacggcac catcatcagg aaggctgtgg 3961 catgtcctgg aactccagcc acaacgccat tcaccttcac caccgcctgg gtcccccact 4021 ccacgacaag cccggccctc ccggtctcca ccgtgtgtgt ccgcgaggtc tgccgctggt 4081 ccagctggta caatgggcac cgcccagagc ccggcctggg aggcggagac tttgagacgt 4141 ttgaaaacct gaggcagaga gggtaccagg tatgccctgt gctggctgac atcgagtgcc 4201 gggcggcgca gcttcccgac atgccgctgg aggagctggg ccagcaggtg gactgtgacc 4261 gcatgcgggg gctgatgtgc gccaacagcc aacagagtcc cccgctctgt cacgactacg 4321 agctgcgggt tctctgctgc gaatacgtgc cctgtggccc ctccccggcc ccaggcacca 4381 gccctcagcc ctccctcagt gccagcacgg agcctgctgt gcctacccca acccagacca 4441 cagcaaccga aaagaccacc ctatgggtga ccccgagcat ccggtcgacg gcggccctca 4501 cctcgcagac tgggtccagc tcaggccccg tgacggtcac cccctcggcc ccaggtacca 4561 ccacctgcca gccccggtgt cagtggacag agtggtttga tgaggactac cccaagtctg 4621 aacaacttgg aggggacgtt gagtcctacg ataagatcag ggccgctgga gggcacttat 4681 gccagcagcc taaggacata gagtgccagg ccgagagctt ccccaactgg accctggcac 4741 aggtggggca gaaggtgcac tgtgacgtcc acttcggcct ggtgtgcagg aactgggagc 4801 aggagggcgt cttcaagatg tgctacaact acaggatccg ggtcctctgc tgcagtgacg 4861 accactgcag gggacgtgcc acaaccccgc caccgaccac agagctggag acggccacca 4921 ccaccaccac ccaggccctg ttctcaacgc cgcagcctac gagtagcccg gggctgacca 4981 gggctccccc ggccagcacc acagcagtcc ccaccctctc agaaggactg acatccccca 5041 gatacacaag cacccttggt acagccacca cgggaggccc cacgacgcct gcaggctcca 5101 cagaacccac tgtcccaggg gtggccacat ccacccttcc aacacgctca gcccttccag 5161 ggacgacggg gagcttgggc acatggcgcc cctcacagcc acccacgctg gccccaacaa 5221 caatggcaac ctccagagct cgcccgacag gcacagccag caccgcttcc aaagagccgc 5281 tgaccacgag cctggcgcca acactcacga gcgagctgtc cacctctcag gccgagacca 5341 gcacgcccag gacagagacg acaatgagcc ccttgactaa caccaccacc agccagggca 5401 cgacccgctg tcaaccgaag tgtgagtgga cagagtggtt tgacgtggac ttcccaacct 5461 caggggttgc aggcggggac atggaaactt ttgaaaacat cagggctgct gggggcaaga 5521 tgtgctgggc accaaagagc atagagtgcc gggcggagaa ctaccccgag gtaagcatcg 5581 accaggtcgg gcaggtgctg acctgcagcc tggagacggg gctgacctgc aagaacgaag 5641 accagacagg caggttcaac atgtgcttca actacaacgt gcgtgtgctt tgctgtgacg 5701 actacagcca ctgccccagt accccagcca ccagctccac ggccacgccc tcctcaactc 5761 cggggacgac ctggatcctc acaaagccga ccacaacagc cactacgact gcgtccactg 5821 gatccacggc caccccgacc tccaccctga gaacagctcc ccctcccaaa gtgctgacca 5881 ccacggccac cacacccaca gtcaccagct ccaaagccac tccctcctcc agtccaggga 5941 ctgcaaccgc ccttccagca ctgagaagca cagccaccac acccacagct accagcgtta 6001 cacccatccc ctcttcctcc ctgggcacca cctggacccg cctatcacag accaccacac 6061 ccacggccac catgtccaca gccacaccct cctccactcc agagactgcc cacacctcca 6121 cagtgcttac cgccacggcc accacaactg gggccaccgg ctctgtggcc accccctcct 6181 ccaccccagg aacagctcac actaccaaag tgccaactac cacaaccacg ggcttcacag 6241 ccaccccctc ctccagccca gggacggcac tcacgcctcc agtgtggatc agcacaacca 6301 ccacacccac aaccagaggc tccacggtga ccccctcctc catcccgggg accacccaca 6361 ccgccacagt gctgaccacc accaccacaa ctgtggccac tggttctatg gcaacaccct 6421 cctctagcac acagaccagt ggtactcccc catcactgac caccacggcc actacgatca 6481 cggccaccgg ctccaccacc aacccctcct caactcctgg gacaactccc atccccccag 6541 tgctgaccac caccgccacc acacctgcag ccaccagcaa cacagtgact ccctcctctg 6601 ccctagggac cacccacaca cccccagtgc cgaacaccat ggccaccaca cacgggcgat 6661 ccctgccccc cagcagtccc cacacggtgc gcacagcctg gacttcggcc acctcgggca 6721 tcttgggcac cacccacatc acagagcctt ccacggtgac ttcccacacc ctagcagcaa 6781 ccaccggtac cacccagcac tcgactccag ccctttccag ccctcaccct agcagcagaa 6841 ccaccgagtc acccccttct ccagggacga ccaccccggg ccacaccacg gccacctcca 6901 ggaccacagc cacggccaca cccagcaaga cccgcacctc gaccctgctg cccagcagcc 6961 ccacatcggc ccccataacc acggtggtga ccatgggctg tgagccccag tgtgcctggt 7021 cagagtggct ggactacagc taccccatgc cggggccctc tggcggggac tttgacacct 7081 actccaacat ccgtgcggcc ggaggggccg tctgtgagca gcccctgggc ctcgagtgcc 7141 gtgcccaggc ccagcctggt gtccccctgc gggagttggg ccaggtcgtg gaatgcagcc 7201 tggactttgg cctggtctgc aggaaccgtg agcaggtggg gaagttcaag atgtgcttca 7261 actatgaaat ccgtgtgttc tgctgcaact acggccactg ccccagcacc ccggccacca 7321 gctctacggc catgccctcc tccactccgg ggacgacctg gatcctcaca gagctgacca 7381 caacagccac tacgactgag tccactggat ccacggccac cccgtcctcc accccaggga 7441 ccacctggat cctcacagag ccgagcacta cagccaccgt gacggtgccc accggatcca

7501 cggccaccgc ctcctccacc caggcaactg ctggcacccc acatgtgagc accacggcca 7561 cgacacccac agtcaccagc tccaaagcca ctcccttctc cagtccaggg actgcaaccg 7621 cccttccagc actgagaagc acagccacca cacccacagc taccagcttt acagccatcc 7681 cctcctcctc cctgggcacc acctggaccc gcctatcaca gaccaccaca cccacggcca 7741 ccatgtccac agccacaccc tcctccactc cagagactgt ccacacctcc acagtgctta 7801 ccaccacggc caccacaacc ggggccaccg gctctgtggc caccccctcc tccaccccag 7861 gaacagctca cactaccaaa gtgctgacta ccacaaccac gggcttcaca gccaccccct 7921 cctccagccc agggacggca cgcacgcttc cagtgtggat cagcacaacc accacaccca 7981 caaccagagg ttccacggtg accccctcct ccatcccggg gaccacccac acccccacag 8041 tgctgaccac caccaccaca actgtggcca ctggttctat ggcaacaccc tcctctagca 8101 cacagaccag tggtactccc ccatcactga ccaccacggc cactacgatc acggccaccg 8161 gctccaccac caacccctcc tcaactccag ggacaacacc tatcccccca gtgctgacca 8221 ccaccgccac cacacctgca gccaccagca gcacagtgac tccctcctct gccctaggga 8281 ccacccacac acccccagtg ccgaacacca cggccaccac acacgggcga tccctgtccc 8341 ccagcagtcc ccacacggtg cgcacagcct ggacttcggc cacctcaggc accttgggca 8401 ccacccacat cacagagcct tccacgggga cttcccacac cccagcagca accaccggta 8461 ccacccagca ctcgactcca gccctgtcca gccctcaccc tagcagcagg accaccgagt 8521 cacccccttc tccagggacg accaccccgg gccacaccag ggccacctcc aggaccacgg 8581 ccacggccac acccagcaag acccgcacct cgaccctgct gcccagcagc cccacatcgg 8641 ccccaataac cacggtggtg accatgggct gtgagcccca gtgtgcctgg tcagagtggc 8701 tggactacag ctaccccatg ccggggccct ctggcgggga ctttgacacc tactccaaca 8761 tccgtgcggc cggaggggcc gtctgtgagc agcccctggg cctcgagtgc cgtgcccagg 8821 cccagcctgg tgtccccctg cgggagttgg gccaggtcgt ggaatgcagc ctggactttg 8881 gcctggtctg caggaaccgt gagcaggtgg ggaagttcaa gatgtgcttc aactatgaaa 8941 tccgtgtgtt ctgctgcaac tacggccact gccccagcac cccggccacc agctctacgg 9001 ccacgccctc ctccactcca gggacgacct ggatcctcac agagcagacc acagcagcca 9061 ctacgaccgc aaccactgga tccacggcca tcccgtcctc caccccggga acagctcccc 9121 ctcccaaagt gctgaccagc acggccacca cacccacagc caccagttcc aaagccactt 9181 cctcctccag tccaaggact gcaaccaccc ttccagtgct gacaagcaca gccaccaaat 9241 ccacagctac cagctttaca cccatcccct ccttcaccct tgggaccacc gggaccctcc 9301 cagaacagac caccacaccc atggccacca tgtccacaat ccacccctcc tccactccgg 9361 agaccaccca cacctccaca gtgctgacca cgaaggccac cacgacaagg gccaccagtt 9421 ccatgtccac cccctcctcc actccgggga cgacctggat cctcacagag ctgaccacag 9481 cagccactac aactgcagcc actggcccca cggccacccc gtcctccacc ccagggacca 9541 cctggatcct cacagagccc agcactacag ccaccgtgac ggtgcccacc ggatccacgg 9601 ccaccgcctc ctccacccgg gcaactgctg gcaccctcaa agtgctgacc agcacggcca 9661 ccacacccac agtcatcagc tccagagcca ctccctcctc cagtccaggg actgcaaccg 9721 cccttccagc actgagaagc acagccacca cacccacagc taccagcgtt acagccatcc 9781 cctcttcctc cctgggcacc gcctggaccc gcctatcaca gaccaccaca cccacggcca 9841 ccatgtccac agccacaccc tcctctactc cagagactgt ccacacctcc acagtgctta 9901 ccaccacgac caccacaacc agggccaccg gctctgtggc caccccctcc tccaccccag 9961 gaacagctca cactaccaaa gtgccgacta ccacaaccac gggcttcaca gccaccccct 10021 cctccagccc agggacggca ctcacgcctc cagtgtggat cagcacaacc accacaccca 10081 caaccagagg ctccacggtg accccctcct ccatcccggg gaccacccac accgccacag 10141 tgctgaccac caccaccaca actgtggcca ctggttctat ggcaacaccc tcctctagca 10201 cacagaccag tggtactccc ccatcactga ccaccacggc cactacgatc acagccaccg 10261 gctccaccac caacccctcc tcaactccag ggacaactcc catcccccca gtgctgacca 10321 ccaccgccac cacacctgca gccaccagca gcacagtgac tccctcctct gccctaggga 10381 ccacccacac acccccagtg ccgaacacca cggccaccac acacgggcgg tccctgcccc 10441 ccagcagtcc ccacacggtg cgcacagcct ggacttcggc cacctcgggc atcttgggca 10501 ccacccacat cacagagcct tccacggtga cttcccacac cccagcagca accaccagta 10561 ccacccagca ctcgactcca gccctgtcca gccctcaccc tagcagcagg accaccgagt 10621 cacccccttc tccagggacg accaccccgg gccacaccag gggcacctcc aggaccacag 10681 ccacagccac acccagcaag acccgcacct cgaccctgct gcccagcagc cccacatcgg 10741 cccccataac cacggtggtg accacgggct gtgagcccca gtgtgcctgg tcagagtggc 10801 tggactacag ctaccccatg ccggggccct ctggcgggga ctttgacacc tactccaaca 10861 tccgtgcggc cggaggggca gtctgtgagc agcccctggg cctcgagtgc cgtgcccagg 10921 cccagcctgg tgtccccctg cgggagttgg gccaggtcgt ggaatgcagc ctggactttg 10981 gcctggtctg caggaaccgt gagcaggtgg ggaagttcaa gatgtgcttc aactatgaaa 11041 tccgtgtgtt ctgctgcaac tacggccact gccccagcac cccggccacc agctctacgg 11101 ccacgccctc ctcaactccg gggacgacct ggatcctcac aaagctgacc acaacagcca 11161 ctacgactga gtccactgga tccacggcca ccccgtcctc caccccaggg accacctgga 11221 tcctcacaga gccgagcact acagccaccg tgacggtgcc caccggatcc acggccaccg 11281 cctcctccac ccaggcaact gctggcaccc cacatgtgag caccacggcc acgacaccca 11341 cagtcaccag ctccaaagcc actcccttct ccagtccagg gactgcaacc gcccttccag 11401 cactgagaag cacagccacc acacccacag ctaccagctt tacagccatc ccctcctcct 11461 ccctgggcac cacctggacc cgcctatcac agaccaccac acccacggcc accatgtcca 11521 cagccacacc ctcctccact ccagagactg cccacacctc cacagtgctt accaccacgg 11581 ccaccacaac cagggccacc ggctctgtgg ccaccccctc ttccacccca ggaacagctc 11641 acactaccaa agtgccgact accacaacca cgggcttcac agtcaccccc tcctccagcc 11701 cagggacggc acgcacgcct ccagtgtgga tcagcacaac caccacaccc acaaccagtg 11761 gctccacggt gaccccctcc tccgtcccgg ggaccaccca cacccccaca gtgctgacca 11821 ccaccaccac aactgtggcc actggttcta tggcaacacc ctcctctagc acacagacca 11881 gtggtactcc cccatcactg atcaccacgg ccactacgat cacggccacc ggctccacca 11941 ccaacccctc ctcaactcca gggacaacac ctatcccccc agtgctgacc accaccgcca 12001 ccacacctgc agccaccagc agcacagtga ctccctcctc tgccctaggg accacccaca 12061 cacccccagt gccgaacacc acggccacca cacacgggcg atccctgtcc cccagcagtc 12121 cccacacggt gcgcacagcc tggacttcgg ccacctcagg caccttgggc accacccaca 12181 tcacagagcc ttccacgggg acttcccaca ccccagcagc aaccaccggt accacccagc 12241 actcgactcc agccctgtcc agccctcacc ctagcagcag gaccaccgag tcaccccctt 12301 ccccagggac gaccaccccg ggccacacca cggccacctc caggaccacg gccacggcca 12361 cacccagcaa gacccgcacc tcgaccctgc tgcccagcag ccccacatcg gcccccataa 12421 ccacggtggt gaccacgggc tgtgagcccc agtgtgcctg gtcagagtgg ctggactaca 12481 gctaccccat gccggggccc tctggcgggg actttgacac ctactccaac atccgtgcgg 12541 ccggaggggc cgtctgtgag cagcccctgg gcctcgagtg ccgtgcccag gcccagcctg 12601 gtgtccccct gggggagttg ggccaggtcg tggaatgcag cctggacttt ggcctggtct 12661 gcaggaaccg tgagcaggtg gggaagttca agatgtgctt caactatgaa atccgtgtgt 12721 tctgctgcaa ctacggccac tgccccagca ccccggccac cagctctacg gccatgccct 12781 cctccactcc ggggacgacc tggatcctca cagagctgac cacaacagcc actacgactg 12841 catccactgg atccacggcc accccgtcct ccaccccggg aacagctccc cctcccaaag 12901 tgctgaccag cccggccacc acacccacag ccaccagttc caaagccact tcctcctcca 12961 gtccaaggac tgcaaccacc cttccagtgc tgacaagcac agccaccaaa tccacagcta 13021 ccagcgttac acccatcccc tcctccaccc ttgggaccac cgggaccctc ccagaacaga 13081 ccaccacacc cgtggccacc atgtccacaa tccacccctc ctccactccg gagaccaccc 13141 acacctccac agtgctgacc acgaaggcca ccacgacaag ggccaccagt tccacgtcca 13201 ccccctcctc cactccgggg acgacctgga tcctcacaga gctgaccaca gcagccacta 13261 caactgcagc cactggcccc acggccaccc cgtcctccac cccagggacc acctggatcc 13321 tcacagagct gaccacaaca gccactacga ctgcgtccac tggatccacg gccaccccgt 13381 cctccacccc agggaccacc tggatcctca cagagccgag cactacagcc accgtgacgg 13441 tgcccaccgg atccacggcc accgcctcct ccacccaggc aactgctggc accccacatg 13501 tgagcaccac ggccacgaca cccacagtca ccagctccaa agccactccc tcctccagtc 13561 cagggactgc aactgccctt ccagcactga gaagcacagc caccacaccc acagctacca 13621 gctttacagc catcccctcc tcctccctgg gcaccacctg gacccgccta tcacagacca 13681 ccacacccac ggccaccatg tccacagcca caccctcctc cactccagag actgtccaca 13741 cctccacagt gcttaccgcc acggccacca caaccggggc caccggctct gtggccaccc 13801 cctcctccac cccaggaaca gctcacacta ccaaagtgcc gactaccaca accacgggct 13861 tcacagccac cccctcctcc agcccaggga cggcactcac gcctccagtg tggatcagca 13921 caaccaccac acccacaacc accacaccca caaccagtgg ctccacggtg accccctcct 13981 ccatcccggg gaccacccac accgccagag tgctgaccac caccaccaca actgtggcca 14041 ctggttctat ggcaacaccc tcctctagca cacagaccag tggtactccc ccatcactga 14101 ccaccacggc cactacgatc acggccaccg gctccaccac caacccctcc tcaactccag 14161 ggacaacacc catcacccca gtgctgacca gcacggccac cacacccgca gccaccagct 14221 ccaaagccac ttcctcctcc agtccaagga ctgcaaccac ccttccagtg ctgacaagca 14281 cagccacaaa atccacagct accagcttta cacccatccc ctcctccacc ctgtggacca 14341 cgtggaccgt cccagcacag accaccacac ccatgtccac catgtccaca atccacacct 14401 cctctactcc agagaccacc cacacctcca cagtgctgac caccacagcc accatgacaa 14461 gggccaccaa ttccacggcc acaccctcct ccactctggg gacgacccgg atcctcactg 14521 agctgaccac aacagccact acaactgcag ccactggatc cacggccacc ctgtcctcca 14581 ccccagggac cacctggatc ctcacagagc cgagcactat agccaccgtg atggtgccca 14641 ccggttccac ggccaccgcc tcctccactc tgggaacagc tcacaccccc aaagtggtga 14701 ccaccatggc cactatgccc acagccactg cctccacggt tcccagctcg tccaccgtgg 14761 ggaccacccg cacccctgca gtgctcccca gcagcctgcc aaccttcagc gtgtccactg 14821 tgtcctcctc agtcctcacc accctgagac ccactggctt ccccagctcc cacttctcta 14881 ctccctgctt ctgcagggca tttggacagt ttttctcgcc cggggaagtc atctacaata 14941 agaccgaccg agccggctgc catttctacg cagtgtgcaa tcagcactgt gacattgacc

15001 gcttccaggg cgcctgtccc acctccccac cgccagtgtc ctccgccccg ctgtcctcgc 15061 cctcccctgc ccctggctgt gacaatgcca tccctctccg gcaggtgaat gagacctgga 15121 ccctggagaa ctgcacggtg gccaggtgcg tgggtgacaa ccgtgtcgtc ctgctggacc 15181 caaagcctgt ggccaacgtc acctgcgtga acaagcacct gcccatcaaa gtgtcggacc 15241 cgagccagcc ctgtgacttc cactatgagt gcgagtgcat ctgcagcatg tggggcggct 15301 cccactattc cacctttgac ggcacctctt acaccttccg gggcaactgc acctatgtcc 15361 tcatgagaga gatccatgca cgctttggga atctcagcct ctacctggac aaccactact 15421 gcacggcctc tgccactgcc gctgccgccc gctgcccccg cgccctcagc atccactaca 15481 agtccatgga tatcgtcctc actgtcacca tggtgcatgg gaaggaggag ggcctgatcc 15541 tgtttgacca aattccggtg agcagcggtt tcagcaagaa cggcgtgctt gtgtctgtgc 15601 tggggaccac caccatgcgt gtggacattc ctgccctggg cgtgagcgtc accttcaatg 15661 gccaagtctt ccaggcccgg ctgccctaca gcctcttcca caacaacacc gagggccagt 15721 gcggcacctg caccaacaac cagagggacg actgtctcca gcgggacgga accactgccg 15781 ccagttgcaa ggacatggcc aagacgtggc tggtccccga cagcagaaag gatggctgct 15841 gggccccgac tggcacaccc cccactgcca gccccgcagc cccggtgtct agcacaccca 15901 cccccacccc atgcccacca cagccgctct gtgatctgat gctgagccag gtctttgctg 15961 agtgccacaa ccttgtgccc ccgggcccat tcttcaacgc ctgcatcagc gaccactgca 16021 ggggccgcct tgaggtgccc tgccagagcc tggaggctta cgcagagctc tgccgcgccc 16081 ggggagtgtg cagtgactgg cgaggtgcaa ccggtggcct gtgcgacctc acctgcccac 16141 ccaccaaagt gtacaagcca tgcggcccca tacagcctgc cacctgcaac tctaggaacc 16201 agagcccaca gctggagggg atggcggagg gctgcttctg ccctgaggac cagatcctct 16261 tcaacgcaca catgggcatc tgcgtgcagg cctgcccctg cgtgggaccc gatgggtttc 16321 ctaaatttcc cggggagcgg tgggtcagca actgccagtc ctgcgtgtgt gacgagggtt 16381 cagtgtcggt gcagtgcaag cccctgccct gtgacgccca gggtcagccc ccgccgtgca 16441 accgtcccgg cttcgtaacc gtgaccaggc cccgggccga gaacccctgc tgccccgaga 16501 cggtgtgcgt gtgcaacaca accacctgcc cccagagcct gcctgtgtgc ccgccagggc 16561 aggagtccat ctgcacccag gaggagggcg actgctgtcc caccttccgc tgcagacctc 16621 agctgtgttc gtacaatggc accttctacg gggttggtgc aaccttccca ggcgcccttc 16681 cctgccacat gtgtacctgc ctctctgggg acacccagga cccaacggtg caatgtcagg 16741 aggatgcctg caacaatact acctgtcccc agggctttga gtacaagaga gtggccgggc 16801 agtgctgtgg ggagtgcgtc cagaccgcct gcctcacgcc cgatggccag ccagtccagc 16861 tgaatgaaac ctgggtcaac agccatgtgg acaactgcac cgtgtacctc tgtgaggctg 16921 agggtggagt ccatttgctg accccacagc ctgcatcctg cccagatgtg tccagctgca 16981 gggggagcct caggaaaacc ggctgctgct actcctgtga ggaggactcc tgtcaagtcc 17041 gcatcaacac gaccatcctg tggcaccagg gctgcgagac cgaggtcaac atcaccttct 17101 gcgagggctc ctgccccgga gcgtccaagt actcagcaga ggcccaggcc atgcagcacc 17161 agtgcacctg ctgccaggag aggcgggtcc acgaggagac ggtgcccttg cactgtccta 17221 acggctcagc catcctgcac acctacaccc acgtggatga gtgtggctgc acgcccttct 17281 gtgtccctgc gcccatggct cccccacaca cccgtggctt cccggcccag gaggccactg 17341 ctgtctgaga acgttctgcc tccatcccca tgctctgtcc acctggagcc aggatgtgca 17401 ttgtctgatc atgaaaacct tgggcctcct ctgcggagcc ccccggcctg tgtgtggcac 17461 cccgcgctcc gtgctcctgc tgcccacccc gtgggtgaaa ccggccccag aagggtgagg 17521 ggccagcagg acccctttcg ggagggcgcc actcaggagt cctaccctgg gagagcctgt 17581 ggcccacctt ggccttgccc ctccctgatg tcactgggac gccctggaac aaactaagca 17641 tgtgcgggcc tatgtgtccc tgccacggcc ggagcgcccg cgcagcacgg attccagctg 17701 gccacgtccg gccgctgggg cagacaggct ggtccaggca aggccagctg ctgccaggaa 17761 gctgcgacag gcaaggcggc cgcctgtcca tgcctgctgc agggtaactc agggctgagg 17821 tcgcaacggc caggtcagag aggggtcagc atcccaaagc cccctctgct caacccagcc 17881 cagttttgca aataaaccct gagcattgag tacgtt

[0241] In some embodiments of the methods of the disclosure, the wild type human MUC5B gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: NP_002449.2):

TABLE-US-00014 (SEQ ID NO: 12) 1 mgapsacrtl vlalaamlvv pqaetqgpve pswenaghtm dggaptsspt rrvsfvppvt 61 vfpslspinp ahngrvcstw gdfhyktfdg dvfrfpglcn yvfsehcraa yedfnvqlrr 121 glvgsrpvvt rvvikaqglv leasngsvli ngqreelpys rtgllveqsg dyikvsirlv 181 ltflwngeds alleldpkya nqtcglcgdf nglpafnefy ahnarltplq fgnlqkldgp 241 teqcpdplpl pagnctdeeg ichrtllgpa faechalvds taylaacaqd lcrcptcpca 301 tfveysrqca haggqprnwr cpelcprtcp lnmqhqecgs pctdtcsnpq raqlcedhcv 361 dgcfcppgtv lddithsgcl plgqcpcthg grtyspgtsf nttcssctcs gglwqcqdlp 421 cpgtcsvqgg ahistydekl ydlhgdcsyv lskkcadssf tvlaelrkcg ltdnenclka 481 vtlsldggdt airvqadggv flnsiytqlp lsaanitlft pssffivvqt glglqllvql 541 vplmqvfvrl dpahqgqmcg lcgnfnqnqa ddftalsgvv eatgaafant wkaqaacana 601 rnsfedpcsl svenenyarh wcsrltdpns afsrchsiin pkpfhsncmf dtcncersed 661 cicaalssyv hacaakgvql sdwrdgvctk ymqncpksqr yayvvdacqp tcrglseadv 721 tcsysfvpvd gctcpagtfl ndagacvpaq ecpcyahgtv lapgevvhde gavcsctggk 781 lsclgaslqk stgcaapmvy ldcsnssagt pgaeclrsch tldvgcfsth cvsgcvcppg 841 lvsdgsggci aeedcpcvhn eatykpgeti rvdcntctcr nrrwecshrl clgtcvaygd 901 ghfitfdgdr ysfegsceyi laqdycgdnt thgtfrivte nipcgttgtt cskaiklfve 961 syelilqegt fkavargpgg dppykirymg iflviethgm ayswdrktsv firlhqdykg 1021 rvcglcgnfd dnaindfatr srsvvgdale fgnswklsps cpdalapkdp ctanpfrksw 1081 aqkqcsilhg ptfaacrsqv dstkyyeacv ndacacdsgg dcecfctava ayaqachdag 1141 lcvswrtpdt cplfcdfynp hggcewhyqp cgapclktcr npsghclvdl pglegcypkc 1201 ppsqpffned qmkcvaqcgc ydkdgnyydv garvptaenc qscnctpsgi qcahsleact 1261 ctyedrtysy qdviynttdg lgacliaicg sngtiirkav acpgtpattp ftfttawvph 1321 sttspalpvs tvcvrevcrw sswynghrpe pglgggdfet fenlrqrgyq vcpvladiec 1381 raaqlpdmpl eelgqqvdcd rmrglmcans qqspplchdy elrvlcceyv pcgpspapgt 1441 spqpslsast epavptptqt tatekttlwv tpsirstaal tsqtgsssgp vtvtpsapgt 1501 ttcqprcqwt ewfdedypks eqlggdvesy dkiraagghl cqqpkdiecq aesfpnwtla 1561 qvgqkvhcdv hfglvcrnwe qegvfkmcyn yrirvlccsd dhcrgrattp pptteletat 1621 ttttqalfst pqptsspglt rappasttav ptlsegltsp rytstlgtat tggpttpags 1681 teptvpgvat stlptrsalp gttgslgtwr psqpptlapt tmatsrarpt gtastaskep 1741 lttslaptlt selstsqaet stprtettms pltntttsqg ttrcqpkcew tewfdvdfpt 1801 sgvaggdmet feniraaggk mcwapksiec raenypevsi dqvgqvltcs letgltckne 1861 dqtgrfnmcf nynvrvlccd dyshcpstpa tsstatpsst pgttwiltkp tttatttast 1921 gstatptstl rtapppkvlt ttattptvts skatpssspg tatalpalrs tattptatsv 1981 tpipssslgt twtrlsqttt ptatmstatp sstpetahts tvltatattt gatgsvatps 2041 stpgtahttk vptttttgft atpssspgta ltppvwistt ttpttrgstv tpssipgtth 2101 tatvlttttt tvatgsmatp ssstqtsgtp psltttatti tatgsttnps stpgttpipp 2161 vltttattpa atsntvtpss algtthtppv pntmatthgr slppssphtv rtawtsatsg 2221 ilgtthitep stvtshtlaa ttgttqhstp alssphpssr ttesppspgt ttpghttats 2281 rttatatpsk trtstllpss ptsapittvv tmgcepqcaw sewldysypm pgpsggdfdt 2341 ysniraagga vceqplglec raqaqpgvpl relgqvvecs ldfglvcrnr eqvgkfkmcf 2401 nyeirvfccn yghcpstpat sstampsstp gttwiltelt ttatttestg statpsstpg 2461 ttwiltepst tatvtvptgs tatasstqat agtphvstta ttptvtsska tpfsspgtat 2521 alpalrstat tptatsftai pssslgttwt rlsqtttpta tmstatpsst petvhtstvl 2581 tttatttgat gsvatpsstp gtahttkvlt ttttgftatp ssspgtartl pvwisttttp 2641 ttrgstvtps sipgtthtpt vlttttttva tgsmatpsss tqtsgtppsl tttattitat 2701 gsttnpsstp gttpippvlt ttattpaats stvtpssalg tthtppvpnt tatthgrsls 2761 pssphtvrta wtsatsgtlg tthitepstg tshtpaattg ttqhstpals sphpssrtte 2821 sppspgtttp ghtratsrtt atatpsktrt stllpsspts apittvvtmg cepqcawsew 2881 ldysypmpgp sggdfdtysn iraaggavce qplglecraq aqpgvplrel gqvvecsldf 2941 glvcrnreqv gkfkmcfnye irvfccnygh cpstpatsst atpsstpgtt wilteqttaa 3001 tttattgsta ipsstpgtap ppkvltstat tptatsskat ssssprtatt 1pvltstatk 3061 statsftpip sftlgttgtl peqtttpmat mstihpsstp etthtstvlt tkatttrats 3121 smstpsstpg ttwilteltt aatttaatgp tatpsstpgt twiltepstt atvtvptgst 3181 atasstrata gtlkvltsta ttptvissra tpssspgtat alpalrstat tptatsvtai 3241 pssslgtawt rlsqtttpta tmstatpsst petvhtstvl tttttttrat gsvatpsstp 3301 gtahttkvpt ttttgftatp ssspgtaltp pvwisttttp ttrgstvtps sipgtthtat 3361 vlttttttva tgsmatpsss tqtsgtppsl tttattitat gsttnpsstp gttpippvlt 3421 ttattpaats stvtpssalg tthtppvpnt tatthgrslp pssphtvrta wtsatsgilg 3481 tthitepstv tshtpaatts ttqhstpals sphpssrtte sppspgtttp ghtrgtsrtt 3541 atatpsktrt stllpsspts apittvvttg cepqcawsew ldysypmpgp sggdfdtysn 3601 iraaggavce qplglecraq aqpgvplrel gqvvecsldf glvcrnreqv gkfkmcfnye 3661 irvfccnygh cpstpatsst atpsstpgtt wiltklttta tttestgsta tpsstpgttw 3721 iltepsttat vtvptgstat asstqatagt phvsttattp tvtsskatpf sspgtatalp 3781 alrstattpt atsftaipss slgttwtrls qtttptatms tatpsstpet ahtstvlttt 3841 atttratgsv atpsstpgta httkvptttt tgftvtpsss pgtartppvw isttttptts 3901 gstvtpssvp gtthtptvlt tttttvatgs matpssstqt sgtppslitt attitatgst 3961 tnpsstpgtt pippvlttta ttpaatsstv tpssalgtth tppvpnttat thgrslspss 4021 phtvrtawts atsgtlgtth itepstgtsh tpaattgttq hstpalssph pssrttespp 4081 spgtttpght tatsrttata tpsktrtstl 1pssptsapi ttvvttgcep qcawsewldy 4141 sypmpgpsgg dfdtysnira aggavceqpl glecraqaqp gvplgelgqv vecsldfglv 4201 crnreqvgkf kmcfnyeiry fccnyghcps tpatsstamp sstpgttwil teltttattt 4261 astgstatps stpgtapppk vltspattpt atsskatsss sprtattlpv ltstatksta 4321 tsvtpipsst lgttgtlpeq tttpvatmst ihpsstpett htstvlttka tttratssts 4381 tpsstpgttw iltelttaat ttaatgptat psstpgttwi lteltttatt tastgstatp 4441 sstpgttwil tepsttatvt vptgstatas stqatagtph vsttattptv tsskatpsss 4501 pgtatalpal rstattptat sftaipsssl gttwtrlsqt ttptatmsta tpsstpetvh 4561 tstvltatat ttgatgsvat psstpgtaht tkvptttttg ftatpssspg taltppvwis 4621 ttttpttttp ttsgstvtps sipgtthtar vlttttttva tgsmatpsss tqtsgtppsl 4681 tttattitat gsttnpsstp gttpitpvlt stattpaats skatsssspr tattlpvlts 4741 tatkstatsf tpipsstlwt twtvpaqttt pmstmstiht sstpetthts tvltttatmt 4801 ratnstatps stlgttrilt eltttattta atgstatlss tpgttwilte pstiatvmvp 4861 tgstatasst lgtahtpkvv ttmatmptat astvpssstv gttrtpavlp sslptfsyst 4921 vsssvlttlr ptgfpsshfs tpcfcrafgq ffspgeviyn ktdragchfy avcnqhcdid 4981 rfqgacptsp ppvssaplss pspapgcdna iplrqvnetw tlenctvarc vgdnrvvlld 5041 pkpvanvtcv nkhlpikvsd psqpcdfhye cecicsmwgg shystfdgts ytfrgnctyv 5101 lmreiharfg nlslyldnhy ctasataaaa rcpralsihy ksmdivltvt mvhgkeegli 5161 lfdqipvssg fskngvlvsv lgtttmrvdi palgvsvtfn gqvfqarlpy slfhnntegq 5221 cgtctnnqrd dclqrdgtta asckdmaktw lvpdsrkdgc waptgtppta spaapvsstp 5281 tptpcppqpl cdlmlsqvfa echnlvppgp ffnacisdhc rgrlevpcqs leayaelcra 5341 rgvcsdwrga tgglcdltcp ptkvykpcgp iqpatcnsrn qspqlegmae gcfcpedqil 5401 fnahmgicvq acpcvgpdgf pkfpgerwvs ncqscvcdeg sysvqckplp cdaqgqpppc 5461 nrpgfvtvtr praenpccpe tvcvcntttc pqslpvcppg qesictqeeg dccptfrcrp 5521 qlcsyngtfy gvgatfpgal pchmctclsg dtqdptvqcq edacnnttcp qgfeykrvag 5581 qccgecvqta cltpdgqpvq lnetwvnshv dnctvylcea eggvhlltpq pascpdvssc 5641 rgslrktgcc ysceedscqv rinttilwhq gcetevnitf cegscpgask ysaeaqamqh 5701 qctccqerry heetvplhcp ngsailhtyt hvdecgctpf cvpapmapph trgfpaqeat 5761 av

[0242] In some embodiments of the methods of the disclosure, the wild type human TERT gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_198253.2, transcript variant 1):

TABLE-US-00015 (SEQ ID NO: 13) 1 caggcagcgc tgcgtcctgc tgcgcacgtg ggaagccctg gccccggcca cccccgcgat 61 gccgcgcgct ccccgctgcc gagccgtgcg ctccctgctg cgcagccact accgcgaggt 121 gctgccgctg gccacgttcg tgcggcgcct ggggccccag ggctggcggc tggtgcagcg 181 cggggacccg gcggctttcc gcgcgctggt ggcccagtgc ctggtgtgcg tgccctggga 241 cgcacggccg ccccccgccg ccccctcctt ccgccaggtg tcctgcctga aggagctggt 301 ggcccgagtg ctgcagaggc tgtgcgagcg cggcgcgaag aacgtgctgg ccttcggctt 361 cgcgctgctg gacggggccc gcgggggccc ccccgaggcc ttcaccacca gcgtgcgcag 421 ctacctgccc aacacggtga ccgacgcact gcgggggagc ggggcgtggg ggctgctgct 481 gcgccgcgtg ggcgacgacg tgctggttca cctgctggca cgctgcgcgc tctttgtgct 541 ggtggctccc agctgcgcct accaggtgtg cgggccgccg ctgtaccagc tcggcgctgc 601 cactcaggcc cggcccccgc cacacgctag tggaccccga aggcgtctgg gatgcgaacg 661 ggcctggaac catagcgtca gggaggccgg ggtccccctg ggcctgccag ccccgggtgc 721 gaggaggcgc gggggcagtg ccagccgaag tctgccgttg cccaagaggc ccaggcgtgg 781 cgctgcccct gagccggagc ggacgcccgt tgggcagggg tcctgggccc acccgggcag 841 gacgcgtgga ccgagtgacc gtggtttctg tgtggtgtca cctgccagac ccgccgaaga 901 agccacctct ttggagggtg cgctctctgg cacgcgccac tcccacccat ccgtgggccg 961 ccagcaccac gcgggccccc catccacatc gcggccacca cgtccctggg acacgccttg 1021 tcccccggtg tacgccgaga ccaagcactt cctctactcc tcaggcgaca aggagcagct 1081 gcggccctcc ttcctactca gctctctgag gcccagcctg actggcgctc ggaggctcgt 1141 ggagaccatc tttctgggtt ccaggccctg gatgccaggg actccccgca ggttgccccg 1201 cctgccccag cgctactggc aaatgcggcc cctgtttctg gagctgcttg ggaaccacgc 1261 gcagtgcccc tacggggtgc tcctcaagac gcactgcccg ctgcgagctg cggtcacccc 1321 agcagccggt gtctgtgccc gggagaagcc ccagggctct gtggcggccc ccgaggagga 1381 ggacacagac ccccgtcgcc tggtgcagct gctccgccag cacagcagcc cctggcaggt 1441 gtacggcttc gtgcgggcct gcctgcgccg gctggtgccc ccaggcctct ggggctccag 1501 gcacaacgaa cgccgcttcc tcaggaacac caagaagttc atctccctgg ggaagcatgc 1561 caagctctcg ctgcaggagc tgacgtggaa gatgagcgtg cgggactgcg cttggctgcg 1621 caggagccca ggggttggct gtgttccggc cgcagagcac cgtctgcgtg aggagatcct 1681 ggccaagttc ctgcactggc tgatgagtgt gtacgtcgtc gagctgctca ggtctttctt 1741 ttatgtcacg gagaccacgt ttcaaaagaa caggctcttt ttctaccgga agagtgtctg 1801 gagcaagttg caaagcattg gaatcagaca gcacttgaag agggtgcagc tgcgggagct 1861 gtcggaagca gaggtcaggc agcatcggga agccaggccc gccctgctga cgtccagact 1921 ccgcttcatc cccaagcctg acgggctgcg gccgattgtg aacatggact acgtcgtggg 1981 agccagaacg ttccgcagag aaaagagggc cgagcgtctc acctcgaggg tgaaggcact 2041 gttcagcgtg ctcaactacg agcgggcgcg gcgccccggc ctcctgggcg cctctgtgct 2101 gggcctggac gatatccaca gggcctggcg caccttcgtg ctgcgtgtgc gggcccagga 2161 cccgccgcct gagctgtact ttgtcaaggt ggatgtgacg ggcgcgtacg acaccatccc 2221 ccaggacagg ctcacggagg tcatcgccag catcatcaaa ccccagaaca cgtactgcgt 2281 gcgtcggtat gccgtggtcc agaaggccgc ccatgggcac gtccgcaagg ccttcaagag 2341 ccacgtctct accttgacag acctccagcc gtacatgcga cagttcgtgg ctcacctgca 2401 ggagaccagc ccgctgaggg atgccgtcgt catcgagcag agctcctccc tgaatgaggc 2461 cagcagtggc ctcttcgacg tcttcctacg cttcatgtgc caccacgccg tgcgcatcag 2521 gggcaagtcc tacgtccagt gccaggggat cccgcagggc tccatcctct ccacgctgct 2581 ctgcagcctg tgctacggcg acatggagaa caagctgttt gcggggattc ggcgggacgg 2641 gctgctcctg cgtttggtgg atgatttctt gttggtgaca cctcacctca cccacgcgaa 2701 aaccttcctc aggaccctgg tccgaggtgt ccctgagtat ggctgcgtgg tgaacttgcg 2761 gaagacagtg gtgaacttcc ctgtagaaga cgaggccctg ggtggcacgg cttttgttca 2821 gatgccggcc cacggcctat tcccctggtg cggcctgctg ctggataccc ggaccctgga 2881 ggtgcagagc gactactcca gctatgcccg gacctccatc agagccagtc tcaccttcaa 2941 ccgcggcttc aaggctggga ggaacatgcg tcgcaaactc tttggggtct tgcggctgaa 3001 gtgtcacagc ctgtttctgg atttgcaggt gaacagcctc cagacggtgt gcaccaacat 3061 ctacaagatc ctcctgctgc aggcgtacag gtttcacgca tgtgtgctgc agctcccatt 3121 tcatcagcaa gtttggaaga accccacatt tttcctgcgc gtcatctctg acacggcctc 3181 cctctgctac tccatcctga aagccaagaa cgcagggatg tcgctggggg ccaagggcgc 3241 cgccggccct ctgccctccg aggccgtgca gtggctgtgc caccaagcat tcctgctcaa 3301 gctgactcga caccgtgtca cctacgtgcc actcctgggg tcactcagga cagcccagac 3361 gcagctgagt cggaagctcc cggggacgac gctgactgcc ctggaggccg cagccaaccc 3421 ggcactgccc tcagacttca agaccatcct ggactgatgg ccacccgccc acagccaggc 3481 cgagagcaga caccagcagc cctgtcacgc cgggctctac gtcccaggga gggaggggcg 3541 gcccacaccc aggcccgcac cgctgggagt ctgaggcctg agtgagtgtt tggccgaggc 3601 ctgcatgtcc ggctgaaggc tgagtgtccg gctgaggcct gagcgagtgt ccagccaagg 3661 gctgagtgtc cagcacacct gccgtcttca cttccccaca ggctggcgct cggctccacc 3721 ccagggccag cttttcctca ccaggagccc ggcttccact ccccacatag gaatagtcca 3781 tccccagatt cgccattgtt cacccctcgc cctgccctcc tttgccttcc acccccacca 3841 tccaggtgga gaccctgaga aggaccctgg gagctctggg aatttggagt gaccaaaggt 3901 gtgccctgta cacaggcgag gaccctgcac ctggatgggg gtccctgtgg gtcaaattgg 3961 ggggaggtgc tgtgggagta aaatactgaa tatatgagtt tttcagtttt gaaaaaaa

[0243] In some embodiments of the methods of the disclosure, the wild type human TERT gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: NP_937983.2, transcript variant 1):

TABLE-US-00016 (SEQ ID NO: 14) 1 mpraprcrav rsllrshyre vlplatfvrr lgpqgwrlvq rgdpaafral vaqclvcvpw 61 darpppaaps frqvsclkel varvlqrlce rgaknvlafg falldgargg ppeafttsvr 121 sylpntvtda lrgsgawgll lrrvgddvlv hllarcalfv lvapscayqv cgpplyqlga 181 atqarpppha sgprrrlgce rawnhsvrea gvplglpapg arrrggsasr slplpkrprr 241 gaapepertp vgqgswahpg rtrgpsdrgf cvvsparpae eatslegals gtrhshpsvg 301 rqhhagppst srpprpwdtp cppvyaetkh flyssgdkeq lrpsfllssl rpsltgarrl 361 vetiflgsrp wmpgtprrlp rlpqrywqmr plflellgnh aqcpygvllk thcplraavt 421 paagvcarek pqgsvaapee edtdprrlvq llrqhsspwq vygfvraclr rlvppglwgs 481 rhnerrflrn tkkfislgkh aklslqeltw kmsvrdcawl rrspgvgcvp aaehrlreei 541 lakflhwlms vyvvellrsf fyvtettfqk nrlffyrksv wsklqsigir qhlkrvqlre 601 lseaevrqhr earpalltsr lrfipkpdgl rpivnmdyvv gartfrrekr aerltsrvka 661 lfsvinyera rrpgllgasv lglddihraw rtfvlrvraq dpppelyfvk vdvtgaydti 721 pqdrltevia siikpqntyc vrryavvqka ahghvrkafk shvstltdlq pymrqfvahl 781 qetsplrdav vieqssslne assglfdvfl rfmchhavri rgksyvqcqg ipqgsilstl 841 lcslcygdme nklfagirrd glllrlvddf llvtphltha ktflrtivrg vpeygcvvnl 901 rktvvnfpve dealggtafv qmpahglfpw cglildtrtl evqsdyssya rtsirasltf 961 nrgfkagrnm rrklfgvlrl kchslfldlq vnslqtvctn iykilllqay rfhacvlqlp 1021 fhqqvwknpt fflrvisdta slcysilkak nagmslgakg aagplpseav qwlchqafll 1081 kltrhrvtyv pllgslrtaq tqlsrklpgt tltaleaaan palpsdfkti ld

[0244] In some embodiments of the methods of the disclosure, the wild type human TERT gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_001193376.1, transcript variant 2):

TABLE-US-00017 (SEQ ID NO: 15) 1 caggcagcgc tgcgtcctgc tgcgcacgtg ggaagccctg gccccggcca cccccgcgat 61 gccgcgcgct ccccgctgcc gagccgtgcg ctccctgctg cgcagccact accgcgaggt 121 gctgccgctg gccacgttcg tgcggcgcct ggggccccag ggctggcggc tggtgcagcg 181 cggggacccg gcggctttcc gcgcgctggt ggcccagtgc ctggtgtgcg tgccctggga 241 cgcacggccg ccccccgccg ccccctcctt ccgccaggtg tcctgcctga aggagctggt 301 ggcccgagtg ctgcagaggc tgtgcgagcg cggcgcgaag aacgtgctgg ccttcggctt 361 cgcgctgctg gacggggccc gcgggggccc ccccgaggcc ttcaccacca gcgtgcgcag 421 ctacctgccc aacacggtga ccgacgcact gcgggggagc ggggcgtggg ggctgctgct 481 gcgccgcgtg ggcgacgacg tgctggttca cctgctggca cgctgcgcgc tctttgtgct 541 ggtggctccc agctgcgcct accaggtgtg cgggccgccg ctgtaccagc tcggcgctgc 601 cactcaggcc cggcccccgc cacacgctag tggaccccga aggcgtctgg gatgcgaacg 661 ggcctggaac catagcgtca gggaggccgg ggtccccctg ggcctgccag ccccgggtgc 721 gaggaggcgc gggggcagtg ccagccgaag tctgccgttg cccaagaggc ccaggcgtgg 781 cgctgcccct gagccggagc ggacgcccgt tgggcagggg tcctgggccc acccgggcag 841 gacgcgtgga ccgagtgacc gtggtttctg tgtggtgtca cctgccagac ccgccgaaga 901 agccacctct ttggagggtg cgctctctgg cacgcgccac tcccacccat ccgtgggccg 961 ccagcaccac gcgggccccc catccacatc gcggccacca cgtccctggg acacgccttg 1021 tcccccggtg tacgccgaga ccaagcactt cctctactcc tcaggcgaca aggagcagct 1081 gcggccctcc ttcctactca gctctctgag gcccagcctg actggcgctc ggaggctcgt 1141 ggagaccatc tttctgggtt ccaggccctg gatgccaggg actccccgca ggttgccccg 1201 cctgccccag cgctactggc aaatgcggcc cctgtttctg gagctgcttg ggaaccacgc 1261 gcagtgcccc tacggggtgc tcctcaagac gcactgcccg ctgcgagctg cggtcacccc 1321 agcagccggt gtctgtgccc gggagaagcc ccagggctct gtggcggccc ccgaggagga 1381 ggacacagac ccccgtcgcc tggtgcagct gctccgccag cacagcagcc cctggcaggt 1441 gtacggcttc gtgcgggcct gcctgcgccg gctggtgccc ccaggcctct ggggctccag 1501 gcacaacgaa cgccgcttcc tcaggaacac caagaagttc atctccctgg ggaagcatgc 1561 caagctctcg ctgcaggagc tgacgtggaa gatgagcgtg cgggactgcg cttggctgcg 1621 caggagccca ggggttggct gtgttccggc cgcagagcac cgtctgcgtg aggagatcct 1681 ggccaagttc ctgcactggc tgatgagtgt gtacgtcgtc gagctgctca ggtctttctt 1741 ttatgtcacg gagaccacgt ttcaaaagaa caggctcttt ttctaccgga agagtgtctg 1801 gagcaagttg caaagcattg gaatcagaca gcacttgaag agggtgcagc tgcgggagct 1861 gtcggaagca gaggtcaggc agcatcggga agccaggccc gccctgctga cgtccagact 1921 ccgcttcatc cccaagcctg acgggctgcg gccgattgtg aacatggact acgtcgtggg 1981 agccagaacg ttccgcagag aaaagagggc cgagcgtctc acctcgaggg tgaaggcact 2041 gttcagcgtg ctcaactacg agcgggcgcg gcgccccggc ctcctgggcg cctctgtgct 2101 gggcctggac gatatccaca gggcctggcg caccttcgtg ctgcgtgtgc gggcccagga 2161 cccgccgcct gagctgtact ttgtcaaggt ggatgtgacg ggcgcgtacg acaccatccc 2221 ccaggacagg ctcacggagg tcatcgccag catcatcaaa ccccagaaca cgtactgcgt 2281 gcgtcggtat gccgtggtcc agaaggccgc ccatgggcac gtccgcaagg ccttcaagag 2341 ccacgtctct accttgacag acctccagcc gtacatgcga cagttcgtgg ctcacctgca 2401 ggagaccagc ccgctgaggg atgccgtcgt catcgagcag agctcctccc tgaatgaggc 2461 cagcagtggc ctcttcgacg tcttcctacg cttcatgtgc caccacgccg tgcgcatcag 2521 gggcaagtcc tacgtccagt gccaggggat cccgcagggc tccatcctct ccacgctgct 2581 ctgcagcctg tgctacggcg acatggagaa caagctgttt gcggggattc ggcgggacgg 2641 gctgctcctg cgtttggtgg atgatttctt gttggtgaca cctcacctca cccacgcgaa 2701 aaccttcctc agctatgccc ggacctccat cagagccagt ctcaccttca accgcggctt 2761 caaggctggg aggaacatgc gtcgcaaact ctttggggtc ttgcggctga agtgtcacag 2821 cctgtttctg gatttgcagg tgaacagcct ccagacggtg tgcaccaaca tctacaagat 2881 cctcctgctg caggcgtaca ggtttcacgc atgtgtgctg cagctcccat ttcatcagca 2941 agtttggaag aaccccacat ttttcctgcg cgtcatctct gacacggcct ccctctgcta 3001 ctccatcctg aaagccaaga acgcagggat gtcgctgggg gccaagggcg ccgccggccc 3061 tctgccctcc gaggccgtgc agtggctgtg ccaccaagca ttcctgctca agctgactcg 3121 acaccgtgtc acctacgtgc cactcctggg gtcactcagg acagcccaga cgcagctgag 3181 tcggaagctc ccggggacga cgctgactgc cctggaggcc gcagccaacc cggcactgcc 3241 ctcagacttc aagaccatcc tggactgatg gccacccgcc cacagccagg ccgagagcag 3301 acaccagcag ccctgtcacg ccgggctcta cgtcccaggg agggaggggc ggcccacacc 3361 caggcccgca ccgctgggag tctgaggcct gagtgagtgt ttggccgagg cctgcatgtc 3421 cggctgaagg ctgagtgtcc ggctgaggcc tgagcgagtg tccagccaag ggctgagtgt 3481 ccagcacacc tgccgtcttc acttccccac aggctggcgc tcggctccac cccagggcca 3541 gcttttcctc accaggagcc cggcttccac tccccacata ggaatagtcc atccccagat 3601 tcgccattgt tcacccctcg ccctgccctc ctttgccttc cacccccacc atccaggtgg 3661 agaccctgag aaggaccctg ggagctctgg gaatttggag tgaccaaagg tgtgccctgt 3721 acacaggcga ggaccctgca cctggatggg ggtccctgtg ggtcaaattg gggggaggtg 3781 ctgtgggagt aaaatactga atatatgagt ttttcagttt tgaaaaaaa

[0245] In some embodiments of the methods of the disclosure, the wild type human TERT gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: NP_001180305.1, transcript variant 21:

TABLE-US-00018 (SEQ ID NO: 16) 1 mpraprcrav rsllrshyre vlplatfvrr lgpqgwrlvq rgdpaafral vaqclvcvpw 61 darpppaaps frqvsclkel varvlqrlce rgaknvlafg falldgargg ppeafttsvr 121 sylpntvtda lrgsgawgll lrrvgddvlv hllarcalfv lvapscayqv cgpplyqlga 181 atqarpppha sgprrrlgce rawnhsvrea gvplglpapg arrrggsasr slplpkrprr 241 gaapepertp vgqgswahpg rtrgpsdrgf cvvsparpae eatslegals gtrhshpsvg 301 rqhhagppst srpprpwdtp cppvyaetkh flyssgdkeq lrpsfllssl rpsltgarrl 361 vetiflgsrp wmpgtprrlp rlpqrywqmr plflellgnh aqcpygvllk thcplraavt 421 paagvcarek pqgsvaapee edtdprrlvq llrqhsspwq vygfvraclr rlvppglwgs 481 rhnerrflrn tkkfislgkh aklslqeltw kmsvrdcawl rrspgvgcvp aaehrlreei 541 lakflhwlms vyvvellrsf fyvtettfqk nrlffyrksv wsklqsigir qhlkrvqlre 601 lseaevrqhr earpalltsr lrfipkpdgl rpivnmdyvv gartfrrekr aerltsrvka 661 lfsvinyera rrpgllgasv lglddihraw rtfvlrvraq dpppelyfvk vdvtgaydti 721 pqdrltevia siikpqntyc vrryavvqka ahghvrkafk shvstltdlq pymrqfvahl 781 qetsplrdav vieqssslne assglfdvfl rfmchhavri rgksyvqcqg ipqgsilstl 841 lcslcygdme nklfagirrd glllrlvddf llvtphltha ktflsyarts irasltfnrg 901 fkagrnmrrk lfgvlrlkch slfldlqvns lqtvctniyk illlqayrfh acvlqlpfhq 961 qvwknptffl rvisdtaslc ysilkaknag mslgakgaag plpseavqwl chqafllklt 1021 rhrvtyvpll gslrtaqtql srklpgttlt aleaaanpal psdfktild

[0246] In some embodiments of the methods of the disclosure, the wild type human FAM13A gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_014883.3, transcript variant 1):

TABLE-US-00019 (SEQ ID NO: 36) 1 atcaaatttc aactccaggc agtccttcca gccatgtggg ttcagcggaa agagaagcaa 61 aaccactctt cctaaaatgt tagaagctgc tcttcgctta ccttggggcc tttgcattgg 121 gagctgtttt tcacatcaaa gaatatgtgc tgaatggaat tttagtattt tgctgtcgtt 181 ttaatatttt cgtctggtct tcctcagttc ttccagacgc tttctgagag aatgggggca 241 ggagctctag ccatctgtca aagtaaagca gcggttcggc tgaaagaaga catgaaaaag 301 atagtggcag tgccattaaa tgaacagaag gattttacct atcagaagtt atttggagtc 361 agtctccaag aacttgaacg gcaggggctc accgagaatg gcattccagc agtagtgtgg 421 aatatagtgg aatatttgac gcagcatgga cttacccaag aaggtctttt tagggtgaat 481 ggtaacgtga aggtggtgga acaacttcga ctgaagttcg agagtggagt gcccgtggag 541 ctcgggaagg acggtgatgt ctgctcagca gccagtctgt tgaagctgtt tctgagggag 601 ctgcctgaca gtctgatcac ctcagcgttg cagcctcgat tcattcaact ctttcaggat 661 ggcagaaatg atgttcagga gagtagctta agagacttaa taaaagagct gccagacacc 721 cactactgcc tcctcaagta cctttgccag ttcttgacaa aagtagccaa gcatcatgtg 781 cagaatcgca tgaatgttca caatctcgcc actgtatttg ggccaaattg ctttcatgtg 841 ccacctgggc ttgaaggcat gaaggaacag gacctgtgca acaagataat ggctaaaatt 901 ctagaaaatt acaataccct gtttgaagta gagtatacag aaaatgatca tctgagatgt 961 gaaaacctgg ctaggcttat catagtaaaa gaggtctatt ataagaactc cctgcccatc 1021 cttttaacaa gaggcttaga aagagacatg ccaaaaccac ctccaaaaac caagatccca 1081 aaatccagga gtgagggatc tattcaggcc cacagagtac tgcaaccaga gctatctgat 1141 ggcattcctc agctcagctt gcggctaagt tatagaaaag cctgcttgga agacatgaat 1201 tcagcagagg gtgctattag tgccaagttg gtacccagtt cacaggaaga tgaaagacct 1261 ctgtcacctt tctatttgag tgctcatgta ccccaagtca gcaatgtgtc tgcaaccgga 1321 gaactcttag aaagaaccat ccgatcagct gtagaacaac atctttttga tgttaataac 1381 tctggaggtc aaagttcaga ggactcagaa tctggaacac tatcagcatc ttctgccaca 1441 tctgccagac agcgccgccg ccagtccaag gagcaggatg aagttcgaca tgggagagac 1501 aagggactta tcaacaaaga aaatactcct tctgggttca accaccttga tgattgtatt 1561 ttgaatactc aggaagtcga aaaggtacac aaaaatactt ttggttgtgc tggagaaagg 1621 agcaagccta aacgtcagaa atccagtact aaactttctg agcttcatga caatcaggac 1681 ggtcttgtga atatggaaag tctcaattcc acacgatctc atgagagaac tggacctgat 1741 gattttgaat ggatgtctga tgaaaggaaa ggaaatgaaa aagatggtgg acacactcag 1801 cattttgaga gccccacaat gaagatccag gagcatccca gcctatctga caccaaacag 1861 cagagaaatc aagatgccgg tgaccaggag gagagctttg tctccgaagt gccccagtcg 1921 gacctgactg cattgtgtga tgaaaagaac tgggaagagc ctatccctgc tttctcctcc 1981 tggcagcggg agaacagtga ctctgatgaa gcccacctct cgccgcaggc tgggcgcctg 2041 atccgtcagc tgctggacga agacagcgac cccatgctct ctcctcggtt ctacgcttat 2101 gggcagagca ggcaatacct ggatgacaca gaagtgcctc cttccccacc aaactcccat 2161 tctttcatga ggcggcgaag ctcctctctg gggtcctatg atgatgagca agaggacctg 2221 acacctgccc agctcacacg aaggattcag agccttaaaa agaagatccg gaagtttgaa 2281 gatagattcg aagaagagaa gaagtacaga ccttcccaca gtgacaaagc agccaatccg 2341 gaggttctga aatggacaaa tgaccttgcc aaattccgga gacaacttaa agaatcaaaa 2401 ctaaagatat ctgaagagga cctaactccc aggatgcggc agcgaagcaa cacactcccc 2461 aagagttttg gttcccaact tgagaaagaa gatgagaaga agcaagagct ggtggataaa 2521 gcaataaagc ccagtgttga agccacattg gaatctattc agaggaagct ccaggagaag 2581 cgagcggaaa gcagccgccc tgaggacatt aaggatatga ccaaagacca gattgctaat 2641 gagaaagtgg ctctgcagaa agctctgtta tattatgaaa gcattcatgg acggccggta 2701 acaaagaacg aacggcaggt gatgaagcca ctatacgaca ggtaccggct ggtcaaacag 2761 atcctctccc gagctaacac catacccatc attggttccc cctccagcaa gcggagaagc 2821 cctttgctgc agccaattat cgagggcgaa actgcttcct tcttcaagga gataaaggaa 2881 gaagaggagg ggtcagaaga cgatagcaat gtgaagccag acttcatggt cactctgaaa 2941 accgatttca gtgcacgatg ctttctggac caattcgaag atgacgctga tggatttatt 3001 tccccaatgg atgataaaat accatcaaaa tgcagccagg acacagggct ttcaaatctc 3061 catgctgcct caatacctga actcctggaa cacctccagg aaatgagaga agaaaagaaa 3121 aggattcgaa agaaacttcg ggattttgaa gacaactttt tcagacagaa tggaagaaat 3181 gtccagaagg aagaccgcac tcctatggct gaagaataca gtgaatataa gcacataaag 3241 gcgaaactga ggctcctgga ggtgctcatc agcaagagag acactgattc caagtccatg 3301 tgaggggcat ggccaagcac agggggctgg cagctgcggt gagagtttac tgtccccaga 3361 gaaagtgcag ctctggaagg cagccttggg gctggccctg caaagcatgc agcccttctg 3421 cctctagacc atttggcatc ggctcctgtt tccattgcct gccttagaaa ctggctggaa 3481 gaagacaatg tgacctgact taggcatttt gtaattggaa agtcaagact gcagtatgtg 3541 cacatgcgca cgcgcatgca cgcacacaca cacacagtag tggagctttc ctaacactag 3601 cagagattaa tcactacatt agacaacact catctacaga gaatatacac tgttcttccc 3661 tggataactg agaaacaaga gaccattctc tgtctaactg tgataaaaac aagctcagga 3721 ctttattcta tagagcaaac ttgctgtgga gggccatgct ctccttggac ccagttaact 3781 gcaaacgtgc attggagccc tatttgctgc cgctgccatt ctagtgacct ttccacagag 3841 ctgcgccttc ctcacgtgtg tgaaaggttt tccccttcag ccctcaggta gatggaagct 3901 gcatctgccc acgatggcag tgcagtcatc atcttcagga tgtttcttca ggacttcctc 3961 agctgacaag gaattttggt ccctgcctag gaccgggtca tctgcagagg acagagagat 4021 ggtaagcagc tgtatgaatg ctgattttaa aaccaggtca tgggagaaga gcctggagat 4081 tctttcctga acactgactg cacttaccag tctgatttta tcgtcaaaca ccaagccagg 4141 ctagcatgct catggcaatc tgtttggggc tgttttgttg tggcactagc caaacataaa 4201 ggggcttaag tcagcctgca tacagaggat cggggagaga aggggcctgt gttctcagcc 4261 tcctgagtac ttaccagagt ttaatttttt taaaaaaaat ctgcactaaa atccccaaac 4321 tgacaggtaa atgtagccct cagagctcag cccaaggcag aatctaaatc acactatttt 4381 cgagatcatg tataaaaaga aaaaaaagaa gtcatgctgt gtggccaatt ataatttttt 4441 tcaaagactt tgtcacaaaa ctgtctatat tagacatttt ggagggacca ggaaatgtaa 4501 gacaccaaat cctccatctc ttcagtgtgc ctgatgtcac ctcatgattt gctgttactt 4561 ttttaactcc tgcgccaagg acagtgggtt ctgtgtccac ctttgtgctt tgcgaggccg 4621 agcccaggca tctgctcgcc tgccacggct gaccagagaa ggtgcttcag gagctctgcc 4681 ttagacgacg tgttacagta tgaacacaca gcagaggcac cctcgtatgt tttgaaagtt 4741 gccttctgaa agggcacagt tttaaggaaa agaaaaagaa tgtaaaacta tactgacccg 4801 ttttcagttt taaagggtcg tgagaaactg gctggtccaa tgggatttac agcaacattt 4861 tccattgctg aagtgaggta gcagctctct tctgtcagct gaatgttaag gatggggaaa 4921 aagaatgcct ttaagtttgc tcttaatcgt atggaagctt gagctatgtg ttggaagtgc 4981 cctggtttta atccatacac aaagacggta cataatccta caggtttaaa tgtacataaa 5041 aatatagttt ggaattcttt gctctactgt ttacattgca gattgctata atttcaagga 5101 gtgagattat aaataaaatg atgcacttta ggatgtttcc tatttttgaa atctgaacat 5161 gaatcattca catgaccaaa aattgtgttt ttttaaaaat acatgtctag tctgtccttt 5221 aatagctctc ttaaataagc tatgatatta atcagatcat taccagttag cttttaaagc 5281 acatttgttt aagactatgt ttttggaaaa atacgctaca gaattttttt ttaagctaca 5341 aataaatgag atgctactaa ttgttttgga atctgttgtt tctgccaaag gtaaattaac 5401 taaagattta ttcaggaatc cccatttgaa tttgtatgat tcaataaaag aaaacaccaa 5461 gtaagttata taaaataaat tgtgtatgag atgttgtgtt ttcctttgta atttccacta 5521 actaactaac taacttatat tcttcatgga atggagccca gaagaaatga gaggaagccc 5581 ttttcacact agatcttatt tgaagaaatg tttgttagtc agtcagtcag tggtttctgg 5641 ctctgccgag ggagatgtgt tccccagcaa ccatttctgc agcccagaat ctcaaggcac 5701 tagaggcggt gtcttaatta attggcttca caaagacaaa atgctctgga ctgggatttt 5761 tcctttgctg tgttgggaat atgtgtttat taattagcac atgccaacaa aataaatgtc 5821 aagagttatt tcataagtgt aagtaaactt aagaattaaa gagtgcagac ttataatttt 5881 ca

[0247] In some embodiments of the methods of the disclosure, the wild type human FAM13A gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: NP_055698.2, transcript variant 1):

TABLE-US-00020 (SEQ ID NO: 37) 1 mgagalaicq skaavrlked mkkivavpln eqkdftyqkl fgvslqeler qgltengipa 61 vvwniveylt qhgltqeglf rvngnvkvve qlrlkfesgv pvelgkdgdv csaasllklf 121 lrelpdslit salqprfiql fqdgrndvqe sslrdlikel pdthycllky lcqfltkvak 181 hhvqnrmnvh nlatvfgpnc fhvppglegm keqdlcnkim akilenyntl feveytendh 241 lrcenlarli ivkevyykns lpilltrgle rdmpkpppkt kipksrsegs iqahrvlqpe 301 lsdgipqlsl rlsyrkacle dmnsaegais aklvpssqed erplspfyls ahvpqvsnvs 361 atgellerti rsaveqhlfd vnnsggqsse dsesgtlsas satsarqrrr qskeqdevrh 421 grdkglinke ntpsgfnhld dcilntqeve kvhkntfgca gerskpkrqk sstklselhd 481 nqdglvnmes lnstrshert gpddfewmsd erkgnekdgg htqhfesptm kigehpslsd 541 tkqqrnqdag dqeesfvsev pqsdltalcd eknweepipa fsswqrensd sdeahlspqa 601 grlirqllde dsdpmlsprf yaygqsrqyl ddtevppspp nshsfmrrrs sslgsyddeq 661 edltpaqltr riqslkkkir kfedrfeeek kyrpshsdka anpevlkwtn dlakfrrqlk 721 esklkiseed ltprmrqrsn tlpksfgsql ekedekkqel vdkaikpsve atlesiqrkl 781 qekraessrp edikdmtkdq ianekvalqk allyyesihg rpvtknerqv mkplydryrl 841 vkqilsrant ipiigspssk rrspllqpii egetasffke ikeeeegsed dsnvkpdfmv 901 tlktdfsarc fldqfeddad gfispmddki pskcsqdtgl snlhaasipe llehlqemre 961 ekkrirkklr dfednffrqn grnvqkedrt pmaeeyseyk hikaklrlle vliskrdtds 1021 ksm

[0248] In some embodiments of the methods of the disclosure, the wild type human FAM13A gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_001015045.2, transcript variant 2):

TABLE-US-00021 (SEQ ID NO: 17) 1 attgaggagc agaaggagta gggtgcgggg gaggaggagg agcgccttta gtgctgcagc 61 agctgctgct ctgattggcc cggtggttca gctgcttccc tggaacaaaa ggtcaaagtg 121 gactgcagtg taaatgtaga gaagcagccg ataaaatagc attgcctgaa gaagtttgga 181 ggctgagagc agcagtagac tggccaactg cagagcaagt tgtttctcca gccgtgcggt 241 gcagcctcat gcccccaacc cagcttagcc actgtaagaa gacgttcact gtacagacga 301 ccaaacttgc cgtggaagag acagttgtga gattcccttg caaatttaca tacgagaatg 361 gcttgtgaaa tcatgcctct gcaaagttca caggaagatg aaagacctct gtcacctttc 421 tatttgagtg ctcatgtacc ccaagtcagc aatgtgtctg caaccggaga actcttagaa 481 agaaccatcc gatcagctgt agaacaacat ctttttgatg ttaataactc tggaggtcaa 541 agttcagagg actcagaatc tggaacacta tcagcatctt ctgccacatc tgccagacag 601 cgccgccgcc agtccaagga gcaggatgaa gttcgacatg ggagagacaa gggacttatc 661 aacaaagaaa atactccttc tgggttcaac caccttgatg attgtatttt gaatactcag 721 gaagtcgaaa aggtacacaa aaatactttt ggttgtgctg gagaaaggag caagcctaaa 781 cgtcagaaat ccagtactaa actttctgag cttcatgaca atcaggacgg tcttgtgaat 841 atggaaagtc tcaattccac acgatctcat gagagaactg gacctgatga ttttgaatgg 901 atgtctgatg aaaggaaagg aaatgaaaaa gatggtggac acactcagca ttttgagagc 961 cccacaatga agatccagga gcatcccagc ctatctgaca ccaaacagca gagaaatcaa 1021 gatgccggtg accaggagga gagctttgtc tccgaagtgc cccagtcgga cctgactgca 1081 ttgtgtgatg aaaagaactg ggaagagcct atccctgctt tctcctcctg gcagcgggag 1141 aacagtgact ctgatgaagc ccacctctcg ccgcaggctg ggcgcctgat ccgtcagctg 1201 ctggacgaag acagcgaccc catgctctct cctcggttct acgcttatgg gcagagcagg 1261 caatacctgg atgacacaga agtgcctcct tccccaccaa actcccattc tttcatgagg 1321 cggcgaagct cctctctggg gtcctatgat gatgagcaag aggacctgac acctgcccag 1381 ctcacacgaa ggattcagag ccttaaaaag aagatccgga agtttgaaga tagattcgaa 1441 gaagagaaga agtacagacc ttcccacagt gacaaagcag ccaatccgga ggttctgaaa 1501 tggacaaatg accttgccaa attccggaga caacttaaag aatcaaaact aaagatatct 1561 gaagaggacc taactcccag gatgcggcag cgaagcaaca cactccccaa gagttttggt 1621 tcccaacttg agaaagaaga tgagaagaag caagagctgg tggataaagc aataaagccc 1681 agtgttgaag ccacattgga atctattcag aggaagctcc aggagaagcg agcggaaagc 1741 agccgccctg aggacattaa ggatatgacc aaagaccaga ttgctaatga gaaagtggct 1801 ctgcagaaag ctctgttata ttatgaaagc attcatggac ggccggtaac aaagaacgaa 1861 cggcaggtga tgaagccact atacgacagg taccggctgg tcaaacagat cctctcccga 1921 gctaacacca tacccatcat tggttccccc tccagcaagc ggagaagccc tttgctgcag 1981 ccaattatcg agggcgaaac tgcttccttc ttcaaggaga taaaggaaga agaggagggg 2041 tcagaagacg atagcaatgt gaagccagac ttcatggtca ctctgaaaac cgatttcagt 2101 gcacgatgct ttctggacca attcgaagat gacgctgatg gatttatttc cccaatggat 2161 gataaaatac catcaaaatg cagccaggac acagggcttt caaatctcca tgctgcctca 2221 atacctgaac tcctggaaca cctccaggaa atgagagaag aaaagaaaag gattcgaaag 2281 aaacttcggg attttgaaga caactttttc agacagaatg gaagaaatgt ccagaaggaa 2341 gaccgcactc ctatggctga agaatacagt gaatataagc acataaaggc gaaactgagg 2401 ctcctggagg tgctcatcag caagagagac actgattcca agtccatgtg aggggcatgg 2461 ccaagcacag ggggctggca gctgcggtga gagtttactg tccccagaga aagtgcagct 2521 ctggaaggca gccttggggc tggccctgca aagcatgcag cccttctgcc tctagaccat 2581 ttggcatcgg ctcctgtttc cattgcctgc cttagaaact ggctggaaga agacaatgtg 2641 acctgactta ggcattttgt aattggaaag tcaagactgc agtatgtgca catgcgcacg 2701 cgcatgcacg cacacacaca cacagtagtg gagctttcct aacactagca gagattaatc 2761 actacattag acaacactca tctacagaga atatacactg ttcttccctg gataactgag 2821 aaacaagaga ccattctctg tctaactgtg ataaaaacaa gctcaggact ttattctata 2881 gagcaaactt gctgtggagg gccatgctct ccttggaccc agttaactgc aaacgtgcat 2941 tggagcccta tttgctgccg ctgccattct agtgaccttt ccacagagct gcgccttcct 3001 cacgtgtgtg aaaggttttc cccttcagcc ctcaggtaga tggaagctgc atctgcccac 3061 gatggcagtg cagtcatcat cttcaggatg tttcttcagg acttcctcag ctgacaagga 3121 attttggtcc ctgcctagga ccgggtcatc tgcagaggac agagagatgg taagcagctg 3181 tatgaatgct gattttaaaa ccaggtcatg ggagaagagc ctggagattc tttcctgaac 3241 actgactgca cttaccagtc tgattttatc gtcaaacacc aagccaggct agcatgctca 3301 tggcaatctg tttggggctg ttttgttgtg gcactagcca aacataaagg ggcttaagtc 3361 agcctgcata cagaggatcg gggagagaag gggcctgtgt tctcagcctc ctgagtactt 3421 accagagttt aattttttta aaaaaaatct gcactaaaat ccccaaactg acaggtaaat 3481 gtagccctca gagctcagcc caaggcagaa tctaaatcac actattttcg agatcatgta 3541 taaaaagaaa aaaaagaagt catgctgtgt ggccaattat aatttttttc aaagactttg 3601 tcacaaaact gtctatatta gacattttgg agggaccagg aaatgtaaga caccaaatcc 3661 tccatctctt cagtgtgcct gatgtcacct catgatttgc tgttactttt ttaactcctg 3721 cgccaaggac agtgggttct gtgtccacct ttgtgctttg cgaggccgag cccaggcatc 3781 tgctcgcctg ccacggctga ccagagaagg tgcttcagga gctctgcctt agacgacgtg 3841 ttacagtatg aacacacagc agaggcaccc tcgtatgttt tgaaagttgc cttctgaaag 3901 ggcacagttt taaggaaaag aaaaagaatg taaaactata ctgacccgtt ttcagtttta 3961 aagggtcgtg agaaactggc tggtccaatg ggatttacag caacattttc cattgctgaa 4021 gtgaggtagc agctctcttc tgtcagctga atgttaagga tggggaaaaa gaatgccttt 4081 aagtttgctc ttaatcgtat ggaagcttga gctatgtgtt ggaagtgccc tggttttaat 4141 ccatacacaa agacggtaca taatcctaca ggtttaaatg tacataaaaa tatagtttgg 4201 aattctttgc tctactgttt acattgcaga ttgctataat ttcaaggagt gagattataa 4261 ataaaatgat gcactttagg atgtttccta tttttgaaat ctgaacatga atcattcaca 4321 tgaccaaaaa ttgtgttttt ttaaaaatac atgtctagtc tgtcctttaa tagctctctt 4381 aaataagcta tgatattaat cagatcatta ccagttagct tttaaagcac atttgtttaa 4441 gactatgttt ttggaaaaat acgctacaga attttttttt aagctacaaa taaatgagat 4501 gctactaatt gttttggaat ctgttgtttc tgccaaaggt aaattaacta aagatttatt 4561 caggaatccc catttgaatt tgtatgattc aataaaagaa aacaccaagt aagttatata 4621 aaataaattg tgtatgagat gttgtgtttt cctttgtaat ttccactaac taactaacta 4681 acttatattc ttcatggaat ggagcccaga agaaatgaga ggaagccctt ttcacactag 4741 atcttatttg aagaaatgtt tgttagtcag tcagtcagtg gtttctggct ctgccgaggg 4801 agatgtgttc cccagcaacc atttctgcag cccagaatct caaggcacta gaggcggtgt 4861 cttaattaat tggcttcaca aagacaaaat gctctggact gggatttttc ctttgctgtg 4921 ttgggaatat gtgtttatta attagcacat gccaacaaaa taaatgtcaa gagttatttc 4981 ataagtgtaa gtaaacttaa gaattaaaga gtgcagactt ataattttca

[0249] In some embodiments of the methods of the disclosure, the wild type human FAM13A gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: NP_001015045.1, transcript variant 2):

TABLE-US-00022 (SEQ ID NO: 18) 1 maceimplqs sqederplsp fylsahvpqv snvsatgell ertirsaveq hlfdvnnsgg 61 qssedsesgt lsassatsar qrrrqskeqd evrhgrdkgl inkentpsgf nhlddcilnt 121 qevekvhknt fgcagerskp krqksstkls elhdnqdglv nmeslnstrs hertgpddfe 181 wmsderkgne kdgghtqhfe sptmkigehp slsdtkqqrn qdagdqeesf vsevpqsdlt 241 alcdeknwee pipafsswqr ensdsdeahl spqagrlirq lldedsdpml sprfyaygqs 301 rqylddtevp psppnshsfm rrrssslgsy ddeqedltpa qltrriqslk kkirkfedrf 361 eeekkyrpsh sdkaanpevl kwtndlakfr rqlkesklki seedltprmr qrsntlpksf 421 gsqlekedek kqelvdkaik psveatlesi qrklqekrae ssrpedikdm tkdqianekv 481 alqkallyye sihgrpvtkn erqvmkplyd ryrlvkqils rantipiigs psskrrspll 541 qpiiegetas ffkeikeeee gseddsnvkp dfmvtlktdf sarcfldqfe ddadgfispm 601 ddkipskcsq dtglsnlhaa sipellehlq emreekkrir kklrdfednf frqngrnvqk 661 edrtpmaeey seykhikakl rllevliskr dtdsksm

[0250] In some embodiments of the methods of the disclosure, the wild type human FAM13A gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_001265578.1, transcript variant 3):

TABLE-US-00023 (SEQ ID NO: 38) 1 attgaggagc agaaggagta gggtgcgggg gaggaggagg agcgccttta gtgctgcagc 61 agctgctgct ctgattggcc cggtggttca gctgcttccc tggaacaaaa ggtcaaagtg 121 gactgcagtg taaatgtaga gaagcagccg ataaaatagc attgcctgaa gaagtttgga 181 ggctgagagc agcagtagac tggccaactg cagagcaagt tgtttctcca gccgtgcggt 241 gcagcctcat gcccccaacc cagcttagcc actgtaagaa gacgttcact gtacagacga 301 ccaaacttgc cgtggaagag acagttgtga gattcccttg caaatttaca tacgagaatg 361 gcttgtgaaa tcatgcctct gcaaagtgct catgtacccc aagtcagcaa tgtgtctgca 421 accggagaac tcttagaaag aaccatccga tcagctgtag aacaacatct ttttgatgtt 481 aataactctg gaggtcaaag ttcagaggac tcagaatctg gaacactatc agcatcttct 541 gccacatctg ccagacagcg ccgccgccag tccaaggagc aggatgaagt tcgacatggg 601 agagacaagg gacttatcaa caaagaaaat actccttctg ggttcaacca ccttgatgat 661 tgtattttga atactcagga agtcgaaaag gtacacaaaa atacttttgg ttgtgctgga 721 gaaaggagca agcctaaacg tcagaaatcc agtactaaac tttctgagct tcatgacaat 781 caggacggtc ttgtgaatat ggaaagtctc aattccacac gatctcatga gagaactgga 841 cctgatgatt ttgaatggat gtctgatgaa aggaaaggaa atgaaaaaga tggtggacac 901 actcagcatt ttgagagccc cacaatgaag atccaggagc atcccagcct atctgacacc 961 aaacagcaga gaaatcaaga tgccggtgac caggaggaga gctttgtctc cgaagtgccc 1021 cagtcggacc tgactgcatt gtgtgatgaa aagaactggg aagagcctat ccctgctttc 1081 tcctcctggc agcgggagaa cagtgactct gatgaagccc acctctcgcc gcaggctggg 1141 cgcctgatcc gtcagctgct ggacgaagac agcgacccca tgctctctcc tcggttctac 1201 gcttatgggc agagcaggca atacctggat gacacagaag tgcctccttc cccaccaaac 1261 tcccattctt tcatgaggcg gcgaagctcc tctctggggt cctatgatga tgagcaagag 1321 gacctgacac ctgcccagct cacacgaagg attcagagcc ttaaaaagaa gatccggaag 1381 tttgaagata gattcgaaga agagaagaag tacagacctt cccacagtga caaagcagcc 1441 aatccggagg ttctgaaatg gacaaatgac cttgccaaat tccggagaca acttaaagaa 1501 tcaaaactaa agatatctga agaggaccta actcccagga tgcggcagcg aagcaacaca 1561 ctccccaaga gttttggttc ccaacttgag aaagaagatg agaagaagca agagctggtg 1621 gataaagcaa taaagcccag tgttgaagcc acattggaat ctattcagag gaagctccag 1681 gagaagcgag cggaaagcag ccgccctgag gacattaagg atatgaccaa agaccagatt 1741 gctaatgaga aagtggctct gcagaaagct ctgttatatt atgaaagcat tcatggacgg 1801 ccggtaacaa agaacgaacg gcaggtgatg aagccactat acgacaggta ccggctggtc 1861 aaacagatcc tctcccgagc taacaccata cccatcattg gttccccctc cagcaagcgg 1921 agaagccctt tgctgcagcc aattatcgag ggcgaaactg cttccttctt caaggagata 1981 aaggaagaag aggaggggtc agaagacgat agcaatgtga agccagactt catggtcact 2041 ctgaaaaccg atttcagtgc acgatgcttt ctggaccaat tcgaagatga cgctgatgga 2101 tttatttccc caatggatga taaaatacca tcaaaatgca gccaggacac agggctttca 2161 aatctccatg ctgcctcaat acctgaactc ctggaacacc tccaggaaat gagagaagaa 2221 aagaaaagga ttcgaaagaa acttcgggat tttgaagaca actttttcag acagaatgga 2281 agaaatgtcc agaaggaaga ccgcactcct atggctgaag aatacagtga atataagcac 2341 ataaaggcga aactgaggct cctggaggtg ctcatcagca agagagacac tgattccaag 2401 tccatgtgag gggcatggcc aagcacaggg ggctggcagc tgcggtgaga gtttactgtc 2461 cccagagaaa gtgcagctct ggaaggcagc cttggggctg gccctgcaaa gcatgcagcc 2521 cttctgcctc tagaccattt ggcatcggct cctgtttcca ttgcctgcct tagaaactgg 2581 ctggaagaag acaatgtgac ctgacttagg cattttgtaa ttggaaagtc aagactgcag 2641 tatgtgcaca tgcgcacgcg catgcacgca cacacacaca cagtagtgga gctttcctaa 2701 cactagcaga gattaatcac tacattagac aacactcatc tacagagaat atacactgtt 2761 cttccctgga taactgagaa acaagagacc attctctgtc taactgtgat aaaaacaagc 2821 tcaggacttt attctataga gcaaacttgc tgtggagggc catgctctcc ttggacccag 2881 ttaactgcaa acgtgcattg gagccctatt tgctgccgct gccattctag tgacctttcc 2941 acagagctgc gccttcctca cgtgtgtgaa aggttttccc cttcagccct caggtagatg 3001 gaagctgcat ctgcccacga tggcagtgca gtcatcatct tcaggatgtt tcttcaggac 3061 ttcctcagct gacaaggaat tttggtccct gcctaggacc gggtcatctg cagaggacag 3121 agagatggta agcagctgta tgaatgctga ttttaaaacc aggtcatggg agaagagcct 3181 ggagattctt tcctgaacac tgactgcact taccagtctg attttatcgt caaacaccaa 3241 gccaggctag catgctcatg gcaatctgtt tggggctgtt ttgttgtggc actagccaaa 3301 cataaagggg cttaagtcag cctgcataca gaggatcggg gagagaaggg gcctgtgttc 3361 tcagcctcct gagtacttac cagagtttaa tttttttaaa aaaaatctgc actaaaatcc 3421 ccaaactgac aggtaaatgt agccctcaga gctcagccca aggcagaatc taaatcacac 3481 tattttcgag atcatgtata aaaagaaaaa aaagaagtca tgctgtgtgg ccaattataa 3541 tttttttcaa agactttgtc acaaaactgt ctatattaga cattttggag ggaccaggaa 3601 atgtaagaca ccaaatcctc catctcttca gtgtgcctga tgtcacctca tgatttgctg 3661 ttactttttt aactcctgcg ccaaggacag tgggttctgt gtccaccttt gtgctttgcg 3721 aggccgagcc caggcatctg ctcgcctgcc acggctgacc agagaaggtg cttcaggagc 3781 tctgccttag acgacgtgtt acagtatgaa cacacagcag aggcaccctc gtatgttttg 3841 aaagttgcct tctgaaaggg cacagtttta aggaaaagaa aaagaatgta aaactatact 3901 gacccgtttt cagttttaaa gggtcgtgag aaactggctg gtccaatggg atttacagca 3961 acattttcca ttgctgaagt gaggtagcag ctctcttctg tcagctgaat gttaaggatg 4021 gggaaaaaga atgcctttaa gtttgctctt aatcgtatgg aagcttgagc tatgtgttgg 4081 aagtgccctg gttttaatcc atacacaaag acggtacata atcctacagg tttaaatgta 4141 cataaaaata tagtttggaa ttctttgctc tactgtttac attgcagatt gctataattt 4201 caaggagtga gattataaat aaaatgatgc actttaggat gtttcctatt tttgaaatct 4261 gaacatgaat cattcacatg accaaaaatt gtgttttttt aaaaatacat gtctagtctg 4321 tcctttaata gctctcttaa ataagctatg atattaatca gatcattacc agttagcttt 4381 taaagcacat ttgtttaaga ctatgttttt ggaaaaatac gctacagaat ttttttttaa 4441 gctacaaata aatgagatgc tactaattgt tttggaatct gttgtttctg ccaaaggtaa 4501 attaactaaa gatttattca ggaatcccca tttgaatttg tatgattcaa taaaagaaaa 4561 caccaagtaa gttatataaa ataaattgtg tatgagatgt tgtgttttcc tttgtaattt 4621 ccactaacta actaactaac ttatattctt catggaatgg agcccagaag aaatgagagg 4681 aagccctttt cacactagat cttatttgaa gaaatgtttg ttagtcagtc agtcagtggt 4741 ttctggctct gccgagggag atgtgttccc cagcaaccat ttctgcagcc cagaatctca 4801 aggcactaga ggcggtgtct taattaattg gcttcacaaa gacaaaatgc tctggactgg 4861 gatttttcct ttgctgtgtt gggaatatgt gtttattaat tagcacatgc caacaaaata 4921 aatgtcaaga gttatttcat aagtgtaagt aaacttaaga attaaagagt gcagacttat 4981 aattttca

[0251] In some embodiments of the methods of the disclosure, the wild type human FAM13A gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: NP_001252507.1, transcript variant 3):

TABLE-US-00024 (SEQ ID NO: 39) 1 maceimplqs ahvpqvsnvs atgellerti rsaveqhlfd vnnsggqsse dsesgtlsas 61 satsarqrrr qskeqdevrh grdkglinke ntpsgfnhld dcilntqeve kvhkntfgca 121 gerskpkrqk sstklselhd nqdglvnmes lnstrshert gpddfewmsd erkgnekdgg 181 htqhfesptm kigehpslsd tkqqrnqdag dqeesfvsev pqsdltalcd eknweepipa 241 fsswqrensd sdeahlspqa grlirqllde dsdpmlsprf yayggsrqyl ddtevppspp 301 nshsfmrrrs sslgsyddeq edltpaqltr riqslkkkir kfedrfeeek kyrpshsdka 361 anpevlkwtn dlakfrrqlk esklkiseed ltprmrqrsn tlpksfgsql ekedekkqel 421 vdkaikpsve atlesiqrkl qekraessrp edikdmtkdq ianekvalqk allyyesihg 481 rpvtknerqv mkplydryrl vkqilsrant ipiigspssk rrspllqpii egetasffke 541 ikeeeegsed dsnvkpdfmv tlktdfsarc fldqfeddad gfispmddki pskcsqdtgl 601 snlhaasipe llehlqemre ekkrirkklr dfednffrqn grnvqkedrt pmaeeyseyk 661 hikaklrlle vliskrdtds ksm

[0252] In some embodiments of the methods of the disclosure, the wild type human FAM13A gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_001265579.1, transcript variant 4):

TABLE-US-00025 (SEQ ID NO: 40) 1 attgaggagc agaaggagta gggtgcgggg gaggaggagg agcgccttta gtgctgcagc 61 agctgctgct ctgattggcc cggtggttca gctgcttccc tggaacaaaa ggtcaaagtg 121 gactgcagtg taaatgtaga gaagcagccg ataaaatagc attgcctgaa gaagtttgga 181 ggctgagagc agcagtagac tggccaactg cagagcaagt tgtttctcca gccgtgcggt 241 gcagcctcat gcccccaacc cagcttagcc actgtaagaa gacgttcact gtacagacga 301 ccaaacttgc cgtggaagag acagttgtga gattcccttg caaatttaca tacgagaatg 361 gcttgtgaaa tcatgcctct gcaaagttca caggaagatg aaagacctct gtcacctttc 421 tatttgagtg ctcatgtacc ccaagtcagc aatgtgtctg caaccggaga actcttagaa 481 agaaccatcc gatcagctgt agaacaacat ctttttgatg ttaataactc tggaggtcaa 541 agttcagagg actcagaatc tggaacacta tcagcatctt ctgccacatc tgccagacag 601 cgccgccgcc agtccaagga gcaggatgaa gttcgacatg ggagagacaa gggacttatc 661 aacaaagaaa atactccttc tgggttcaac caccttgatg attgtatttt gaatactcag 721 gaagtcgaaa aggtacacaa aaatactttt ggttgtgctg gagaaaggag caagcctaaa 781 cgtcagaaat ccagtactaa actttctgag cttcatgaca atcaggacgg tcttgtgaat 841 atggaaagtc tcaattccac acgatctcat gagagaactg gacctgatga ttttgaatgg 901 atgtctgatg aaaggaaagg aaatgaaaaa gatggtggac acactcagca ttttgagagc 961 cccacaatga agatccagga gcatcccagc ctatctgaca ccaaacagca gagaaatcaa 1021 gatgccggtg accaggagga gagctttgtc tccgaagtgc cccagtcgga cctgactgca 1081 ttgtgtgatg aaaagaactg ggaagagcct atccctgctt tctcctcctg gcagcgggag 1141 aacagtgact ctgatgaagc ccacctctcg ccgcaggctg ggcgcctgat ccgtcagctg 1201 ctggacgaag acagcgaccc catgctctct cctcggttct acgcttatgg gcagagcagg 1261 caatacctgg atgacacaga agtgcctcct tccccaccaa actcccattc tttcatgagg 1321 cggcgaagct cctctctggg gtcctatgat gatgagcaag aggacctgac acctgcccag 1381 ctcacacgaa ggattcagag ccttaaaaag aagatccgga agtttgaaga tagattcgaa 1441 gaagagaaga agtacagacc ttcccacagt gacaaagcag ccaatccgga ggttctgaaa 1501 tggacaaatg accttgccaa attccggaga caacttaaag aatcaaaact aaagatatct 1561 gaagaggacc taactcccag gatgcggcag cgaagcaaca cactccccaa gagttttggt 1621 tcccaacttg agaaagaaga tgagaagaag caagagctgg tggataaagc aataaagccc 1681 agtgttgaag ccacattgga atctattcag aggaagctcc aggagaagcg agcggaaagc 1741 agccgccctg aggacattaa ggatatgacc aaagaccaga ttgctaatga gaaagtggct 1801 ctgcagaaag ctctgttata ttatgaaagc attcatggac ggccggtaac aaagaacgaa 1861 cggcaggtga tgaagccact atacgacagg taccggctgg tcaaacagat cctctcccga 1921 gctaacacca tacccatcat tgaagaagag gaggggtcag aagacgatag caatgtgaag 1981 ccagacttca tggtcactct gaaaaccgat ttcagtgcac gatgctttct ggaccaattc 2041 gaagatgacg ctgatggatt tatttcccca atggatgata aaataccatc aaaatgcagc 2101 caggacacag ggctttcaaa tctccatgct gcctcaatac ctgaactcct ggaacacctc 2161 caggaaatga gagaagaaaa gaaaaggatt cgaaagaaac ttcgggattt tgaagacaac 2221 tttttcagac agaatggaag aaatgtccag aaggaagacc gcactcctat ggctgaagaa 2281 tacagtgaat ataagcacat aaaggcgaaa ctgaggctcc tggaggtgct catcagcaag 2341 agagacactg attccaagtc catgtgaggg gcatggccaa gcacaggggg ctggcagctg 2401 cggtgagagt ttactgtccc cagagaaagt gcagctctgg aaggcagcct tggggctggc 2461 cctgcaaagc atgcagccct tctgcctcta gaccatttgg catcggctcc tgtttccatt 2521 gcctgcctta gaaactggct ggaagaagac aatgtgacct gacttaggca ttttgtaatt 2581 ggaaagtcaa gactgcagta tgtgcacatg cgcacgcgca tgcacgcaca cacacacaca 2641 gtagtggagc tttcctaaca ctagcagaga ttaatcacta cattagacaa cactcatcta 2701 cagagaatat acactgttct tccctggata actgagaaac aagagaccat tctctgtcta 2761 actgtgataa aaacaagctc aggactttat tctatagagc aaacttgctg tggagggcca 2821 tgctctcctt ggacccagtt aactgcaaac gtgcattgga gccctatttg ctgccgctgc 2881 cattctagtg acctttccac agagctgcgc cttcctcacg tgtgtgaaag gttttcccct 2941 tcagccctca ggtagatgga agctgcatct gcccacgatg gcagtgcagt catcatcttc 3001 aggatgtttc ttcaggactt cctcagctga caaggaattt tggtccctgc ctaggaccgg 3061 gtcatctgca gaggacagag agatggtaag cagctgtatg aatgctgatt ttaaaaccag 3121 gtcatgggag aagagcctgg agattctttc ctgaacactg actgcactta ccagtctgat 3181 tttatcgtca aacaccaagc caggctagca tgctcatggc aatctgtttg gggctgtttt 3241 gttgtggcac tagccaaaca taaaggggct taagtcagcc tgcatacaga ggatcgggga 3301 gagaaggggc ctgtgttctc agcctcctga gtacttacca gagtttaatt tttttaaaaa 3361 aaatctgcac taaaatcccc aaactgacag gtaaatgtag ccctcagagc tcagcccaag 3421 gcagaatcta aatcacacta ttttcgagat catgtataaa aagaaaaaaa agaagtcatg 3481 ctgtgtggcc aattataatt tttttcaaag actttgtcac aaaactgtct atattagaca 3541 ttttggaggg accaggaaat gtaagacacc aaatcctcca tctcttcagt gtgcctgatg 3601 tcacctcatg atttgctgtt acttttttaa ctcctgcgcc aaggacagtg ggttctgtgt 3661 ccacctttgt gctttgcgag gccgagccca ggcatctgct cgcctgccac ggctgaccag 3721 agaaggtgct tcaggagctc tgccttagac gacgtgttac agtatgaaca cacagcagag 3781 gcaccctcgt atgttttgaa agttgccttc tgaaagggca cagttttaag gaaaagaaaa 3841 agaatgtaaa actatactga cccgttttca gttttaaagg gtcgtgagaa actggctggt 3901 ccaatgggat ttacagcaac attttccatt gctgaagtga ggtagcagct ctcttctgtc 3961 agctgaatgt taaggatggg gaaaaagaat gcctttaagt ttgctcttaa tcgtatggaa 4021 gcttgagcta tgtgttggaa gtgccctggt tttaatccat acacaaagac ggtacataat 4081 cctacaggtt taaatgtaca taaaaatata gtttggaatt ctttgctcta ctgtttacat 4141 tgcagattgc tataatttca aggagtgaga ttataaataa aatgatgcac tttaggatgt 4201 ttcctatttt tgaaatctga acatgaatca ttcacatgac caaaaattgt gtttttttaa 4261 aaatacatgt ctagtctgtc ctttaatagc tctcttaaat aagctatgat attaatcaga 4321 tcattaccag ttagctttta aagcacattt gtttaagact atgtttttgg aaaaatacgc 4381 tacagaattt ttttttaagc tacaaataaa tgagatgcta ctaattgttt tggaatctgt 4441 tgtttctgcc aaaggtaaat taactaaaga tttattcagg aatccccatt tgaatttgta 4501 tgattcaata aaagaaaaca ccaagtaagt tatataaaat aaattgtgta tgagatgttg 4561 tgttttcctt tgtaatttcc actaactaac taactaactt atattcttca tggaatggag 4621 cccagaagaa atgagaggaa gcccttttca cactagatct tatttgaaga aatgtttgtt 4681 agtcagtcag tcagtggttt ctggctctgc cgagggagat gtgttcccca gcaaccattt 4741 ctgcagccca gaatctcaag gcactagagg cggtgtctta attaattggc ttcacaaaga 4801 caaaatgctc tggactggga tttttccttt gctgtgttgg gaatatgtgt ttattaatta 4861 gcacatgcca acaaaataaa tgtcaagagt tatttcataa gtgtaagtaa acttaagaat 4921 taaagagtgc agacttataa ttttca

[0253] In some embodiments of the methods of the disclosure, the wild type human FAM13A gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: NP_001252508.1, transcript variant 4):

TABLE-US-00026 (SEQ ID NO: 41) 1 maceimplqs sqederplsp fylsahvpqv snvsatgell ertirsaveq hlfdvnnsgg 61 qssedsesgt lsassatsar qrrrqskeqd evrhgrdkgl inkentpsgf nhlddcilnt 121 qevekvhknt fgcagerskp krqksstkls elhdnqdglv nmeslnstrs hertgpddfe 181 wmsderkgne kdgghtqhfe sptmkigehp slsdtkqqrn qdagdqeesf vsevpqsdlt 241 alcdeknwee pipafsswqr ensdsdeahl spqagrlirq lldedsdpml sprfyaygqs 301 rqylddtevp psppnshsfm rrrssslgsy ddeqedltpa qltrriqslk kkirkfedrf 361 eeekkyrpsh sdkaanpevl kwtndlakfr rqlkesklki seedltprmr qrsntlpksf 421 gsqlekedek kqelvdkaik psveatlesi qrklqekrae ssrpedikdm tkdqianekv 481 alqkallyye sihgrpvtkn erqvmkplyd ryrlvkqils rantipiiee eegseddsnv 541 kpdfmvtlkt dfsarcfldq feddadgfis pmddkipskc sqdtglsnlh aasipelleh 601 lqemreekkr irkklrdfed nffrqngrnv qkedrtpmae eyseykhika klrllevlis 661 krdtdsksm

[0254] In some embodiments of the methods of the disclosure, the wild type human FAM13A gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_001265580.1, transcript variant 5):

TABLE-US-00027 (SEQ ID NO: 42) 1 attgaggagc agaaggagta gggtgcgggg gaggaggagg agcgccttta gtgctgcagc 61 agctgctgct ctgattggcc cggtggttca gctgcttccc tggaacaaaa ggtcaaagtg 121 gactgcagtg taaatgtaga gaagcagccg ataaaatagc attgcctgaa gaagtttgga 181 ggctgagagc agcagtagac tggccaactg cagagcaagt tgtttctcca gccgtgcggt 241 gcagcctcat gcccccaacc cagcttagcc actgtaagaa gacgttcact gtacagacga 301 ccaaacttgc cgtggaagag acagttgtga gattcccttg caaatttaca tacgagaatg 361 gcttgtgaaa tcatgcctct gcaaagactc ttagaaagaa ccatccgatc agctgtagaa 421 caacatcttt ttgatgttaa taactctgga ggtcaaagtt cagaggactc agaatctgga 481 acactatcag catcttctgc cacatctgcc agacagcgcc gccgccagtc caaggagcag 541 gatgaagttc gacatgggag agacaaggga cttatcaaca aagaaaatac tccttctggg 601 ttcaaccacc ttgatgattg tattttgaat actcaggaag tcgaaaaggt acacaaaaat 661 acttttggtt gtgctggaga aaggagcaag cctaaacgtc agaaatccag tactaaactt 721 tctgagcttc atgacaatca ggacggtctt gtgaatatgg aaagtctcaa ttccacacga 781 tctcatgaga gaactggacc tgatgatttt gaatggatgt ctgatgaaag gaaaggaaat 841 gaaaaagatg gtggacacac tcagcatttt gagagcccca caatgaagat ccaggagcat 901 cccagcctat ctgacaccaa acagcagaga aatcaagatg ccggtgacca ggaggagagc 961 tttgtctccg aagtgcccca gtcggacctg actgcattgt gtgatgaaaa gaactgggaa 1021 gagcctatcc ctgctttctc ctcctggcag cgggagaaca gtgactctga tgaagcccac 1081 ctctcgccgc aggctgggcg cctgatccgt cagctgctgg acgaagacag cgaccccatg 1141 ctctctcctc ggttctacgc ttatgggcag agcaggcaat acctggatga cacagaagtg 1201 cctccttccc caccaaactc ccattctttc atgaggcggc gaagctcctc tctggggtcc 1261 tatgatgatg agcaagagga cctgacacct gcccagctca cacgaaggat tcagagcctt 1321 aaaaagaaga tccggaagtt tgaagataga ttcgaagaag agaagaagta cagaccttcc 1381 cacagtgaca aagcagccaa tccggaggtt ctgaaatgga caaatgacct tgccaaattc 1441 cggagacaac ttaaagaatc aaaactaaag atatctgaag aggacctaac tcccaggatg 1501 cggcagcgaa gcaacacact ccccaagagt tttggttccc aacttgagaa agaagatgag 1561 aagaagcaag agctggtgga taaagcaata aagcccagtg ttgaagccac attggaatct 1621 attcagagga agctccagga gaagcgagcg gaaagcagcc gccctgagga cattaaggat 1681 atgaccaaag accagattgc taatgagaaa gtggctctgc agaaagctct gttatattat 1741 gaaagcattc atggacggcc ggtaacaaag aacgaacggc aggtgatgaa gccactatac 1801 gacaggtacc ggctggtcaa acagatcctc tcccgagcta acaccatacc catcattggt 1861 tccccctcca gcaagcggag aagccctttg ctgcagccaa ttatcgaggg cgaaactgct 1921 tccttcttca aggagataaa ggaagaagag gaggggtcag aagacgatag caatgtgaag 1981 ccagacttca tggtcactct gaaaaccgat ttcagtgcac gatgctttct ggaccaattc 2041 gaagatgacg ctgatggatt tatttcccca atggatgata aaataccatc aaaatgcagc 2101 caggacacag ggctttcaaa tctccatgct gcctcaatac ctgaactcct ggaacacctc 2161 caggaaatga gagaagaaaa gaaaaggatt cgaaagaaac ttcgggattt tgaagacaac 2221 tttttcagac agaatggaag aaatgtccag aaggaagacc gcactcctat ggctgaagaa 2281 tacagtgaat ataagcacat aaaggcgaaa ctgaggctcc tggaggtgct catcagcaag 2341 agagacactg attccaagtc catgtgaggg gcatggccaa gcacaggggg ctggcagctg 2401 cggtgagagt ttactgtccc cagagaaagt gcagctctgg aaggcagcct tggggctggc 2461 cctgcaaagc atgcagccct tctgcctcta gaccatttgg catcggctcc tgtttccatt 2521 gcctgcctta gaaactggct ggaagaagac aatgtgacct gacttaggca ttttgtaatt 2581 ggaaagtcaa gactgcagta tgtgcacatg cgcacgcgca tgcacgcaca cacacacaca 2641 gtagtggagc tttcctaaca ctagcagaga ttaatcacta cattagacaa cactcatcta 2701 cagagaatat acactgttct tccctggata actgagaaac aagagaccat tctctgtcta 2761 actgtgataa aaacaagctc aggactttat tctatagagc aaacttgctg tggagggcca 2821 tgctctcctt ggacccagtt aactgcaaac gtgcattgga gccctatttg ctgccgctgc 2881 cattctagtg acctttccac agagctgcgc cttcctcacg tgtgtgaaag gttttcccct 2941 tcagccctca ggtagatgga agctgcatct gcccacgatg gcagtgcagt catcatcttc 3001 aggatgtttc ttcaggactt cctcagctga caaggaattt tggtccctgc ctaggaccgg 3061 gtcatctgca gaggacagag agatggtaag cagctgtatg aatgctgatt ttaaaaccag 3121 gtcatgggag aagagcctgg agattctttc ctgaacactg actgcactta ccagtctgat 3181 tttatcgtca aacaccaagc caggctagca tgctcatggc aatctgtttg gggctgtttt 3241 gttgtggcac tagccaaaca taaaggggct taagtcagcc tgcatacaga ggatcgggga 3301 gagaaggggc ctgtgttctc agcctcctga gtacttacca gagtttaatt tttttaaaaa 3361 aaatctgcac taaaatcccc aaactgacag gtaaatgtag ccctcagagc tcagcccaag 3421 gcagaatcta aatcacacta ttttcgagat catgtataaa aagaaaaaaa agaagtcatg 3481 ctgtgtggcc aattataatt tttttcaaag actttgtcac aaaactgtct atattagaca 3541 ttttggaggg accaggaaat gtaagacacc aaatcctcca tctcttcagt gtgcctgatg 3601 tcacctcatg atttgctgtt acttttttaa ctcctgcgcc aaggacagtg ggttctgtgt 3661 ccacctttgt gctttgcgag gccgagccca ggcatctgct cgcctgccac ggctgaccag 3721 agaaggtgct tcaggagctc tgccttagac gacgtgttac agtatgaaca cacagcagag 3781 gcaccctcgt atgttttgaa agttgccttc tgaaagggca cagttttaag gaaaagaaaa 3841 agaatgtaaa actatactga cccgttttca gttttaaagg gtcgtgagaa actggctggt 3901 ccaatgggat ttacagcaac attttccatt gctgaagtga ggtagcagct ctcttctgtc 3961 agctgaatgt taaggatggg gaaaaagaat gcctttaagt ttgctcttaa tcgtatggaa 4021 gcttgagcta tgtgttggaa gtgccctggt tttaatccat acacaaagac ggtacataat 4081 cctacaggtt taaatgtaca taaaaatata gtttggaatt ctttgctcta ctgtttacat 4141 tgcagattgc tataatttca aggagtgaga ttataaataa aatgatgcac tttaggatgt 4201 ttcctatttt tgaaatctga acatgaatca ttcacatgac caaaaattgt gtttttttaa 4261 aaatacatgt ctagtctgtc ctttaatagc tctcttaaat aagctatgat attaatcaga 4321 tcattaccag ttagctttta aagcacattt gtttaagact atgtttttgg aaaaatacgc 4381 tacagaattt ttttttaagc tacaaataaa tgagatgcta ctaattgttt tggaatctgt 4441 tgtttctgcc aaaggtaaat taactaaaga tttattcagg aatccccatt tgaatttgta 4501 tgattcaata aaagaaaaca ccaagtaagt tatataaaat aaattgtgta tgagatgttg 4561 tgttttcctt tgtaatttcc actaactaac taactaactt atattcttca tggaatggag 4621 cccagaagaa atgagaggaa gcccttttca cactagatct tatttgaaga aatgtttgtt 4681 agtcagtcag tcagtggttt ctggctctgc cgagggagat gtgttcccca gcaaccattt 4741 ctgcagccca gaatctcaag gcactagagg cggtgtctta attaattggc ttcacaaaga 4801 caaaatgctc tggactggga tttttccttt gctgtgttgg gaatatgtgt ttattaatta 4861 gcacatgcca acaaaataaa tgtcaagagt tatttcataa gtgtaagtaa acttaagaat 4921 taaagagtgc agacttataa ttttca

[0255] In some embodiments of the methods of the disclosure, the wild type human FAM13A gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: NP_001252509.1, transcript variant 5):

TABLE-US-00028 (SEQ ID NO: 43) 1 maceimplqr llertirsav eqhlfdvnns ggqssedses gtlsassats arqrrrqske 61 qdevrhgrdk glinkentps gfnhlddcil ntqevekvhk ntfgcagers kpkrqksstk 121 lselhdnqdg lvnmeslnst rshertgpdd fewmsderkg nekdgghtqh fesptmkiqe 181 hpslsdtkqq rnqdagdqee sfvsevpqsd ltalcdeknw eepipafssw qrensdsdea 241 hlspqagrli rqlldedsdp mlsprfyayg qsrqylddte vppsppnshs fmrrrssslg 301 syddeqedlt paqltrriqs lkkkirkfed rfeeekkyrp shsdkaanpe vlkwtndlak 361 frrqlkeskl kiseedltpr mrqrsntlpk sfgsqleked ekkqelvdka ikpsveatle 421 siqrklqekr aessrpedik dmtkdqiane kvalqkally yesihgrpvt knerqvmkpl 481 ydryrlvkqi lsrantipii gspsskrrsp llqpiieget asffkeikee eegseddsnv 541 kpdfmvtlkt dfsarcfldq feddadgfis pmddkipskc sqdtglsnlh aasipelleh 601 lqemreekkr irkklrdfed nffrqngrnv qkedrtpmae eyseykhika klrllevlis 661 krdtdsksm

[0256] In some embodiments of the methods of the disclosure, the wild type human DSP gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_004415.3, transcript variant 1):

TABLE-US-00029 (SEQ ID NO: 44) 1 aagaaaccgg ccaggtgtgg cctaggcgcc cagtgccagc ggggaggaga ctcgctccgc 61 cgccgaccaa caccaacacc cagctccgac gcagctcctc tgcgcccttg ccgccctccg 121 agccacagct ttcctcccgc tcctgccccc ggcccgtcgc cgtctccgcg ctcgcagcgg 181 cctcgggagg gcccaggtag cgagcagcga cctcgcgagc cttccgcact cccgcccggt 241 tccccggccg tccgcctatc cttggccccc tccgctttct ccgcgccggc ccgcctcgct 301 tatgcctcgg cgctgagccg ctctcccgat tgcccgccga catgagctgc aacggaggct 361 cccacccgcg gatcaacact ctgggccgca tgatccgcgc cgagtctggc ccggacctgc 421 gctacgaggt gaccagcggc ggcgggggca ccagcaggat gtactattct cggcgcggcg 481 tgatcaccga ccagaactcg gacggctact gtcaaaccgg cacgatgtcc aggcaccaga 541 accagaacac catccaggag ctgctgcaga actgctccga ctgcttgatg cgagcagagc 601 tcatcgtgca gcctgaattg aagtatggag atggaataca actgactcgg agtcgagaat 661 tggatgagtg ttttgcccag gccaatgacc aaatggaaat cctcgacagc ttgatcagag 721 agatgcggca gatgggccag ccctgtgatg cttaccagaa aaggcttctt cagctccaag 781 agcaaatgcg agccctttat aaagccatca gtgtccctcg agtccgcagg gccagctcca 841 agggtggtgg aggctacact tgtcagagtg gctctggctg ggatgagttc accaaacatg 901 tcaccagtga atgtttgggg tggatgaggc agcaaagggc ggagatggac atggtggcct 961 ggggtgtgga cctggcctca gtggagcagc acattaacag ccaccggggc atccacaact 1021 ccatcggcga ctatcgctgg cagctggaca aaatcaaagc cgacctgcgc gagaaatctg 1081 cgatctacca gttggaggag gagtatgaaa acctgctgaa agcgtccttt gagaggatgg 1141 atcacctgcg acagctgcag aacatcattc aggccacgtc cagggagatc atgtggatca 1201 atgactgcga ggaggaggag ctgctgtacg actggagcga caagaacacc aacatcgctc 1261 agaaacagga ggccttctcc atacgcatga gtcaactgga agttaaagaa aaagagctca 1321 ataagctgaa acaagaaagt gaccaacttg tcctcaatca gcatccagct tcagacaaaa 1381 ttgaggccta tatggacact ctgcagacgc agtggagttg gattcttcag atcaccaagt 1441 gcattgatgt tcatctgaaa gaaaatgctg cctactttca gttttttgaa gaggcgcagt 1501 ctactgaagc atacctgaag gggctccagg actccatcag gaagaagtac ccctgcgaca 1561 agaacatgcc cctgcagcac ctgctggaac agatcaagga gctggagaaa gaacgagaga 1621 aaatccttga atacaagcgt caggtgcaga acttggtaaa caagtctaag aagattgtac 1681 agctgaagcc tcgtaaccca gactacagaa gcaataaacc cattattctc agagctctct 1741 gtgactacaa acaagatcag aaaatcgtgc ataaggggga tgagtgtatc ctgaaggaca 1801 acaacgagcg cagcaagtgg tacgtgacgg gcccgggagg cgttgacatg cttgttccct 1861 ctgtggggct gatcatccct cctccgaacc cactggccgt ggacctctct tgcaagattg 1921 agcagtacta cgaagccatc ttggctctgt ggaaccagct ctacatcaac atgaagagcc 1981 tggtgtcctg gcactactgc atgattgaca tagagaagat cagggccatg acaatcgcca 2041 agctgaaaac aatgcggcag gaagattaca tgaagacgat agccgacctt gagttacatt 2101 accaagagtt catcagaaat agccaaggct cagagatgtt tggagatgat gacaagcgga 2161 aaatacagtc tcagttcacc gatgcccaga agcattacca gaccctggtc attcagctcc 2221 ctggctatcc ccagcaccag acagtgacca caactgaaat cactcatcat ggaacctgcc 2281 aagatgtcaa ccataataaa gtaattgaaa ccaacagaga aaatgacaag caagaaacat 2341 ggatgctgat ggagctgcag aagattcgca ggcagataga gcactgcgag ggcaggatga 2401 ctctcaaaaa cctccctcta gcagaccagg gatcttctca ccacatcaca gtgaaaatta 2461 acgagcttaa gagtgtgcag aatgattcac aagcaattgc tgaggttctc aaccagctta 2521 aagatatgct tgccaacttc agaggttctg aaaagtactg ctatttacag aatgaagtat 2581 ttggactatt tcagaaactg gaaaatatca atggtgttac agatggctac ttaaatagct 2641 tatgcacagt aagggcactg ctccaggcta ttctccaaac agaagacatg ttaaaggttt 2701 atgaagccag gctcactgag gaggaaactg tctgcctgga cctggataaa gtggaagctt 2761 accgctgtgg actgaagaaa ataaaaaatg acttgaactt gaagaagtcg ttgttggcca 2821 ctatgaagac agaactacag aaagcccagc agatccactc tcagacttca cagcagtatc 2881 cactttatga tctggacttg ggcaagttcg gtgaaaaagt cacacagctg acagaccgct 2941 ggcaaaggat agataaacag atcgacttta ggttatggga cctggagaaa caaatcaagc 3001 aattgaggaa ttatcgtgat aactatcagg ctttctgcaa gtggctctat gatgctaaac 3061 gccgccagga ttccttagaa tccatgaaat ttggagattc caacacagtc atgcggtttt 3121 tgaatgagca gaagaacttg cacagtgaaa tatctggcaa acgagacaaa tcagaggaag 3181 tacaaaaaat tgctgaactt tgcgccaatt caattaagga ttatgagctc cagctggcct 3241 catacacctc aggactggaa actctgctga acatacctat caagaggacc atgattcagt 3301 ccccttctgg ggtgattctg caagaggctg cagatgttca tgctcggtac attgaactac 3361 ttacaagatc tggagactat tacaggttct taagtgagat gctgaagagt ttggaagatc 3421 tgaagctgaa aaataccaag atcgaagttt tggaagagga gctcagactg gcccgagatg 3481 ccaactcgga aaactgtaat aagaacaaat tcctggatca gaacctgcag aaataccagg 3541 cagagtgttc ccagttcaaa gcgaagcttg cgagcctgga ggagctgaag agacaggctg 3601 agctggatgg gaagtcggct aagcaaaatc tagacaagtg ctacggccaa ataaaagaac 3661 tcaatgagaa gatcacccga ctgacttatg agattgaaga tgaaaagaga agaagaaaat 3721 ctgtggaaga cagatttgac caacagaaga atgactatga ccaactgcag aaagcaaggc 3781 aatgtgaaaa ggagaacctt ggttggcaga aattagagtc tgagaaagcc atcaaggaga 3841 aggagtacga gattgaaagg ttgagggttc tactgcagga agaaggcacc cggaagagag 3901 aatatgaaaa tgagctggca aaggtaagaa accactataa tgaggagatg agtaatttaa 3961 ggaacaagta tgaaacagag attaacatta cgaagaccac catcaaggag atatccatgc 4021 aaaaagagga tgattccaaa aatcttagaa accagcttga tagactttca agggaaaatc 4081 gagatctgaa ggatgaaatt gtcaggctca atgacagcat cttgcaggcc actgagcagc 4141 gaaggcgagc tgaagaaaac gcccttcagc aaaaggcctg tggctctgag ataatgcaga 4201 agaagcagca tctggagata gaactgaagc aggtcatgca gcagcgctct gaggacaatg 4261 cccggcacaa gcagtccctg gaggaggctg ccaagaccat tcaggacaaa aataaggaga 4321 tcgagagact caaagctgag tttcaggagg aggccaagcg ccgctgggaa tatgaaaatg 4381 aactgagtaa ggtaagaaac aattatgatg aggagatcat tagcttaaaa aatcagtttg 4441 agaccgagat caacatcacc aagaccacca tccaccagct caccatgcag aaggaagagg 4501 ataccagtgg ctaccgggct cagatagaca atctcacccg agaaaacagg agcttatctg 4561 aagaaataaa gaggctgaag aacactctaa cccagaccac agagaatctc aggagggtgg 4621 aagaagacat ccaacagcaa aaggccactg gctctgaggt gtctcagagg aaacagcagc 4681 tggaggttga gctgagacaa gtcactcaga tgcgaacaga ggagagcgta agatataagc 4741 aatctcttga tgatgctgcc aaaaccatcc aggataaaaa caaggagata gaaaggttaa 4801 aacaactgat cgacaaagaa acaaatgacc ggaaatgcct ggaagatgaa aacgcgagat 4861 tacaaagggt ccagtatgac ctgcagaaag caaacagtag tgcgacggag acaataaaca 4921 aactgaaggt tcaggagcaa gaactgacac gcctgaggat cgactatgaa agggtttccc 4981 aggagaggac tgtgaaggac caggatatca cgcggttcca gaactctctg aaagagctgc 5041 agctgcagaa gcagaaggtg gaagaggagc tgaatcggct gaagaggacc gcgtcagaag 5101 actcctgcaa gaggaagaag ctggaggaag agctggaagg catgaggagg tcgctgaagg 5161 agcaagccat caaaatcacc aacctgaccc agcagctgga gcaggcatcc attgttaaga 5221 agaggagtga ggatgacctc cggcagcaga gggacgtgct ggatggccac ctgagggaaa 5281 agcagaggac ccaggaagag ctgaggaggc tctcttctga ggtcgaggcc ctgaggcggc 5341 agttactcca ggaacaggaa agtgtcaaac aagctcactt gaggaatgag catttccaga 5401 aggcgataga agataaaagc agaagcttaa atgaaagcaa aatagaaatt gagaggctgc 5461 agtctctcac agagaacctg accaaggagc acttgatgtt agaagaagaa ctgcggaacc 5521 tgaggctgga gtacgatgac ctgaggagag gacgaagcga agcggacagt gataaaaatg 5581 caaccatctt ggaactaagg agccagctgc agatcagcaa caaccggacc ctggaactgc 5641 aggggctgat taatgattta cagagagaga gggaaaattt gagacaggaa attgagaaat 5701 tccaaaagca ggctttagag gcatctaata ggattcagga atcaaagaat cagtgtactc 5761 aggtggtaca ggaaagagag agccttctgg tgaaaatcaa agtcctggag caagacaagg 5821 caaggctgca gaggctggag gatgagctga atcgtgcaaa atcaactcta gaggcagaaa 5881 ccagggtgaa acagcgcctg gagtgtgaga aacagcaaat tcagaatgac ctgaatcagt 5941 ggaagactca atattcccgc aaggaggagg ctattaggaa gatagaatcg gaaagagaaa 6001 agagtgagag agagaagaac agtcttagga gtgagatcga aagactccaa gcagagatca 6061 agagaattga agagaggtgc aggcgtaagc tggaggattc taccagggag acacagtcac 6121 agttagaaac agaacgctcc cgatatcaga gggagattga taaactcaga cagcgcccat 6181 atgggtccca tcgagagacc cagactgagt gtgagtggac cgttgacacc tccaagctgg 6241 tgtttgatgg gctgaggaag aaggtgacag caatgcagct ctatgagtgt cagctgatcg 6301 acaaaacaac cttggacaaa ctattgaagg ggaagaagtc agtggaagaa gttgcttctg 6361 aaatccagcc attccttcgg ggtgcaggat ctatcgctgg agcatctgct tctcctaagg 6421 aaaaatactc tttggtagag gccaagagaa agaaattaat cagcccagaa tccacagtca 6481 tgcttctgga ggcccaggca gctacaggtg gtataattga tccccatcgg aatgagaagc 6541 tgactgtcga cagtgccata gctcgggacc tcattgactt cgatgaccgt cagcagatat 6601 atgcagcaga aaaagctatc actggttttg atgatccatt ttcaggcaag acagtatctg 6661 tttcagaagc catcaagaaa aatttgattg atagagaaac cggaatgcgc ctgctggaag 6721 cccagattgc ttcagggggt gtagtagacc ctgtgaacag tgtctttttg ccaaaagatg 6781 tcgccttggc ccgggggctg attgatagag atttgtatcg atccctgaat gatccccgag 6841 atagtcagaa aaactttgtg gatccagtca ccaaaaagaa ggtcagttac gtgcagctga 6901 aggaacggtg cagaatcgaa ccacatactg gtctgctctt gctttcagta cagaagagaa 6961 gcatgtcctt ccaaggaatc agacaacctg tgaccgtcac tgagctagta gattctggta 7021 tattgagacc gtccactgtc aatgaactgg aatctggtca gatttcttat gacgaggttg 7081 gtgagagaat taaggacttc ctccagggtt caagctgcat agcaggcata tacaatgaga 7141 ccacaaaaca gaagcttggc atttatgagg ccatgaaaat tggcttagtc cgacctggta 7201 ctgctctgga gttgctggaa gcccaagcag ctactggctt tatagtggat cctgttagca 7261 acttgaggtt accagtggag gaagcctaca agagaggtct ggtgggcatt gagttcaaag 7321 agaagctcct gtctgcagaa cgagctgtca ctgggtataa tgatcctgaa acaggaaaca 7381 tcatctcttt gttccaagcc atgaataagg aactcatcga aaagggccac ggtattcgct 7441 tattagaagc acagatcgca accgggggga tcattgaccc aaaggagagc catcgtttac

7501 cagttgacat agcatataag aggggctatt tcaatgagga actcagtgag attctctcag 7561 atccaagtga tgataccaaa ggattttttg accccaacac tgaagaaaat cttacctatc 7621 tgcaactaaa agaaagatgc attaaggatg aggaaacagg gctctgtctt ctgcctctga 7681 aagaaaagaa gaaacaggtg cagacatcac aaaagaatac cctcaggaag cgtagagtgg 7741 tcatagttga cccagaaacc aataaagaaa tgtctgttca ggaggcctac aagaagggcc 7801 taattgatta tgaaaccttc aaagaactgt gtgagcagga atgtgaatgg gaagaaataa 7861 ccatcacggg atcagatggc tccaccaggg tggtcctggt agatagaaag acaggcagtc 7921 agtatgatat tcaagatgct attgacaagg gccttgttga caggaagttc tttgatcagt 7981 accgatccgg cagcctcagc ctcactcaat ttgctgacat gatctccttg aaaaatggtg 8041 tcggcaccag cagcagcatg ggcagtggtg tcagcgatga tgtttttagc agctcccgac 8101 atgaatcagt aagtaagatt tccaccatat ccagcgtcag gaatttaacc ataaggagca 8161 gctctttttc agacaccctg gaagaatcga gccccattgc agccatcttt gacacagaaa 8221 acctggagaa aatctccatt acagaaggta tagagcgggg catcgttgac agcatcacgg 8281 gtcagaggct tctggaggct caggcctgca caggtggcat catccaccca accacgggcc 8341 agaagctgtc acttcaggac gcagtctccc agggtgtgat tgaccaagac atggccacca 8401 ggctgaagcc tgctcagaaa gccttcatag gcttcgaggg tgtgaaggga aagaagaaga 8461 tgtcagcagc agaggcagtg aaagaaaaat ggctcccgta tgaggctggc cagcgcttcc 8521 tggagttcca gtacctcacg ggaggtcttg ttgacccgga agtgcatggg aggataagca 8581 ccgaagaagc catccggaag gggttcatag atggccgcgc cgcacagagg ctgcaagaca 8641 ccagcagcta tgccaaaatc ctgacctgcc ccaaaaccaa attaaaaata tcctataagg 8701 atgccataaa tcgctccatg gtagaagata tcactgggct gcgccttctg gaagccgcct 8761 ccgtgtcgtc caagggctta cccagccctt acaacatgtc ttcggctccg gggtcccgct 8821 ccggctcccg ctcgggatct cgctccggat ctcgctccgg gtcccgcagt gggtcccgga 8881 gaggaagctt tgacgccaca gggaattctt cctactctta ttcctactca tttagcagta 8941 gttctattgg gcactagtag tcagttggga gtggttgcta taccttgact tcatttatat 9001 gaatttccac tttattaaat aatagaaaag aaaatcccgg tgcttgcagt agagtgatag 9061 gacattctat gcttacagaa aatatagcca tgattgaaat caaatagtaa aggctgttct 9121 ggctttttat cttcttagct catcttaaat aagcagtaca cttggatgca gtgcgtctga 9181 agtgctaatc agttgtaaca atagcacaaa tcgaacttag gatttgtttc ttctcttctg 9241 tgtttcgatt tttgatcaat tctttaattt tggaagccta taatacagtt ttctattctt 9301 ggagataaaa attaaatgga tcactgatat tttagtcatt ctgcttctca tctaaatatt 9361 tccatattct gtattaggag aaaattaccc tcccagcacc agcccccctc tcaaaccccc 9421 aacccaaaac caagcatttt ggaatgagtc tcctttagtt tcagagtgtg gattgtataa 9481 cccatatact cttcgatgta cttgtttggt ttggtattaa tttgactgtg catgacagcg 9541 gcaatctttt ctttggtcaa agttttctgt ttattttgct tgtcatattc gatgtacttt 9601 aaggtgtctt tatgaagttt gctattctgg caataaactt ttagactttt gaagtgtttg 9661 tgttttaatt taatatgttt ataagcatgt ataaacattt agcatatttt tatcataggt 9721 ctaaaaatat ttgtttacta aatacctgtg aagaaatacc attaaaaaac tatttggttc 9781 tgaattctta ctagaaaaaa aa

[0257] In some embodiments of the methods of the disclosure, the wild type human DSP gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: NP_004406.2, transcript variant 1):

TABLE-US-00030 (SEQ ID NO: 45) 1 mscnggshpr intlgrmira esgpdlryev tsggggtsrm yysrrgvitd qnsdgycqtg 61 tmsrhqnqnt iqellqncsd clmraelivq pelkygdgiq ltrsreldec faqandqmei 121 ldsliremrq mgqpcdayqk rllqlqeqmr alykaisvpr vrrasskggg gytcqsgsgw 181 deftkhvtse clgwmrqqra emdmvawgvd lasveqhins hrgihnsigd yrwqldkika 241 dlreksaiyq leeeyenllk asfermdhlr qlqniiqats reimwindce eeellydwsd 301 kntniaqkqe afsirmsqle vkekelnklk qesdqlvinq hpasdkieay mdtlqtqwsw 361 ilqitkcidv hlkenaayfq ffeeaqstea ylkglqdsir kkypcdknmp lqhlleqike 421 lekerekile ykrqvqnlvn kskkivqlkp rnpdyrsnkp iilralcdyk qdqkivhkgd 481 ecilkdnner skwyvtgpgg vdmlvpsvgl iipppnplav dlsckieqyy eailalwnql 541 yinmkslvsw hycmidieki ramtiaklkt mrqedymkti adlelhyqef irnsqgsemf 601 gdddkrkiqs qftdaqkhyq tiviqlpgyp qhqtvtttei thhgtcqdvn hnkvietnre 661 ndkqetwmlm elqkirrqie hcegrmtlkn lpladqgssh hitvkinelk svqndsgqia 721 evlnqlkdml anfrgsekyc ylqnevfglf qkleningvt dgylnslctv rallqailqt 781 edmlkvyear lteeetvcld ldkveayrcg lkkikndlnl kksllatmkt elqkaqqihs 841 qtsqqyplyd ldlgkfgekv tqltdrwqri dkqidfrlwd lekqikqlrn yrdnyqafck 901 wlydakrrqd slesmkfgds ntvmrflneq knlhseisgk rdkseevqki aelcansikd 961 yelqlasyts gletllnipi krtmiqspsg vilqeaadvh aryielltrs gdyyrflsem 1021 lksledlklk ntkievleee lrlardanse ncnknkfldq nlqkyqaecs qfkaklasle 1081 elkrqaeldg ksakqnldkc ygqikelnek itrltyeied ekrrrksved rfdqqkndyd 1141 qlqkarqcek enlgwqkles ekaikekeye ierlrvllqe egtrkreyen elakvrnhyn 1201 eemsnlrnky eteinitktt ikeismqked dsknlrnqld rlsrenrdlk deivrlndsi 1261 lqateqrrra eenalqqkac gseimqkkqh leielkqvmq qrsednarhk qsleeaakti 1321 qdknkeierl kaefqeeakr rweyenelsk vrnnydeeii slknqfetei nitkttihql 1381 tmqkeedtsg yraqidnltr enrslseeik rlkntltqtt enlrrveedi qqqkatgsev 1441 sqrkqqleve lrqvtqmrte esvrykqsld daaktiqdkn keierlkqli dketndrkcl 1501 edenarlqry qydlqkanss atetinklkv qeqeltrlri dyervsgert vkdqditrfq 1561 nslkelqlqk qkveeelnrl krtasedsck rkkleeeleg mrrslkeqai kitnitqqle 1621 qasivkkrse ddlrqqrdvl dghlrekqrt qeelrrlsse vealrrqllq eqesvkqahl 1681 rnehfqkaie dksrslnesk ieierlqslt enitkehlml eeelrnlrle yddlrrgrse 1741 adsdknatil elrsqlqisn nrtlelqgli ndlgrerenl rqeiekfqkq aleasnriqe 1801 sknqctqvvq eresllvkik vleqdkarlq rledelnrak stleaetrvk qrlecekqqi 1861 qndlnqwktq ysrkeeairk ieserekser eknslrseie rlqaeikrie ercrrkleds 1921 tretqsqlet ersrygreid klrqrpygsh retqtecewt vdtsklvfdg lrkkvtamql 1981 yecqlidktt ldkllkgkks veevaseiqp flrgagsiag asaspkekys lveakrkkli 2041 spestvmlle aqaatggiid phrnekltvd saiardlidf ddrqqiyaae kaitgfddpf 2101 sgktvsvsea ikknlidret gmrlleaqia sggvvdpvns vflpkdvala rglidrdlyr 2161 slndprdsqk nfvdpvtkkk vsyvqlkerc riephtglll lsvqkrsmsf qgirqpvtvt 2221 elvdsgilrp stvnelesgq isydevgeri kdflqgssci agiynettkq klgiyeamki 2281 glvrpgtale lleaqaatgf ivdpvsnlrl pveeaykrgl vgiefkekll saeravtgyn 2341 dpetgniisl fqamnkelie kghgirllea qiatggiidp keshrlpvdi aykrgyfnee 2401 lseilsdpsd dtkgffdpnt eenitylqlk ercikdeetg lcllplkekk kqvqtsqknt 2461 lrkrrvvivd petnkemsvq eaykkglidy etfkelceqe ceweeititg sdgstrvvlv 2521 drktgsqydi qdaidkglvd rkffdqyrsg slsltqfadm islkngvgts ssmgsgvsdd 2581 vfsssrhesv skistissvr nitirsssfs dtleesspia aifdtenlek isitegierg 2641 ivdsitgqrl leaqactggi ihpttgqkls lqdaysqgvi dqdmatrlkp aqkafigfeg 2701 vkgkkkmsaa eavkekwlpy eagqrflefq yltgglvdpe vhgristeea irkgfidgra 2761 aqrlqdtssy akiltcpktk lkisykdain rsmveditgl rlleaasvss kglpspynms 2821 sapgsrsgsr sgsrsgsrsg srsgsrrgsf datgnssysy sysfssssig h

[0258] In some embodiments of the methods of the disclosure, the wild type human DSP gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_001008844.2, transcript variant 2):

TABLE-US-00031 (SEQ ID NO: 19) 1 aagaaaccgg ccaggtgtgg cctaggcgcc cagtgccagc ggggaggaga ctcgctccgc 61 cgccgaccaa caccaacacc cagctccgac gcagctcctc tgcgcccttg ccgccctccg 121 agccacagct ttcctcccgc tcctgccccc ggcccgtcgc cgtctccgcg ctcgcagcgg 181 cctcgggagg gcccaggtag cgagcagcga cctcgcgagc cttccgcact cccgcccggt 241 tccccggccg tccgcctatc cttggccccc tccgctttct ccgcgccggc ccgcctcgct 301 tatgcctcgg cgctgagccg ctctcccgat tgcccgccga catgagctgc aacggaggct 361 cccacccgcg gatcaacact ctgggccgca tgatccgcgc cgagtctggc ccggacctgc 421 gctacgaggt gaccagcggc ggcgggggca ccagcaggat gtactattct cggcgcggcg 481 tgatcaccga ccagaactcg gacggctact gtcaaaccgg cacgatgtcc aggcaccaga 541 accagaacac catccaggag ctgctgcaga actgctccga ctgcttgatg cgagcagagc 601 tcatcgtgca gcctgaattg aagtatggag atggaataca actgactcgg agtcgagaat 661 tggatgagtg ttttgcccag gccaatgacc aaatggaaat cctcgacagc ttgatcagag 721 agatgcggca gatgggccag ccctgtgatg cttaccagaa aaggcttctt cagctccaag 781 agcaaatgcg agccctttat aaagccatca gtgtccctcg agtccgcagg gccagctcca 841 agggtggtgg aggctacact tgtcagagtg gctctggctg ggatgagttc accaaacatg 901 tcaccagtga atgtttgggg tggatgaggc agcaaagggc ggagatggac atggtggcct 961 ggggtgtgga cctggcctca gtggagcagc acattaacag ccaccggggc atccacaact 1021 ccatcggcga ctatcgctgg cagctggaca aaatcaaagc cgacctgcgc gagaaatctg 1081 cgatctacca gttggaggag gagtatgaaa acctgctgaa agcgtccttt gagaggatgg 1141 atcacctgcg acagctgcag aacatcattc aggccacgtc cagggagatc atgtggatca 1201 atgactgcga ggaggaggag ctgctgtacg actggagcga caagaacacc aacatcgctc 1261 agaaacagga ggccttctcc atacgcatga gtcaactgga agttaaagaa aaagagctca 1321 ataagctgaa acaagaaagt gaccaacttg tcctcaatca gcatccagct tcagacaaaa 1381 ttgaggccta tatggacact ctgcagacgc agtggagttg gattcttcag atcaccaagt 1441 gcattgatgt tcatctgaaa gaaaatgctg cctactttca gttttttgaa gaggcgcagt 1501 ctactgaagc atacctgaag gggctccagg actccatcag gaagaagtac ccctgcgaca 1561 agaacatgcc cctgcagcac ctgctggaac agatcaagga gctggagaaa gaacgagaga 1621 aaatccttga atacaagcgt caggtgcaga acttggtaaa caagtctaag aagattgtac 1681 agctgaagcc tcgtaaccca gactacagaa gcaataaacc cattattctc agagctctct 1741 gtgactacaa acaagatcag aaaatcgtgc ataaggggga tgagtgtatc ctgaaggaca 1801 acaacgagcg cagcaagtgg tacgtgacgg gcccgggagg cgttgacatg cttgttccct 1861 ctgtggggct gatcatccct cctccgaacc cactggccgt ggacctctct tgcaagattg 1921 agcagtacta cgaagccatc ttggctctgt ggaaccagct ctacatcaac atgaagagcc 1981 tggtgtcctg gcactactgc atgattgaca tagagaagat cagggccatg acaatcgcca 2041 agctgaaaac aatgcggcag gaagattaca tgaagacgat agccgacctt gagttacatt 2101 accaagagtt catcagaaat agccaaggct cagagatgtt tggagatgat gacaagcgga 2161 aaatacagtc tcagttcacc gatgcccaga agcattacca gaccctggtc attcagctcc 2221 ctggctatcc ccagcaccag acagtgacca caactgaaat cactcatcat ggaacctgcc 2281 aagatgtcaa ccataataaa gtaattgaaa ccaacagaga aaatgacaag caagaaacat 2341 ggatgctgat ggagctgcag aagattcgca ggcagataga gcactgcgag ggcaggatga 2401 ctctcaaaaa cctccctcta gcagaccagg gatcttctca ccacatcaca gtgaaaatta 2461 acgagcttaa gagtgtgcag aatgattcac aagcaattgc tgaggttctc aaccagctta 2521 aagatatgct tgccaacttc agaggttctg aaaagtactg ctatttacag aatgaagtat 2581 ttggactatt tcagaaactg gaaaatatca atggtgttac agatggctac ttaaatagct 2641 tatgcacagt aagggcactg ctccaggcta ttctccaaac agaagacatg ttaaaggttt 2701 atgaagccag gctcactgag gaggaaactg tctgcctgga cctggataaa gtggaagctt 2761 accgctgtgg actgaagaaa ataaaaaatg acttgaactt gaagaagtcg ttgttggcca 2821 ctatgaagac agaactacag aaagcccagc agatccactc tcagacttca cagcagtatc 2881 cactttatga tctggacttg ggcaagttcg gtgaaaaagt cacacagctg acagaccgct 2941 ggcaaaggat agataaacag atcgacttta ggttatggga cctggagaaa caaatcaagc 3001 aattgaggaa ttatcgtgat aactatcagg ctttctgcaa gtggctctat gatgctaaac 3061 gccgccagga ttccttagaa tccatgaaat ttggagattc caacacagtc atgcggtttt 3121 tgaatgagca gaagaacttg cacagtgaaa tatctggcaa acgagacaaa tcagaggaag 3181 tacaaaaaat tgctgaactt tgcgccaatt caattaagga ttatgagctc cagctggcct 3241 catacacctc aggactggaa actctgctga acatacctat caagaggacc atgattcagt 3301 ccccttctgg ggtgattctg caagaggctg cagatgttca tgctcggtac attgaactac 3361 ttacaagatc tggagactat tacaggttct taagtgagat gctgaagagt ttggaagatc 3421 tgaagctgaa aaataccaag atcgaagttt tggaagagga gctcagactg gcccgagatg 3481 ccaactcgga aaactgtaat aagaacaaat tcctggatca gaacctgcag aaataccagg 3541 cagagtgttc ccagttcaaa gcgaagcttg cgagcctgga ggagctgaag agacaggctg 3601 agctggatgg gaagtcggct aagcaaaatc tagacaagtg ctacggccaa ataaaagaac 3661 tcaatgagaa gatcacccga ctgacttatg agattgaaga tgaaaagaga agaagaaaat 3721 ctgtggaaga cagatttgac caacagaaga atgactatga ccaactgcag aaagcaaggc 3781 aatgtgaaaa ggagaacctt ggttggcaga aattagagtc tgagaaagcc atcaaggaga 3841 aggagtacga gattgaaagg ttgagggttc tactgcagga agaaggcacc cggaagagag 3901 aatatgaaaa tgagctggca aaggcatcta ataggattca ggaatcaaag aatcagtgta 3961 ctcaggtggt acaggaaaga gagagccttc tggtgaaaat caaagtcctg gagcaagaca 4021 aggcaaggct gcagaggctg gaggatgagc tgaatcgtgc aaaatcaact ctagaggcag 4081 aaaccagggt gaaacagcgc ctggagtgtg agaaacagca aattcagaat gacctgaatc 4141 agtggaagac tcaatattcc cgcaaggagg aggctattag gaagatagaa tcggaaagag 4201 aaaagagtga gagagagaag aacagtctta ggagtgagat cgaaagactc caagcagaga 4261 tcaagagaat tgaagagagg tgcaggcgta agctggagga ttctaccagg gagacacagt 4321 cacagttaga aacagaacgc tcccgatatc agagggagat tgataaactc agacagcgcc 4381 catatgggtc ccatcgagag acccagactg agtgtgagtg gaccgttgac acctccaagc 4441 tggtgtttga tgggctgagg aagaaggtga cagcaatgca gctctatgag tgtcagctga 4501 tcgacaaaac aaccttggac aaactattga aggggaagaa gtcagtggaa gaagttgctt 4561 ctgaaatcca gccattcctt cggggtgcag gatctatcgc tggagcatct gcttctccta 4621 aggaaaaata ctctttggta gaggccaaga gaaagaaatt aatcagccca gaatccacag 4681 tcatgcttct ggaggcccag gcagctacag gtggtataat tgatccccat cggaatgaga 4741 agctgactgt cgacagtgcc atagctcggg acctcattga cttcgatgac cgtcagcaga 4801 tatatgcagc agaaaaagct atcactggtt ttgatgatcc attttcaggc aagacagtat 4861 ctgtttcaga agccatcaag aaaaatttga ttgatagaga aaccggaatg cgcctgctgg 4921 aagcccagat tgcttcaggg ggtgtagtag accctgtgaa cagtgtcttt ttgccaaaag 4981 atgtcgcctt ggcccggggg ctgattgata gagatttgta tcgatccctg aatgatcccc 5041 gagatagtca gaaaaacttt gtggatccag tcaccaaaaa gaaggtcagt tacgtgcagc 5101 tgaaggaacg gtgcagaatc gaaccacata ctggtctgct cttgctttca gtacagaaga 5161 gaagcatgtc cttccaagga atcagacaac ctgtgaccgt cactgagcta gtagattctg 5221 gtatattgag accgtccact gtcaatgaac tggaatctgg tcagatttct tatgacgagg 5281 ttggtgagag aattaaggac ttcctccagg gttcaagctg catagcaggc atatacaatg 5341 agaccacaaa acagaagctt ggcatttatg aggccatgaa aattggctta gtccgacctg 5401 gtactgctct ggagttgctg gaagcccaag cagctactgg ctttatagtg gatcctgtta 5461 gcaacttgag gttaccagtg gaggaagcct acaagagagg tctggtgggc attgagttca 5521 aagagaagct cctgtctgca gaacgagctg tcactgggta taatgatcct gaaacaggaa 5581 acatcatctc tttgttccaa gccatgaata aggaactcat cgaaaagggc cacggtattc 5641 gcttattaga agcacagatc gcaaccgggg ggatcattga cccaaaggag agccatcgtt 5701 taccagttga catagcatat aagaggggct atttcaatga ggaactcagt gagattctct 5761 cagatccaag tgatgatacc aaaggatttt ttgaccccaa cactgaagaa aatcttacct 5821 atctgcaact aaaagaaaga tgcattaagg atgaggaaac agggctctgt cttctgcctc 5881 tgaaagaaaa gaagaaacag gtgcagacat cacaaaagaa taccctcagg aagcgtagag 5941 tggtcatagt tgacccagaa accaataaag aaatgtctgt tcaggaggcc tacaagaagg 6001 gcctaattga ttatgaaacc ttcaaagaac tgtgtgagca ggaatgtgaa tgggaagaaa 6061 taaccatcac gggatcagat ggctccacca gggtggtcct ggtagataga aagacaggca 6121 gtcagtatga tattcaagat gctattgaca agggccttgt tgacaggaag ttctttgatc 6181 agtaccgatc cggcagcctc agcctcactc aatttgctga catgatctcc ttgaaaaatg 6241 gtgtcggcac cagcagcagc atgggcagtg gtgtcagcga tgatgttttt agcagctccc 6301 gacatgaatc agtaagtaag atttccacca tatccagcgt caggaattta accataagga 6361 gcagctcttt ttcagacacc ctggaagaat cgagccccat tgcagccatc tttgacacag 6421 aaaacctgga gaaaatctcc attacagaag gtatagagcg gggcatcgtt gacagcatca 6481 cgggtcagag gcttctggag gctcaggcct gcacaggtgg catcatccac ccaaccacgg 6541 gccagaagct gtcacttcag gacgcagtct cccagggtgt gattgaccaa gacatggcca 6601 ccaggctgaa gcctgctcag aaagccttca taggcttcga gggtgtgaag ggaaagaaga 6661 agatgtcagc agcagaggca gtgaaagaaa aatggctccc gtatgaggct ggccagcgct 6721 tcctggagtt ccagtacctc acgggaggtc ttgttgaccc ggaagtgcat gggaggataa 6781 gcaccgaaga agccatccgg aaggggttca tagatggccg cgccgcacag aggctgcaag 6841 acaccagcag ctatgccaaa atcctgacct gccccaaaac caaattaaaa atatcctata 6901 aggatgccat aaatcgctcc atggtagaag atatcactgg gctgcgcctt ctggaagccg 6961 cctccgtgtc gtccaagggc ttacccagcc cttacaacat gtcttcggct ccggggtccc 7021 gctccggctc ccgctcggga tctcgctccg gatctcgctc cgggtcccgc agtgggtccc 7081 ggagaggaag ctttgacgcc acagggaatt cttcctactc ttattcctac tcatttagca 7141 gtagttctat tgggcactag tagtcagttg ggagtggttg ctataccttg acttcattta 7201 tatgaatttc cactttatta aataatagaa aagaaaatcc cggtgcttgc agtagagtga 7261 taggacattc tatgcttaca gaaaatatag ccatgattga aatcaaatag taaaggctgt 7321 tctggctttt tatcttctta gctcatctta aataagcagt acacttggat gcagtgcgtc 7381 tgaagtgcta atcagttgta acaatagcac aaatcgaact taggatttgt ttcttctctt 7441 ctgtgtttcg atttttgatc aattctttaa ttttggaagc ctataataca gttttctatt

7501 cttggagata aaaattaaat ggatcactga tattttagtc attctgcttc tcatctaaat 7561 atttccatat tctgtattag gagaaaatta ccctcccagc accagccccc ctctcaaacc 7621 cccaacccaa aaccaagcat tttggaatga gtctccttta gtttcagagt gtggattgta 7681 taacccatat actcttcgat gtacttgttt ggtttggtat taatttgact gtgcatgaca 7741 gcggcaatct tttctttggt caaagttttc tgtttatttt gcttgtcata ttcgatgtac 7801 tttaaggtgt ctttatgaag tttgctattc tggcaataaa cttttagact tttgaagtgt 7861 ttgtgtttta atttaatatg tttataagca tgtataaaca tttagcatat ttttatcata 7921 ggtctaaaaa tatttgttta ctaaatacct gtgaagaaat accattaaaa aactatttgg 7981 ttctgaattc ttactagaaa aaaaa

[0259] In some embodiments of the methods of the disclosure, the wild type human DSP gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: NP_001008844.1, transcript variant 2):

TABLE-US-00032 (SEQ ID NO: 20) 1 mscnggshpr intlgrmira esgpdlryev tsggggtsrm yysrrgvitd qnsdgycqtg 61 tmsrhqnqnt iqellqncsd clmraelivq pelkygdgiq ltrsreldec faqandqmei 121 ldsliremrq mgqpcdayqk rllqlqeqmr alykaisvpr vrrasskggg gytcqsgsgw 181 deftkhvtse clgwmrqqra emdmvawgvd lasveqhins hrgihnsigd yrwqldkika 241 dlreksaiyq leeeyenllk asfermdhlr qlqniiqats reimwindce eeellydwsd 301 kntniaqkqe afsirmsqle vkekelnklk qesdqlvinq hpasdkieay mdtlqtqwsw 361 ilqitkcidv hlkenaayfq ffeeaqstea ylkglqdsir kkypcdknmp lqhlleqike 421 lekerekile ykrqvqnlvn kskkivqlkp rnpdyrsnkp iilralcdyk qdqkivhkgd 481 ecilkdnner skwyvtgpgg vdmlvpsvgl iipppnplav dlsckieqyy eailalwnql 541 yinmkslvsw hycmidieki ramtiaklkt mrqedymkti adlelhyqef irnsqgsemf 601 gdddkrkiqs qftdaqkhyq tiviqlpgyp qhqtvtttei thhgtcqdvn hnkvietnre 661 ndkqetwmlm elqkirrqie hcegrmtlkn lpladqgssh hitvkinelk svqndsgaia 721 evinqlkdml anfrgsekyc ylqnevfglf qkleningvt dgylnslctv rallqailqt 781 edmlkvyear lteeetvcld ldkveayrcg lkkikndlnl kksllatmkt elqkaqqihs 841 qtsqqyplyd ldlgkfgekv tqltdrwqri dkqidfrlwd lekqikqlrn yrdnyqafck 901 wlydakrrqd slesmkfgds ntvmrflneq knlhseisgk rdkseevqki aelcansikd 961 yelqlasyts gletllnipi krtmiqspsg vilqeaadvh aryielltrs gdyyrflsem 1021 lksledlklk ntkievleee lrlardanse ncnknkfldq nlqkyqaecs qfkaklasle 1081 elkrqaeldg ksakqnldkc ygqikelnek itrltyeied ekrrrksved rfdqqkndyd 1141 qlqkarqcek enlgwqkles ekaikekeye ierlrvllqe egtrkreyen elakasnriq 1201 esknqctqvv qeresllvki kvleqdkarl qrledelnra kstleaetrv kqrlecekqq 1261 iqndlnqwkt qysrkeeair kieserekse reknslrsei erlqaeikri eercrrkled 1321 stretqsqle tersrygrei dklrqrpygs hretqtecew tvdtsklvfd glrkkvtamq 1381 lyecqlidkt tldkllkgkk sveevaseiq pflrgagsia gasaspkeky slveakrkkl 1441 ispestvmll eaqaatggii dphrnekltv dsaiardlid fddrqqiyaa ekaitgfddp 1501 fsgktvsvse aikknlidre tgmrlleaqi asggvvdpvn svflpkdval arglidrdly 1561 rslndprdsq knfvdpvtkk kvsyvqlker criephtgll llsvqkrsms fqgirqpvtv 1621 telvdsgilr pstvnelesg qisydevger ikdflqgssc iagiynettk qklgiyeamk 1681 iglvrpgtal elleaqaatg fivdpvsnlr lpveeaykrg lvgiefkekl lsaeravtgy 1741 ndpetgniis lfqamnkeli ekghgirlle aqiatggiid pkeshrlpvd iaykrgyfne 1801 elseilsdps ddtkgffdpn teenitylql kercikdeet glcllplkek kkqvqtsqkn 1861 tlrkrrvviv dpetnkemsv qeaykkglid yetfkelceq eceweeitit gsdgstrvvl 1921 vdrktgsqyd iqdaidkglv drkffdqyrs gslsltqfad mislkngvgt sssmgsgvsd 1981 dvfsssrhes vskistissv rnltirsssf sdtleesspi aaifdtenle kisitegier 2041 givdsitgqr lleaqactgg iihpttgqkl slqdavsqgv idqdmatrlk paqkafigfe 2101 gvkgkkkmsa aeavkekwlp yeagqrflef qyltgglvdp evhgristee airkgfidgr 2161 aaqrlqdtss yakiltcpkt klkisykdai nrsmveditg lrlleaasvs skglpspynm 2221 ssapgsrsgs rsgsrsgsrs gsrsgsrrgs fdatgnssys ysysfssssi gh

[0260] In some embodiments of the methods of the disclosure, the wild type human DSP gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_001319034.1, transcript variant 3):

TABLE-US-00033 (SEQ ID NO: 46) 1 aagaaaccgg ccaggtgtgg cctaggcgcc cagtgccagc ggggaggaga ctcgctccgc 61 cgccgaccaa caccaacacc cagctccgac gcagctcctc tgcgcccttg ccgccctccg 121 agccacagct ttcctcccgc tcctgccccc ggcccgtcgc cgtctccgcg ctcgcagcgg 181 cctcgggagg gcccaggtag cgagcagcga cctcgcgagc cttccgcact cccgcccggt 241 tccccggccg tccgcctatc cttggccccc tccgctttct ccgcgccggc ccgcctcgct 301 tatgcctcgg cgctgagccg ctctcccgat tgcccgccga catgagctgc aacggaggct 361 cccacccgcg gatcaacact ctgggccgca tgatccgcgc cgagtctggc ccggacctgc 421 gctacgaggt gaccagcggc ggcgggggca ccagcaggat gtactattct cggcgcggcg 481 tgatcaccga ccagaactcg gacggctact gtcaaaccgg cacgatgtcc aggcaccaga 541 accagaacac catccaggag ctgctgcaga actgctccga ctgcttgatg cgagcagagc 601 tcatcgtgca gcctgaattg aagtatggag atggaataca actgactcgg agtcgagaat 661 tggatgagtg ttttgcccag gccaatgacc aaatggaaat cctcgacagc ttgatcagag 721 agatgcggca gatgggccag ccctgtgatg cttaccagaa aaggcttctt cagctccaag 781 agcaaatgcg agccctttat aaagccatca gtgtccctcg agtccgcagg gccagctcca 841 agggtggtgg aggctacact tgtcagagtg gctctggctg ggatgagttc accaaacatg 901 tcaccagtga atgtttgggg tggatgaggc agcaaagggc ggagatggac atggtggcct 961 ggggtgtgga cctggcctca gtggagcagc acattaacag ccaccggggc atccacaact 1021 ccatcggcga ctatcgctgg cagctggaca aaatcaaagc cgacctgcgc gagaaatctg 1081 cgatctacca gttggaggag gagtatgaaa acctgctgaa agcgtccttt gagaggatgg 1141 atcacctgcg acagctgcag aacatcattc aggccacgtc cagggagatc atgtggatca 1201 atgactgcga ggaggaggag ctgctgtacg actggagcga caagaacacc aacatcgctc 1261 agaaacagga ggccttctcc atacgcatga gtcaactgga agttaaagaa aaagagctca 1321 ataagctgaa acaagaaagt gaccaacttg tcctcaatca gcatccagct tcagacaaaa 1381 ttgaggccta tatggacact ctgcagacgc agtggagttg gattcttcag atcaccaagt 1441 gcattgatgt tcatctgaaa gaaaatgctg cctactttca gttttttgaa gaggcgcagt 1501 ctactgaagc atacctgaag gggctccagg actccatcag gaagaagtac ccctgcgaca 1561 agaacatgcc cctgcagcac ctgctggaac agatcaagga gctggagaaa gaacgagaga 1621 aaatccttga atacaagcgt caggtgcaga acttggtaaa caagtctaag aagattgtac 1681 agctgaagcc tcgtaaccca gactacagaa gcaataaacc cattattctc agagctctct 1741 gtgactacaa acaagatcag aaaatcgtgc ataaggggga tgagtgtatc ctgaaggaca 1801 acaacgagcg cagcaagtgg tacgtgacgg gcccgggagg cgttgacatg cttgttccct 1861 ctgtggggct gatcatccct cctccgaacc cactggccgt ggacctctct tgcaagattg 1921 agcagtacta cgaagccatc ttggctctgt ggaaccagct ctacatcaac atgaagagcc 1981 tggtgtcctg gcactactgc atgattgaca tagagaagat cagggccatg acaatcgcca 2041 agctgaaaac aatgcggcag gaagattaca tgaagacgat agccgacctt gagttacatt 2101 accaagagtt catcagaaat agccaaggct cagagatgtt tggagatgat gacaagcgga 2161 aaatacagtc tcagttcacc gatgcccaga agcattacca gaccctggtc attcagctcc 2221 ctggctatcc ccagcaccag acagtgacca caactgaaat cactcatcat ggaacctgcc 2281 aagatgtcaa ccataataaa gtaattgaaa ccaacagaga aaatgacaag caagaaacat 2341 ggatgctgat ggagctgcag aagattcgca ggcagataga gcactgcgag ggcaggatga 2401 ctctcaaaaa cctccctcta gcagaccagg gatcttctca ccacatcaca gtgaaaatta 2461 acgagcttaa gagtgtgcag aatgattcac aagcaattgc tgaggttctc aaccagctta 2521 aagatatgct tgccaacttc agaggttctg aaaagtactg ctatttacag aatgaagtat 2581 ttggactatt tcagaaactg gaaaatatca atggtgttac agatggctac ttaaatagct 2641 tatgcacagt aagggcactg ctccaggcta ttctccaaac agaagacatg ttaaaggttt 2701 atgaagccag gctcactgag gaggaaactg tctgcctgga cctggataaa gtggaagctt 2761 accgctgtgg actgaagaaa ataaaaaatg acttgaactt gaagaagtcg ttgttggcca 2821 ctatgaagac agaactacag aaagcccagc agatccactc tcagacttca cagcagtatc 2881 cactttatga tctggacttg ggcaagttcg gtgaaaaagt cacacagctg acagaccgct 2941 ggcaaaggat agataaacag atcgacttta ggttatggga cctggagaaa caaatcaagc 3001 aattgaggaa ttatcgtgat aactatcagg ctttctgcaa gtggctctat gatgctaaac 3061 gccgccagga ttccttagaa tccatgaaat ttggagattc caacacagtc atgcggtttt 3121 tgaatgagca gaagaacttg cacagtgaaa tatctggcaa acgagacaaa tcagaggaag 3181 tacaaaaaat tgctgaactt tgcgccaatt caattaagga ttatgagctc cagctggcct 3241 catacacctc aggactggaa actctgctga acatacctat caagaggacc atgattcagt 3301 ccccttctgg ggtgattctg caagaggctg cagatgttca tgctcggtac attgaactac 3361 ttacaagatc tggagactat tacaggttct taagtgagat gctgaagagt ttggaagatc 3421 tgaagctgaa aaataccaag atcgaagttt tggaagagga gctcagactg gcccgagatg 3481 ccaactcgga aaactgtaat aagaacaaat tcctggatca gaacctgcag aaataccagg 3541 cagagtgttc ccagttcaaa gcgaagcttg cgagcctgga ggagctgaag agacaggctg 3601 agctggatgg gaagtcggct aagcaaaatc tagacaagtg ctacggccaa ataaaagaac 3661 tcaatgagaa gatcacccga ctgacttatg agattgaaga tgaaaagaga agaagaaaat 3721 ctgtggaaga cagatttgac caacagaaga atgactatga ccaactgcag aaagcaaggc 3781 aatgtgaaaa ggagaacctt ggttggcaga aattagagtc tgagaaagcc atcaaggaga 3841 aggagtacga gattgaaagg ttgagggttc tactgcagga agaaggcacc cggaagagag 3901 aatatgaaaa tgagctggca aaggtaagaa accactataa tgaggagatg agtaatttaa 3961 ggaacaagta tgaaacagag attaacatta cgaagaccac catcaaggag atatccatgc 4021 aaaaagagga tgattccaaa aatcttagaa accagcttga tagactttca agggaaaatc 4081 gagatctgaa ggatgaaatt gtcaggctca atgacagcat cttgcaggcc actgagcagc 4141 gaaggcgagc tgaagaaaac gcccttcagc aaaaggcctg tggctctgag ataatgcaga 4201 agaagcagca tctggagata gaactgaagc aggtcatgca gcagcgctct gaggacaatg 4261 cccggcacaa gcagtccctg gaggaggctg ccaagaccat tcaggacaaa aataaggaga 4321 tcgagagact caaagctgag tttcaggagg aggccaagcg ccgctgggaa tatgaaaatg 4381 aactgagtaa ggcatctaat aggattcagg aatcaaagaa tcagtgtact caggtggtac 4441 aggaaagaga gagccttctg gtgaaaatca aagtcctgga gcaagacaag gcaaggctgc 4501 agaggctgga ggatgagctg aatcgtgcaa aatcaactct agaggcagaa accagggtga 4561 aacagcgcct ggagtgtgag aaacagcaaa ttcagaatga cctgaatcag tggaagactc 4621 aatattcccg caaggaggag gctattagga agatagaatc ggaaagagaa aagagtgaga 4681 gagagaagaa cagtcttagg agtgagatcg aaagactcca agcagagatc aagagaattg 4741 aagagaggtg caggcgtaag ctggaggatt ctaccaggga gacacagtca cagttagaaa 4801 cagaacgctc ccgatatcag agggagattg ataaactcag acagcgccca tatgggtccc 4861 atcgagagac ccagactgag tgtgagtgga ccgttgacac ctccaagctg gtgtttgatg 4921 ggctgaggaa gaaggtgaca gcaatgcagc tctatgagtg tcagctgatc gacaaaacaa 4981 ccttggacaa actattgaag gggaagaagt cagtggaaga agttgcttct gaaatccagc 5041 cattccttcg gggtgcagga tctatcgctg gagcatctgc ttctcctaag gaaaaatact 5101 ctttggtaga ggccaagaga aagaaattaa tcagcccaga atccacagtc atgcttctgg 5161 aggcccaggc agctacaggt ggtataattg atccccatcg gaatgagaag ctgactgtcg 5221 acagtgccat agctcgggac ctcattgact tcgatgaccg tcagcagata tatgcagcag 5281 aaaaagctat cactggtttt gatgatccat tttcaggcaa gacagtatct gtttcagaag 5341 ccatcaagaa aaatttgatt gatagagaaa ccggaatgcg cctgctggaa gcccagattg 5401 cttcaggggg tgtagtagac cctgtgaaca gtgtcttttt gccaaaagat gtcgccttgg 5461 cccgggggct gattgataga gatttgtatc gatccctgaa tgatccccga gatagtcaga 5521 aaaactttgt ggatccagtc accaaaaaga aggtcagtta cgtgcagctg aaggaacggt 5581 gcagaatcga accacatact ggtctgctct tgctttcagt acagaagaga agcatgtcct 5641 tccaaggaat cagacaacct gtgaccgtca ctgagctagt agattctggt atattgagac 5701 cgtccactgt caatgaactg gaatctggtc agatttctta tgacgaggtt ggtgagagaa 5761 ttaaggactt cctccagggt tcaagctgca tagcaggcat atacaatgag accacaaaac 5821 agaagcttgg catttatgag gccatgaaaa ttggcttagt ccgacctggt actgctctgg 5881 agttgctgga agcccaagca gctactggct ttatagtgga tcctgttagc aacttgaggt 5941 taccagtgga ggaagcctac aagagaggtc tggtgggcat tgagttcaaa gagaagctcc 6001 tgtctgcaga acgagctgtc actgggtata atgatcctga aacaggaaac atcatctctt 6061 tgttccaagc catgaataag gaactcatcg aaaagggcca cggtattcgc ttattagaag 6121 cacagatcgc aaccgggggg atcattgacc caaaggagag ccatcgttta ccagttgaca 6181 tagcatataa gaggggctat ttcaatgagg aactcagtga gattctctca gatccaagtg 6241 atgataccaa aggatttttt gaccccaaca ctgaagaaaa tcttacctat ctgcaactaa 6301 aagaaagatg cattaaggat gaggaaacag ggctctgtct tctgcctctg aaagaaaaga 6361 agaaacaggt gcagacatca caaaagaata ccctcaggaa gcgtagagtg gtcatagttg 6421 acccagaaac caataaagaa atgtctgttc aggaggccta caagaagggc ctaattgatt 6481 atgaaacctt caaagaactg tgtgagcagg aatgtgaatg ggaagaaata accatcacgg 6541 gatcagatgg ctccaccagg gtggtcctgg tagatagaaa gacaggcagt cagtatgata 6601 ttcaagatgc tattgacaag ggccttgttg acaggaagtt ctttgatcag taccgatccg 6661 gcagcctcag cctcactcaa tttgctgaca tgatctcctt gaaaaatggt gtcggcacca 6721 gcagcagcat gggcagtggt gtcagcgatg atgtttttag cagctcccga catgaatcag 6781 taagtaagat ttccaccata tccagcgtca ggaatttaac cataaggagc agctcttttt 6841 cagacaccct ggaagaatcg agccccattg cagccatctt tgacacagaa aacctggaga 6901 aaatctccat tacagaaggt atagagcggg gcatcgttga cagcatcacg ggtcagaggc 6961 ttctggaggc tcaggcctgc acaggtggca tcatccaccc aaccacgggc cagaagctgt 7021 cacttcagga cgcagtctcc cagggtgtga ttgaccaaga catggccacc aggctgaagc 7081 ctgctcagaa agccttcata ggcttcgagg gtgtgaaggg aaagaagaag atgtcagcag 7141 cagaggcagt gaaagaaaaa tggctcccgt atgaggctgg ccagcgcttc ctggagttcc 7201 agtacctcac gggaggtctt gttgacccgg aagtgcatgg gaggataagc accgaagaag 7261 ccatccggaa ggggttcata gatggccgcg ccgcacagag gctgcaagac accagcagct 7321 atgccaaaat cctgacctgc cccaaaacca aattaaaaat atcctataag gatgccataa 7381 atcgctccat ggtagaagat atcactgggc tgcgccttct ggaagccgcc tccgtgtcgt 7441 ccaagggctt acccagccct tacaacatgt cttcggctcc ggggtcccgc tccggctccc

7501 gctcgggatc tcgctccgga tctcgctccg ggtcccgcag tgggtcccgg agaggaagct 7561 ttgacgccac agggaattct tcctactctt attcctactc atttagcagt agttctattg 7621 ggcactagta gtcagttggg agtggttgct ataccttgac ttcatttata tgaatttcca 7681 ctttattaaa taatagaaaa gaaaatcccg gtgcttgcag tagagtgata ggacattcta 7741 tgcttacaga aaatatagcc atgattgaaa tcaaatagta aaggctgttc tggcttttta 7801 tcttcttagc tcatcttaaa taagcagtac acttggatgc agtgcgtctg aagtgctaat 7861 cagttgtaac aatagcacaa atcgaactta ggatttgttt cttctcttct gtgtttcgat 7921 ttttgatcaa ttctttaatt ttggaagcct ataatacagt tttctattct tggagataaa 7981 aattaaatgg atcactgata ttttagtcat tctgcttctc atctaaatat ttccatattc 8041 tgtattagga gaaaattacc ctcccagcac cagcccccct ctcaaacccc caacccaaaa 8101 ccaagcattt tggaatgagt ctcctttagt ttcagagtgt ggattgtata acccatatac 8161 tcttcgatgt acttgtttgg tttggtatta atttgactgt gcatgacagc ggcaatcttt 8221 tctttggtca aagttttctg tttattttgc ttgtcatatt cgatgtactt taaggtgtct 8281 ttatgaagtt tgctattctg gcaataaact tttagacttt tgaagtgttt gtgttttaat 8341 ttaatatgtt tataagcatg tataaacatt tagcatattt ttatcatagg tctaaaaata 8401 tttgtttact aaatacctgt gaagaaatac cattaaaaaa ctatttggtt ctgaattctt 8461 actagaaaaa aaa

[0261] In some embodiments of the methods of the disclosure, the wild type human DSP gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: NP_001305963.1, transcript variant 3):

TABLE-US-00034 (SEQ ID NO: 47) 1 mscnggshpr intlgrmira esgpdlryev tsggggtsrm yysrrgvitd qnsdgycqtg 61 tmsrhqnqnt iqellqncsd clmraelivq pelkygdgiq ltrsreldec faqandqmei 121 ldsliremrq mgqpcdayqk rllqlqeqmr alykaisvpr vrrasskggg gytcqsgsgw 181 deftkhvtse clgwmrqqra emdmvawgvd lasveqhins hrgihnsigd yrwqldkika 241 dlreksaiyq leeeyenllk asfermdhlr qlqniiqats reimwindce eeellydwsd 301 kntniaqkqe afsirmsqle vkekelnklk qesdqlvlnq hpasdkieay mdtlqtqwsw 361 ilqitkcidv hlkenaayfq ffeeaqstea ylkglqdsir kkypcdknmp lqhlleqike 421 lekerekile ykrqvqnlvn kskkivqlkp rnpdyrsnkp iilralcdyk qdqkivhkgd 481 ecilkdnner skwyvtgpgg vdmlvpsvgl iipppnplav dlsckieqyy eailalwnql 541 yinmkslvsw hycmidieki ramtiaklkt mrqedymkti adlelhyqef irnsqgsemf 601 gdddkrkiqs qftdaqkhyq tlviqlpgyp qhqtvtttei thhgtcqdvn hnkvietnre 661 ndkqetwmlm elqkirrqie hcegrmtlkn lpladqgssh hitvkinelk svqndsqaia 721 evlnqlkdml anfrgsekyc ylqnevfglf qkleningvt dgylnslctv rallqailqt 781 edmlkvyear lteeetvcld ldkveayrcg lkkikndlnl kksllatmkt elqkaqqihs 841 qtsqqyplyd ldlgkfgekv tqltdrwqri dkqidfrlwd lekqikqlrn yrdnyqafck 901 wlydakrrqd slesmkfgds ntvmrflneq knlhseisgk rdkseevqki aelcansikd 961 yelqlasyts gletllnipi krtmiqspsg vilqeaadvh aryielltrs gdyyrflsem 1021 lksledlklk ntkievleee lrlardanse ncnknkfldq nlqkyqaecs qfkaklasle 1081 elkrqaeldg ksakqnldkc ygqikelnek itrltyeied ekrrrksved rfdqqkndyd 1141 qlqkarqcek enlgwqkles ekaikekeye ierlrvllqe egtrkreyen elakvrnhyn 1201 eemsnlrnky eteinitktt ikeismqked dsknlrnqld rlsrenrdlk deivrlndsi 1261 lqateqrrra eenalqqkac gseimqkkqh leielkqvmq qrsednarhk qsleeaakti 1321 qdknkeierl kaefqeeakr rweyenelsk asnriqeskn qctqvvqere sllvkikvle 1381 qdkarlqrle delnrakstl eaetrvkqrl ecekqqiqnd lnqwktqysr keeairkies 1441 erekserekn slrseierlq aeikrieerc rrkledstre tqsqleters ryqreidklr 1501 qrpygshret qtecewtvdt sklvfdglrk kvtamqlyec qlidkttldk llkgkksvee 1561 vaseiqpflr gagsiagasa spkekyslve akrkklispe stvmlleaqa atggiidphr 1621 nekltvdsai ardlidfddr qqiyaaekai tgfddpfsgk tvsyseaikk nlidretgmr 1681 lleaqiasgg vvdpvnsvfl pkdvalargl idrdlyrsln dprdsqknfv dpvtkkkvsy 1741 vqlkercrie phtgllllsv qkrsmsfqgi rqpvtvtelv dsgilrpstv nelesgqisy 1801 devgerikdf lqgssciagi ynettkqklg iyeamkiglv rpgtalelle aqaatgfivd 1861 pvsnlrlpve eaykrglvgi efkekllsae ravtgyndpe tgniislfqa mnkeliekgh 1921 girlleaqia tggiidpkes hrlpvdiayk rgyfneelse ilsdpsddtk gffdpnteen 1981 ltylqlkerc ikdeetglcl lplkekkkqv qtsqkntlrk rrvvivdpet nkemsvqeay 2041 kkglidyetf kelceqecew eeititgsdg strvvlvdrk tgsqydiqda idkglvdrkf 2101 fdqyrsgsls ltqfadmisl kngvgtsssm gsgvsddvfs ssrhesvski stissvrnlt 2161 irsssfsdtl eesspiaaif dtenlekisi tegiergivd sitgqrllea qactggiihp 2221 ttgqklslqd aysqgvidqd matrlkpaqk afigfegvkg kkkmsaaeav kekwlpyeag 2281 qrflefqylt gglvdpevhg risteeairk gfidgraaqr lqdtssyaki ltcpktklki 2341 sykdainrsm veditglrll eaasysskgl pspynmssap gsrsgsrsgs rsgsrsgsrs 2401 gsrrgsfdat gnssysysys fssssigh

[0262] In some embodiments of the methods of the disclosure, the wild type human AZGP1 gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_001185.3):

TABLE-US-00035 (SEQ ID NO: 21) 1 ccattggcct gtagattcac ctcccctggg cagggcccca ggacccagga taatatctgt 61 gcctcctgcc cagaaccctc caagcagaca caatggtaag aatggtgcct gtcctgctgt 121 ctctgctgct gcttctgggt cctgctgtcc cccaggagaa ccaagatggt cgttactctc 181 tgacctatat ctacactggg ctgtccaagc atgttgaaga cgtccccgcg tttcaggccc 241 ttggctcact caatgacctc cagttcttta gatacaacag taaagacagg aagtctcagc 301 ccatgggact ctggagacag gtggaaggaa tggaggattg gaagcaggac agccaacttc 361 agaaggccag ggaggacatc tttatggaga ccctgaaaga catcgtggag tattacaacg 421 acagtaacgg gtctcacgta ttgcagggaa ggtttggttg tgagatcgag aataacagaa 481 gcagcggagc attctggaaa tattactatg atggaaagga ctacattgaa ttcaacaaag 541 aaatcccagc ctgggtcccc ttcgacccag cagcccagat aaccaagcag aagtgggagg 601 cagaaccagt ctacgtgcag cgggccaagg cttacctgga ggaggagtgc cctgcgactc 661 tgcggaaata cctgaaatac agcaaaaata tcctggaccg gcaagatcct ccctctgtgg 721 tggtcaccag ccaccaggcc ccaggagaaa agaagaaact gaagtgcctg gcctacgact 781 tctacccagg gaaaattgat gtgcactgga ctcgggccgg cgaggtgcag gagcctgagt 841 tacggggaga tgttcttcac aatggaaatg gcacttacca gtcctgggtg gtggtggcag 901 tgcccccgca ggacacagcc ccctactcct gccacgtgca gcacagcagc ctggcccagc 961 ccctcgtggt gccctgggag gccagctagg aagcaagggt tggaggcaat gtgggatctc 1021 agacccagta gctgcccttc ctgcctgatg tgggagctga accacagaaa tcacagtcaa 1081 tggatccaca aggcctgagg agcagtgtgg ggggacagac aggaggtgga tttggagacc 1141 gaagactggg atgcctgtct tgagtagact tggacccaaa aaatcatctc accttgagcc 1201 cacccccacc ccattgtcta atctgtagaa gctaataaat aatcatccct ccttgcctag 1261 cataaaaaaa aaaaaaaa

[0263] In some embodiments of the methods of the disclosure, the wild type human AZGP1 gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NP_001176.1):

TABLE-US-00036 (SEQ ID NO: 22) 1 mvrmvpvlls lllllgpavp qenqdgrysl tyiytglskh vedvpafqal gslndlqffr 61 ynskdrksqp mglwrqvegm edwkqdsqlq karedifmet lkdiveyynd sngshvlqgr 121 fgceiennrs sgafwkyyyd gkdyiefnke ipawvpfdpa aqitkqkwea epvyvqraka 181 yleeecpatl rkylkyskni ldrqdppsvv vtshqapgek kklkclaydf ypgkidvhwt 241 ragevqepel rgdvlhngng tyqswvvvav ppqdtapysc hvqhsslaqp lvvpweas

[0264] In some embodiments of the methods of the disclosure, the wild type human OBFC1 gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_024928):

TABLE-US-00037 (SEQ ID NO: 23) 1 aaatgcgctg gcggggagac cggggttggt ccctggcggg gcagggggcg ggctcaggcc 61 ggaactccag agacgacctc agccaactgc tcctgcgccg ggcggggtcg tcgccgccag 121 cggctccgag cgccggaagg gccaggtctc agggctcctg gagctgcagg cggcgggagg 181 ggctacaaat gcttgactca gtgatgcaga acctttcaga gttagctgga agccacagcc 241 ctgcctcttg atgcagcctg gatccagccg gtgtgaagag gagacccctt ccctcttgtg 301 gggtttggat cctgtgtttc tagcctttgc aaaactctac atcagggata tcctggacat 361 gaaggagtcc cgccaggtgc caggtgtatt tttgtacaat ggacatccaa taaaacaggt 421 agatgtcttg ggaactgtca ttggagtgag agaaagagat gctttctaca gttatggagt 481 ggatgacagc actggagtta taaactgcat ctgctggaaa aagttgaata ctgagtctgt 541 atcagctgct ccaagtgcag caagagagct cagcttaacc tcacaactta agaagctaca 601 agagaccatt gagcagaaaa caaagataga gatcggggac acgatccgag tcagaggcag 661 tatccgcaca tacagagaag agcgagagat tcatgccacc acttactata aagtggacga 721 cccagtgtgg aacattcaaa ttgcaaggat gcttgagctg cccactatct acaggaaagt 781 ttatgaccag ccttttcaca gctcagccct agagaaagaa gaggcactaa gcaatccagg 841 cgccctggac ctccccagtc tcacgagttt gctgagtgaa aaagccaaag aattcctcat 901 ggagaacaga gtgcagagct tttaccagca ggagctggaa atggtggagt ctttgctgtc 961 ccttgccaat cagcctgtga ttcacagtgc ctcctccgac caagtgaatt ttaagaagga 1021 caccacttcc aaggcaattc atagtatatt taagaatgct atacaactgc tgcaggaaaa 1081 aggacttgtt ttccagaaag atgatggttt tgataaccta tactatgtaa ccagagaaga 1141 caaagacctg cacagaaaga tccaccggat cattcagcag gactgccaga aaccaaatca 1201 catggagaag ggctgtcact tcctgcacat cttggcctgt gctcgcctga gcatccgccc 1261 gggcctgagc gaggctgtgc tgcagcaagt tctggagctc ctggaggacc agagtgacat 1321 tgtcagcaca atggagcact actacacagc gttctgagca gagacacgca gaccagctga 1381 ggaggacaaa gataaggtgg cattcacccc caggctctga ctttcagcat catgcagggg 1441 cttatctgtc tggaggcagt tacctcataa taaactataa aatatagtca tcttgggaat 1501 gggatttggc ataaatgttg ttggctccct tctgtccact atgtccttgg tgtacaatga 1561 ctttgatctc agccatgaca caacaagaaa accctccctg ttgagctcct ggctggactg 1621 tgcgttgttc gcagagcaga atggggagga aacagtgttg gcagcttaac tgatgtgtgt 1681 ggttggagtc tcttccatgg caaagggaca ccacagggta gtgaacattc aggaactgag 1741 gggcatatgg cctgatcaca cagttctaag cttttcaaaa cttcaggtta tcagagacct 1801 tcctgtgggc ctctcttgct ggctaagaac cggtttaggg gagtagttct ccctggatga 1861 gtgcttacag tttctgtggc tcagttacca gcagtggggt tgagacctgg gtcgatgctc 1921 tttacaggcc tgcccagaga tgggaataaa cagggatcca cagcgtgact atgtgtttgt 1981 cattttcctt ttatttcctt gggaatcgaa aggtgtccca gtacatttcc ctgcacttac 2041 agaggtgcat gactaaatac attgtccctc gatgcccctg aagatcacgg aggcagtcag 2101 ccaattgcct ggcaggtggt agatgttatt ttcagggttg ccgctgagtg tgcaggatgt 2161 gctgacacca tccagacaaa gactcggtat gtgcccagac aggtgatgga gtcatgcttt 2221 tgctcagaat gacaaggtaa aggaaaaaca tctgaggtat gttgtaggcc tgttctgaca 2281 gcaaaatgac aaatccagcc agcaaaaata aagtgtggag aaagatttgg agttaattac 2341 agtcatttca cagaaggcac tgccttcgtc tgctgcattt gctcttgatg tgataagctc 2401 ttcgtggctc agctggagat cctttaggcc tggagagttg ctcctctctc cgtggaaaca 2461 ggacagtctt tatacgcaga agtccgctgc agctcgatac gtcaggctga gagctagaac 2521 cagtagattg cctcctgtca tagacttttg taatgatgca aacctttgct gatttctaac 2581 agtgattatg tagtggctgc cctgcatctt ctctgtgtac agaagggtcc ctagcataga 2641 gtctgcctgg aatgatgtcc tgggcagttc ttccttgagg tcagcagctg ttccacgttg 2701 aatgcatctg attagtgggg ctgcccagga aggagttcag aatcagaagg taaaaagggc 2761 atacccttgc ctatagcaac tctgctctta ggggtttatc tcaaggagat ggctacacaa 2821 gtgtgaaagg atggttgcac aaggtgttca ttgctgtata atctagaatt ctatattggg 2881 gaaaatacct atagggaaaa agttaattac ggttcttggg cacaatgaaa tactatgcag 2941 ctatgaaaaa aatgatgaaa gcagacagac agtgttgcca tggcacactg tccctagtag 3001 atttagtggg aagtagatag agttatagat ctgtttctat agtataacac cattatctac 3061 agctccctgt gtgtatgtat atatccgtag agagagtgta tatttctgca tggaggtctt 3121 tataaatgta gcacatgtac atatatatat atatacacac acacagtcga ccactccctt 3181 ctcctggaag tactttccgc gtttggcttt caggacacca agctctctgg ttgctccttc 3241 tcaggttcct ttgttcagtg ctctgcctcc ctgaggactc agtcccagac ctcttttcta 3301 tctggcttgc tcactggggt gtctccagca gccacatgga ttataccatc tacatgctgt 3361 ctaacacctc agtttaaacc cagaatgggc ctcttccctg aactgcagac ccctatattc 3421 agtttgctac tgacatctcc acttaggtct ctaatggaca tctcagattt cacaggccca 3481 aagccaggct cccaattact cctgacccca ggcttgctcc tgatagtgac atgaggcagc 3541 caaatgccta ggcagagagg ggagggtccc aaatgaaacc ccacgttcaa gcaaagatca 3601 gcctgaaggc taaaagacca gattgctggt cctggatgaa acccaccacg cagagtggga 3661 acttctgttc ctgtttgccc accctttccc aattgttctt tctgaataac gccttaacca 3721 atcgaatgtt gccttttcca gtaataccta cagcctgccc ctccccccat tctgagccca 3781 taaaaagacc cagactcccc catattaagg ggactttcct gcctttgggt agggggacca 3841 cccccacgtc tcctctctgt tgaaaactgt ttcatcactc aataaaactc ccagctttgc 3901 tcactcttcc actgtcagca cattctcatt cttctttggt gctgggcaag aactcaacca 3961 gtgtggaagc catacttggc ccaggcgggt gaagtgggcg ggccgtctcc tgcagcaggt 4021 agcatggtca agcgaggccc aggtgggccg tcaccagcca gaggtccctg gcttgcaaag 4081 tgaccgagaa aaaaatcctg tgccactcct ttggaaaatg tccctgattc aggaagaggt 4141 agctccatcc agttgctcaa accaaatcca ttggcttctt tctttctatc atacctcaca 4201 tccaatctgt ctgcaagtct tttggctcta ccttcagaat atctccagaa tcttaactgc 4261 ttcaccctcc tccccggcct cctcagtcct ctctgcttcc gccctggccc ctcttgggct 4321 gttcacagca cagcagctgt tgccaccctg ttaatgctcc cactctccta cagccttcgg 4381 tcttgcccca ggtaggagcc tgaggctgca cagaggtcag cacggccccg cttaccctgc 4441 cctcccagcc cagccgcacg ggccttgcac acatgcctcg gcatattcct gccttagggc 4501 tggtgctcct gctatttcct cttcccaggt aaccatgtga agtgcctccc tctgccctct 4561 ttccagcctt tacttgagtg tcaccttctc agtgaggcct gccctcattc ctctttcgct 4621 gtttgcaacc catctcctgt cccccttccc agaactccct ttcctacttc gtttttcttc 4681 acagtacttg atactgccta acacactcca tggtttctta cttgccctgt ttattatttt 4741 cccccaatag acagaatgtt ccatgatggc agaattctct gttttgtttc cttccatgtc 4801 cccagcacct agaacagtgc ctgacgcatc tcctaagcaa tacgaccaat aagtatgtgt 4861 ctggctgcct tccggctgcc agtgtctgcc tctttcctag gggcagtggt tgcgggggtg 4921 ctttctcaca tgtcttagta ggctgtgcag gctggaagtg ctcagaagtc acacccccag 4981 ggagcagcct cagccaacag caccttggct gtaaatgccc cagctccctc gccctcaggt 5041 aagcattgct gaggcacacg ttccatactc ttttccacag ttcctccgtg ggactgagca 5101 ccacccagcc acccacagga gcagctaacc tgataaccac cagcctcacc ctccctgcct 5161 tacttccccg ctccccttta ccacatgctg acctcccaga tgcatttctt gctttccggt 5221 ctctgtctca ggattggctc ctggatgaac acaaactaac actatgttca caaatatatt 5281 tgggaaatgc tggatgaata attatacaca tcagacagat tactagaaat tctcaccaaa 5341 gggatgcaca tgttacctct gcatggtgag atctcaggtg ctttttaccc cacatagcta 5401 tcctttggca tttttataat tagcaagtgc tcactcttcc actgtcagta cattctcatt 5461 cttcttgggc gctggacaag aattcaaccg gtgtgtaagc cagactcggc ccgggcagtc 5521 tcaaactcct gactccttat ataatttcta caaaaattat aaagctattt cccactcccc 5581 accccacatt catgtaacct gaagcatgag taaaccaaga atgaggtagg cctctgtctt 5641 ctaagcaaca tcagaactct aagaacatga gggactctta gaaaactctc tggagctaac 5701 cacagctggg tcactgctca tgtactgaag accagccaga gggttcccct gaaaaggagg 5761 gaaactgagc aaacattctc cagttctctt agtgtgcaca tgtttcagga ggtgtgaacc 5821 ccacatgtag cttgtgtagg caagaagaca aatagtgcta ctgtctggtc aaggatttgt 5881 ttgaagagcc atgattatgc ccatatggta agccaccagt gctccccatc cctgtaagac 5941 acttctttct cattattttc tcctctgatg gtgtgccagg atgctggcca agagaagcca 6001 agtggaaaga aggctgttca gtgacaagga acctaagact tagtgccaag gactgaaacc 6061 aagtaaactt gtaattttcc atgatggaaa catctacact ttctcattag tggcctctac 6121 agcagttgcc ccaaagaagc gtctcattgt ttttttacta catttatgtg aagcatacag 6181 gcaaactcag aaagactgtg ataaggctcg ccagagatgc ctgcacaggt gctgggggaa 6241 aagcaggacc atcctgaagg gagatggtgt ctgtggacaa agaactctgc agtggttctt 6301 atttgcatga tttctgctgg tggaggctgt aaatgtgagc tcaaactccc acataagtga 6361 gttttcattg taatccagaa tgtttttaaa tcaccctact tctattgaac ttgcactatc 6421 atctgttaac ctctactgta tttattaaat aaacctgaat aggtaaatca cagtacagca 6481 aaa

[0265] In some embodiments of the methods of the disclosure, the wild type human OBFC1 gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: NP_079204.2):

TABLE-US-00038 (SEQ ID NO: 24) 1 mqpgssrcee etpsllwgld pvflafakly irdildmkes rqvpgvflyn ghpikqvdvl 61 gtvigvrerd afysygvdds tgvincicwk klntesvsaa psaarelslt sqlkklqeti 121 eqktkieigd tirvrgsirt yreereihat tyykvddpvw niqiarmlel ptiyrkvydq 181 pfhssaleke ealsnpgald lpsltsllse kakeflmenr vqsfyqqele mvesllslan 241 qpvihsassd qvnfkkdtts kaihsifkna iqllqekglv fqkddgfdnl yyvtredkdl 301 hrkihriiqq dcqkpnhmek gchflhilac arlsirpgls eavlqqvlel ledqsdivst 361 mehyytaf

[0266] In some embodiments of the methods of the disclosure, the wild type human ATP11A gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_015205.2, transcript variant 1):

TABLE-US-00039 (SEQ ID NO: 25) 1 gcggccgcac tagtaccccg gagcccatgg gcgcgccgag ccgggcgcgg gggcgctgaa 61 cggcggagcg ggagcggccg gaggagccat ggactgcagc ctcgtgcgga cgctcgtgca 121 cagatactgt gcaggagaag agaattgggt ggacagcagg accatctacg tgggacacag 181 ggagccacct ccgggcgcag aggcctacat cccacagaga tacccagaca acaggatcgt 241 ctcgtccaag tacacatttt ggaactttat acccaagaat ttatttgaac aattcagaag 301 agtagccaac ttttatttcc ttatcatatt tctggtgcag ttgattattg atacacccac 361 aagtccagtg acaagcggac ttccactctt ctttgtcatt actgtgacgg ctatcaaaca 421 gggttatgaa gactggcttc gacataaagc agacaatgcc atgaaccagt gtcctgttca 481 tttcattcag cacggcaagc tcgttcggaa acaaagtcga aagctgcgag ttggggacat 541 tgtcatggtt aaggaggacg agacctttcc ctgcgacttg atcttccttt ccagcaaccg 601 gggagatggg acgtgccacg tcaccaccgc cagcttggat ggagaatcca gccataaaac 661 gcattacgcg gtccaggaca ccaaaggctt ccacacagag gaggatatcg gcggacttca 721 cgccaccatc gagtgtgagc agccccagcc cgacctctac aagttcgtgg gtcgcatcaa 781 cgtttacagt gacctgaatg accccgtggt gaggccctta ggatcggaaa acctgctgct 841 tagaggagct acactgaaga acactgagaa aatctttggt gtggctattt acacgggaat 901 ggaaaccaag atggcattaa attatcaatc aaaatctcag aagcgatctg ccgtggaaaa 961 atcgatgaat gcgttcctca ttgtgtatct ctgcattctg atcagcaaag ccctgataaa 1021 cactgtgctg aaatacatgt ggcagagtga gccctttcgg gatgagccgt ggtataatca 1081 gaaaacggag tcggaaaggc agaggaatct gttcctcaag gcattcacgg acttcctggc 1141 cttcatggtc ctctttaact acatcatccc tgtgtccatg tacgtcacgg tcgagatgca 1201 gaagttcctc ggctcttact tcatcacctg ggacgaagac atgtttgacg aggagactgg 1261 cgaggggcct ctggtgaaca cgtcggacct caatgaagag ctgggacagg tggagtacat 1321 cttcacagac aagaccggca ccctcacgga aaacaacatg gagttcaagg agtgctgcat 1381 cgaaggccat gtctacgtgc cccacgtcat ctgcaacggg caggtcctcc cagagtcgtc 1441 aggaatcgac atgattgact cgtcccccag cgtcaacggg agggagcgcg aggagctgtt 1501 tttccgggcc ctctgtctct gccacaccgt ccaggtgaaa gacgatgaca gcgtagacgg 1561 ccccaggaaa tcgccggacg gggggaaatc ctgtgtgtac atctcatcct cgcccgacga 1621 ggtggcgctg gtcgaaggtg tccagagact tggctttacc tacctaaggc tgaaggacaa 1681 ttacatggag atattaaaca gggagaacca catcgaaagg tttgaattgc tggaaatttt 1741 gagttttgac tcagtcagaa ggagaatgag tgtaattgta aaatctgcta caggagaaat 1801 ttatctgttt tgcaaaggag cagattcttc gatattcccc cgagtgatag aaggcaaagt 1861 tgaccagatc cgagccagag tggagcgtaa cgcagtggag gggctccgaa ctttgtgtgt 1921 tgcttataaa aggctgatcc aagaagaata tgaaggcatt tgtaagctgc tgcaggctgc 1981 caaagtggcc cttcaagatc gagagaaaaa gttagcagaa gcctatgagc aaatagagaa 2041 agatcttact ctgcttggtg ctacagctgt tgaggaccgg ctgcaggaga aagctgcaga 2101 caccatcgag gccctgcaga aggccgggat caaagtctgg gttctcacgg gagacaagat 2161 ggagacggcc gcggccacgt gctacgcctg caagctcttc cgcaggaaca cgcagctgct 2221 ggagctgacc accaagagga tcgaggagca gagcctgcac gacgtcctgt tcgagctgag 2281 caagacggtc ctgcgccaca gcgggagcct gaccagagac aacctgtccg gactttcagc 2341 agatatgcag gactacggtt taattatcga cggagctgca ctgtctctga taatgaagcc 2401 tcgagaagac gggagttccg gcaactacag ggagctcttc ctggaaatct gccggagctg 2461 cagcgcggtg ctctgctgcc gcatggcgcc cttgcagaag gctcagattg ttaaattaat 2521 caaattttca aaagagcacc caatcacgtt agcaattggc gatggtgcaa atgatgtcag 2581 catgattctg gaagcgcacg tgggcatagg tgtcatcggc aaggaaggcc gccaggctgc 2641 caggaacagc gactatgcaa tcccaaagtt taagcatttg aagaagatgc tgcttgttca 2701 cgggcatttt tattacatta ggatctctga gctcgtgcag tacttcttct ataagaacgt 2761 ctgcttcatc ttccctcagt ttttatacca gttcttctgt gggttttcac aacagacttt 2821 gtacgacacc gcgtatctga ccctctacaa catcagcttc acctccctcc ccatcctcct 2881 gtacagcctc atggagcagc atgttggcat tgacgtgctc aagagagacc cgaccctgta 2941 cagggacgtc gccaagaatg ccctgctgcg ctggcgcgtg ttcatctact ggacgctcct 3001 gggactgttt gacgcactgg tgttcttctt tggtgcttat ttcgtgtttg aaaatacaac 3061 tgtgacaagc aacgggcaga tatttggaaa ctggacgttt ggaacgctgg tattcaccgt 3121 gatggtgttc acagttacac taaagcttgc attggacaca cactactgga cttggatcaa 3181 ccattttgtc atctgggggt cgctgctgtt ctacgttgtc ttttcgcttc tctggggagg 3241 agtgatctgg ccgttcctca actaccagag gatgtactac gtgttcatcc agatgctgtc 3301 cagcgggccc gcctggctgg ccatcgtgct gctggtgacc atcagcctcc ttcccgacgt 3361 cctcaagaaa gtcctgtgcc ggcagctgtg gccaacagca acagagagag tccagactaa 3421 gagccagtgc ctttctgtcg agcagtcaac catctttatg ctttctcaga cttccagcag 3481 cctgagtttc tgatggaaca agagcccagg ctaccagagc acctgtccct cggccgcctg 3541 gtacagctcc cactctcagc aggtgacact cgcggcctgg aaggagaagg tgtccacgga 3601 gcccccaccc atcctcggcg gttcccatca ccactgcagt tccatcccaa gtcacagctg 3661 ccctaggtcc cgtgtgggaa tgctcgtgtg atggatggtc ctaagcctgt ggagactgtg 3721 cacgtgcctc ttcctggccc ccagcaggca aggagggggg tcacaggcct tgccctcgag 3781 catggcaccc tggccgcctg gacccagcac tgtggttgtt gagccacacc agtggcctct 3841 gggcattcgg ctcaacgcag gagggacatt ctgctggccc accctgcgcg ctgtcatgca 3901 gaggccattc ccccaggcct gtgtcttcac ccacctgcca tcattggcct ttgctgtcac 3961 tgggagagaa gagccgtcca gggacccatg gtggcccaca tgtggatgcc acatgctgct 4021 gtttcctgct tgcccggcca ccacccatgc cctccatagg gtgaggtgga gccatggtgg 4081 tgcgtccttt actcaacaac cctccaatcc ggatgctgtg ggaagggccg ggtcactcgg 4141 ataccatcat ccctgcggat gcaccgccgt accctgctca tctgggagtg gtttccctgc 4201 ggttacgtcc aagcccgcct gccctgtgtg ttggggctgg ctgagtttcg gtctccccat 4261 caccggccgc ctcgtggaga aggcagtgcc acgtgggagg acaaggccac gccggcagct 4321 tccagccctg ccgcagaagt gccaggatgt ccatcagcca ctcgccaggg cacggagccg 4381 tcagtccact gttacgggag aatgttgatt tcgcgggtgc gagggccggg agacagatac 4441 ttggctgtga tgagcagaca tcctctgtcc ccgtggaggg gtcaacacca aggtggtgtt 4501 cgtgcaccag aacctgtctc gggctgacgg gggtggcaca caggacacgg gtggatccca 4561 acaggcagca ccgcacctct gcccgcctcc cgcactgcag ctccgcccgc cgggctctgc 4621 gtccccacgt cccctcgtcc catccccacg tcccctcatc ccgtcacctc gtccccacat 4681 ccccttgccc cgtcacctcg tcctcatgtc cccttgtcct gtcacctcgt ccccacgtcc 4741 cctcgtctcc tcatccccac gtcctctcgt ccccttgtcc cgtccccaca taccctcgtc 4801 cccatgtccc cacgcagggc tctccttcgt cttaggatct gtccagcgct gctctgggtg 4861 ggttagcaac cccagggctg ctgtgatagg aagtccctgt tgttctccgt actggcattt 4921 ctatttctag aaataatatt tgacatagcc ttaatggtcc ttaaagaaga catttcagtg 4981 tgagattcag acttcagacg ctgaaactgc tgcctttcag gaaagcacca ccaacgctgg 5041 aggaggagcc ggccctcacg cccgccccgc gccacgctgt ggaacggggc tccggcaagt 5101 gaaacccaga gggtgtttcc gaggtgctcg acagtaggta tttttggaag ctcagatttc 5161 accatttgat tgtataatct tttacctata aaatatttat ttgaagtaga gggtaaatca 5221 gcggtaagaa cagtgaacac agtggttggg ataaaataag gtgacaaaca tcacaccaaa 5281 gatgagggta gcgagcaact ggcttgagca gacagaacgg ggaagactcc actctgtccc 5341 gaggggccag ccgcaggcgt ccccagggcc accctgccct gaggtccttg tgtggccgcc 5401 ctggcttggc agccctgccc acgctgcccc cgcaaacaat ggtgtgtgcg tttttacagc 5461 cctttttagg aacccaatat gggcataaat gtaacacctg tagcgggggc agattctctg 5521 tatgttcagt taacaaatta tttgtaatgt atttttttag aaatcttaaa attgcctttg 5581 cactgaagta ttttcatagc tgtttatatc tcttttattc atttatttaa catactgtct 5641 aattttaaaa ataggttttt aaagctttca tttttaagtt tatgaaattt tggccacttt 5701 acatttagat tctggtgaga gttttgactg aatgttccaa tctctgatga atgcgaattt 5761 tcagatttga ttttattctc tacacacacc tcttcttttc ttggtatttc tggtggcagt 5821 gattagttga acagcacatt taaggcacga taatttgcta cactttttct ttacaatttg 5881 ttgcaatttc atctgctttc tatgtttcat tgttaattgc catccttcag ccttaaaaat 5941 agaagattct cacgtgaagg tttagtaagt tgggtcccag ctctgcctgt gtggagatag 6001 tcaccatgta cctctgacaa caagttttag tgtgaaagtc actaaacttt tacacactcc 6061 caaacgtctt tttaaaaatt gcttgggaaa ttattaaatg aatgtgcctg atgatttgaa 6121 atagacaagg ggcacgagat aaaaaagaaa aggatgagaa gatcctcagt gaatgacgtt 6181 gcagggtctt catgcaattt tccacctcgc agtagttagt atttacttgc cttaaactaa 6241 ctttgaagca agtaatgtca actttgagca ctttgttgag ttttgaaaaa tcttatttgt 6301 tgctgcacag gttaataaat tatcaatttg taattcagca tgttggtcag agacacggtc 6361 actgattcac acccagtccc tgccacagac cgtctcagac acgcacagtg ggcctgctgc 6421 atgattcaca cccagtccct gccacagacc gtctcagaca cgcacagtgg gcctgctgca 6481 tgattcacac ccagtccctg ccacagaccg tctcagacac gcacagtggg cctgctgcat 6541 gcgtgttacc tggcttttgg ctccacgctc actcatagcc atgtccacat gggggcttgc 6601 acacaggatc actcacatat gtacatgtac ccaccacaaa cgtgcaagct cctgcacaca 6661 tgcatgcaca caaacgtgta cacaagtgtg agctcctaca cgcatacaca cacacacgtg 6721 tacatgcacc aaagcatgtg tgacctacag acatgcagaa catgcacgtg tacacatacc 6781 acagacacgc gtgtgcatgc tcctacacaa tacatatgca catatcatga acagcgtaag 6841 ttcctacaca cggacgtgtg atacacacat gcatgtacag gtaagcacac atgtacaagc 6901 tcctacaggc ttgctctcac acacgtgtat gcacagcaga gagacgtatg agcttctact 6961 gcacacatgc acacacacac gcacacgtac attcactaca aacgtgcagc ctcctgcaca 7021 cgtgcacatt catgtgtaca ccacaaatga gttcccagac gtgtaaacac acgtgcacac 7081 atcgtacaca tgtgagctcc cacacgtaca cacagatgca catggacaca ccccaaacac 7141 gcacaggctc ctacacacat gcacacacgt gtacaccaca aacgagctcc cagacatgta 7201 aacacacgtc tcccacacgt gagctcccac acgtacacat gcacatgtac gcaccacaaa 7261 cacatgcgca ggctcctgca ggcgtgaata cacacatgca cacacatata cacacatgtg 7321 ccacaaacaa gtgcacactg tcctggtgtc ctgcactgca tcctgcctcc ttgctgaggg 7381 gcccctgtga gaggcctctg gatgggcatg ggaagatggg ctccctggcc cccagcccat 7441 gcctccctgg gatgaagagt ccccctcctg gcagaatgtc tgggctttgc agagcaggcc

7501 ccgggggtga agtcgcagct tcacttacac cagctgctct gtgagcaagg cttggtgccc 7561 tggacaaggc ccttcccctt tagggaggtc cagcctcgca agctgaaacc tcccctcggc 7621 tcagccctat accaggcggc cacagcagga ctggccacac ccacgccgca cctcatccgt 7681 gcacgcgtcg gagcacggcc agccttccgc cacgagccag ctgggaaggg ccgcggccgc 7741 ctaaagcccc agtcaaccca gcctgtgtct gagcagacag ggcgaacaag caggccacac 7801 cgtctcgagg gaggaggcca gatgcggcca gcgtctccaa cagggtgacc atccgctcgg 7861 cttgctgagc gtttaaacaa atgtttagac aggctgtggg gactcccctg agttgagcct 7921 tggccagggg tccggtgctg tcgcgggaaa cctccagcct tgttcttcaa accactcagc 7981 tcatgtgttt tgcactgact agtactgaat aatacaacca ctcttattta atgttagtat 8041 tatttatttg acaactcagt gtctaacagc ttgatatgca ggtccttgca tcctacattt 8101 ctttaggaag ttacccattt gtaactttaa aaacaggaaa aatatcagtt ggcaaatgca 8161 atcttttttt tttttaagct aaaggtgggt gaactggaat gaaaatcttt ctgatgttgt 8221 gtctataagc agccttgatg ggatatgtta gaagtgtcat gaaagtgtga ttctactttt 8281 gcagaaaaat ctaaagatca atttatatag ctttattttt tactttatca aagtatacag 8341 aattttaata tgcatatatt gtgtctgact taaaattata atgtctgcgt caccatttaa 8401 aatgtctgtt cattatgtaa tgtaataaaa gaaggtcttc aaaaatgtat ttaacatgaa 8461 tggtatccat agttgtcatc atcataaata ctggagttta tttttaaatt attaaacata 8521 gtaggtgcat taacataaat cagtctccac acagtaacat ttaactgata attcattaat 8581 cagctttgaa aaattaaatt gttaattaaa ccaatctaac atttcagtaa agtttatttt 8641 gtatgcttct gtttttaact tttatttctg tagataaact gactggataa tattatattg 8701 gacttttctc tagattatct aagcaggaga cctgaatctg cttgcaataa agaataaaag 8761 tctgcttcag tttctttata aagaaactca cacaa

[0267] In some embodiments of the methods of the disclosure, the wild type human

[0268] ATP11A gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NP_056020.2, transcript variant 1):

TABLE-US-00040 (SEQ ID NO: 26) 1 mdcslvrtlv hrycageenw vdsrtiyvgh repppgaeay ipqrypdnri vsskytfwnf 61 ipknlfeqfr rvanfyflii flvqliidtp tspvtsglpl ffvitvtaik qgyedwlrhk 121 adnamnqcpv hfiqhgklvr kqsrklrvgd ivmvkedetf pcdliflssn rgdgtchvtt 181 asldgesshk thyavqdtkg fhteediggl hatieceqpq pdlykfvgri nvysdlndpv 241 vrplgsenll lrgatlknte kifgvaiytg metkmalnyq sksqkrsave ksmnaflivy 301 lciliskali ntvlkymwqs epfrdepwyn qkteserqrn lflkaftdfl afmvlfnyii 361 pvsmyvtvem qkflgsyfit wdedmfdeet gegplvntsd lneelgqvey iftdktgtlt 421 ennmefkecc ieghvyvphv icngqvlpes sgidmidssp svngrereel ffralclcht 481 vqvkdddsvd gprkspdggk scvyissspd evalvegvqr lgftylrlkd nymeilnren 541 hierfellei lsfdsvrrrm svivksatge iylfckgads sifprviegk vdqirarver 601 naveglrtlc vaykrliqee yegickllqa akvalqdrek klaeayeqie kdltllgata 661 vedrlqekaa dtiealqkag ikvwvltgdk metaaatcya cklfrrntql lelttkriee 721 qslhdvlfel sktvlrhsgs ltrdnlsgls admqdyglii dgaalslimk predgssgny 781 relfleicrs csavlccrma plqkaqivkl ikfskehpit laigdgandv smileahvgi 841 gvigkegrqa arnsdyaipk fkhlkkmllv hghfyyiris elvqyffykn vcfifpqfly 901 qffcgfsqqt lydtayltly nisftslpil lyslmeqhvg idvlkrdptl yrdvaknall 961 rwrvfiywtl lglfdalvff fgayfvfent tvtsngqifg nwtfgtlvft vmvftvtlkl 1021 aldthywtwi nhfviwgsll fyvvfsllwg gviwpflnyq rmyyvfiqml ssgpawlaiv 1081 llvtisllpd vlkkvlcrql wptatervqt ksqclsveqs tifmlsqtss slsf

[0269] In some embodiments of the methods of the disclosure, the wild type human ATP11A gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_032189.3, transcript variant 2):

TABLE-US-00041 (SEQ ID NO: 48) 1 gcggccgcac tagtaccccg gagcccatgg gcgcgccgag ccgggcgcgg gggcgctgaa 61 cggcggagcg ggagcggccg gaggagccat ggactgcagc ctcgtgcgga cgctcgtgca 121 cagatactgt gcaggagaag agaattgggt ggacagcagg accatctacg tgggacacag 181 ggagccacct ccgggcgcag aggcctacat cccacagaga tacccagaca acaggatcgt 241 ctcgtccaag tacacatttt ggaactttat acccaagaat ttatttgaac aattcagaag 301 agtagccaac ttttatttcc ttatcatatt tctggtgcag ttgattattg atacacccac 361 aagtccagtg acaagcggac ttccactctt ctttgtcatt actgtgacgg ctatcaaaca 421 gggttatgaa gactggcttc gacataaagc agacaatgcc atgaaccagt gtcctgttca 481 tttcattcag cacggcaagc tcgttcggaa acaaagtcga aagctgcgag ttggggacat 541 tgtcatggtt aaggaggacg agacctttcc ctgcgacttg atcttccttt ccagcaaccg 601 gggagatggg acgtgccacg tcaccaccgc cagcttggat ggagaatcca gccataaaac 661 gcattacgcg gtccaggaca ccaaaggctt ccacacagag gaggatatcg gcggacttca 721 cgccaccatc gagtgtgagc agccccagcc cgacctctac aagttcgtgg gtcgcatcaa 781 cgtttacagt gacctgaatg accccgtggt gaggccctta ggatcggaaa acctgctgct 841 tagaggagct acactgaaga acactgagaa aatctttggt gtggctattt acacgggaat 901 ggaaaccaag atggcattaa attatcaatc aaaatctcag aagcgatctg ccgtggaaaa 961 atcgatgaat gcgttcctca ttgtgtatct ctgcattctg atcagcaaag ccctgataaa 1021 cactgtgctg aaatacatgt ggcagagtga gccctttcgg gatgagccgt ggtataatca 1081 gaaaacggag tcggaaaggc agaggaatct gttcctcaag gcattcacgg acttcctggc 1141 cttcatggtc ctctttaact acatcatccc tgtgtccatg tacgtcacgg tcgagatgca 1201 gaagttcctc ggctcttact tcatcacctg ggacgaagac atgtttgacg aggagactgg 1261 cgaggggcct ctggtgaaca cgtcggacct caatgaagag ctgggacagg tggagtacat 1321 cttcacagac aagaccggca ccctcacgga aaacaacatg gagttcaagg agtgctgcat 1381 cgaaggccat gtctacgtgc cccacgtcat ctgcaacggg caggtcctcc cagagtcgtc 1441 aggaatcgac atgattgact cgtcccccag cgtcaacggg agggagcgcg aggagctgtt 1501 tttccgggcc ctctgtctct gccacaccgt ccaggtgaaa gacgatgaca gcgtagacgg 1561 ccccaggaaa tcgccggacg gggggaaatc ctgtgtgtac atctcatcct cgcccgacga 1621 ggtggcgctg gtcgaaggtg tccagagact tggctttacc tacctaaggc tgaaggacaa 1681 ttacatggag atattaaaca gggagaacca catcgaaagg tttgaattgc tggaaatttt 1741 gagttttgac tcagtcagaa ggagaatgag tgtaattgta aaatctgcta caggagaaat 1801 ttatctgttt tgcaaaggag cagattcttc gatattcccc cgagtgatag aaggcaaagt 1861 tgaccagatc cgagccagag tggagcgtaa cgcagtggag gggctccgaa ctttgtgtgt 1921 tgcttataaa aggctgatcc aagaagaata tgaaggcatt tgtaagctgc tgcaggctgc 1981 caaagtggcc cttcaagatc gagagaaaaa gttagcagaa gcctatgagc aaatagagaa 2041 agatcttact ctgcttggtg ctacagctgt tgaggaccgg ctgcaggaga aagctgcaga 2101 caccatcgag gccctgcaga aggccgggat caaagtctgg gttctcacgg gagacaagat 2161 ggagacggcc gcggccacgt gctacgcctg caagctcttc cgcaggaaca cgcagctgct 2221 ggagctgacc accaagagga tcgaggagca gagcctgcac gacgtcctgt tcgagctgag 2281 caagacggtc ctgcgccaca gcgggagcct gaccagagac aacctgtccg gactttcagc 2341 agatatgcag gactacggtt taattatcga cggagctgca ctgtctctga taatgaagcc 2401 tcgagaagac gggagttccg gcaactacag ggagctcttc ctggaaatct gccggagctg 2461 cagcgcggtg ctctgctgcc gcatggcgcc cttgcagaag gctcagattg ttaaattaat 2521 caaattttca aaagagcacc caatcacgtt agcaattggc gatggtgcaa atgatgtcag 2581 catgattctg gaagcgcacg tgggcatagg tgtcatcggc aaggaaggcc gccaggctgc 2641 caggaacagc gactatgcaa tcccaaagtt taagcatttg aagaagatgc tgcttgttca 2701 cgggcatttt tattacatta ggatctctga gctcgtgcag tacttcttct ataagaacgt 2761 ctgcttcatc ttccctcagt ttttatacca gttcttctgt gggttttcac aacagacttt 2821 gtacgacacc gcgtatctga ccctctacaa catcagcttc acctccctcc ccatcctcct 2881 gtacagcctc atggagcagc atgttggcat tgacgtgctc aagagagacc cgaccctgta 2941 cagggacgtc gccaagaatg ccctgctgcg ctggcgcgtg ttcatctact ggacgctcct 3001 gggactgttt gacgcactgg tgttcttctt tggtgcttat ttcgtgtttg aaaatacaac 3061 tgtgacaagc aacgggcaga tatttggaaa ctggacgttt ggaacgctgg tattcaccgt 3121 gatggtgttc acagttacac taaagcttgc attggacaca cactactgga cttggatcaa 3181 ccattttgtc atctgggggt cgctgctgtt ctacgttgtc ttttcgcttc tctggggagg 3241 agtgatctgg ccgttcctca actaccagag gatgtactac gtgttcatcc agatgctgtc 3301 cagcgggccc gcctggctgg ccatcgtgct gctggtgacc atcagcctcc ttcccgacgt 3361 cctcaagaaa gtcctgtgcc ggcagctgtg gccaacagca acagagagag tccagaatgg 3421 gtgcgcacag cctcgggacc gcgactcaga attcacccct cttgcctctc tgcagagccc 3481 aggctaccag agcacctgtc cctcggccgc ctggtacagc tcccactctc agcaggtgac 3541 actcgcggcc tggaaggaga aggtgtccac ggagccccca cccatcctcg gcggttccca 3601 tcaccactgc agttccatcc caagtcacag ctgccctagg tcccgtgtgg gaatgctcgt 3661 gtgatggatg gtcctaagcc tgtggagact gtgcacgtgc ctcttcctgg cccccagcag 3721 gcaaggaggg gggtcacagg ccttgccctc gagcatggca ccctggccgc ctggacccag 3781 cactgtggtt gttgagccac accagtggcc tctgggcatt cggctcaacg caggagggac 3841 attctgctgg cccaccctgc gcgctgtcat gcagaggcca ttcccccagg cctgtgtctt 3901 cacccacctg ccatcattgg cctttgctgt cactgggaga gaagagccgt ccagggaccc 3961 atggtggccc acatgtggat gccacatgct gctgtttcct gcttgcccgg ccaccaccca 4021 tgccctccat agggtgaggt ggagccatgg tggtgcgtcc tttactcaac aaccctccaa 4081 tccggatgct gtgggaaggg ccgggtcact cggataccat catccctgcg gatgcaccgc 4141 cgtaccctgc tcatctggga gtggtttccc tgcggttacg tccaagcccg cctgccctgt 4201 gtgttggggc tggctgagtt tcggtctccc catcaccggc cgcctcgtgg agaaggcagt 4261 gccacgtggg aggacaaggc cacgccggca gcttccagcc ctgccgcaga agtgccagga 4321 tgtccatcag ccactcgcca gggcacggag ccgtcagtcc actgttacgg gagaatgttg 4381 atttcgcggg tgcgagggcc gggagacaga tacttggctg tgatgagcag acatcctctg 4441 tccccgtgga ggggtcaaca ccaaggtggt gttcgtgcac cagaacctgt ctcgggctga 4501 cgggggtggc acacaggaca cgggtggatc ccaacaggca gcaccgcacc tctgcccgcc 4561 tcccgcactg cagctccgcc cgccgggctc tgcgtcccca cgtcccctcg tcccatcccc 4621 acgtcccctc atcccgtcac ctcgtcccca catccccttg ccccgtcacc tcgtcctcat 4681 gtccccttgt cctgtcacct cgtccccacg tcccctcgtc tcctcatccc cacgtcctct 4741 cgtccccttg tcccgtcccc acataccctc gtccccatgt ccccacgcag ggctctcctt 4801 cgtcttagga tctgtccagc gctgctctgg gtgggttagc aaccccaggg ctgctgtgat 4861 aggaagtccc tgttgttctc cgtactggca tttctatttc tagaaataat atttgacata 4921 gccttaatgg tccttaaaga agacatttca gtgtgagatt cagacttcag acgctgaaac 4981 tgctgccttt caggaaagca ccaccaacgc tggaggagga gccggccctc acgcccgccc 5041 cgcgccacgc tgtggaacgg ggctccggca agtgaaaccc agagggtgtt tccgaggtgc 5101 tcgacagtag gtatttttgg aagctcagat ttcaccattt gattgtataa tcttttacct 5161 ataaaatatt tatttgaagt agagggtaaa tcagcggtaa gaacagtgaa cacagtggtt 5221 gggataaaat aaggtgacaa acatcacacc aaagatgagg gtagcgagca actggcttga 5281 gcagacagaa cggggaagac tccactctgt cccgaggggc cagccgcagg cgtccccagg 5341 gccaccctgc cctgaggtcc ttgtgtggcc gccctggctt ggcagccctg cccacgctgc 5401 ccccgcaaac aatggtgtgt gcgtttttac agcccttttt aggaacccaa tatgggcata 5461 aatgtaacac ctgtagcggg ggcagattct ctgtatgttc agttaacaaa ttatttgtaa 5521 tgtatttttt tagaaatctt aaaattgcct ttgcactgaa gtattttcat agctgtttat 5581 atctctttta ttcatttatt taacatactg tctaatttta aaaataggtt tttaaagctt 5641 tcatttttaa gtttatgaaa ttttggccac tttacattta gattctggtg agagttttga 5701 ctgaatgttc caatctctga tgaatgcgaa ttttcagatt tgattttatt ctctacacac 5761 acctcttctt ttcttggtat ttctggtggc agtgattagt tgaacagcac atttaaggca 5821 cgataatttg ctacactttt tctttacaat ttgttgcaat ttcatctgct ttctatgttt 5881 cattgttaat tgccatcctt cagccttaaa aatagaagat tctcacgtga aggtttagta 5941 agttgggtcc cagctctgcc tgtgtggaga tagtcaccat gtacctctga caacaagttt 6001 tagtgtgaaa gtcactaaac ttttacacac tcccaaacgt ctttttaaaa attgcttggg 6061 aaattattaa atgaatgtgc ctgatgattt gaaatagaca aggggcacga gataaaaaag 6121 aaaaggatga gaagatcctc agtgaatgac gttgcagggt cttcatgcaa ttttccacct 6181 cgcagtagtt agtatttact tgccttaaac taactttgaa gcaagtaatg tcaactttga 6241 gcactttgtt gagttttgaa aaatcttatt tgttgctgca caggttaata aattatcaat 6301 ttgtaattca gcatgttggt cagagacacg gtcactgatt cacacccagt ccctgccaca 6361 gaccgtctca gacacgcaca gtgggcctgc tgcatgattc acacccagtc cctgccacag 6421 accgtctcag acacgcacag tgggcctgct gcatgattca cacccagtcc ctgccacaga 6481 ccgtctcaga cacgcacagt gggcctgctg catgcgtgtt acctggcttt tggctccacg 6541 ctcactcata gccatgtcca catgggggct tgcacacagg atcactcaca tatgtacatg 6601 tacccaccac aaacgtgcaa gctcctgcac acatgcatgc acacaaacgt gtacacaagt 6661 gtgagctcct acacgcatac acacacacac gtgtacatgc accaaagcat gtgtgaccta 6721 cagacatgca gaacatgcac gtgtacacat accacagaca cgcgtgtgca tgctcctaca 6781 caatacatat gcacatatca tgaacagcgt aagttcctac acacggacgt gtgatacaca 6841 catgcatgta caggtaagca cacatgtaca agctcctaca ggcttgctct cacacacgtg 6901 tatgcacagc agagagacgt atgagcttct actgcacaca tgcacacaca cacgcacacg 6961 tacattcact acaaacgtgc agcctcctgc acacgtgcac attcatgtgt acaccacaaa 7021 tgagttccca gacgtgtaaa cacacgtgca cacatcgtac acatgtgagc tcccacacgt 7081 acacacagat gcacatggac acaccccaaa cacgcacagg ctcctacaca catgcacaca 7141 cgtgtacacc acaaacgagc tcccagacat gtaaacacac gtctcccaca cgtgagctcc 7201 cacacgtaca catgcacatg tacgcaccac aaacacatgc gcaggctcct gcaggcgtga 7261 atacacacat gcacacacat atacacacat gtgccacaaa caagtgcaca ctgtcctggt 7321 gtcctgcact gcatcctgcc tccttgctga ggggcccctg tgagaggcct ctggatgggc 7381 atgggaagat gggctccctg gcccccagcc catgcctccc tgggatgaag agtccccctc 7441 ctggcagaat gtctgggctt tgcagagcag gccccggggg tgaagtcgca gcttcactta

7501 caccagctgc tctgtgagca aggcttggtg ccctggacaa ggcccttccc ctttagggag 7561 gtccagcctc gcaagctgaa acctcccctc ggctcagccc tataccaggc ggccacagca 7621 ggactggcca cacccacgcc gcacctcatc cgtgcacgcg tcggagcacg gccagccttc 7681 cgccacgagc cagctgggaa gggccgcggc cgcctaaagc cccagtcaac ccagcctgtg 7741 tctgagcaga cagggcgaac aagcaggcca caccgtctcg agggaggagg ccagatgcgg 7801 ccagcgtctc caacagggtg accatccgct cggcttgctg agcgtttaaa caaatgttta 7861 gacaggctgt ggggactccc ctgagttgag ccttggccag gggtccggtg ctgtcgcggg 7921 aaacctccag ccttgttctt caaaccactc agctcatgtg ttttgcactg actagtactg 7981 aataatacaa ccactcttat ttaatgttag tattatttat ttgacaactc agtgtctaac 8041 agcttgatat gcaggtcctt gcatcctaca tttctttagg aagttaccca tttgtaactt 8101 taaaaacagg aaaaatatca gttggcaaat gcaatctttt ttttttttaa gctaaaggtg 8161 ggtgaactgg aatgaaaatc tttctgatgt tgtgtctata agcagccttg atgggatatg 8221 ttagaagtgt catgaaagtg tgattctact tttgcagaaa aatctaaaga tcaatttata 8281 tagctttatt ttttacttta tcaaagtata cagaatttta atatgcatat attgtgtctg 8341 acttaaaatt ataatgtctg cgtcaccatt taaaatgtct gttcattatg taatgtaata 8401 aaagaaggtc ttcaaaaatg tatttaacat gaatggtatc catagttgtc atcatcataa 8461 atactggagt ttatttttaa attattaaac atagtaggtg cattaacata aatcagtctc 8521 cacacagtaa catttaactg ataattcatt aatcagcttt gaaaaattaa attgttaatt 8581 aaaccaatct aacatttcag taaagtttat tttgtatgct tctgttttta acttttattt 8641 ctgtagataa actgactgga taatattata ttggactttt ctctagatta tctaagcagg 8701 agacctgaat ctgcttgcaa taaagaataa aagtctgctt cagtttcttt ataaagaaac 8761 tcacacaa

[0270] In some embodiments of the methods of the disclosure, the wild type human ATP11A gene of the disclosure consists of or comprises the amino acid sequence (Genbank

[0271] Accession number: NP_115565.3, transcript variant 2):

TABLE-US-00042 (SEQ ID NO: 49) 1 mdcslvrtlv hrycageenw vdsrtiyvgh repppgaeay ipqrypdnri vsskytfwnf 61 ipknlfeqfr rvanfyflii flvqliidtp tspvtsglpl ffvitvtaik qgyedwlrhk 121 adnamnqcpv hfiqhgklvr kqsrklrvgd ivmvkedetf pcdliflssn rgdgtchvtt 181 asldgesshk thyavqdtkg fhteediggl hatieceqpq pdlykfvgri nvysdlndpv 241 vrplgsenll lrgatlknte kifgvaiytg metkmalnyq sksqkrsave ksmnaflivy 301 lciliskali ntvlkymwqs epfrdepwyn qkteserqrn lflkaftdfl afmvlfnyii 361 pvsmyvtvem qkflgsyfit wdedmfdeet gegplvntsd lneelgqvey iftdktgtlt 421 ennmefkecc ieghvyvphv icngqvlpes sgidmidssp svngrereel ffralclcht 481 vqvkdddsvd gprkspdggk scvyissspd evalvegvqr lgftylrlkd nymeilnren 541 hierfellei lsfdsvrrrm svivksatge iylfckgads sifprviegk vdqirarver 601 naveglrtlc vaykrliqee yegickllqa akvalqdrek klaeayeqie kdltllgata 661 vedrlqekaa dtiealqkag ikvwvltgdk metaaatcya cklfrrntql lelttkriee 721 qslhdvlfel sktvlrhsgs ltrdnlsgls admqdyglii dgaalslimk predgssgny 781 relfleicrs csavlccrma plqkaqivkl ikfskehpit laigdgandv smileahvgi 841 gvigkegrqa arnsdyaipk fkhlkkmllv hghfyyiris elvqyffykn vcfifpqfly 901 qffcgfsqqt lydtayltly nisftslpil lyslmeqhvg idvlkrdptl yrdvaknall 961 rwrvfiywtl lglfdalvff fgayfvfent tvtsngqifg nwtfgtlvft vmvftvtlkl 1021 aldthywtwi nhfviwgsll fyvvfsllwg gviwpflnyq rmyyvfiqml ssgpawlaiv 1081 llvtisllpd vlkkvlcrql wptatervqn gcaqprdrds eftplaslqs pgyqstcpsa 1141 awysshsqqv tlaawkekvs tepppilggs hhhcssipsh scprsrvgml v

[0272] In some embodiments of the methods of the disclosure, the wild type human IVD/DISP2 gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_002225.3, transcript variant 1):

TABLE-US-00043 (SEQ ID NO: 50) 1 tttccgcagt taggggctgc tatttcaacg cagggagata aaaagaaaaa aacacttgct 61 cttctacccc gctaaaaaca ctcatcctag ggagcacgcc agcatttgca gcgttcgggg 121 cagggccact cggcctgcgg ccgttgcact ggctggaagc tggcaggcga tcacggttga 181 ttggctcggg tgcggtccaa gggcagcaac gccttcggcg ggccgcctag ggtgattggc 241 tgctgcagcc caccccctag ccggtttggt gggcggcgaa gcctggattg gtggagctaa 301 gagctggctc agtttcagcg ctggctcttc gtgcatggca gagatggcga ctgcgactcg 361 gctgctgggg tggcgtgtgg cgagctggag gctgcggccg ccgcttgccg gcttcgtttc 421 ccagcgggcc cactcgcttt tgcccgtgga cgatgcaatc aatgggctaa gcgaggagca 481 gaggcagctt cgtcagacca tggctaagtt ccttcaggag cacctggccc ccaaggccca 541 ggagatcgat cgcagcaatg agttcaagaa cctgcgagaa ttttggaagc agctggggaa 601 cctgggcgta ttgggcatca cagcccctgt tcagtatggc ggctccggcc tgggctacct 661 ggagcatgtg ctggtgatgg aggagatatc ccgagcttcc ggagcagtgg ggctcagtta 721 cggtgcccac tccaacctct gcatcaacca gcttgtacgc aatgggaatg aggcccagaa 781 agagaagtat ctcccgaagc tgatcagtgg tgagtacatc ggagccctgg ccatgagtga 841 gcccaatgca ggctctgatg ttgtctctat gaagctcaaa gcggaaaaga aaggaaatca 901 ctacatcctg aatggcaaca agttctggat cactaatggc cctgatgctg acgtcctgat 961 tgtctatgcc aagacagatc tggctgctgt gccagcttct cggggcatca cagccttcat 1021 tgtggagaag ggtatgcctg gctttagcac ctctaagaag ctggacaagc tggggatgag 1081 gggctctaac acctgtgagc taatctttga agactgcaag attcctgctg ccaacatcct 1141 gggccatgag aataagggtg tctacgtgct gatgagtggg ctggacctgg agcggctggt 1201 gctggccggg gggcctcttg ggctcatgca agcggtcctg gaccacacca ttccctacct 1261 gcacgtgagg gaagcctttg gccagaagat cggccacttc cagttgatgc aggggaagat 1321 ggctgacatg tacacccgcc tcatggcgtg tcggcagtat gtctacaatg tcgccaaggc 1381 ctgcgatgag ggccattgca ctgctaagga ctgtgcaggt gtgattcttt actcagctga 1441 gtgtgccaca caggtagccc tggacggcat tcagtgtttt ggtggcaatg gctacatcaa 1501 tgactttccc atgggccgct ttcttcgaga tgccaagctg tatgagatag gggctgggac 1561 cagcgaggtg aggcggctgg tcatcggcag agccttcaat gcagactttc actagtcctg 1621 agacccttcg cccccttttc ctgcacctag tggcctttct tgggaagtag agatgtggcg 1681 gctttcccac cctgcccaca gcaggccctc ctgcccagct gctcttgtca gccctctggc 1741 ctctggatga ggttgagttc tccacaacag ctcccaagca tcatgggcct cgcagccggg 1801 cctgtgccac ggctagtgtt gtgtgattta aaatggactc agcaggaagc atattgtctg 1861 gggattgttg ggacaggttt tggtgactct gtgcccttgc tctctaactt ctgagcccac 1921 ctcccagggt aggcacctgg gggcatgcag gtgcccacct cccagggtag gcacctgggg 1981 gcatgcaggt acccacctct ttctcttggg tgaggctctg gcaaggagat ctctctgctc 2041 aagcacagca gaatcatggc ccctctccat gaattggaac ttggtacagg ttaagtatcc 2101 ctaatcctga aatctgaaac acttgtggtt ccaagcattt tggataaggc aaattcaact 2161 ttcagtctct tttctggggg aaaaaaataa taaacctagc ctagccaggc gtggtggctc 2221 atgcttgtaa tcccagcact tcaggaggct gagatgggtg gatcacctga ggtcaggagt 2281 tcaagaccag cctggccaac atgtggaaac ctcgcctcaa ctaaaaatag aaaaaaatta 2341 gttgggcatg gtggtgggca cctgtaatcc cagctacttc aggaggctga ggcaggagaa 2401 ttacttgaac ccaggaggcg gacgttgcag tgagccgagc ttgtgccatt gcactccagc 2461 ctgggcgaca agagcaaaac tcttcaaaaa acaaaacaaa acaaaaaaac cctggccctt 2521 gtttcttcca gtttctagag gtatcagctc ctagcagctt atgaacacat atgcttgctt 2581 ggccaggcaa ggtggtgtgt gcctgtaatc ccagcacttt gggaggccaa ggcaggtgga 2641 tcacttgcag tcaggagttc aagaccagcc tgtccaacgt ggtgaaaccc catctctact 2701 aaaaatacaa aaattagcca ggggtggtgg tgcacgtctg taatcccagc tactcaggag 2761 gctgaggcag gagaatcact tgaacccggg aggtggaggt tgcaatgagc caatatgaca 2821 ccgctgcagt ccagcctggg ccatagagtg agactctgtc tcaaaaaagg aaagaaaaat 2881 aggctgggca cagtgactca tgcctgtaat cccaacactt tgggaggccg aggcaggtgg 2941 atcacgaggt caggagttca agaccagcct ggccaagatg gtaaaacctc gtctctacta 3001 aaaatacaaa aattagccag gtgtggtggc aggctcctgt aatcccagct actcaggagg 3061 ctgaggcaga gaattgcttg aacccgggag gcagagtttg cagtgagcca agatcacacc 3121 actgcactcc agcttggacg acagagcgag actctgtctc aaaaaataat aggccaggca 3181 tggtggctca acgtctgtaa tcccagcact ttgggaggcc gaggcgggca gatcacaagg 3241 tcaggagttc gagaccagcc tgacgaccaa catggtgaaa cctcgtctct actaaaaata 3301 caaaaattag ccaggcctgg tggcacgcgc ctgtaatccc agttacacag aagactgagg 3361 caggagaatc gcttgaacgc aggaggcaga ggttgcagga gctgagatcg cgccattgca 3421 ctccagcctg ggcaacagag tgagactctg tctcaaaaaa taataataaa ataaatgaac 3481 acacatgctg ctgagtccgc agggggggca gagcagagga cagcgtgctt ttgtgtactg 3541 ttggaagact ggctcctcct gtacagcacc tctgagccct tgtgcaccgc cctgccacgg 3601 gcaccatcca gtcctggccg tgtgaccacc cacagctgac tgggcagcag gcacaggccc 3661 tacccgagca ggccggagtt ggctcgcatg actccagctg aggctgcctg tgtacatttc 3721 tccagatacc ctatggctaa ttttgttata actgcacagt ggctgctgcc attttgtatt 3781 aaatatattg tgaaacaaac ctatctgggg agaagcaatc tacttgccgc tgcttcctgt 3841 ctggatccag cttgtgtcct tggagagtgg ctggcccagg tcctattcct gtcctccagc 3901 ccgttctttc atgagggaca ggaaggtaaa atcagccctt aggagagagg tctcagcctc 3961 cctttcccag atctcccagt gagttttaaa ggaagcaggg agcccagagt gctaagttct 4021 tacagccaga aggaagctta tagatttctg aaaaccgccc ctttgttttt aaaaagatca 4081 acacaatttg actttctcaa ggtcaaaacg aactagaatc cagatctgct catggcaaaa 4141 atgggggtgt tctgagaatt ccagctttgg gccgcactgt acagcagtct ggatagagtg 4201 tgatctgaga agggaatggg tctgggttgt tccacccctt ccgagttcca aaaagaggga 4261 actggttttc ttggttctca gcccagcagc acctatcctg gctcttggtc ctggcctgca 4321 gccaagtgct gttcctagcc tgaggcttga gacaggtggg gttggctcct caccaacccc 4381 agttccgtcc catcctgagg gcaagatcct gggctcatag gcagtccctt tcacttcctt 4441 gtcttgctcc ctgctatgtt ggagatgaat gtgactaaaa gggccatctt gctggcttaa 4501 tgtgtggctg gagagaccag cctggagaca atgtggcaaa atggggcgct tcatccagtc 4561 tgtctaagcc ctgtcgactt ggggaggtga tttctttcct ggttctatat gtgaagcaaa 4621 ataaatgttt taaaattaaa agcaaaaaaa acaaaatgaa ccatgaaaaa aaa

[0273] In some embodiments of the methods of the disclosure, the wild type human IVD/DISP2 gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: transcript variant 1):

TABLE-US-00044 (SEQ ID NO: 51) 1 maematatrl lgwrvaswrl rpplagfvsq rahsllpvdd ainglseeqr qlrqtmakfl 61 qehlapkage idrsnefknl refwkqlgnl gvlgitapvq yggsglgyle hvlvmeeisr 121 asgavglsyg ahsnlcinql vrngneaqke kylpklisge yigalamsep nagsdvvsmk 181 lkaekkgnhy ilngnkfwit ngpdadvliv yaktdlaavp asrgitafiv ekgmpgfsts 241 kkldklgmrg sntcelifed ckipaanilg henkgvyvlm sgldlerlvl aggplglmqa 301 vldhtipylh vreafgqkig hfqlmqgkma dmytrlmacr qyvynvakac deghctakdc 361 agvilysaec atqvaldgiq cfggngyind fpmgrflrda klyeigagts evrrlvigra 421 fnadfh

[0274] In some embodiments of the methods of the disclosure, the wild type human IVD/DISP2 gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_001159508.1, transcript variant 2):

TABLE-US-00045 (SEQ ID NO: 27) 1 tttccgcagt taggggctgc tatttcaacg cagggagata aaaagaaaaa aacacttgct 61 cttctacccc gctaaaaaca ctcatcctag ggagcacgcc agcatttgca gcgttcgggg 121 cagggccact cggcctgcgg ccgttgcact ggctggaagc tggcaggcga tcacggttga 181 ttggctcggg tgcggtccaa gggcagcaac gccttcggcg ggccgcctag ggtgattggc 241 tgctgcagcc caccccctag ccggtttggt gggcggcgaa gcctggattg gtggagctaa 301 gagctggctc agtttcagcg ctggctcttc gtgcatggca gagatggcga ctgcgactcg 361 gctgctgggg tggcgtgtgg cgagctggag gctgcggccg ccgcttgccg gcttcgtttc 421 ccagcgggcc cactcgcttt tgcccgtgga cgatgcaatc aatgggctaa gcgaggagca 481 gaggcaggaa ttttggaagc agctggggaa cctgggcgta ttgggcatca cagcccctgt 541 tcagtatggc ggctccggcc tgggctacct ggagcatgtg ctggtgatgg aggagatatc 601 ccgagcttcc ggagcagtgg ggctcagtta cggtgcccac tccaacctct gcatcaacca 661 gcttgtacgc aatgggaatg aggcccagaa agagaagtat ctcccgaagc tgatcagtgg 721 tgagtacatc ggagccctgg ccatgagtga gcccaatgca ggctctgatg ttgtctctat 781 gaagctcaaa gcggaaaaga aaggaaatca ctacatcctg aatggcaaca agttctggat 841 cactaatggc cctgatgctg acgtcctgat tgtctatgcc aagacagatc tggctgctgt 901 gccagcttct cggggcatca cagccttcat tgtggagaag ggtatgcctg gctttagcac 961 ctctaagaag ctggacaagc tggggatgag gggctctaac acctgtgagc taatctttga 1021 agactgcaag attcctgctg ccaacatcct gggccatgag aataagggtg tctacgtgct 1081 gatgagtggg ctggacctgg agcggctggt gctggccggg gggcctcttg ggctcatgca 1141 agcggtcctg gaccacacca ttccctacct gcacgtgagg gaagcctttg gccagaagat 1201 cggccacttc cagttgatgc aggggaagat ggctgacatg tacacccgcc tcatggcgtg 1261 tcggcagtat gtctacaatg tcgccaaggc ctgcgatgag ggccattgca ctgctaagga 1321 ctgtgcaggt gtgattcttt actcagctga gtgtgccaca caggtagccc tggacggcat 1381 tcagtgtttt ggtggcaatg gctacatcaa tgactttccc atgggccgct ttcttcgaga 1441 tgccaagctg tatgagatag gggctgggac cagcgaggtg aggcggctgg tcatcggcag 1501 agccttcaat gcagactttc actagtcctg agacccttcg cccccttttc ctgcacctag 1561 tggcctttct tgggaagtag agatgtggcg gctttcccac cctgcccaca gcaggccctc 1621 ctgcccagct gctcttgtca gccctctggc ctctggatga ggttgagttc tccacaacag 1681 ctcccaagca tcatgggcct cgcagccggg cctgtgccac ggctagtgtt gtgtgattta 1741 aaatggactc agcaggaagc atattgtctg gggattgttg ggacaggttt tggtgactct 1801 gtgcccttgc tctctaactt ctgagcccac ctcccagggt aggcacctgg gggcatgcag 1861 gtgcccacct cccagggtag gcacctgggg gcatgcaggt acccacctct ttctcttggg 1921 tgaggctctg gcaaggagat ctctctgctc aagcacagca gaatcatggc ccctctccat 1981 gaattggaac ttggtacagg ttaagtatcc ctaatcctga aatctgaaac acttgtggtt 2041 ccaagcattt tggataaggc aaattcaact ttcagtctct tttctggggg aaaaaaataa 2101 taaacctagc ctagccaggc gtggtggctc atgcttgtaa tcccagcact tcaggaggct 2161 gagatgggtg gatcacctga ggtcaggagt tcaagaccag cctggccaac atgtggaaac 2221 ctcgcctcaa ctaaaaatag aaaaaaatta gttgggcatg gtggtgggca cctgtaatcc 2281 cagctacttc aggaggctga ggcaggagaa ttacttgaac ccaggaggcg gacgttgcag 2341 tgagccgagc ttgtgccatt gcactccagc ctgggcgaca agagcaaaac tcttcaaaaa 2401 acaaaacaaa acaaaaaaac cctggccctt gtttcttcca gtttctagag gtatcagctc 2461 ctagcagctt atgaacacat atgcttgctt ggccaggcaa ggtggtgtgt gcctgtaatc 2521 ccagcacttt gggaggccaa ggcaggtgga tcacttgcag tcaggagttc aagaccagcc 2581 tgtccaacgt ggtgaaaccc catctctact aaaaatacaa aaattagcca ggggtggtgg 2641 tgcacgtctg taatcccagc tactcaggag gctgaggcag gagaatcact tgaacccggg 2701 aggtggaggt tgcaatgagc caatatgaca ccgctgcagt ccagcctggg ccatagagtg 2761 agactctgtc tcaaaaaagg aaagaaaaat aggctgggca cagtgactca tgcctgtaat 2821 cccaacactt tgggaggccg aggcaggtgg atcacgaggt caggagttca agaccagcct 2881 ggccaagatg gtaaaacctc gtctctacta aaaatacaaa aattagccag gtgtggtggc 2941 aggctcctgt aatcccagct actcaggagg ctgaggcaga gaattgcttg aacccgggag 3001 gcagagtttg cagtgagcca agatcacacc actgcactcc agcttggacg acagagcgag 3061 actctgtctc aaaaaataat aggccaggca tggtggctca acgtctgtaa tcccagcact 3121 ttgggaggcc gaggcgggca gatcacaagg tcaggagttc gagaccagcc tgacgaccaa 3181 catggtgaaa cctcgtctct actaaaaata caaaaattag ccaggcctgg tggcacgcgc 3241 ctgtaatccc agttacacag aagactgagg caggagaatc gcttgaacgc aggaggcaga 3301 ggttgcagga gctgagatcg cgccattgca ctccagcctg ggcaacagag tgagactctg 3361 tctcaaaaaa taataataaa ataaatgaac acacatgctg ctgagtccgc agggggggca 3421 gagcagagga cagcgtgctt ttgtgtactg ttggaagact ggctcctcct gtacagcacc 3481 tctgagccct tgtgcaccgc cctgccacgg gcaccatcca gtcctggccg tgtgaccacc 3541 cacagctgac tgggcagcag gcacaggccc tacccgagca ggccggagtt ggctcgcatg 3601 actccagctg aggctgcctg tgtacatttc tccagatacc ctatggctaa ttttgttata 3661 actgcacagt ggctgctgcc attttgtatt aaatatattg tgaaacaaac ctatctgggg 3721 agaagcaatc tacttgccgc tgcttcctgt ctggatccag cttgtgtcct tggagagtgg 3781 ctggcccagg tcctattcct gtcctccagc ccgttctttc atgagggaca ggaaggtaaa 3841 atcagccctt aggagagagg tctcagcctc cctttcccag atctcccagt gagttttaaa 3901 ggaagcaggg agcccagagt gctaagttct tacagccaga aggaagctta tagatttctg 3961 aaaaccgccc ctttgttttt aaaaagatca acacaatttg actttctcaa ggtcaaaacg 4021 aactagaatc cagatctgct catggcaaaa atgggggtgt tctgagaatt ccagctttgg 4081 gccgcactgt acagcagtct ggatagagtg tgatctgaga agggaatggg tctgggttgt 4141 tccacccctt ccgagttcca aaaagaggga actggttttc ttggttctca gcccagcagc 4201 acctatcctg gctcttggtc ctggcctgca gccaagtgct gttcctagcc tgaggcttga 4261 gacaggtggg gttggctcct caccaacccc agttccgtcc catcctgagg gcaagatcct 4321 gggctcatag gcagtccctt tcacttcctt gtcttgctcc ctgctatgtt ggagatgaat 4381 gtgactaaaa gggccatctt gctggcttaa tgtgtggctg gagagaccag cctggagaca 4441 atgtggcaaa atggggcgct tcatccagtc tgtctaagcc ctgtcgactt ggggaggtga 4501 tttctttcct ggttctatat gtgaagcaaa ataaatgttt taaaattaaa agcaaaaaaa 4561 acaaaatgaa ccatg

[0275] In some embodiments of the methods of the disclosure, the wild type human IVD/DISP2 gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NP_001152980.1, transcript variant 2):

TABLE-US-00046 (SEQ ID NO: 28) 1 maematatrl lgwrvaswrl rpplagfvsq rahsllpvdd ainglseeqr qefwkqlgnl 61 gvlgitapvq yggsglgyle hvlvmeeisr asgavglsyg ahsnlcinql vrngneaqke 121 kylpklisge yigalamsep nagsdvvsmk lkaekkgnhy ilngnkfwit ngpdadvliv 181 yaktdlaavp asrgitafiv ekgmpgfsts kkldklgmrg sntcelifed ckipaanilg 241 henkgvyvlm sgldlerlvl aggplglmqa vldhtipylh vreafgqkig hfqlmqgkma 301 dmytrlmacr qyvynvakac deghctakdc agvilysaec atqvaldgiq cfggngyind 361 fpmgrflrda klyeigagts evrrlvigra fnadfh

[0276] In some embodiments of the methods of the disclosure, the wild type human DPP9 gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_139159.41:

TABLE-US-00047 (SEQ ID NO: 29) 1 caacttccgg gtcaaaggtg cctgagccgg cgggtcccct gtgtccgccg cggctgtcgt 61 cccccgctcc cgccacttcc ggggtcgcag tcccgggcat ggagccgcga ccgtgaggcg 121 ccgctggacc cgggacgacc tgcccagtcc ggccgccgcc ccacgtcccg gtctgtgtcc 181 cacgcctgca gctggaatgg aggctctctg gaccctttag aaggcacccc tgccctcctg 241 aggtcagctg agcggttaat gcggaaggtt aagaaactgc gcctggacaa ggagaacacc 301 ggaagttgga gaagcttctc gctgaattcc gagggggctg agaggatggc caccaccggg 361 accccaacgg ccgaccgagg cgacgcagcc gccacagatg acccggccgc ccgcttccag 421 gtgcagaagc actcgtggga cgggctccgg agcatcatcc acggcagccg caagtactcg 481 ggcctcattg tcaacaaggc gccccacgac ttccagtttg tgcagaagac ggatgagtct 541 gggccccact cccaccgcct ctactacctg ggaatgccat atggcagccg agagaactcc 601 ctcctctact ctgagattcc caagaaggtc cggaaagagg ctctgctgct cctgtcctgg 661 aagcagatgc tggatcattt ccaggccacg ccccaccatg gggtctactc tcgggaggag 721 gagctgctga gggagcggaa acgcctgggg gtcttcggca tcacctccta cgacttccac 781 agcgagagtg gcctcttcct cttccaggcc agcaacagcc tcttccactg ccgcgacggc 841 ggcaagaacg gcttcatggt gtcccctatg aaaccgctgg aaatcaagac ccagtgctca 901 gggccccgga tggaccccaa aatctgccct gccgaccctg ccttcttctc cttcatcaat 961 aacagcgacc tgtgggtggc caacatcgag acaggcgagg agcggcggct gaccttctgc 1021 caccaaggtt tatccaatgt cctggatgac cccaagtctg cgggtgtggc caccttcgtc 1081 atacaggaag agttcgaccg cttcactggg tactggtggt gccccacagc ctcctgggaa 1141 ggttcagagg gcctcaagac gctgcgaatc ctgtatgagg aagtcgatga gtccgaggtg 1201 gaggtcattc acgtcccctc tcctgcgcta gaagaaagga agacggactc gtatcggtac 1261 cccaggacag gcagcaagaa tcccaagatt gccttgaaac tggctgagtt ccagactgac 1321 agccagggca agatcgtctc gacccaggag aaggagctgg tgcagccctt cagctcgctg 1381 ttcccgaagg tggagtacat cgccagggcc gggtggaccc gggatggcaa atacgcctgg 1441 gccatgttcc tggaccggcc ccagcagtgg ctccagctcg tcctcctccc cccggccctg 1501 ttcatcccga gcacagagaa tgaggagcag cggctagcct ctgccagagc tgtccccagg 1561 aatgtccagc cgtatgtggt gtacgaggag gtcaccaacg tctggatcaa tgttcatgac 1621 atcttctatc ccttccccca atcagaggga gaggacgagc tctgctttct ccgcgccaat 1681 gaatgcaaga ccggcttctg ccatttgtac aaagtcaccg ccgttttaaa atcccagggc 1741 tacgattgga gtgagccctt cagccccggg gaagatgaat ttaagtgccc cattaaggaa 1801 gagattgctc tgaccagcgg tgaatgggag gttttggcga ggcacggctc caagatctgg 1861 gtcaatgagg agaccaagct ggtgtacttc cagggcacca aggacacgcc gctggagcac 1921 cacctctacg tggtcagcta tgaggcggcc ggcgagatcg tacgcctcac cacgcccggc 1981 ttctcccata gctgctccat gagccagaac ttcgacatgt tcgtcagcca ctacagcagc 2041 gtgagcacgc cgccctgcgt gcacgtctac aagctgagcg gccccgacga cgaccccctg 2101 cacaagcagc cccgcttctg ggctagcatg atggaggcag ccagctgccc cccggattat 2161 gttcctccag agatcttcca tttccacacg cgctcggatg tgcggctcta cggcatgatc 2221 tacaagcccc acgccttgca gccagggaag aagcacccca ccgtcctctt tgtatatgga 2281 ggcccccagg tgcagctggt gaataactcc ttcaaaggca tcaagtactt gcggctcaac 2341 acactggcct ccctgggcta cgccgtggtt gtgattgacg gcaggggctc ctgtcagcga 2401 gggcttcggt tcgaaggggc cctgaaaaac caaatgggcc aggtggagat cgaggaccag 2461 gtggagggcc tgcagttcgt ggccgagaag tatggcttca tcgacctgag ccgagttgcc 2521 atccatggct ggtcctacgg gggcttcctc tcgctcatgg ggctaatcca caagccccag 2581 gtgttcaagg tggccatcgc gggtgccccg gtcaccgtct ggatggccta cgacacaggg 2641 tacactgagc gctacatgga cgtccctgag aacaaccagc acggctatga ggcgggttcc 2701 gtggccctgc acgtggagaa gctgcccaat gagcccaacc gcttgcttat cctccacggc 2761 ttcctggacg aaaacgtgca ctttttccac acaaacttcc tcgtctccca actgatccga 2821 gcagggaaac cttaccagct ccagatctac cccaacgaga gacacagtat tcgctgcccc 2881 gagtcgggcg agcactatga agtcacgttg ctgcactttc tacaggaata cctctgagcc 2941 tgcccaccgg gagccgccac atcacagcac aagtggctgc agcctccgcg gggaaccagg 3001 cgggagggac tgagtggccc gcgggcccca gtgaggcact ttgtcccgcc cagcgctggc 3061 cagccccgag gagccgctgc cttcaccgcc ccgacgcctt ttatcctttt ttaaacgctc 3121 ttgggtttta tgtccgctgc ttcttggttg ccgagacaga gagatggtgg tctcgggcca 3181 gcccctcctc tccccgcctt ctgggaggag gaggtcacac gctgatgggc actggagagg 3241 ccagaagaga ctcagaggag cgggctgcct tccgcctggg gctccctgtg acctctcagt 3301 cccctggccc ggccagccac cgtccccagc acccaagcat gcaattgcct gtcccccccg 3361 gccagcctcc ccaacttgat gtttgtgttt tgtttggggg gatatttttc ataattattt 3421 aaaagacagg ccgggcgcgg tggctcacgt ctgtaatccc agcactttgg gaggctgagg 3481 cgggcggatc acctgaggtt gggagttcaa gaccagcctg gccaacatgg ggaaaccccg 3541 tctctactaa aaatacaaaa aattagccgg gtgtggtggc gcgtgcctat aatcccagct 3601 actcgggagg ctgaggcagg agaatcgctt gaacccggga ggtggaggtt gcggtgagcc 3661 aagatcgcac cattgcactc cagcctgggc aacaagagcg aaactctgtc tcaaaataaa 3721 taaaaaataa aagacagaaa gcaaggggtg cctaaatcta gacttggggt ccacaccggg 3781 cagcggggtt gcaacccagc acctggtagg ctccatttct tcccaagccc gagcagaggg 3841 tcatgcgggc cccacaggag aagcggccag ggcccgcggg gggcaccacc tgtggacagc 3901 cctcctgtcc ccaagctttc aggcaggcac tgaaacgcac cgaacttcca cgctctgctg 3961 gtcagtggcg gctgtcccct ccccagccca gccgcccagc cacatgtgtc tgcctgaccc 4021 gtacacacca ggggttccgg ggttgggagc tgaaccatcc ccacctcagg gttatatttc 4081 cctctcccct tccctccccg ccaagagctc tgccaggggc gggcaaaaaa aaaagtaaaa 4141 agaaaagaaa aaaaaaaaaa agaaacaaac cacctctaca tattatggaa agaaaatatt 4201 tttgtcgatt cttattcttt tataattatg cgtggaagaa gtagacacat taaacgattc 4261 cagttggaaa aaaaaaaaaa aaaaaa

[0277] In some embodiments of the methods of the disclosure, the wild type human

[0278] DPP9 gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: NP_631898.3):

TABLE-US-00048 (SEQ ID NO: 30) 1 mrkvkklrld kentgswrsf slnsegaerm attgtptadr gdaaatddpa arfqvqkhsw 61 dglrsiihgs rkysglivnk aphdfqfvqk tdesgphshr lyylgmpygs rensllysei 121 pkkvrkeall llswkqmldh fqatphhgvy sreeellrer krlgvfgits ydfhsesglf 181 lfqasnslfh crdggkngfm vspmkpleik tqcsgprmdp kicpadpaff sfinnsdlwv 241 anietgeerr ltfchqglsn vlddpksagv atfviqeefd rftgywwcpt aswegseglk 301 tlrilyeevd esevevihvp spaleerktd syryprtgsk npkialklae fqtdsqgkiv 361 stqekelvqp fsslfpkvey iaragwtrdg kyawamfldr pqqwlqlvll ppalfipste 421 neeqrlasar avprnvqpyv vyeevtnvwi nvhdifypfp qsegedelcf lranecktgf 481 chlykvtavl ksqgydwsep fspgedefkc pikeeialts gewevlarhg skiwvneetk 541 lvyfqgtkdt plehhlyvvs yeaageivrl ttpgfshscs msqnfdmfvs hyssystppc 601 vhvyklsgpd ddplhkqprf wasmmeaasc ppdyvppeif hfhtrsdvrl ygmiykphal 661 qpgkkhptvl fvyggpqvql vnnsfkgiky lrlntlaslg yavvvidgrg scqrglrfeg 721 alknqmgqve iedqveglqf vaekygfidl srvaihgwsy ggflslmgli hkpqvfkvai 781 agapvtvwma ydtgyterym dvpennqhgy eagsvalhve klpnepnrll ilhgfldenv 841 hffhtnflvs qliragkpyq lqiypnerhs ircpesgehy evtllhflqe yl

[0279] In some embodiments of the methods of the disclosure, the wild type human SIGLEC14 gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_001098612.1):

TABLE-US-00049 (SEQ ID NO: 31) 1 actcaccctc cggcttcctg tcggggcttt ctcagcccca ccccacgttt ggacatttgg 61 agcatttcct tccctgacag ccggacctgg gactgggctg gggccctggc ggatggagac 121 atgctgcccc tgctgctgct gcccctgctg tggggggggt ccctgcagga gaagccagtg 181 tacgagctgc aagtgcagaa gtcggtgacg gtgcaggagg gcctgtgcgt ccttgtgccc 241 tgctccttct cttacccctg gagatcctgg tattcctctc ccccactcta cgtctactgg 301 ttccgggacg gggagatccc atactacgct gaggttgtgg ccacaaacaa cccagacaga 361 agagtgaagc cagagaccca gggccgattc cgcctccttg gggatgtcca gaagaagaac 421 tgctccctga gcatcggaga tgccagaatg gaggacacgg gaagctattt cttccgcgtg 481 gagagaggaa gggatgtaaa atatagctac caacagaata agctgaactt ggaggtgaca 541 gccctgatag agaaacccga catccacttt ctggagcctc tggagtccgg ccgccccaca 601 aggctgagct gcagccttcc aggatcctgt gaagcgggac cacctctcac attctcctgg 661 acggggaatg ccctcagccc cctggacccc gagaccaccc gctcctcgga gctcaccctc 721 acccccaggc ccgaggacca tggcaccaac ctcacctgtc aggtgaaacg ccaaggagct 781 caggtgacca cggagagaac tgtccagctc aatgtctcct atgctccaca gaacctcgcc 841 atcagcatct tcttcagaaa tggcacaggc acagccctgc ggatcctgag caatggcatg 901 tcggtgccca tccaggaggg ccagtccctg ttcctcgcct gcacagttga cagcaacccc 961 cctgcctcac tgagctggtt ccgggaggga aaagccctca atccttccca gacctcaatg 1021 tctgggaccc tggagctgcc taacatagga gctagagagg gaggggaatt cacctgccgg 1081 gttcagcatc cgctgggctc ccagcacctg tccttcatcc tttctgtgca gagaagctcc 1141 tcttcctgca tatgtgtaac tgagaaacag cagggctcct ggcccctcgt cctcaccctg 1201 atcagggggg ctctcatggg ggctggcttc ctcctcacct atggcctcac ctggatctac 1261 tataccaggt gtggaggccc ccagcagagc agggctgaga ggcctggctg agcccctccc 1321 gctcaagaca gaactgaggt gtggacactt agccctgtgg gacacatgca ggacatcact 1381 gtcagcttct ttctggaagc tcacatccca ctgactaccc ctcttttcct tcctgcccca 1441 taccccttct acttattccc ctctgcttgt gagtcttgcc ccaccacacc tgcatcccca 1501 tctgcacccc atcccctctc cacctgccct tctcttccct ctccatccac catctccagc 1561 cctgtgaagg gaatgtactt tcggtcttat acccccatta cccattaccc aaaagttacc 1621 tttttttttt tttttttttt ttgagacaga gtctcactct gttgcacagg ctggagttca 1681 gtggcacaat ctccgttcac tgcaacctcc acctctgggg ttcaagcaat tctcctgcct 1741 cagcctccct agtagctggg attacaggtg cctgccacca catccagtta attttttttt 1801 tttgtatgtt agtagagatg gggttttacc atgttggcca ggtctcgaac tcctgacctc 1861 aagcaatcca ctgcattggc ctcccaaagt gctggcatta caggtatgag ccaccgtgcc 1921 tggctgccaa aagttacctt cttaacactt gaatttctgg tctcctcagc ttccctatcc 1981 atataggcac agagaggcag catttgtttt ccagttaaaa ctctacctca ttgtgattat 2041 tatccaatac aattgttaca aaataagtaa aacttttatg aaacaataca acataactga 2101 ttttactctt taa

[0280] In some embodiments of the methods of the disclosure, the wild type human SIGLEC14 gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: NP_001092082.1):

TABLE-US-00050 (SEQ ID NO: 32) 1 mlpllllpll wggslqekpv yelqvqksvt vqeglcvlvp csfsypwrsw ysspplyvyw 61 frdgeipyya evvatnnpdr rvkpetqgrf rllgdvqkkn cslsigdarm edtgsyffry 121 ergrdvkysy qqnklnlevt aliekpdihf leplesgrpt rlscslpgsc eagppltfsw 181 tgnalspldp ettrsseltl tprpedhgtn ltcqvkrqga qvttertvql nvsyapqnla 241 isiffrngtg talrilsngm svpiqegqsl flactvdsnp paslswfreg kalnpsqtsm 301 sgtlelpnig areggeftcr vqhplgsqhl sfilsvqrss sscicvtekq qgswplvltl 361 irgalmgagf lltygltwiy ytrcggpqqs raerpg

[0281] In some embodiments of the methods of the disclosure, the wild type human ADM2 gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_001253845.1):

TABLE-US-00051 (SEQ ID NO: 33) 1 cgcccacgcc cggcgccccg accgcggagg actccccgag ccccgcccgc catggcccgg 61 atcccgacgg ccgccctggg ttgcatcagc ctcctctgcc tgcagctccc tggctcgctg 121 tcccgcagcc tgggcgggga cccgcgaccc gtcaaaccca gggagccccc agcccggagc 181 ccttccagca gcctgcagcc caggcacccc gcaccccgac ctgtggtctg gaagcttcac 241 cgggccctcc aggcacagag gggtgccggc ctggcccctg ttatgggtca gcctctccgg 301 gatggtggcc gccaacactc gggcccccga agacactcgg gcccccgcag gacccaagcc 361 cagctcctgc gagtgggctg tgtgctgggc acctgccagg tgcagaatct cagccaccgc 421 ctgtggcaac tcatgggacc ggccggccgg caggactcag ctcctgtgga ccccagcagc 481 ccccacagct atggctgagg tggggccggg ccacacccct gcccatccca gccagggtgc 541 tgtgcccccg tccagagctg cagctgagcc ccatctgaag cccagtccct cggagctgca 601 gacagcaggt cctgcagcaa caatacctgc acggctttgc acacgtaaac ctaggctggt 661 ctacacgcag tgctggtacg tcaaggagcc taaacaccct gaaattgtga ccccctgggg 721 gacagctgcc agacacagct ggcggcagca ccagatgcta agcgcttcag agaggaggtg 781 tctgcccaga gatgtggagc agaagctggg ccctgaacac acggggccat gtctggacga 841 gcaggggaga gaggctgaac tggccagaag tggcccctcc gctgctggtc cagtcagact 901 gaagcccggc cttgtgcctg ggctgttcct gctctcatgc acaaccagcc cttccacgtg 961 cctgcctgtg ggacaggagg gggagcgtgg gatgctgtag cccccggggt tgggcaaggg 1021 aaggatggtg gccctccaga ggtcatgaag ggacctctgt ggctccagct gccaaccctg 1081 gagcccagac cgaggtggcc atggagactc cacctggatc ccctgtagga ggccagggag 1141 gggaactcag cagttcagga gccaccccaa accattctgg gacagggaca cccctttcta 1201 ccccagggca gggcagggct gggtggggca agatccccca gcccgactag acccacctca 1261 cctgaagggg gtgagaccct tgttggcagc cagacaaggg tggggctcca caggcagcac 1321 aggcgcccca ccaccaccca gtttggggac ccagtgggac caggtgcggg ggcagagggt 1381 gacttaccaa gagccaggga gggcagccca ggcccaagtg acagcaagaa caagaaccac 1441 tgccggcgtg cacagacttg gtgtgtgtcc ttccctgggg ggacggggga ctcacatgtg 1501 cctgccactg gagcctctca accgtccagc agaacacggg gttcagaaag ggctccttct 1561 gctatttagc gaacactgag catttaattt acaaatgttt gctagggtca ccctctcggc 1621 catcccacga gggtcgccat gatcacccca actctagagg ccgcagcaga gctcaggaca 1681 ttcccccaca gagcttgccc ctcagttcct acctccaagg gggagggtcc tggaagcgcc 1741 cacccaggcg ccgcccctgt gcttgctccc cgagctcagg gattgccgag tccacgtaac 1801 tgacctgtac tccacgaggc cctgtgggaa cggtccaggc tggtcctgcc ctgtggaggc 1861 ctccgtgcac tgagagatgt actaggattg cagcaaaggt ggtcagggtg atgggccgca 1921 cagcgaggca gtcaaggcca gctccctggg agaagcactg ggtcaggtga ggtctgagga 1981 cagcaggcct tccctagggg aaggagctgg gagtgccaag gccccaggtg cacaggaggc 2041 gtggctgctg agaggctgca gggtggaggg gcctcggcct cagagtcatg tgccctgtga 2101 ccactgaagg gtgtcagcag agcacacggc atgaggacag agggaggggc acggggagtg 2161 aaggaggggg ccctggggca aggctcgggg gtcaggagct cagcgtccgc tactcagccc 2221 agccaaaacc ctcccagacg tctcctctcc tgcctgggca aagtccagct tggcaccccg 2281 tctggggcct gcctgtggtc agggccaagt gttccctcct ccaggaaagc ctttaccctc 2341 ctcatgccct gtagtcagga ggccgcctgc tgtaaccctc cgtgtcgcct cgggtgcgaa 2401 atcagaccca cctgacacca tcacgcggag gcccagcagc acctgcaccc acttccagct 2461 gctctggcca aaatctccgc tcggccaggc cccgtggctc acacctgtaa tcctagcaca 2521 ttgggaggcc aaggcaggca catcacctga gttcaggagt tcaagaccag cctggccaac 2581 atggtgaaat cccgtctcta ctaaaaacag aaaattatcc gggcgtggtg gcacatgact 2641 gtaatcccag ctactcagga ggctgaggca ggaggatcac ttgaacctgg gaggcggagg 2701 ttgcagtgag ctgagattgc gccattgcac tccagcctgg gcaacaagag caaaattctg 2761 cctcaaaaaa aaaaatagta ataatacaaa aattagctgg gcgtggtggc acatgccagt 2821 aattccatct actcgggagg ctgaggcagg agaatcgtct aagcccggga ggtggaggtt 2881 gcagtgagcc cagatggcgc tgctgcactc aagcttggat gacagagcaa gactccgttt 2941 caaaaaaaaa aaacctcctc tcttccttca caccttcctc tgaatcccac ccggtcccac 3001 ctcctgaacc tatccagaca ccttctcctg acccaggcac cacctgcttt cggggcgatg 3061 gccgtagcct cctcccaggc acctgtctgc atccctctgg ccagtgcatg ctgagcacgt 3121 gacctacccg tgttgggaca cgtgaggata cagccttgac ccccaggggc tgacattcta 3181 gggggagata gaaggagaca aacgtagaag gtagaataag tgggtggtgg agtggcaggg 3241 agtgctgagt gccacaggaa gtcagacaag gaaggagagt gtggggcagg tgccgtttaa 3301 atggggggcg ctggggtctc ctcacagttg cttctcagct cagctgtgcc aggatcttgt 3361 tgagtcaggt cagctgccca cagccctctt gcctgacccc tgaagcccag aactctgatc 3421 ttcacagccc taggtatggc cccagcaccc cactgccctc tctcctgccc cagccgactg 3481 ctgttcccag acttccctgg ccacgctcca agacgccagc tctgccgcgg gcactttgtt 3541 ctcacggtgt cctccatgcc tgcagggccc atgcatggga agttgcgttg gcggcctggg 3601 tgttggcggt tccgtgcctg ctccaactct ccgtgaggcc cctctcccag agcctgacac 3661 actctgtggc cgaactctag gcaggtgccc ctgagtcctt tcctcgacga ggcctgaccc 3721 catccccatc ctcgctgggc ccgccgaccc cggtgttagc aagaatcctc taaatcagtt 3781 tatggagaat tacccaccct cgatatctga tcccattcct catctcccac ccttgatctc 3841 atcaccctgc cggcctcctg caagatcctc attgagccac tccagtgaga atccccctac 3901 cctcgaaggc cgccctaaca acttcccatc cgctgacccc tccaacgcca tcaatctcca 3961 gctgtggttg ttgaactcgg aggtgagctc ctctcaccac tctcttgaat aaagcttttc 4021 tcaccatttt aaaaaaaaaa aaaaa

[0282] In some embodiments of the methods of the disclosure, the wild type human ADM2 gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: NP_001240774.1):

TABLE-US-00052 (SEQ ID NO: 34) 1 mariptaalg cisllclqlp gslsrslggd prpvkprepp arspssslqp rhpaprpvvw 61 klhralqaqr gaglapvmgq plrdggrqhs gprrhsgprr tqaqllrvgc vlgtcqvqnl 121 shrlwqlmgp agrqdsapvd pssphsyg

[0283] In some embodiments of the methods of the disclosure, the wild type human TSPAN5 gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_005723.3):

TABLE-US-00053 (SEQ ID NO: 35) 1 aggcgggcgg agcgaggggt gggagggcgc gcgcgaacgg gcgggcgagc aagcgagcgg 61 cgtctccacc agcatctgcc gcggccgcct ttgcccgaag cccggggacg aaccgacgga 121 ccgaccgcct ggcgcacgga cgcgggcgct cgctttgtgt tcggggctag cgtcggcgag 181 gcttgagctt gcagcgcgcg gcttccctgc tttctcgcgg ccaccccggc tccggcggcc 241 tcggcgcgcg aggggctgga ggtgcgggag ccgctctccg ccggtcggtc cccgcgcggc 301 tgagcccagg ccgccagcgc cgcggccccg tgcggtgtcc ctgagctcct gctccccgcc 361 gggctgctcc gagcaacggt gcttcggagc tccaaactcg ggctgccggg gcaagtgtct 421 tcatgaaccc agaggatgtc cgggaagcac tacaagggtc ctgaagtcag ttgttgcatc 481 aaatacttca tatttggctt caatgtcata ttttggtttt tgggaataac atttcttgga 541 attggactgt gggcatggaa tgaaaaagga gttctgtcca acatctcttc catcaccgat 601 ctcggcggct ttgacccagt ttggctcttc cttgtggtgg gaggagtgat gttcattttg 661 ggatttgcag ggtgcattgg agcgctacgg gaaaacactt tccttctcaa gtttttttct 721 gtgttcctgg gaattatttt cttcctggag ctcactgccg gagttctagc atttgttttc 781 aaagactgga tcaaagacca gctgtatttc tttataaaca acaacatcag agcatatcgg 841 gatgacattg atttgcaaaa cctcatagac ttcacccagg aatattggca gtgctgtggg 901 gcttttggag ctgatgattg gaacctaaat atttacttca attgcacaga ttccaatgca 961 agtcgagagc gatgtggcgt tccattctcc tgctgcacta aagatcccgc agaagatgtc 1021 atcaacactc agtgtggcta tgatgccagg caaaaaccag aagttgacca gcagattgta 1081 atctacacga aaggctgtgt gccccagttt gagaagtggt tgcaggacaa tttaaccatc 1141 gttgctggta ttttcatagg cattgcattg ctgcagatat ttgggatatg cctggcccag 1201 aatttggtta gcgatatcga agctgtcagg gcgagctggt agaccccctg caaccgctgc 1261 tgcaagacac tggacagacc cagctttcgg gaccctcccg cgtgccgaac tgatcttcga 1321 gctgcatgga cctaatcaca gatgcagcct gcagtctcgc ctaatggagc tgccattagg 1381 ggagtgtaaa actgggaaat gctgctcact gacagaatta aaaaaaaaaa taaccagtat 1441 gaaagtcgtt gcgccgtgaa tctctactgt agccatgaat ttatggacag ttagatgctt 1501 accaaaaaag aaaaaaaggg agggtagggg acccagatgt acttgaatgt gcagaaaata 1561 cattcttgtc ctcatcttcc gtaattggag ggctgggaga ggcagctttg ctcttcacca 1621 caccttggac ggaccacctt ctttctgttc catggcctga aggagtgcat ctcctcaaag 1681 actcagcccc tcacctggga gggcagtggt ttgtgggcat ccctccatgt acattttagg 1741 aaacacttgc aactctcatc tgaagaagaa aacaactcat ctttgggttc agattttgtg 1801 atggtattca gcaagtcact tgggcgagca cacttggtct atcctggaaa gtctccttat 1861 aagagaagtt gtgtatttca tgtgcaccga gcaagggcat tggaagacgt catgaggctg 1921 tattttagca ggactgatcg tttttctaag tagacctgag ctttgtttat cagtgaaatt 1981 caaggagaaa atgaggttaa tgaagaggta tcagttaaat atccccttct tctcaccctg 2041 ccaaaattag cagttggatt tttggaaact ctggaatatt ctgggtcatt ttgttttgta 2101 tgtttgttgt ttttcgtctt ccaaaggtga aagctatgat acagttccac ttaaatttta 2161 gtgttttctt actcagctca agcattaatt tttgattaag tcttaatctg catgacctgt 2221 gaatctgaat ccatcatctc cctttcctgc cagcttttct acaaacattg aaatatgtta 2281 tttggtcagc acttatttcc taggttcaca gccttgggag gttgtggcat gtcctcccag 2341 tctggctggg aagagaccag ctgtaccatc caaatgcttc cctggtcttg atgatctctt 2401 ccagagtcga tctgagtggc cttttctgca ccctcccctt ctttctcttt gaatggaatt 2461 aaacccaatt tggaaacaac attgacccag tcaaaagctt ctaatggttt ctttttcttc 2521 ctccagtttt agtttgcttt tattaaaaaa agaaaatagt gcatggccat agctccttca 2581 gttctcttat tgcagactaa ccatcaggat ggtatcaaag cacaaatact ttggagggga 2641 atgcgttgaa ctggggcaag tactctgtaa cacaaagtgg gaaaccactt cctggtgctg 2701 ccgctcctgc ccccacttta ggtgggaggg acgagttttg ccctctagat tttaatccag 2761 ctggtgtcca ccggatgttg ccctcctggg gagcagatat cagtctgtgg aactctggga 2821 aaaccacagg cacatttttc ggtgcggaca gatttgccag cacataactg ggcagccagc 2881 tagaatactt tgtggaaatt aagcgaggtt ttccatttca gccccatggt gcatggtggt 2941 ggccgatgaa tgtgtcagtc tgctcagaga aaggacaaaa aggaaattat tttcaaaact 3001 gtgttcactg tttgggtgtg tgtatggctc tgcatgtgtg tgtttttgtc tctgtatagg 3061 tagaggtatt cacatcttac tccgactgta aggttgtctt acttcatctc tgcccccacc 3121 acagttgcca ttttgtaatg tccttccaac atggagaaga cacgagctct ctccagttgg 3181 catcatttgt cttttttgtt gattgcctca ttctccagtg aactccatct ggccaattga 3241 ttcagaatca ggcaagatcc ctgccctttg gcacatccac tgaaaggcca aacagcaagt 3301 ccgagtgagt tttaaatatt aattaatcac cctttatttt ttacacttga gagtgattgt 3361 aataaaggct gtcattaata aacttggttc taccttaaaa aaaaaa

[0284] In some embodiments of the methods of the disclosure, the wild type human TSPAN5 gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: NP_005714.2):

TABLE-US-00054 (SEQ ID NO: 52) 1 msgkhykgpe vsccikyfif gfnvifwflg itflgiglwa wnekgvlsni ssitdlggfd 61 pvwlflvvgg vmfilgfagc igalrentfl lkffsvflgi iffleltagv lafvfkdwik 121 dqlyffinnn irayrddidl qnlidftqey wqccgafgad dwnlniyfnc tdsnasrerc 181 gvpfscctkd paedvintqc gydarqkpev dqqiviytkg cvpqfekwlq dnitivagif 241 igiallqifg iclaqnlvsd ieavrasw

[0285] In some embodiments of the methods of the disclosure, the wild type human CAMKK1 gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_032294.2, transcript variant 1):

TABLE-US-00055 (SEQ ID NO: 53) 1 ctgggcccca gcgaggcggt ggggcggggc ggggcggggc ggggcgcgca gcaggagcga 61 gtggggccgc ccgccgggcc gcggacactg tcgcccggcg cccaggttcc caacaaggct 121 acgcagaaga acccccttga ctgaagcaat ggaggggggt ccagctgtct gctgccagga 181 tcctcgggca gagctggtag aacgggtggc agccatcgat gtgactcact tggaggaggc 241 agatggtggc ccagagccta ctagaaacgg tgtggacccc ccaccacggg ccagagctgc 301 ctctgtgatc cctggcagta cttcaagact gctcccagcc cggcctagcc tctcagccag 361 gaagctttcc ctacaggagc ggccagcagg aagctatctg gaggcgcagg ctgggcctta 421 tgccacgggg cctgccagcc acatctcccc ccgggcctgg cggaggccca ccatcgagtc 481 ccaccacgtg gccatctcag atgcagagga ctgcgtgcag ctgaaccagt acaagctgca 541 gagtgagatt ggcaagggtg cctacggtgt ggtgaggctg gcctacaacg aaagtgaaga 601 cagacactat gcaatgaaag tcctttccaa aaagaagtta ctgaagcagt atggctttcc 661 acgtcgccct cccccgagag ggtcccaggc tgcccaggga ggaccagcca agcagctgct 721 gcccctggag cgggtgtacc aggagattgc catcctgaag aagctggacc acgtgaatgt 781 ggtcaaactg atcgaggtcc tggatgaccc agctgaggac aacctctatt tggtgtttga 841 cctcctgaga aaggggcccg tcatggaagt gccctgtgac aagcccttct cggaggagca 901 agctcgcctc tacctgcggg acgtcatcct gggcctcgag tacttgcact gccagaagat 961 cgtccacagg gacatcaagc catccaacct gctcctgggg gatgatgggc acgtgaagat 1021 cgccgacttt ggcgtcagca accagtttga ggggaacgac gctcagctgt ccagcacggc 1081 gggaacccca gcattcatgg cccccgaggc catttctgat tccggccaga gcttcagtgg 1141 gaaggccttg gatgtatggg ccactggcgt cacgttgtac tgctttgtct atgggaagtg 1201 cccattcatc gacgatttca tcctggccct ccacaggaag atcaagaatg agcccgtggt 1261 gtttcctgag gagccagaaa tcagcgagga gctcaaggac ctgatcctga agatgttaga 1321 caagaatccc gagacgagaa ttggggtgcc agacatcaag ttgcaccctt gggtgaccaa 1381 gaacggggag gagccccttc cttcggagga ggagcactgc agcgtggtgg aggtgacaga 1441 ggaggaggtt aagaactcag tcaggctcat ccccagctgg accacggtga tcctggtgaa 1501 gtccatgctg aggaagcgtt cctttgggaa cccgtttgag ccccaagcac ggagggaaga 1561 gcgatccatg tctgctccag gaaacctact ggtgaaagaa gggtttggtg aagggggcaa 1621 gagcccagag ctccccggcg tccaggaaga cgaggctgca tcctgagccc ctgcatgcac 1681 ccagggccac ccggcagcac actcatcccg cgcctccaga ggcccacccc tcatgcaaca 1741 gccgcccccg caggcagggg gctggggact gcagccccac tcccgcccct cccccatcgt 1801 gctgcatgac ctccacgcac gcacgtccag ggacagactg gaatgtatgt catttggggt 1861 cttgggggca gggctcccac gaggccatcc tcctcttctt ggacctcctt ggcctgaccc 1921 attctgtggg gaaaccgggt gcccatggag cctcagaaat gccacccggc tggttggcat 1981 ggcctggggc aggaggcaga ggcaggagac caagatggca ggtggaggcc aggcttacca 2041 caacggaaga gacctcccgc tggggccggg caggcctggc tcagctgcca caggcatatg 2101 gtggagaggg gggtaccctg cccaccttgg ggtggtggca ccagagctct tgtctattca 2161 gacgctggta tgggggctcg gacccctcac tggggacagg gccagtgttg gagaattctg 2221 attccttttt tgttgtcttt tacttttgtt tttaacctgg gggttcgggg agaggccctg 2281 cttgggaaca tctcacgagc tttcctacat cttccgtggt tcccagcaca gcccaagatt 2341 atttggcagc caagtggatg gaactaactt tcctggactg tgtttcgcat tcggcgttat 2401 ctggaaagtg gactgaacgg aatcaagctc tgagcagagg cctgaagcgg aagcaccaca 2461 tcgtccctgc ccatctcact ctctcccttg atgatgcccc tagagctgag gctggagaag 2521 acaccagggc tgactttgac cgagggccat ggacgcgaca ggcctgtggc cctgcgcatg 2581 ctgaaataac tggaacccag cctctcctcc tacaccggcc tacccatctg ggcccaagag 2641 ctgcactcac actcctacaa cgaaggacaa actgtccagg tcggagggat cacgagacac 2701 agaacctgga ggggtgtgca cgctggcagg tggcctctgc ggcaattgcc tcaccctgag 2761 gacatcagca gtcagcctgc tcagagcggg ggtgctggag cgcgtgcaga cacagctctt 2821 ccggagcagc cttcaccttc tctctgggat cagtgtccgg ctggccgacg tggcatttgc 2881 tgaccgaatg ctcatagagg ttgaccccca cagggtcacg caggactcgg acactgccct 2941 ggaaacatgg atggacaagg gcttttggcc acaggtgtgg gtgtcctgtt ggaggagggc 3001 ttgtttggag aagggaggct ggctggggga gaaacccgga tcccgctgca tctccgcgcc 3061 tgtgggtgca tgtcgcgtgc tcatctgttg cacacagctc actcgtatgt cctgcactgg 3121 tacatgcatc tgtaatacag tttctacgtc tatttaaggc taggagccga atgtgcccca 3181 ttgtcagtgg gtccacgttt ctccccggct cctctgggct aaggcagtgt ggcccgaagc 3241 ttaaaaagtt actcggtact gtttttaaga acacttttat agagttagtg gaaggcaagt 3301 taagagccaa tcactgatcc ccaagtgttt cttgagcatc tggtctgggg ggaccacttt 3361 gatcggaccc acccttggaa agctcagggg taggcccagg tgggatgctc accctgtcac 3421 tgagggtttt ggttggcatc gttgtttttg aatgtagcac aagcgatgag caaactctat 3481 aagagtgttt taaaaattaa cttcccagga agtgagttaa aaacaataaa agccctttct 3541 tgagttaaaa agaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaa

[0286] In some embodiments of the methods of the disclosure, the wild type human CAMKK1 gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: NP_115670.1, transcript variant 1):

TABLE-US-00056 (SEQ ID NO: 54) 1 meggpavccq dpraelvery aaidvthlee adggpeptrn gvdppprara asvipgstsr 61 llparpslsa rklslqerpa gsyleaqagp yatgpashis prawrrptie shhvaisdae 121 dcvqlnqykl qseigkgayg vvrlaynese drhyamkvls kkkllkqygf prrppprgsq 181 aaqggpakql lplervyqei ailkkldhvn vvklievldd paednlylvf dllrkgpvme 241 vpcdkpfsee qarlylrdvi lgleylhcqk ivhrdikpsn lllgddghvk iadfgvsnqf 301 egndaqlsst agtpafmape aisdsgqsfs gkaldvwatg vtlycfvygk cpfiddfila 361 lhrkiknepv vfpeepeise elkdlilkml dknpetrigv pdiklhpwvt kngeeplpse 421 eehcsvvevt eeevknsvrl ipswttvilv ksmlrkrsfg npfepqarre ersmsapgnl 481 lvkegfgegg kspelpgvqe deaas

[0287] In some embodiments of the methods of the disclosure, the wild type human CAMKK1 gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_172206.1, transcript variant 2):

TABLE-US-00057 (SEQ ID NO: 55) 1 agcagaacag agtatgcaat ttgggaagct gtggtgtggc tgcagtggag agttcccaac 61 aaggctacgc agaagaaccc ccttgactga agcaatggag gggggtccag ctgtctgctg 121 ccaggatcct cgggcagagc tggtagaacg ggtggcagcc atcgatgtga ctcacttgga 181 ggaggcagat ggtggcccag agcctactag aaacggtgtg gaccccccac cacgggccag 241 agctgcctct gtgatccctg gcagtacttc aagactgctc ccagcccggc ctagcctctc 301 agccaggaag ctttccctac aggagcggcc agcaggaagc tatctggagg cgcaggctgg 361 gccttatgcc acggggcctg ccagccacat ctccccccgg gcctggcgga ggcccaccat 421 cgagtcccac cacgtggcca tctcagatgc agaggactgc gtgcagctga accagtacaa 481 gctgcagagt gagattggca agggtgccta cggtgtggtg aggctggcct acaacgaaag 541 tgaagacaga cactatgcaa tgaaagtcct ttccaaaaag aagttactga agcagtatgg 601 ctttccacgt cgccctcccc cgagagggtc ccaggctgcc cagggaggac cagccaagca 661 gctgctgccc ctggagcggg tgtaccagga gattgccatc ctgaagaagc tggaccacgt 721 gaatgtggtc aaactgatcg aggtcctgga tgacccagct gaggacaacc tctatttggt 781 gtttgacctc ctgagaaagg ggcccgtcat ggaagtgccc tgtgacaagc ccttctcgga 841 ggagcaagct cgcctctacc tgcgggacgt catcctgggc ctcgagtact tgcactgcca 901 gaagatcgtc cacagggaca tcaagccatc caacctgctc ctgggggatg atgggcacgt 961 gaagatcgcc gactttggcg tcagcaacca gtttgagggg aacgacgctc agctgtccag 1021 cacggcggga accccagcat tcatggcccc cgaggccatt tctgattccg gccagagctt 1081 cagtgggaag gccttggatg tatgggccac tggcgtcacg ttgtactgct ttgtctatgg 1141 gaagtgccca ttcatcgacg atttcatcct ggccctccac aggaagatca agaatgagcc 1201 cgtggtgttt cctgaggagc cagaaatcag cgaggagctc aaggacctga tcctgaagat 1261 gttagacaag aatcccgaga cgagaattgg ggtgccagac atcaagttgc acccttgggt 1321 gaccaagaac ggggaggagc cccttccttc ggaggaggag cactgcagcg tggtggaggt 1381 gacagaggag gaggttaaga actcagtcag gctcatcccc agctggacca cggtgatcct 1441 ggtgaagtcc atgctgagga agcgttcctt tgggaacccg tttgagcccc aagcacggag 1501 ggaagagcga tccatgtctg ctccaggaaa cctactggtg aaagaagggt ttggtgaagg 1561 gggcaagagc ccagagctcc ccggcgtcca ggaagacgag gctgcatcct gagcccctgc 1621 atgcacccag ggccacccgg cagcacactc atcccgcgcc tccagaggcc cacccctcat 1681 gcaacagccg cccccgcagg cagggggctg gggactgcag ccccactccc gcccctcccc 1741 catcgtgctg catgacctcc acgcacgcac gtccagggac agactggaat gtatgtcatt 1801 tggggtcttg ggggcagggc tcccacgagg ccatcctcct cttcttggac ctccttggcc 1861 tgacccattc tgtggggaaa ccgggtgccc atggagcctc agaaatgcca cccggctggt 1921 tggcatggcc tggggcagga ggcagaggca ggagaccaag atggcaggtg gaggccaggc 1981 ttaccacaac ggaagagacc tcccgctggg gccgggcagg cctggctcag ctgccacagg 2041 catatggtgg agaggggggt accctgccca ccttggggtg gtggcaccag agctcttgtc 2101 tattcagacg ctggtatggg ggctcggacc cctcactggg gacagggcca gtgttggaga 2161 attctgattc cttttttgtt gtcttttact tttgttttta acctgggggt tcggggagag 2221 gccctgcttg ggaacatctc acgagctttc ctacatcttc cgtggttccc agcacagccc 2281 aagattattt ggcagccaag tggatggaac taactttcct ggactgtgtt tcgcattcgg 2341 cgttatctgg aaagtggact gaacggaatc aagctctgag cagaggcctg aagcggaagc 2401 accacatcgt ccctgcccat ctcactctct cccttgatga tgcccctaga gctgaggctg 2461 gagaagacac cagggctgac tttgaccgag ggccatggac gcgacaggcc tgtggccctg 2521 cgcatgctga aataactgga acccagcctc tcctcctaca ccggcctacc catctgggcc 2581 caagagctgc actcacactc ctacaacgaa ggacaaactg tccaggtcgg agggatcacg 2641 agacacagaa cctggagggg tgtgcacgct ggcaggtggc ctctgcggca attgcctcac 2701 cctgaggaca tcagcagtca gcctgctcag agcgggggtg ctggagcgcg tgcagacaca 2761 gctcttccgg agcagccttc accttctctc tgggatcagt gtccggctgg ccgacgtggc 2821 atttgctgac cgaatgctca tagaggttga cccccacagg gtcacgcagg actcggacac 2881 tgccctggaa acatggatgg acaagggctt ttggccacag gtgtgggtgt cctgttggag 2941 gagggcttgt ttggagaagg gaggctggct gggggagaaa cccggatccc gctgcatctc 3001 cgcgcctgtg ggtgcatgtc gcgtgctcat ctgttgcaca cagctcactc gtatgtcctg 3061 cactggtaca tgcatctgta atacagtttc tacgtctatt taaggctagg agccgaatgt 3121 gccccattgt cagtgggtcc acgtttctcc ccggctcctc tgggctaagg cagtgtggcc 3181 cgaagcttaa aaagttactc ggtactgttt ttaagaacac ttttatagag ttagtggaag 3241 gcaagttaag agccaatcac tgatccccaa gtgtttcttg agcatctggt ctggggggac 3301 cactttgatc ggacccaccc ttggaaagct caggggtagg cccaggtggg atgctcaccc 3361 tgtcactgag ggttttggtt ggcatcgttg tttttgaatg tagcacaagc gatgagcaaa 3421 ctctataaga gtgttttaaa aattaacttc ccaggaagtg agttaaaaac aataaaagcc 3481 ctttcttgag ttaaaaagaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaa

[0288] In some embodiments of the methods of the disclosure, the wild type human CAMKK1 gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: NP_757343.2, transcript variant 2):

TABLE-US-00058 (SEQ ID NO: 56) 1 mqfgklwcgc sgefptrlrr rtplteameg gpavccqdpr aelvervaai dvthleeadg 61 gpeptrngvd pppraraasv ipgstsrllp arpslsarkl slgerpagsy leaqagpyat 121 gpashispra wrrptieshh vaisdaedcv qlnqyklqse igkgaygvvr laynesedrh 181 yamkvlskkk llkqygfprr ppprgsqaaq ggpakqllpl ervyqeiail kkldhvnvvk 241 lievlddpae dnlylvfdll rkgpvmevpc dkpfseeqar lylrdvilgl eylhcqkivh 301 rdikpsnlll gddghvkiad fgvsnqfegn daqlsstagt pafmapeais dsgqsfsgka 361 ldvwatgvtl ycfvygkcpf iddfilalhr kiknepvvfp eepeiseelk dlilkmldkn 421 petrigvpdi klhpwvtkng eeplpseeeh csvvevteee vknsvrlips wttvilvksm 481 lrkrsfgnpf epqarreers msapgnllvk egfgeggksp elpgvqedea as

[0289] In some embodiments of the methods of the disclosure, the wild type human CAMKK1 gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_172207.2, transcript variant 3):

TABLE-US-00059 (SEQ ID NO: 57) 1 ctgggcccca gcgaggcggt ggggcggggc ggggcggggc ggggcgcgca gcaggagcga 61 gtggggccgc ccgccgggcc gcggacactg tcgcccggcg cccaggttcc caacaaggct 121 acgcagaaga acccccttga ctgaagcaat ggaggggggt ccagctgtct gctgccagga 181 tcctcgggca gagctggtag aacgggtggc agccatcgat gtgactcact tggaggaggc 241 agatggtggc ccagagccta ctagaaacgg tgtggacccc ccaccacggg ccagagctgc 301 ctctgtgatc cctggcagta cttcaagact gctcccagcc cggcctagcc tctcagccag 361 gaagctttcc ctacaggagc ggccagcagg aagctatctg gaggcgcagg ctgggcctta 421 tgccacgggg cctgccagcc acatctcccc ccgggcctgg cggaggccca ccatcgagtc 481 ccaccacgtg gccatctcag atgcagagga ctgcgtgcag ctgaaccagt acaagctgca 541 gagtgagatt ggcaagggtg cctacggtgt ggtgaggctg gcctacaacg aaagtgaaga 601 cagacactat gcaatgaaag tcctttccaa aaagaagtta ctgaagcagt atggctttcc 661 acgtcgccct cccccgagag ggtcccaggc tgcccaggga ggaccagcca agcagctgct 721 gcccctggag cgggtgtacc aggagattgc catcctgaag aagctggacc acgtgaatgt 781 ggtcaaactg atcgaggtcc tggatgaccc agctgaggac aacctctatt tggccctgca 841 gaaccaggcc cagaatatcc agttagattc aacaaatatc gccaagcccc actccctgct 901 tccctctgag cagcaagaca gtggatccac gtgggctgcg cgctcagtgt ttgacctcct 961 gagaaagggg cccgtcatgg aagtgccctg tgacaagccc ttctcggagg agcaagctcg 1021 cctctacctg cgggacgtca tcctgggcct cgagtacttg cactgccaga agatcgtcca 1081 cagggacatc aagccatcca acctgctcct gggggatgat gggcacgtga agatcgccga 1141 ctttggcgtc agcaaccagt ttgaggggaa cgacgctcag ctgtccagca cggcgggaac 1201 cccagcattc atggcccccg aggccatttc tgattccggc cagagcttca gtgggaaggc 1261 cttggatgta tgggccactg gcgtcacgtt gtactgcttt gtctatggga agtgcccatt 1321 catcgacgat ttcatcctgg ccctccacag gaagatcaag aatgagcccg tggtgtttcc 1381 tgaggagcca gaaatcagcg aggagctcaa ggacctgatc ctgaagatgt tagacaagaa 1441 tcccgagacg agaattgggg tgccagacat caagttgcac ccttgggtga ccaagaacgg 1501 ggaggagccc cttccttcgg aggaggagca ctgcagcgtg gtggaggtga cagaggagga 1561 ggttaagaac tcagtcaggc tcatccccag ctggaccacg gtgatcctgg tgaagtccat 1621 gctgaggaag cgttcctttg ggaacccgtt tgagccccaa gcacggaggg aagagcgatc 1681 catgtctgct ccaggaaacc tactggtgta agtactggtg ggccagggac tgccgggcac 1741 tccctggagt tgggtgggga ggtctgaggc ccatcctccc actctcactg tcgttgggcc 1801 aaggccagag cctggggact tggccaggtc tcggtgttgg ccccatttgc atctctgtcc 1861 ccaaggttag tcggggctag aagggacctt ttgggcccag ctcttgcttc attcctgggg 1921 ccagcatccc tcacacacac acttccaggg atgaggagct cacgcagccc ctccatggga 1981 caggaagacc cttcttccat gcagcttgat gtcactctct cactgggtcc agcccctctg 2041 gggcttcaaa tctgtggccc cctcagccct tggcagcctg gcagaggttt gcagacaggc 2101 tgatgttggc ttcctgtagg aggctggcgg gctgtagagg aggggtgctg gcccctctgc 2161 ctggccctgg ggactgttgg ctgctctccc aagtggccca ggctgcctgc agccattgct 2221 ggggctctgt gcccagtcag cactttgtga gtgcttgttc agtgagtaag cagggacagg 2281 ctggccggtg gaccacggga gaggaacccg cattggccga gggctcccta tggtgagcca 2341 cgcctgtggg ttcaccacct cctaggaggg tccagaaaag cagctcccca agcctgtgcg 2401 cctcgtcctc agcagatcca ccttcttcac tataataaaa gccagtctgg gatgctaaaa 2461 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2521 aaaaaaaaaa aaaaa

[0290] In some embodiments of the methods of the disclosure, the wild type human CAMKK1 gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: NP_757344.2, transcript variant 3):

TABLE-US-00060 (SEQ ID NO: 58) 1 meggpavccq dpraelvery aaidvthlee adggpeptrn gvdppprara asvipgstsr 61 llparpslsa rklslqerpa gsyleaqagp yatgpashis prawrrptie shhvaisdae 121 dcvqlnqykl qseigkgayg vvrlaynese drhyamkvls kkkllkqygf prrppprgsq 181 aaqggpakql lplervyqei ailkkldhvn vvklievldd paednlylal qnqaqniqld 241 stniakphsl lpseqqdsgs twaarsvfdl lrkgpvmevp cdkpfseeqa rlylrdvilg 301 leylhcqkiv hrdikpsnll lgddghvkia dfgvsnqfeg ndaqlsstag tpafmapeai 361 sdsgqsfsgk aldvwatgvt lycfvygkcp fiddfilalh rkiknepvvf peepeiseel 421 kdlilkmldk npetrigvpd iklhpwvtkn geeplpseee hcsvvevtee evknsvrlip 481 swttvilvks mlrkrsfgnp fepqarreer smsapgnllv

[0291] In some embodiments of the methods of the disclosure, the wild type human MMPI gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NM_002423.4):

TABLE-US-00061 (SEQ ID NO: 59) 1 gaaaacacca aatcaaccat aggtccaaga acaattgtct ctggacggca gctatgcgac 61 tcaccgtgct gtgtgctgtg tgcctgctgc ctggcagcct ggccctgccg ctgcctcagg 121 aggcgggagg catgagtgag ctacagtggg aacaggctca ggactatctc aagagatttt 181 atctctatga ctcagaaaca aaaaatgcca acagtttaga agccaaactc aaggagatgc 241 aaaaattctt tggcctacct ataactggaa tgttaaactc ccgcgtcata gaaataatgc 301 agaagcccag atgtggagtg ccagatgttg cagaatactc actatttcca aatagcccaa 361 aatggacttc caaagtggtc acctacagga tcgtatcata tactcgagac ttaccgcata 421 ttacagtgga tcgattagtg tcaaaggctt taaacatgtg gggcaaagag atccccctgc 481 atttcaggaa agttgtatgg ggaactgctg acatcatgat tggctttgcg cgaggagctc 541 atggggactc ctacccattt gatgggccag gaaacacgct ggctcatgcc tttgcgcctg 601 ggacaggtct cggaggagat gctcacttcg atgaggatga acgctggacg gatggtagca 661 gtctagggat taacttcctg tatgctgcaa ctcatgaact tggccattct ttgggtatgg 721 gacattcctc tgatcctaat gcagtgatgt atccaaccta tggaaatgga gatccccaaa 781 attttaaact ttcccaggat gatattaaag gcattcagaa actatatgga aagagaagta 841 attcaagaaa gaaatagaaa cttcaggcag aacatccatt cattcattca ttggattgta 901 tatcattgtt gcacaatcag aattgataag cactgttcct ccactccatt tagcaattat 961 gtcacccttt tttattgcag ttggtttttg aatgtctttc actcctttta aggataaact 1021 cctttatggt gtgactgtgt cttattcatc tatacttgca gtgggtagat gtcaataaat 1081 gttacataca caaataaata aaatgtttat tccatggtaa atttaaaaaa aaaaaaaaaa 1141 aaaaaaaaaa aaa

[0292] In some embodiments of the methods of the disclosure, the wild type human MMPI gene of the disclosure consists of or comprises the amino acid sequence (Genbank Accession number: NP_002414.1):

TABLE-US-00062 (SEQ ID NO: 60) 1 mrltvlcavc llpgslalpl pqeaggmsel qweqaqdylk rfylydsetk nansleaklk 61 emqkffglpi tgmlnsrvie imqkprcgvp dvaeyslfpn spkwtskvvt yrivsytrdl 121 phitvdrlvs kalnmwgkei plhfrkvvwg tadimigfar gahgdsypfd gpgntlahaf 181 apgtglggda hfdederwtd gsslginfly aathelghsl gmghssdpna vmyptygngd 241 pqnfklsqdd ikgiqklygk rsnsrkk

[0293] In some embodiments of the methods of the disclosure, the wild type human TERC gene of the disclosure consists of or comprises the nucleic acid sequence (Genbank Accession number: NR_001566.1):

TABLE-US-00063 (SEQ ID NO: 61) 1 gggttgcgga gggtgggcct gggaggggtg gtggccattt tttgtctaac cctaactgag 61 aagggcgtag gcgccgtgct tttgctcccc gcgcgctgtt tttctcgctg actttcagcg 121 ggcggaaaag cctcggcctg ccgccttcca ccgttcattc tagagcaaac aaaaaatgtc 181 agctgctggc ccgttcgccc ctcccgggga cctgcggcgg gtcgcctgcc cagcccccga 241 accccgcctg gaggccgcgg tcggcccggg gcttctccgg aggcacccac tgccaccgcg 301 aagagttggg ctctgtcagc cgcgggtctc tcgggggcga gggcgaggtt caggcctttc 361 aggccgcagg aagaggaacg gagcgagtcc ccgcgcgcgg cgcgattccc tgagctgtgg 421 gacgtgcacc caggactcgg ctcacacatg c

Definitions

[0294] The following definitions are included for the purpose of understanding the present subject matter and for constructing the appended patent claims. Abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0295] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. Any methods, devices and materials similar or equivalent to those described herein can be used in the practice of this disclosure. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure.

[0296] As used herein, the term "FILD" refers to fibrotic interstitial lung disease.

[0297] As used herein, the term "FIP" refers to Familial Interstitial Pneumonia.

[0298] As used herein, the term "HRCT" refers to high-resolution CT (HRCT).

[0299] As used herein, the term "ILA" refers to asymptomatic interstitial lung abnormalities.

[0300] As used herein, the term "IPF" refers to idiopathic pulmonary fibrosis.

[0301] As used herein, the term "PBMC" refers to peripheral blood mononuclear cell.

[0302] As used herein, the term "alleviate" is meant to describe a process by which the severity of a sign or symptom of a disorder is decreased. Importantly, a sign or symptom can be alleviated without being eliminated. In a preferred embodiment, the administration of pharmaceutical compositions disclosed herein leads to the elimination of a sign or symptom, however, elimination is not required. Effective dosages are expected to decrease the severity of a sign or symptom. A sign is an objective indication of a medical condition that is observable or detectable by a medical professional or lay person (e.g. family member) (for example, with respect to fibrotic pulmonary disease, signs include, but are not limited to, changes in body weight, changes in body temperature and the presence of a fibrotic lesion in one or both lungs detectable by radiography).

[0303] A symptom is an indication of disease that may be a sign but may also be exclusively observable or subjectively experienced by the subject (for example, with respect to fibrotic pulmonary disease, symptoms may include but are not limited to, a dry or hacking cough, a sore throat, a tight chest, shortness of breath, and a feeling of exhaustion or malaise).

[0304] In one aspect, the terms "co-administered" and "co-administration" as relating to a subject refer to administering to the subject a compound of the invention or salt thereof along with a compound that may also treat the disorders or diseases contemplated within the invention. In one embodiment, the co-administered compounds are administered separately, or in any kind of combination as part of a single therapeutic approach. The co-administered compound may be formulated in any kind of combinations as mixtures of solids and liquids under a variety of solid, gel, and liquid formulations, and as a solution.

[0305] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful within the disclosure with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, nasal, pulmonary and topical administration.

[0306] A "disease" as used herein is a state of health of an animal or subject wherein the animal or subject cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's or subject's health continues to deteriorate.

[0307] A "disorder" as used herein in an animal is a state of health in which the animal or subject is able to maintain homeostasis, but in which the animal's or subject's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's or subject's state of health.

[0308] As used herein, the terms "effective amount," "pharmaceutically effective amount" and "therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0309] As used herein, the term "fibrotic lung disease" or "fibroid lung disease" or "pulmonary fibrosis" or "scarring of the lung" refers to a group of diseases characterized by the formation or development of excess fibrous connective tissue (fibrosis) in the lungs. Symptoms of pulmonary fibrosis are mainly: shortness of breath, particularly with exertion; chronic dry, hacking coughing; fatigue and weakness; chest discomfort; and loss of appetite and rapid weight loss. Pulmonary fibrosis may be a secondary effect of other diseases, most of them being classified as interstitial lung diseases, such as autoimmune disorders, viral infections or other microscopic injuries to the lung. Pulmonary fibrosis can also appear without any known cause ("idiopathic"). Idiopathic pulmonary fibrosis is a diagnosis of exclusion of a characteristic set of histologic/pathologic features known as usual interstitial pneumonia (UIP).

[0310] Diseases and conditions that may cause pulmonary fibrosis as a secondary effect include: inhalation of environmental and occupational pollutants (asbestosis, silicosis and gas exposure); hypersensitivity pneumonitis, most often resulting from inhaling dust contaminated with bacterial, fungal, or animal products; cigarette smoking; connective tissue diseases such as rheumatoid arthritis, SLE; scleroderma, sarcoidosis and Wegener's granulomatosis; infections; medications such as amiodarone, bleomycin (pingyangmycin), busulfan, methotrexate, apomorphine and nitrofurantoin; and radiation therapy to the chest.

[0311] As used herein, a "subject in need thereof" is a subject suffering from fibrotic lung disease relative to the population at large. For example, the subject is a patient who is or is about to be administered with comprising administering to the subject an effective amount of a therapeutic agent. For example, the subject is asymptomatic and is at risk of developing the fibrotic lung disease. A "subject" includes a mammal. The mammal can be e.g., any mammal, e.g., a human, primate, bird, mouse, rat, fowl, dog, cat, cow, horse, goat, camel, sheep or pig. Preferably, the mammal is a human.

[0312] As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0313] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0314] Pharmaceutically acceptable carriers of the disclosure include, but are not limited to, pharmaceutically acceptable materials, compositions or carriers, such as a liquid or solid fillers, stabilizers, dispersing agents, suspending agents, diluents, excipients, thickening agents, solvents or encapsulating materials, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0315] Suitable forms for administration include forms suitable for systemic administration, oral administration, for example by a capsule or tablet. Once formulated, the compositions of the disclosure can be administered directly to the subject.

[0316] The term "prevent," "preventing" or "prevention," as used herein, means avoiding or delaying the onset of symptoms associated with a disease or condition in a subject that has not developed such symptoms at the time the administering of an agent or compound commences.

Compounds and Compositions

[0317] In some embodiments, compounds known to be useful in treating pulmonary fibrosis are useful within the methods of the invention. Non-limiting examples of such compounds are pirfenidone (5-methyl-1-phenylpyridin-2-one, or a salt or solvate thereof) and nintedanib (methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](ph- enyl)methylidene}-2-oxo-2,3-dihydro-1 H-indole-6-carboxylate, or a salt or solvate thereof).

[0318] In some embodiments, the subject identified as having MUC5B promoter polymorphism rs35705950 is administered a compound contemplated within the disclosure. In some embodiments, the subject is a mammal. In other embodiments, the mammal is a human.

Administration/Dosage/Formulations

[0319] The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after the onset of a disease or disorder contemplated in the invention. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

[0320] Administration of the compositions of the present disclosure to a patient, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat a disease or disorder contemplated in the invention. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat a disease or disorder contemplated in the invention. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound of the invention is from about 1 and 5,000 mg/kg of body weight/per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation. Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0321] The precise therapeutically effective amount for a human subject will depend upon the severity of the disease state, the general health of the subject, the age, weight and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities and tolerance/response to therapy. This amount can be determined by routine experimentation and is within the judgement of the clinician.

[0322] A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0323] A suitable dose of a compound of the disclosure may be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses.

[0324] In some embodiments of the methods of the disclosure, the therapeutic agent comprises pirfenidone. In some embodiments, the effective dosage is administered orally as a capsule or a tablet. In some embodiments, including those embodiments wherein the therapeutic agent comprises pirfenidone, the effective dosage is about 2400 mg/day. In some embodiments, the effective dosage is administered according to an escalating dosage regimen. In some embodiments, including those embodiments wherein the therapeutic agent comprises pirfenidone, the escalating dosage regimen comprises (a) administering to the subject about 800 mg of pirfenidone per day for a first week; (b) administering to the subject about 1600 mg of pirfenidone per day for a second week; and (c) administering to the subject about 2400 mg of pirfenidone per day for the remainder of the treatment. In some embodiments, including those embodiments wherein the therapeutic agent comprises pirfenidone, the escalating dosage regimen comprises (a) administering to the subject a capsule or tablet comprising about 250 mg of pirfenidone three times a day for a first week; (b) administering to the subject two capsules or tablets comprising about 250 mg of pirfenidone three times a day for a second week; and (c) administering to the subject three capsules or tablets comprising about 250 mg of pirfenidone three times a day for the remainder of the treatment. In some embodiments of the escalating dosage regimen, the capsule or tablet comprises 267 mg of pirfenidone.

[0325] In some embodiments of the methods of the disclosure, the therapeutic agent comprises nintedanib. In some embodiments, the effective dosage is administered orally as a capsule or a tablet. In some embodiments, including those embodiments wherein the therapeutic agent comprises nintedanib, the effective dosage is about 300 mg/day. In some embodiments, the effective dosage is about 150 mg administered twice per day, wherein the daily doses are administered about 12 hours apart from one another. In some embodiments, including those embodiments wherein the therapeutic agent comprises nintedanib, the effective dosage is about 200 mg/day. In some embodiments, the effective dosage is about 100 mg administered twice per day, wherein the daily doses are administered about 12 hours apart from one another. In some embodiments, including those embodiments wherein the therapeutic agent comprises nintedanib, the effective dosage is administered according to a modified or interrupted dosage regimen. In some embodiments, the modified or interrupted dosage regimen comprises (a) administering to the subject about 300 mg of nintedanib per day until the subject presents an elevated level of liver enzymes compared to a control level of liver enzymes; (b) administering to the subject about 200 mg of nintedanib per day until the subject presents the control level of liver enzymes; and (c) administering to the subject about 300 mg of nintedanib per day for the remainder of the treatment; wherein the control level of liver enzymes is a level detected in the subject prior to an initiation of the treatment. In some embodiments, including those embodiments wherein the therapeutic agent comprises nintedanib, the modified or interrupted regimen comprises (a) administering to the subject a capsule or tablet comprising about 150 mg of nintedanib twice per day until the subject presents an elevated level of liver enzymes compared to a control level of liver enzymes; (b) administering to the subject two capsules or tablets comprising about 100 mg twice per day until the subject presents an elevated level of liver enzymes compared to a control level of liver enzymes; and (c) administering to the subject a capsule or tablet comprising about 150 mg of nintedanib twice per day for the remainder of the treatment; wherein the control level of liver enzymes is a level detected in the subject prior to an initiation of the treatment.

[0326] In some embodiments, the compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier.

[0327] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.

[0328] It is also noted that the term "comprising" is intended to be open and permits but does not require the inclusion of additional elements or steps. When the term "comprising" is used herein, the terms "consisting essentially of" and "consisting of" are thus also encompassed and disclosed. Throughout the description, where compositions or combinations are described as having, including, or comprising specific components or steps, it is contemplated that compositions or combinations also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps.

[0329] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference.

EXAMPLES

[0330] In order that the invention disclosed herein may be more efficiently understood, examples are provided below. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any manner.

Example 1: Genetic Background of Asymptomatic Siblings of FIP Subjects

[0331] Asymptomatic siblings (>50 years old) of patients with established FIP underwent HRCT scan of the chest. HRCT scans were assessed for FILD by blinded thoracic radiologists; when possible, specific radiographic patterns were identified. PBMCs RNA and DNA were isolated. Genotyping for rs35705950 and microarray analysis were performed (SurePrint G3 Human Gene Expression Microarray). Data were analyzed using Partek Genomics Suite and RStudio. Four-hundred eighty-eight FIP siblings from 271 families were evaluated, 25 HRCT scans were excluded due to technically inadequacy, leaving 463 to be interpreted. Of these, 19% (n=88) met criteria for FILD. A subset of the positive FILD scans (n=58) were evaluated for specific interstitial patterns: the predominant radiographic finding was Usual Interstitial Pneumonia (UIP), documented as possible (n=37), probable (n=6), or definite (n=5) in 82.8% of these cases. DNA was available for 443 subjects (358 without and 85 with FILD). The minor allele (T) frequency (MAF) of rs35705950 was higher among those with evidence of FILD (MAF=0.29) than among those with normal appearing HRCT scans (MAF=0.21, p=0.005). The rs35705950 variant was associated with the presence of FILD (OR=1.90, 95% CI 1.10-3.30, p=0.02), and FILD was associated with age (OR=1.09, 95% CI 1.06-1.12, p=7.24.times.10-9), male sex (OR=1.81, 95% CI 1.04-3.16, p=0.04), and history of smoking (OR=1.94, 95% CI 1.11-3.40, p=0.02). Microarray analysis on PBMC RNA from 40 subjects with FILD and 105 unaffected siblings revealed 1,272 differentially expressed genes (FDR<0.05, fold-change>2); hierarchical clustering performed on the top 194 differentially expressed probes illustrates segregation of FILD subjects from unaffected siblings (FIG. 1).

Example 2: Role of MUC5B in Pathogenesis of IPF

[0332] Common genetic variants play major and similar roles in the development of both familial and sporadic IPF (Table 3), indicating a similar etiology for familial and sporadic IPF. A common gain-of-function MUC5B promoter variant rs35705950 is a strong risk factor (genetic and otherwise), accounting for at least 30% of the total risk of developing IPF (10) confirmed in 10 independent studies, including a GWAS (OR for T (minor) allele=4.51; 95% CI=3.91-5.21; P=7.21.times.10-95); 3) rs35705950 may be used to identify individuals with PrePF and is predictive of radiographic progression of PrePF. MUC5B promoter variant rs35705950 is present in over 50% of non-Hispanic white (NHW) patients with IPF and is associated with unique biological and clinical IPF phenotypes. PrePF can be predicted using a combination of clinical risk factors, the MUC5B promoter variant rs35705950, and a panel of biomarkers.

TABLE-US-00064 TABLE 1 Common IPF risk variants identified by targeted sequencing of risk loci in 3,642 IPF cases and 4,442 unaffected controls Common Nearest Minor MAF in OR Aa vs AA OR aa vs AA Chrm Variant Gene Annotation.sup.a Allele cases (95% CI) (95% CI) P.sup.b 3q26 rs2293607 TERC 3' UTR C 0.2999 1.30 (1.18-1.43) 1.79 (1.49-2.15) 9.11 .times. 10.sup.-13 4q22 rs2609260 FAM13A Intronic C 0.2289 1.35 (1.22-1.50) 1.96 (1.56-2.47) 1.03 .times. 10.sup.-13 5p15 rs4449583 TERT Intronic T 0.2641 0.68 (0.62-0.75) 0.46 (0.39-0.55) 2.67 .times. 10.sup.-25 6p24 rs2076295 DSP Intronic G 0.5428 1.27 (1.14-1.42) 2.08 (1.83-2.37) 1.11 .times. 10.sup.-29 7q22 rs6963345 ZKSCAN1 Intronic A 0.4444 1.35 (1.22-1.50) 1.73 (1.51-1.99) 1.89 .times. 10.sup.-15 10q24 rs2488000 OBFC1 Intronic T 0.08 0.70 (0.62-0.79).sup.c 7.13 .times. 10.sup.-9 11p15 rs35705950 MUC5B Promoter T 0.3533 5.45 (4.91-6.06) 18.68 (13.34-6.17) .sup. 9.60 .times. 10.sup.-295 13q34 rs1278769 AK025511 3' UTR A 0.1996 0.77 (0.70-0.85) 0.69 (0.56-0.86) 7.48 .times. 10.sup.-8 15q15 rs35700143 IVD -- C 0.4118 0.76 (0.68-0.84) 0.63 (0.55-0.71) 3.44 .times. 10.sup.-12 19p13 rs12610495 DPP9 Intronic G 0.3398 1.22 (1.11-1.35) 1.59 (1.36-1.87) 3.11 .times. 10.sup.-9 OR, odds ratio. The minor allele is defined as the minor allele in the combined case and control group. .sup.aBased on SNPDOC; .sup.bP value adjusted for sex; .sup.cOR resulting from dominant test.

[0333] MUC5B is predicted is involved in the pathogenesis of IPF. FIG. 5 shows that MUC5B promoter variant is associated with enhanced MUC5B expression in both unaffected subjects and in patients with IPF and in IPF, MUC5B message and protein are expressed in bronchoalveolar epithelia (FIG. 6) and honeycomb cysts. In mice, the concentration of Muc5b is directly related to the fibroproliferative response to bleomycin (FIG. 7), Muc5b protein is expressed in the injured lung following bleomycin challenge, and enhanced production of Muc5b in mice appears to initiate endoplasmic reticulum (ER) stress in peripheral airways (FIGS. 8 and 9). Preliminary studies, also show that mucociliary clearance is decreased in mice that over-express Muc5b (SFTPC-Muc5b.sup.Tg) and in humans with IPF (FIG. 10).

[0334] Interstitial lung abnormalities on HRCT scans show asymptomatic relatives of patients with familial IPF and in the elderly. Similar to patients with IPF, interstitial lung abnormalities in asymptomatic subjects are associated with advanced age, cigarette smoking, reduced lung volume and decreased exercise tolerance. Moreover, the MUC5B promoter variant rs35705950 is associated with a higher prevalence of interstitial lung abnormalities on HRCT scan and is predictive of radiographic progression. Suggesting that interstitial lung abnormalities on HRCT scan are a precursor of IPF. However, interstitial lung abnormalities are not specific and include non-fibrotic and fibrotic HRCT defects, and consequently, the prevalence of interstitial lung abnormalities (>5% in the general population .gtoreq.50 years of age is orders of magnitude higher than IPF.

[0335] To address the non-specificity of interstitial lung abnormalities, a novel entity--Preclinical Pulmonary Fibrosis (PrePF) was used. PrePF is reported more frequently among smokers and in families with two or more cases of pulmonary fibrosis. In the Framingham population, data shows that PrePF is present in 1.8% of the general population .gtoreq.50 years of age (in contrast, interstitial lung abnormalities were seen in 6.7%) and that the MUC5B promoter variant rs35705950 is predictive of those with PrePF (OR=6.3 per allele [95% CI 3.1-12.7). As shown herein, among asymptomatic first-degree family members of familial interstitial pneumonia (FIP) 14% have fibrotic interstitial changes on CT scan and 35% have interstitial abnormalities on transbronchial biopsy. Moreover, in the Framingham population, it is shown that rs35705950 is predictive of radiographic progression of PrePF (OR=2.8 per allele [95% CI 1.8-4.4]) which is associated with a greater FVC decline (P=0.0001) and an increased risk of death (HR=3.7 [95% CI 1.3, 10.7]; P=0.02), indicating that in addition to having radiographic features of IPF, PrePF has similar risk factors (age, gender, smoking, and MUC5B variant) and a progressive clinical course. While the MUC5B promoter variant is predictive of PrePF, rs35705950 is present in .apprxeq.19% (minor allele frequency (MAF)=0.09) of the NHW population, however IPF occurs infrequently (<0.1%). Thus, additional biomarkers may be used in combination with rs35705950 identify PrePF within at-risk populations.

[0336] The data provided herein suggest that 1) IPF is under-diagnosed; 2) PrePF is prevalent in at-risk populations; 3) approximately 75% of the cases of PrePF are progressive; 4) radiographic progression of PrePF is associated with increased morbidity and mortality; and 5) MUC5B variant rs35705950, peripheral blood biomarkers, clinical/biological, and radiographic screening should be useful in identifying those with PrePF (FIG. 11). While IPF takes years to develop, most patients with IPF are diagnosed in the advanced stage when little can be done to influence survival. Once the lung has undergone remodeling, the non-compliant, stiff lung matrix causes additional remodeling through activation of myofibroblasts, resulting in a feed-forward loop of lung remodeling. Earlier diagnosis of IPF detects subjects with a lower burden of fibrotic lung disease.

[0337] This disclosure provides a strategic approach to screening for early forms of IPF needs to be established (FIG. 11). While the MUC5B promoter variant is predictive of PrePF (defined as chest HRCT consistent with probable or definite fibrosis (e.g., bilateral subpleural reticular changes, honeycombing, or traction bronchiectasis) occurring in asymptomatic subjects .gtoreq.40 years of age that emerge from at-risk populations), the MUC5B promoter variant is present in .apprxeq.19% of the NHW population and IPF occurs infrequently (<0.1%). To study at-risk populations (asymptomatic siblings .gtoreq.40 years of age of patients with family or sporadic IPF), identification of genetic variants and biomarkers that increase the yield of patients with PrePF are used to establish screening tools and approaches that identify early stages of IPF. This approach changes the way IPF is diagnosed and treated, and is critical to developing interventions to prevent PrePF progression to established IPF. The methods provided in this disclosure fundmentally alter the clinical approach to patients with IPF from palliative to preventive (FIG. 10).

Example 3: Predictive Biomarker Profile for Established IPF

[0338] To address the development of a peripheral blood biomarker profile for IPF, an assay of the expression levels of >3700 plasma proteins was performed on plasma from 70 patients with established IPF and 70 controls. After controlling for multiple comparisons and appropriate co-variables, 57 proteins were up-regulated >1.5-fold (including surfactant proteins, MMPI, and C3) in the plasma of patients with IPF and 12 were significantly down-regulated (FIG. 2).

Example 4: Predictive Biomarker Profile for Early IPF

[0339] To evaluate a predictive biomarker profile in cases of preclinical pulmonary fibrosis (PrePF) derived from families with familial IPF (.gtoreq.2 cases of IPF in a family), HRCT scans were performed on 496 asymptomatic family members .gtoreq.40 years of age previously phenotyped as unaffected from 263 families with familial IPF. PrePF, consistent with the operational definition (defined as abnormalities on chest HRCT consistent with probable or definite fibrosis (e.g., bilateral subpleural reticular changes, honeycombing, or traction bronchiectasis) occurring in asymptomatic subjects .gtoreq.40 years that emerge from at-risk populations), was present in 77 (15.5%) of 496 asymptomatic individuals from families with familial IPF. The minor allele frequency (MAF) of the MUC5B promoter variant was 0.29 in those with PrePF versus 0.21 in those without fibrosis (P=0.025). Preliminary analysis of PBMC gene expression profiles evaluated by microarrays from 38 cases of PrePF and 187 subjects without fibrosis identified 16 genes significantly differentially expressed between the two groups (p-value <0.05 and >1.5 fold change). Among genes differentially expressed in PrePF are those involved in innate immunity and inflammatory responses (SIGLEC14), antibacterial effects (ADM2), growth and motility (TSPAN5), and protein phosyphorylation (CAMKK1). Moreover, PBMC gene expression appears to contribute to the ability to predict PrePF in an at-risk population (FIG. 3).

[0340] Additionally, RNA-sequencing analysis was performed on 40 PrePF subjects and 80 subjects with a normal HRCT scan. Sequencing of the polyA-enriched libraries was prepared using Illumina TrueSEQ reagents and multiplexing 10 samples on each lane of HiSEQ4000 to obtain on average 35-40 million reads per sample. This high coverage allows for the consideration of a broad dynamic range of mRNA transcripts for biomarker selection. Platform selection of serum and plasma samples from the same subjects are used for proteomic analysis.

Example 5: Biomarker Identification

[0341] To examine for association between each biomarkers and PrePF, a multivariable logistic regression model for PrePF with biomarkers and covariates is used for inclusion and a step-wise forward selection procedure is constructed. Variables stay in the model if associated at P.ltoreq.0.01 after adjustment for the variables already in the model. Protein biomarkers that are significantly associated with established IPF and the top 20 differentially expressed genes in PrePF are considered for inclusion in a multivariable model. The number of potential biomarkers allowed in the joint model is restricted to approximately 20 given the number cases of PrePF expected. Secondarily, interactions between MUC5B genotype and the other biomarkers are tested for, which allow for the possibility that different biomarker profiles are diagnostic in IPF patients with/without the MUC5B risk allele.

Example 6: Predictive Ability of Biomarkers

[0342] To test the predictive value of the combination of biomarkers associated with PrePF, the observed expression and other biomarker values from those associated with PrePF in the siblings of FIP patients is used to obtain the probability, for each sibling, having PrePF.

[0343] Following, a construct receiver operating characteristic (ROC) curves (see M. S. Pepe et al., Phases of biomarker development for early detection of cancer. Journal of the National Cancer Institute 93, 1054-1061 (2001)), is used to choose the probability threshold that maximizes the area under the ROC curve. This probability threshold is used to classify each individual as predicted to have PrePF or not, allowing calculation of the sensitivity, specificity, positive predictive value, and negative predictive value of the predictive model. The properties of the predictive model(s) in the independent set of siblings of patients with IPF are evaluated. Different aliquots are run for 10 samples for each assay at each time the assays is run in order to use those 10 samples to evaluate the need for standardization of the absolute values for each assay over time. Either the raw or standardized values, for a given model, is used to observe biomarker values in the PrePF siblings and non-PrePF siblings to obtain the probability of being in the disease group based on the model parameters developed using the FIP siblings. The thresholds identified among the FIP siblings are used to classify each individual as predicted to have PrePF or not. This categorization allows for the calculation of the sensitivity, specificity, positive predictive value, and negative predictive value of the predictive model among the siblings of independent cases of IPF to that observed in the siblings of FIP cases.

[0344] Power is calculated to detect differences between those with and without PrePF assuming 500 siblings and 10% (N=50) with PrePF. Assuming .alpha.=0.00005 (conservatively correcting for up to 1000 independent tests), we have 80% (90%) power to detect differences in protein or expression level of 0.74 (0.80) standard deviation between PrePF and unaffected siblings. These differences are larger than previously-observed protein and gene-expression levels in IPF patients and controls (see I. V. Yang et al., The peripheral blood transcriptome identifies the presence and extent of disease in idiopathic pulmonary fibrosis. PLoS One 7, e37708 (2012). With 50 PrePF and 450 unaffected, there is 90% power to bound the sensitivity of the biomarker-based classification of PrePF with a margin of error of 11% if the sensitivity is 65%, and 6.5% if the sensitivity is 95%; the margins of error for 65% and 95% sensitivity are 4.5% and 2.5%, respectively.

Example 7: MUC5B Promoter Variant r35705950is a Risk Factor for Rheumatoid Arthritis--Interstitial Lung Disease

Methods

Study Cohorts

[0345] This study included a discovery cohort and multi-ethnic replication cohorts. The discovery cohort included patients with RA, with and without ILD (RA-noILD) as assessed by chest HRCT, and controls, from the French RA-ILD network. The multi-ethnic replication cohorts were obtained from six countries (China, Greece, Japan, Mexico, the Netherlands and United States). This included patients with RA-ILD and RA-noILD patients, and controls. All cases fulfilled the 2010 European League Against Rheumatism-American College of Rheumatology (EULAR-ACR) and/or 1987 ACR revised criteria for RA. The ILD status of patients with RA was established by chest HRCT images that were centrally reviewed by experienced readers for each participating cohort. There was one cohort, the RA-noILD cases from the USA1 cohort, which was determined by self-report. The chest HRCT ILD pattern was classified as UIP, possible UIP or inconsistent with UIP according to international criteria and all readers were blinded to the clinical and genetic data. The institutional review boards at each institution approved all protocols, and all patients provided written informed consent.

Genotyping

[0346] Genotyping of the MUC5B rs35705950 single nucleotide polymorphism (SNP) involved use of Taqman Genotyping Assays (Applied Biosystems, Foster City, Calif., USA) as previously reported, by direct Sanger Sequencing or imputation from genome-wide association study data.

[0347] The additional common IPF risk variants on 3q26, 4q22, 5p15, 6p21.3, 6p24, 7q22, 10q24, 11p15.5, 13q34, 15q14-15, and 19p13 were genotyped by Taqman qPCR (Thermo Fisher Scientific, California) per the manufacturer's instructions.

Lung Tissue Analysis

[0348] In order to determine if MUC5B was expressed in RA-ILD ling tissue, we analyzed lung tissue was analyzed from nine patients with RA-ILD undergoing lung transplantation (University of California, San Francisco) compared to six unaffected controls with ILD (NHLBI Lung Tissue Research Consortium; https://ltrcpublic.com) or concordant expression of other relevant markers of pulmonary fibrosis. The tissue was formalin fixed, paraffin embedded and cut in 4 um sections. Tissue sections were deparaffinized in xylene, followed by dehydration in series of ethanol. Following citrate buffer antigen retrieval, slides were incubated overnight with primary antibodies against MUC5B (1:4000, Santa Cruz, Dallas, Tex.). Secondary antibody diluted 1:1000 tagged with HRP (Life Technologies) was visualized using an Aperio CS2 slide scanner (Leica, Buffalo Grove, Ill.).

Results

Study Cohorts

[0349] This case-control genetic study included 620 RA-ILD cases, 614 RA-noILD cases and 5448 unaffected controls. The discovery cohort included 118 RA-ILD cases, 105 RAnoILD cases and 1229 unaffected controls. The multi-ethnic replication sample included 502 RA-ILD, 509 RA-noILD cases and 4219 unaffected controls.

Characteristics of the Discovery Cohort

[0350] As compared with RA-noILD, patients with RA-ILD were more frequently male, older and more frequently smoked cigarettes (54.7% versus 36.1%) (FIG. 13). However, after adjusting for sex, the relationship between RA-ILD and cigarette smoking was no longer statistically significant (FIG. 13). After adjustment, RA-ILD and RA-noILD patients did not differ in rheumatoid factor (RF) and/or anti-citrullinated protein antibody (ACPA) positivity, erosive status of RA, exposure to methotrexate or the mean RA duration from diagnosis at inclusion in the cohort. Overall, 41% of patients with RA-ILD had a UIP or possible UIP HRCT pattern.

MUC5B Promoter Variant and Risk of Rheumatoid Arthritis-Associated Interstitial Lung Disease

[0351] Comparison of RA-noILD and controls revealed that none of the cohorts (discovery cohort and multi-ethnic cohorts) demonstrated a significant difference in the frequency of the MUC5B promoter variant (FIG. 14; FIG. 16A), suggesting a lack of association between the MUC5B promoter variant and RA. In the discovery cohort, the minor allele frequency (MAF) of the MUC5B promoter variant was 10.9% in unaffected controls and 32.6% in cases of RAILD; this variant was in Hardy-Weinberg equilibrium (HWE) in both study groups. I In the discovery population, after controlling for sex we detected a significant association between the MUC5B promoter variant and RA-ILD when compared to non-RA controls (ORadj=3.8; 95% CI, 2.8 to 5.2; P=9.7.times.10-17) (FIG. 14). Similar to the discovery population, the MUC5B promoter variant was significantly over-represented among the

cases of RA-ILD compared to unaffected non-RA controls in all of the multi-ethnic study case series, except in the two Asian case series (FIG. 14). Given that the MUC5B promoter variant is under-represented in Asian populations compared to non-Hispanic whites (FIG. 14; www.ncbi.nlm.nih.gov/projects/SNP/snp_refcgi?rs=35705950), a likely explanation, especially given the consistent point estimates, for the absence of a significant relationship between the MUC5B promoter variant and RA-ILD is that the analysis of the two Asian case series is likely underpowered. The relationship between the MUC5B promoter variant and RA-ILD in combined multi-ethnic study case series (ORadj=4.7; 95% CI, 3.9 to 5.8; P=1.3.times.10-49) (FIG. 14) (FIG. 16B) validated the observed association between the MUC5B promoter variant and RA-ILD in the discovery study population.n addition, the cases of RA-ILD in the study populations from Greece and USA-1 were not in HWE, suggesting (as has been observed in cases of IPF 14), that the MUC5B promoter variant and/or common variants in high or complete linkage disequilibrium with the MUC5B promoter variant should be considered as causative in these cases of RA-ILD. For the comparison with non-RA controls, the best-fitting genetic model for the three study populations (discovery population, combined multi-ethnic case series, and combined analysis) for the association of the MUC5B MUC5B RS35705950 AND RISK OF ITNERSTITIAL LUNG DISEASE AMONG PATIENTS WITH RHEUMATOID ARTHRITIS

[0352] To further investigate whether the MUC5B promoter variant rs35705950 contributes to the risk of ILD among patients with RA, we compared RA-ILD and RA-noILD patients, adjusting for sex, age at inclusion and cigarette smoking. In the discovery cohort, the MUC5B variant was associated with RA-ILD (ORadj=3.1; 95% CI, 1.6 to 6.3; P=9.4.times.10.sup.-4), and this finding was replicated in the aggregate multi-ethnic cohort (ORadj=2.9; 95% CI, 1.1 to 8.4; P=0.04) and the combined analysis (ORadj, 3.1; 95% CI, 1.8 to 5.4; P=7.4.times.10.sup.-5) (FIG. 14; FIG. 16C). For the comparison of RA-ILD with RA-noILD, the best-fitting genetic model for the three study cohorts (discovery population, combined multi-ethnic case series, and combined analysis) was dominant. After adjusting for covariates, no association between tobacco smoking and the risk of ILD among patients with RA was found and no interaction of tobacco smoke exposure with the MUC5B promoter variant was observed (ORadj=0.7; 95% CI, 0.3 to 1.9; P=0.51).

MUC5B rs35705950 and UIP on HRCT Scan

[0353] Limiting the RA-ILD cases to those with radiographic evidence of definite or possible UIP on HRCT scan, the association observed in the discovery cohort (ORadj=5.0; 95% CI, 2.1 to 12.3; P=3.0.times.10.sup.-4), was replicated in the combined multi-ethnic cohort (ORadj=9.2; 95% CI, 2.3 to 38.7; P=1.8.times.10.sup.-3) (FIG. 16C), and was observed in the combined cohort analysis (ORadj=6.1; 95% CI, 2.9 to 13.1; P=2.5.times.10.sup.-6) (FIG. 16C). In the combined analysis, the comparison of odds ratios for UIP RA-ILD vs RA-noILD (ORadj=6.1; 95% CI, 2.9 to 13.1; P=2.5.times.10.sup.-6) to non-UIP RA-ILD vs RA-noILD (ORadj=1.3; 95% CI, 0.6 to 2.8; P=0.46) was statistically significant (P=0.02), suggesting that the effect of the MUC5B promoter variant was restricted to the UIP RA-ILD sub-phenotype (FIG. 16C). Finally, consistent with our previous findings, the MUC5B promoter variant was found to increase the risk of developing a UIP pattern among patients with RA-ILD through a dominant model in the discovery, replication and combined analysis; the odds of having a UIP and possible UIP pattern for patients with RA-ILD carrying at least one MUC5B rs35705950 T risk allele were 2.9 times greater than individuals having the GG genotype (ORadj=2.9; 95% CI, 1.7 to 4.8; P=5.1.times.10-5) (FIG. 15; FIG. 16C). After adjusting for covariates, tobacco smoking exposure did not contribute to a specific HRCT pattern for RA-ILD and no interaction with the MUC5B rs35705950 variant was detected.

Sites of MUC5B Expression in RA-ILD

[0354] We performed immunohistochemical staining for MUC5B in nine RA-ILD lung tissue explants (5 GG and 4 GT) and 6 unaffected controls (3 GG and 3 GT). Similar to what has been reported in IPF, RA-ILD lung tissue demonstrated MUC5B in the cytoplasm of the bronchioles and in areas of microscopic honeycombing, including staining of the metaplastic epithelia lining the honeycomb cysts and the mucous within the cyst (FIG. 17). The controls demonstrated MUC5B expression in the bronchioles only. There were no obvious differences in MUC5B expression by genotype.

Exploratory Genetic Association Study of 12 Common IPF Risk Variants in RA-ILD

[0355] Having provided evidence for the contribution of the dominant IPF genetic risk variant, i.e. the MUC5B promoter variant, to RA-ILD, we decided to test the association of 12 additional common IPF risk variants with RA-ILD (FIG. 29). This exploratory study included 272 RA-ILD and 242 RA-noILD patients from the France, USA-1 and Mexico case series. Taking into account the relatively small sample size and related low power of detection corresponding P-values, Odds Ratio and 95% CI for the 12 candidate variants were considered as descriptive and Bonferoni correction was therefore not applied (Table 4). Comparison between RA-ILD and RA-noILD revealed that 2 common IPF risk variants, TOLLIP rs5743890 and IVD rs2034650, were significantly associated with RA-ILD. The TOLLIP rs5743890 minor allele was associated with increased risk of RA-ILD and the IVD rs2034650 minor allele was associated with decreased risk of RA-ILD (ORadj=2.13; 95% CI, 1.13 to 4.10; P=0.02 and ORadj=0.59; 95% CI, 0.38 to 0.89; P=0.01, respectively) and the directionality of these relationships is consistent with what has been observed for IPF.16,17 No association with RA-ILD was detected for the 10 other IPF risk variants (FIG. 29).

Example 8: MUC5B Promoter Variant is Associated with Visually and Quantitatively Detected Preclinical Pulmonary Fibrosis

[0356] Better understanding and recognition of early pulmonary fibrosis is critical because medical therapies have been shown to slow progression, not to reverse or even stabilize established fibrosis--therefore, intervention before irreversible fibrosis has become extensive has the potential to improve quality of life and decrease morbidity. While IPF affects approximately 5 million people worldwide, between 1.8 and 14% of the general population .gtoreq.50 years of age have radiologic findings of undiagnosed pulmonary fibrosis. Large cohort studies indicate that interstitial lung abnormalities, postulated to represent early pulmonary fibrosis, are associated with increased mortality, and that most of these abnormalities progress over time. Members of families with 2 or more cases of pulmonary fibrosis (FIP, Familial Interstitial Pneumonia) have been identified as an "at-risk" population. In a previous study of FIP relatives, 14% had interstitial lung abnormalities on high resolution computed tomography (HRCT), and 35% had an abnormal transbronchial biopsy indicating interstitial lung disease.

[0357] HRCT provides visualization of the lung parenchyma and plays a key role in the diagnosis of the Idiopathic Interstitial Pneumonias (IIPs), including IPF. Currently, visual diagnosis by thoracic radiologists, in conjunction with multidisciplinary clinical conference, is the gold standard for diagnosing IIPs. However, visual assessment is imprecise and hampered by inter-observer variation. Quantitative HRCT (qHRCT) evaluation provides measures of fibrosis extent that, in subjects diagnosed with IPF, correlate with degree of physiologic impairment at baseline, and may be more sensitive to subtle changes in disease status than routinely used physiological metrics. The design and utility of quantitative methods in the context of early forms of fibrotic ILD requires further study. Deep learning methods have been increasingly used in imaging to identify and classify CT patterns, and may be particularly valuable in detection of early lung fibrosis.

[0358] This study aims to: (1) examine risk factors, including two common fibrosis-associated genetic variants in MUC5B and TERT, for undiagnosed pulmonary fibrosis (PrePF) in FIP first-degree relatives; and (2) determine the utility of a deep learning, texture-based qHRCT method in the detection of early fibrosis in this cohort.

Materials and Methods

FIP Relatives Screening:

[0359] As part of a study of FIP conducted at the University of Colorado, National Jewish Health, and Vanderbilt University (COMIRB #15-1147; NJH IRB 1441a; Vanderbilt IRB #020343), non-Hispanic white (NHW) relatives of FIP patients, defined as those in families with two or more cases of pulmonary fibrosis, were contacted for enrollment. First-degree relatives without a known prior diagnosis of pulmonary fibrosis and greater than 40 years of age were offered HRCT scans of the chest and asked to undergo peripheral blood draw. Study subjects younger than 40 years of age or older than 40 years of age who reported on pre-study questionnaires to be personally affected by pulmonary fibrosis were excluded (FIG. 18).

Visual CT Review:

[0360] HRCT scans were interpreted by study radiologists and examined for the presence of fibrotic ILD. "PrePF" was defined as the presence of "probable" or "definite" fibrotic ILD on HRCT in FIP relatives who had no known diagnosis of pulmonary fibrosis at the time of study enrollment (FIGS. 18, 19).

Quantitative CT:

[0361] Inspiratory HRCT series with slice thickness .ltoreq.125 mm and spacing .ltoreq.200 mm were selected for quantitative analysis. This included 212 volumetric series with thin, contiguous sections (slice thickness and spacing both <=125 mm) and 191 non-volumetric scans (56 with slice spacing >125 mm and <10 mm, 65 with slice spacing of 10 mm and 70 with slice spacing=20 mm). Scans identified as technically inadequate were omitted. In addition, 100 inspiratory volumetric HRCT of never-smoking control subjects from the COPDGene cohort were analyzed (FIG. 20). The lungs were segmented in a semi-automatic fashion using open source software followed by manual editing, if necessary, performed by trained analysts. Examples of the categorization of different parts of CT scans are shown in FIG. 21. Some studies were acquired with contiguous thin axial sections while others used 1 or 2 cm intervals. Also, reconstruction kernel, a parameter that affects image sharpness and noise, was not standardized.

[0362] Fibrosis quantification on CT scans was performed using a deep learning technique, with a convolutional neural network (CNN) algorithm trained with image regions of normal and abnormal lung identified by expert radiologists. Training data and an earlier algorithm version were described previously. Here, a more complex CNN architecture was employed that classifies image regions using pixel and texture features extracted by multiple convolutional layers at different scales. Classification categories included normal lung, airways, reticular abnormality, honeycombing and ground glass. An additional category, "not normal", was also included for lung regions not classified into any of the named categories. Further, pixels in the "not normal" category were split into two subcategories: "not normal" low density and "not normal" high density using the threshold value of -650 Hounsfield Units (HU). Subject level scores were computed as the percentage of total lung volume classified in each category. HRCT fibrosis score was defined as the sum of CNN classification scores for reticular abnormality, honeycombing, ground glass, and "not normal high density" (FIG. 21).

[0363] A simpler previously described densitometric analysis of HRCTs was also performed for comparison. Percent high attenuation area (% HAA), the percentage of total lung volume with HRCT pixel intensity greater than -600 HU and less than -250 HU, has been used as a measure of interstitial lung disease on CT.

Statistical Analysis:

[0364] Analysis of the effect of specific alleles on PrePF risk was performed using minor allele frequency (MAF) for comparison of variant prevalence in the study groups; statistical significance was determined utilizing either a z-score test for proportions or a mixed effects logistic regression model when controlling for other clinical factors (age, sex, and history of smoking) and family [random effect]) in both dominant and log-additive models.

[0365] Distribution of qHRCT fibrosis scores was left skewed as was % HAA, and therefore these values were log transformed prior to analyses. Log of qHRCT fibrosis score (hereafter, "fibrosis score") and log (% HAA) were compared with visual scores using ANOVA and Tukey's honest significant difference (HSD) test. To determine the ability of qHRCT scores to predict visual diagnosis of PrePF, receiver-operating characteristic (ROC) analysis was performed. Optimal threshold for discriminating visual diagnosis of fibrotic ILD was determined with Youden's method. Five-fold cross-validation was performed to test detection accuracy, sensitivity and specificity, and consistency of optimal threshold. Linear regression was performed to test association between the MUC5B genotype and qHRCT fibrosis score and log (% HAA).

[0366] A p-value of <0.05 was considered statistically significant for differences between groups as well as for associations between individual variables and outcomes in linear and logistic regression modeling. Statistical analyses were performed using RStudio (Version 0.99.473).

Results

Study Cohort Characteristics

[0367] A total of 1,090 FIP relatives were contacted, and 523 eligible subjects were recruited and underwent HRCT screening (FIG. 18). Of the 523 subjects, 26 were excluded due to technical inadequacy of images and one for an equivocal consensus read by study radiologists. The remaining 496 subjects from 263 families were included in the final analyses. The mean age of study subjects was 57 years (95% CI: 56.5-58), 189 (38%) were male, and 148 (29%) were either current or former smokers. The minor allele (T) frequency of the MUC5B promoter polymorphism rs35705950 was 0.22 in this cohort; 45% of the subjects in this cohort had one or two copies of the minor allele (FIG. 22). The minor allele (C) frequency of the TERT variant rs2736100 was 0.47 in the entire cohort; 69% of the subjects in the cohort having one or two copies of the minor allele (FIG. 22).

Prevalence of Preclinical Pulmonary Fibrosis (PrePF) in FIP Relatives

[0368] Of the 496 HRCT scans, 401 showed no CT evidence of interstitial lung disease (ILD), and 95 showed evidence of ILD, either fibrotic (27 probable and 50 definite) or non-fibrotic (n=18). Therefore, among these 496 subjects who reported being personally unaffected by pulmonary fibrosis, the PrePF prevalence was 15.5% (n=77) (FIG. 18).

[0369] The CT patterns noted in PrePF subjects (FIG. 23) show that possible, probable, or definite UIP pattern was the most commonly considered (n=59, 77% of all PrePF cases). NSIP was considered in 45 subjects (58% of all PrePF cases). The fibrotic changes were most commonly lower-lobe predominant and subpleural in nature, consistent with a UIP pattern (FIG. 23). Non-fibrotic ILD scans, on the other hand, generally had more diffuse, upper-lobe predominant abnormalities.

[0370] There were 402 study subjects with HRCT scans that were technically adequate for quantitative assessment. 212 of the scans had both slice thickness and spacing <=125 mm (thin, contiguous); of the remaining 191 scans, 56 had slice spacing >125 mm and <10 mm, 65 had slice spacing=10 mm, and 70 had slice spacing=20 mm. Volumetric HRCT scans on an additional 100 COPDGene subjects were included as normal controls. Fibrosis score means were significantly different (p<00001) across groups defined by visual diagnosis (FIG. 24). Comparison of means showed fibrosis score were significantly different comparing each group (all between-group comparisons p<001). Means of log (% HAA) scores were also significantly different across visual scoring groups (p<00001), and individual between-group comparisons showed log (% HAA) was significantly different in most comparisons (p<00001), except between the "probable" and "definite" visual scores (p=035).

[0371] ROC analysis showed that fibrosis score discriminates subjects with visual diagnosis of PrePF (FIG. 25B). Average area under the curve (AUC) in five-fold cross validation was 0.85 (range 0.83-0.87) and average accuracy, sensitivity, and specificity in the test partitions were 0.83 (range 0.74-0.86), 0.74 (range 0.56-0.92), and 0.84 (range 0.76-0.89), respectively. Optimal threshold for fibrosis score ranged from 1.40-1.42, corresponding to 4.1% fibrotic area in examined lung. Utilizing a cutoff of 1.40 for fibrosis score on the entire dataset, the sensitivity was 74%, specificity was 82%, and accuracy was 81%; the negative predictive value of this test was 95%, exceeding its positive predictive value (42%) (FIG. 25C).

[0372] Compared to the classification achieved with the CNN as described above, ROC analysis of log % HAA had lower mean AUC 0.80 (range 0.79-0.81) and average accuracy, sensitivity, and specificity of 0.67 (range 0.63-0.70), 0.82 (range 0.75-0.91) and 0.64 (range 0.62-0.70) respectively (FIG. 25A). Optimal threshold for log % HAA ranged from 1.49-1.57. Utilizing a cutoff of 1.49 for log % HAA, the sensitivity was 88%, specificity was 55%, and accuracy was 60%; the negative predictive value of this test was 96%, exceeding its positive predictive value (26%).

Risk Factors for PrePF

[0373] Subjects with PrePF were older (mean age 65.8 years, 95% CI 63.5-68.1) than those without fibrosis (mean age 55.8, 95% CI 54.9-56.6, p=6.36.times.10.sup.-13); they were also more likely to have ever smoked (43% versus 27%, p=0007), and to be male (48% versus 36%, p=005). However, there was no difference in breathlessness between the PrePF and subjects without fibrosis (mean score 0.5 versus 06, p=024, FIG. 26). When fibrosis was defined by quantitative fibrosis score cutoff (1.4), there was a significant difference between groups in terms of mean breathlessness score (0.39 versus 0.78, p=0003). Quantitative fibrosis score was positively associated with breathlessness score (p=0.001), even after controlling for age (p=1.9.times.10.sup.-9), male sex (p=0.7), and smoking history (p=0.8).

[0374] Screening for autoantibodies in this cohort revealed that there were no differences between PrePF and No Fibrosis subjects in terms of overall seropositivity or individual antibodies' testing in this cohort. For quantitatively defined fibrosis, there was no significant difference between groups in terms of auto-antibody testing, with similar overall seropositivity rates (11% versus 16%, p=0.30).

[0375] The MUC5B promoter polymorphism rs35705950 was associated with the visual diagnosis of PrePF (present in 40% of those without fibrosis versus 53% with PrePF; MAF 0.29 versus 0.21, respectively, p=0.03, FIG. 22). After age 60, there was a statistically significant difference in the proportion of subjects with visually diagnosed PrePF when the cohort was stratified by MUC5B genotype (23.8% versus 39.8% prevalence, p=0.02) (FIG. 27).

[0376] MUC5B variant carriers, regardless of their visual CT diagnosis, had significantly higher qHRCT fibrosis scores (1.3 [95% CI 1.2-1.5] versus 1.1 [95% CI 1.0-1.2], p=0.02). The association between MUC5B genotype and fibrosis score was significant even when controlling for age and male sex in linear regression (p=0.03, FIG. 28). Age was significantly associated with fibrosis score (p=2.17.times.10.sup.-9), but male sex (p=0.63) and smoking (p=0.94) were not. To determine whether individual textural components were driving the association of the composite fibrosis score with genotype, each score component was tested individually for association with the MUC5B variant, controlling for age and sex. Quantitative scores for reticulation, honeycombing, and ground glass were significantly associated with the MUC5B variant (p=0.02, p=0.02, p=004, respectively), while "not normal high density" was not (p=018). The simpler quantitative scoring method, log % HAA, was not significantly different in MUC5B variant carriers (p=0.4).

[0377] In contrast to the MUC5B variant, the common IPF-associated TERT polymorphism (rs2736100) was not significantly associated with PrePF assessed either qualitatively (MAF 0.47 in PrePF versus 0.46 in unaffected, p=0.77) or quantitatively (MAF 0.50 fibrotic versus 0.47 not fibrotic, p=0.40).

[0378] When these factors were examined individually for their contributions to risk of PrePF in our study cohort, we used a mixed effects logistic regression model to test the independent effects of age sex, smoking, and MUC5B or TERT genotypes while controlling for family. Age and the MUC5B genotype remained statistically significantly associated with PrePF (OR 1.15, 95% CI 1.09-1.22, p=7.34.times.10.sup.-7 and OR 2.18, 95% CI 1.00-4.73, p=0.05, respectively) (FIG. 22). The common TERT polymorphism (rs2736100) associated with fibrotic idiopathic interstitial pneumonia (29) was not significantly associated with PrePF (MAF was 0.45 in PrePF versus 0.45 in unaffected, p=0.88) or in a log-additive model controlling for age, sex, and smoking history (p=0.57).

[0379] Given the presence of non-fibrotic ILD (n=18, FIG. 18) in the "No Fibrosis" cohort, secondary analyses were performed that (1) excluded non-fibrotic ILDs and (2) compared all ILD (inclusive of non-fibrotic ILD) to those without any ILD. When non-fibrotic ILDs were excluded from analyses, PrePF subjects were older (p=4.7.times.10.sup.-13), more commonly male (p=0.04), more often had a smoking history (p=0.003), and had a higher prevalence of the MUC5B promoter variant (MAF 0.29 versus 0.20, p=0.02). However, when controlling for family relatedness and the other risk factors in a mixed effects logistic regression, only age and the MUC5B promoter variant were significantly associated with PrePF with odds ratios 1.15 (95% CI 1.09-1.22, p=9.5.times.10.sup.-7) and 2.16 (95% CI 1.00-4.75, p=0.05), respectively. Another secondary analysis of the data was performed in which all subjects with CT findings of ILD (fibrotic or non-fibrotic) were compared to those without any evidence of ILD. Those with CT evidence of ILD were older (mean age 64.3 years, 95% CI 62.2-66.3) compared to those without any evidence of ILD (mean age 55.7 years, 95% CI 54.8-56.6, p=4.1.times.10.sup.-12), more likely to be male (p=0.01), more likely to have smoked (p=0.0003), and more likely to carry the MUC5B promoter variant (MAF 0.21 versus 0.30, p=0.006). When controlling for family relatedness in a mixed effects logistic regression model, age (OR 1.10, 95% CI 1.07-1.14, p=1.21.times.10.sup.-9), smoking history (OR 1.72, 95% CI 1.00-2.99, p=0.04), and the MUC5B promoter variant (OR 1.73, 95% CI 1.08-2.76, p=002) were significantly associated with risk of ILD.

OTHER EMBODIMENTS

[0380] It is to be understood that while the disclosure has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the disclosure, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Sequence CWU 1

1

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ctaagcttca gggtgcttat 720caaagcaggg aagatacaca agaggagatg attcaggtcc agggcaggtc aggtatctaa 780acccagtctc ttaggaagct ggatcctccg aaccagggag aacaagctgg atatgcactg 840gatttcccag cagtactgat ctagagactc tcatagagtc ccttttattc cttggcctag 900ggttacaact gcttatagca tctggaaaga ctcaacacct caaaagagac tttcagtaga 960tacagcaaat acactcatgg aattgataat taagcttcaa t 100131001DNAHomo sapiens 3attgtcgttg tttgcttttg tttattgaga cagtctcact ctgtcaccca ggctggagtg 60taatggcaca atctcggctc actgcaacct ctgcctcctc ggttcaagca gttctcattc 120ctcaacctca tgagtagctg ggattacagg cgcccaccac cacgcctggc taatttttgt 180atttttagta gagataggct ttcaccatgt tggccaggct ggtctcaaac tcctgacctc 240aagtgatctg cccgccttgg cctcccacag tgctgggatt acaggtgcaa gccaccgtgc 300ccggcatacc ttgatctttt aaaatgaagt ctgaaacatt gctacccttg tcctgagcaa 360taagaccctt agtgtatttt agctctggcc accccccagc ctgtgtgctg ttttccctgc 420tgacttagtt ctatctcagg catcttgaca cccccacaag ctaagcatta ttaatattgt 480tttccgtgtt gagtgtttct ktagctttgc ccccgccctg cttttcctcc tttgttcccc 540gtctgtcttc tgtctcaggc ccgccgtctg gggtcccctt ccttgtcctt tgcgtggttc 600ttctgtcttg ttattgctgg taaaccccag ctttacctgt gctggcctcc atggcatcta 660gcgacgtccg gggacctctg cttatgatgc acagatgaag atgtggagac tcacgaggag 720ggcggtcatc ttggcccgtg agtgtctgga gcaccacgtg gccagcgttc cttagccagt 780gagtgacagc aacgtccgct cggcctgggt tcagcctgga aaaccccagg catgtcgggg 840tctggtggct ccgcggtgtc gagtttgaaa tcgcgcaaac ctgcggtgtg gcgccagctc 900tgacggtgct gcctggcggg ggagtgtctg cttcctccct tctgcttggg aaccaggaca 960aaggatgagg ctccgagccg ttgtcgccca acaggagcat g 100141001DNAHomo sapiens 4atttgggaac ctttaaaaaa tattctggct tcaaaaatac tccatattta catctttggt 60tctatctgaa gtaaagccgt gatggtgtgc gtaagtgaaa caggtgcaaa ggggcaacaa 120caaagggcgc ctctctttgt ctttgtgtcg caggcggaga tggacatggt ggcctggggt 180gtggacctgg cctcagtgga gcagcacatt aacagccacc ggggcatcca caactccatc 240ggcgactatc gctggcagct ggacaaaatc aaagccgacc tggtacttgt ctgtgtttca 300ttttagagtc ttcaaaatat ctaccgaagg atcgtgtaat tactcaatcc cagggagttt 360cttctgaaac attgctatta tttctttccc agaagactgg aaatgtttag aaatcccact 420tcttaaatgg ggaagtggaa tcagtagccc tattagagat tatgttaaca cttgaagagg 480agttaaacca gaggctgagg ktgtgcaaac actcatttgc agtttgtgaa taagtctctt 540taggggtggc agtttgtttc tgcggtaagc agaacatctt tttgaatagg ggaaatgcaa 600cagtcttata cagtagtttg tgtcattggt gaatcctttc ctaggtggta attaaaacat 660tatttctact gagcaaagcc atatgtcatc ccgacacccg ctcccatgct gaaaaaagtc 720agacttgaaa ctgggttgag aattacagca taaaatcata actgatctta agtgcttagt 780ttcccgcagg tctctacact tgtaaatcac taaacttttt tttttttttt ttacctgaga 840ccatagcttc tcatcctcat ttcttcttct ggctttttgg ggcttacttt tgtccacctg 900agcccctgac caactttctc cttcatttct ctaagaccta gggaatccta aatgatgtct 960ttaaacttta agacaatttt ctaacacgtg agtctttaag t 10015941DNAHomo sapiens 5ttctctgtga gtctttagga aatgaggagc atgatcttct agcagtaaaa cacctgtaga 60gaattgcctt atgttttttg tttgtttatt tgtttgtgtg ctttggtttg gtttgctttt 120tttttttttt tttttttttt tttgagatgg agtctcgccc tgttgcccag gctggagtgt 180agtggcgaaa tctcggctca ctgcaacctc cacctccctg gttcaagcaa ttcccctgtc 240tcagcctccc gagtagctga gattacaggt gcacaccacc acgcccggct aatttttttg 300tatttttagt agagatgggg tttcaccatg ttggccagac tggtctcgaa cttctgacct 360caggcaatcc gcctgcctca gcctcccaaa gcgctgggat tacaggcatg agccactgcg 420ccccgcctcc atgttaatca mtctttctga tttcaaataa ctcattatcc ccatgacctt 480atggatttgt ttttcctctt catccacaaa attctccaga gaagtctccc ttgttatctc 540ttggctgtgc tttctatctc accagttatc tttctccaaa gagcttcctc tgcaaagaag 600ctttgtatat gaagaccatg tgggggctga atcaagacca agtttcacaa cctaaaagta 660gttcacaaag cttccttgcc tctattctct gcaaatctgt aaactcttca gctgacccaa 720tttctctctt tagccttcag agattatttt attttatttt atttcatttc atttcatttc 780attttgacag aatctagctc tgtcgcccag gctggagtgc agtggcacca tctttgctca 840ctgcaacctc cccctcacag gttcaagcaa ctgtcctgcc tcagcctccc gagtagctgg 900gattacaggc gtgagccacc acgcccagct gatttttttt t 94161001DNAHomo sapiens 6cctctactgc cgtacacccc accactcagc cttggagtgc ctgtgtgcag agcagggctg 60aggcatggtg ctgctttggt ggtctaggtt tgctgcaggg ccaggtggcc tgagctccag 120gcaggatctc tggctgcact cagccctttc tgcctcccca aatgctctat atcactattt 180gtacactgag cagagtaaag ttagagagaa ctgttttata gaatagggct ggcccccgct 240cccctggcct acgtgatggt ccttcctggc tgccaggtac ttgtttgtat tagagacaga 300cactccacag ggtctgttgt ggcccacagc acataggcaa tcagaggcag aaagcagagc 360tgtttggacc cacagagggc cggctgtctg ccactgaaat gtctttccag ttggttgaga 420agcagcagga tgctctgctg gtgatgtctg aaagtcccag gattctttgg gtctccaagg 480agatcctagc atataccact rtcgtggttt taataaagag caaaaacact ttcagatggg 540gagaagagtg gaacaaaagg tattcttcct gggttgaagt ctgggggaaa ggcattgaga 600agactgggct aatggcacaa accaatgaag tactcaagtc acctgtgatg gaggccagtc 660atccaatggt atcaactttg tatgtggcaa cacttaataa aaatctgaac aggtcttcac 720ttgtggacac agtagacttt cttgaaaaag gacagaaaag tgagccctgt gaattttcat 780ctcacggact gacaacaatg acttgccttt aaggacagtc actcaagatg aagatgcaac 840aaaacccttc cagttccaag tggctgatga aaaaaaaaaa atcttaaaag catcacagaa 900caacggagaa agagatcaga agactataac agatagtttg aattttaaaa ctcagagaaa 960agcaactgag gaggaaatac actgcttaga aagaagaaac t 10017601DNAHomo sapiens 7tggacggcct ctgaaggggt ctgtggggtc ctggacgggt ccccattcat ggcaggatta 60acccccctcg ggttctgtgt ggtccaggcc gcccctttgt ctccactgcc ccctggccag 120aatgagggac agtgacccac ccagggctgg gcctggctca gactccgtca gagccgcagg 180gcaagttcct ggcacgtccg aggtgggagg ctcctctgcg ctccaggagg ctgtgcctgg 240ccccccttcc cggcaggaac cggctgtgtc cctttccttc ctttatcttc tgttttcagc 300dccttcaact gtgaagaggt gaactcttca aacacgctga gcaaacaggc ccgactccca 360gggccgcatc cgggatgtct caatagctgt ggccttgacg tccacctcgg acccctgccc 420cggacccagc ccagttccca atgggccctc tgcccgggga ggtgcctagt gggagggacg 480agggcaaagt cggggccccc acttgtttgg tgtcactgtg tgccagcggc cactggcggg 540cgaggctgtt ccagggtgga ggcggggagg gttggaccac aggcactgag cggggacaga 600g 6018732DNAHomo sapiens 8gtcattggtc aaatgtggcc tgtatctaaa ttccaactgt tagaatcata gacatctaga 60gcttacgtca gttttagata tttcttatga attctcagaa ttcatagatt ctcattttta 120ttcttagact tctcagatat tccgtttttg atagtatacc cttctgagtc taatatgtcc 180taaagtgcga acttgtacaa tttttttttt tttttttttt tttttttttt tktgataagg 240agttttactc tgtcacccag gctggagtgc agtgacccga tctcggctca ctgcaacctc 300tgcctcccgg gttcaagtga ttgtgatgtc tcagtctccc aagtagctgg gattacaggc 360tcctgccacc acatgcctag ctaattgtta tactttagta gaaatggggc ttcgccgtgt 420tagtcaggct ggtcttgtac tcctgacctc agttgatctg cctaccttgg cccccaaggt 480gctgggatta caggcatgag ccaccgcgcc tgacccagct tcttaaatta ttctgggcca 540ccagtaatgt gaatcatgta aattaaaata tataattaaa caaaatcata tagcgattag 600agataatagt tgtgaaatgc ttgaaaaatc ataggcattt aataaataga agccattcca 660attaggattc ttcttgattt tttttcaaga ccaaaaaaat actcttttaa atatttatta 720taatactcca tg 73291320DNAHomo sapiens 9aggctgcagt tagtcatgac tgcgcgctgc actccagcct gggtgacaaa gtgaggccct 60gtctcaaaaa caataaaaaa tttaaaagag ctgagcatgg aggccacttt gggaggctga 120ggcaggcaga tctcttaagc ccaggagtct gagaccagcc tgggcgacat gatgaagccc 180catctctaca aaaaatacaa aaaaattagc tgagctttat ggcaaatccc tgtaatccca 240gttacctagg aggcccaggc aggaagatgg cttgagccca aaaggttgag gctgtagtga 300gctgtgatca tgaacagagt gagaccctgt ttcaaaacaa aatgaaaaac aaacaaacaa 360aaaaaccaag aaaacaagaa aacaaaaact atacaatgat gagccaaaaa gcaagatatg 420gaagaatata tatatatata tatatatata tatagtatga gtccagctat agaaagtttg 480aaatcaggca acctaaacaa tattgttcag ggatctatac agaggcagga agccattgag 540aaaggtaagg ggaggattat caccaaattc aggatggtgg ctcccctggg gagaatatgt 600caaggagggg cacatgggct tggaatactg tcttcattga cctgcgtgtt gggtacacag 660gagtttgtta tttttcacac tgcatatgtg catgtatata ctctcccata tataccatgc 720atttcacaca agaacacaaa ggctgtgtgg ctctgctctg cccctttccc cttccagctc 780ccattctcgt cytcagctag cagaggaggg tcagggtctt ttagcacagc ttccttctgt 840ctctgagtgg gtcagaggag tacggggatg agggcctccc ttctgcggct gggctctggc 900cactccaggg tgggaaggcc tggagaaaac agggccaggc aaagccggct ggccctgctg 960tttctgccaa tgctgggatt aggccagggc tctggcccac ctgtcatttc actcattcag 1020catgaacata gccactgagc acttactgtg agccccgggt gctattggga gagttcagat 1080aagtgagaga gggtctttga cctcaaagat cttacagaga ggaccgtata cacaaataac 1140agtataccag caaaatgtga gctaagtgtc atgtgactac tcatctactc tttcaataaa 1200tatttgttgt gcacctatta catgccagga actgtgctgg atggtgatca tgtaaagaca 1260gtcaaatcac agtcctagct ctcagattca cagcctgcct aatgctgggg aaactggaat 1320101001DNAHomo sapiens 10ccagccagaa ggggcgcagt ttgttagttc agctcctcct gagacagaaa taaagacacg 60aaccaaagga catcagcact tacagggctc tcaggtcaca cacaggatgt ccgcgcccac 120tgcagagctg caggtcccct ccagggcagt ggggagccac aagcagcgtt aggcagcggc 180tgggaccagg accgcctgag cactcaagaa cccccactgc cccaagcact gctggcagca 240agcccagaaa actgagcccg gggagctcct ctgagcggcc taagcacccc tctaagctgt 300gctgccccaa ttcaagcctg gctcacggca gcaaagaaaa aatgtgacct tcggagctcc 360caaaggggcc acccataagc tgagagcctg cccggaagca cttatagacc cgcgtggctt 420gttttcattg caaagaacaa taaaaattat cttgcctctg atcaccactg atagcccaag 480aagcaaaaat tcgatcccgg dgatgagaaa tgaaatgaaa catcgcgaga aacttccagg 540aatcttctgg atgtggctag actctttagc ttgagcttcc agacaggccg aggcttggtg 600ctggagcctg gccctccgct gacctctctt ctacccgggg gcacagcccg gattgcagag 660aggctggcgc aagagtgagg gagcgagggc tagcctgtga tgggctttct ccacctagca 720ccaccctatg ctgtggctca ggggagtcaa gagtttacac agctgcagag atggattcca 780ggccacttac tcaagtctac ctactccttc cttcggccaa tcagctgggt gcctctgcgg 840cctgtgacac caccagcaaa cagctccaga cctcctagca tggtctctgt caaggctggg 900tggcagatct gtgatctcct ttttaaattt ttcatttttt ttaagagatg gggtcttgct 960atattgccca ggctggtctc aaactcctgg gctccagcga t 10011117916DNAHomo sapiens 11cacccggccc ggctccctcc ctgcccgtcc ccgtcccccc acccgtgcca gcccccagga 60tgggtgcccc gagcgcgtgc cggacgctgg tgttggctct ggcggccatg ctcgtggtgc 120cgcaggcaga gacccagggc cctgtggagc cgagctggga gaatgcaggg cacaccatgg 180atggcggtgc cccgacgtcc tcgcccaccc ggcgcgtgag ctttgttcca cccgtcactg 240tcttccccag cctgagcccc ctgaacccgg cgcacaatgg gcgggtgtgc agcacctggg 300gtgacttcca ctacaagacc ttcgacggcg acgtcttccg cttccctggc ctttgcaact 360acgtgttctc tgagcactgc cgcgccgcct acgaggactt caacgtccag ctacgccgag 420gcctagtggg ctccaggcct gtggtcaccc gtgttgtcat caaggcccag gggctggtgc 480tggaggcgtc caacggctcc gtcctcatca atgggcagcg ggaggagctg ccttacagcc 540gcactggcct cctggtggag cagagcgggg actacatcaa ggtcagcatc cggctggtgc 600tgacattcct gtggaacgga gaggacagtg ccctgctgga gctggatccc aaatacgcca 660accagacctg tggcctgtgt ggggacttca acggcctccc ggccttcaac gagttctatg 720cccacaacgc caggctgacc ccgctccagt ttgggaacct gcagaagttg gatgggccca 780cggagcagtg cccggacccg ctgcccttgc cggccggcaa ctgcacggac gaggagggca 840tctgccaccg caccctgctg gggccggcct ttgcggagtg ccacgcactg gtggacagca 900ctgcgtacct ggccgcctgc gcccaggacc tgtgccgctg ccccacctgc ccgtgtgcca 960cctttgtgga atactcacgc cagtgcgccc acgcgggggg ccagccgcgg aactggaggt 1020gccctgagct ctgcccccgg acctgccccc tcaacatgca gcaccaggag tgtggctcac 1080cctgcacgga cacctgctcc aacccccagc gcgcgcagct ctgcgaggac cactgtgtgg 1140acggctgctt ctgcccccca ggcacggtgc tggatgacat cacgcactct ggctgcctgc 1200ccctcgggca gtgcccctgc acccacggcg gccgcaccta cagcccgggc acctccttca 1260acaccacctg cagctcctgc acctgctccg gggggctatg gcagtgccag gacctgccgt 1320gccctggcac ctgctctgtg cagggcgggg cccacatctc cacctatgat gagaaactct 1380acgacctgca tggtgactgc agctacgttc tgtccaagaa atgtgccgac agcagcttca 1440ccgtgctggc tgagctgcgg aagtgcggcc tgacggacaa cgagaactgc ctgaaagcgg 1500tgacgctcag cctggacggc ggggacacgg ccatccgggt ccaagcggac ggcggcgtgt 1560tcctcaactc catctacacg cagctgcccc tgtcggcagc caacatcacc ctgttcacac 1620cctcgagctt cttcatcgtg gtgcagacag gcctggggct gcagctgctg gtgcagctgg 1680tgccactcat gcaggtgttt gtcaggctgg accccgccca ccagggccag atgtgcggcc 1740tgtgtgggaa cttcaaccag aaccaggctg acgacttcac ggccctcagc ggggtggtgg 1800aggccacggg cgcagccttc gccaacacct ggaaggccca ggctgcctgt gccaatgcca 1860ggaacagctt tgaggacccc tgctccctca gtgtggagaa tgagaactac gcccggcact 1920ggtgctcgcg cctgaccgat cccaacagtg ccttctcgcg ctgccactcc atcatcaacc 1980ccaagccctt ccactcgaac tgcatgtttg acacctgcaa ctgtgagcgg agcgaggact 2040gcctgtgcgc cgcgctgtcc tcctatgtgc acgcctgtgc cgccaagggc gtacagctca 2100gcgactggag ggacggcgtc tgcaccaagt acatgcagaa ctgccccaag tcccagcgct 2160acgcctacgt ggtggatgcc tgccagccca cttgccgcgg cctgagtgag gccgacgtca 2220cctgcagcgt ttccttcgtg cctgtggacg gctgcacctg ccccgcgggc accttcctca 2280atgacgcggg cgcctgtgtg cccgcccagg agtgcccctg ctacgctcac ggcaccgtgc 2340tggctcctgg agaggtggtg cacgacgagg gcgccgtgtg ttcatgtacg ggtgggaagc 2400taagctgcct gggagcctct ctgcagaaaa gcacagggtg tgcagccccc atggtgtacc 2460tggactgcag caacagctcg gcgggcaccc ctggggccga gtgcctccgg agctgccaca 2520cgctggacgt gggctgtttc agcacacact gcgtgtccgg ctgtgtctgt cccccggggc 2580tggtgtcgga tgggagtggg ggctgcattg ccgaggagga ctgcccctgt gtgcacaacg 2640aggccaccta caagcctgga gagaccatca gggtcgactg caacacctgc acctgcagga 2700accggaggtg ggagtgcagc caccggctct gcctgggcac ctgcgtggcc tacggggatg 2760gccacttcat cacctttgat ggcgatcgct acagctttga aggcagctgc gagtacatct 2820tggcccagga ctactgtggg gacaacacca cccacgggac cttccgcatc gtcaccgaga 2880acatcccctg tgggaccacc ggcaccacct gctccaaggc catcaagctc ttcgtggaga 2940gctacgagct gatcctccaa gaggggacct ttaaggcggt ggcgagaggg ccgggtgggg 3000acccacccta caagatacgc tacatgggga tcttcctggt catcgagacc cacgggatgg 3060ccgtgtcctg ggaccggaag accagcgtgt tcatccgact gcaccaggac tacaagggca 3120gggtctgcgg cctgtgcggg aacttcgacg acaatgccat caatgacttt gccacgcgta 3180gccggtccgt ggtgggggac gcactggagt ttgggaacag ctggaagctc tccccctcct 3240gcccggacgc cctggcaccc aaggacccct gcacggccaa ccccttccgc aagtcctggg 3300cccagaagca gtgcagcatc ctccacggcc ccaccttcgc cgcctgccgc tcccaggttg 3360actccaccaa gtactacgag gcctgcgtga acgacgcgtg tgcctgcgac tcgggtggcg 3420actgcgagtg tttctgcacg gctgtggctg cctacgccca ggcctgccac gacgcgggcc 3480tgtgtgtgtc ctggcggact ccggacacct gccccttgtt ctgtgacttc tacaacccac 3540atgggggctg tgagtggcac taccagccct gcggggcacc ctgcctaaaa acctgccgga 3600accccagtgg gcactgcctg gtggacctgc ctggcctgga aggctgctac ccgaagtgcc 3660cacccagcca gcccttcttc aatgaggacc agatgaagtg cgtggcccag tgtggctgct 3720acgacaagga cggaaactac tatgacgtcg gtgcaagggt ccccacagcg gagaactgcc 3780agagctgtaa ctgcacaccc agtggcatcc agtgcgctca cagccttgag gcctgcacct 3840gcacctatga ggacaggacc tacagctacc aggacgtcat ctacaacacc accgatgggc 3900ttggcgcctg cttgatcgcc atctgcggaa gcaacggcac catcatcagg aaggctgtgg 3960catgtcctgg aactccagcc acaacgccat tcaccttcac caccgcctgg gtcccccact 4020ccacgacaag cccggccctc ccggtctcca ccgtgtgtgt ccgcgaggtc tgccgctggt 4080ccagctggta caatgggcac cgcccagagc ccggcctggg aggcggagac tttgagacgt 4140ttgaaaacct gaggcagaga gggtaccagg tatgccctgt gctggctgac atcgagtgcc 4200gggcggcgca gcttcccgac atgccgctgg aggagctggg ccagcaggtg gactgtgacc 4260gcatgcgggg gctgatgtgc gccaacagcc aacagagtcc cccgctctgt cacgactacg 4320agctgcgggt tctctgctgc gaatacgtgc cctgtggccc ctccccggcc ccaggcacca 4380gccctcagcc ctccctcagt gccagcacgg agcctgctgt gcctacccca acccagacca 4440cagcaaccga aaagaccacc ctatgggtga ccccgagcat ccggtcgacg gcggccctca 4500cctcgcagac tgggtccagc tcaggccccg tgacggtcac cccctcggcc ccaggtacca 4560ccacctgcca gccccggtgt cagtggacag agtggtttga tgaggactac cccaagtctg 4620aacaacttgg aggggacgtt gagtcctacg ataagatcag ggccgctgga gggcacttat 4680gccagcagcc taaggacata gagtgccagg ccgagagctt ccccaactgg accctggcac 4740aggtggggca gaaggtgcac tgtgacgtcc acttcggcct ggtgtgcagg aactgggagc 4800aggagggcgt cttcaagatg tgctacaact acaggatccg ggtcctctgc tgcagtgacg 4860accactgcag gggacgtgcc acaaccccgc caccgaccac agagctggag acggccacca 4920ccaccaccac ccaggccctg ttctcaacgc cgcagcctac gagtagcccg gggctgacca 4980gggctccccc ggccagcacc

acagcagtcc ccaccctctc agaaggactg acatccccca 5040gatacacaag cacccttggt acagccacca cgggaggccc cacgacgcct gcaggctcca 5100cagaacccac tgtcccaggg gtggccacat ccacccttcc aacacgctca gcccttccag 5160ggacgacggg gagcttgggc acatggcgcc cctcacagcc acccacgctg gccccaacaa 5220caatggcaac ctccagagct cgcccgacag gcacagccag caccgcttcc aaagagccgc 5280tgaccacgag cctggcgcca acactcacga gcgagctgtc cacctctcag gccgagacca 5340gcacgcccag gacagagacg acaatgagcc ccttgactaa caccaccacc agccagggca 5400cgacccgctg tcaaccgaag tgtgagtgga cagagtggtt tgacgtggac ttcccaacct 5460caggggttgc aggcggggac atggaaactt ttgaaaacat cagggctgct gggggcaaga 5520tgtgctgggc accaaagagc atagagtgcc gggcggagaa ctaccccgag gtaagcatcg 5580accaggtcgg gcaggtgctg acctgcagcc tggagacggg gctgacctgc aagaacgaag 5640accagacagg caggttcaac atgtgcttca actacaacgt gcgtgtgctt tgctgtgacg 5700actacagcca ctgccccagt accccagcca ccagctccac ggccacgccc tcctcaactc 5760cggggacgac ctggatcctc acaaagccga ccacaacagc cactacgact gcgtccactg 5820gatccacggc caccccgacc tccaccctga gaacagctcc ccctcccaaa gtgctgacca 5880ccacggccac cacacccaca gtcaccagct ccaaagccac tccctcctcc agtccaggga 5940ctgcaaccgc ccttccagca ctgagaagca cagccaccac acccacagct accagcgtta 6000cacccatccc ctcttcctcc ctgggcacca cctggacccg cctatcacag accaccacac 6060ccacggccac catgtccaca gccacaccct cctccactcc agagactgcc cacacctcca 6120cagtgcttac cgccacggcc accacaactg gggccaccgg ctctgtggcc accccctcct 6180ccaccccagg aacagctcac actaccaaag tgccaactac cacaaccacg ggcttcacag 6240ccaccccctc ctccagccca gggacggcac tcacgcctcc agtgtggatc agcacaacca 6300ccacacccac aaccagaggc tccacggtga ccccctcctc catcccgggg accacccaca 6360ccgccacagt gctgaccacc accaccacaa ctgtggccac tggttctatg gcaacaccct 6420cctctagcac acagaccagt ggtactcccc catcactgac caccacggcc actacgatca 6480cggccaccgg ctccaccacc aacccctcct caactcctgg gacaactccc atccccccag 6540tgctgaccac caccgccacc acacctgcag ccaccagcaa cacagtgact ccctcctctg 6600ccctagggac cacccacaca cccccagtgc cgaacaccat ggccaccaca cacgggcgat 6660ccctgccccc cagcagtccc cacacggtgc gcacagcctg gacttcggcc acctcgggca 6720tcttgggcac cacccacatc acagagcctt ccacggtgac ttcccacacc ctagcagcaa 6780ccaccggtac cacccagcac tcgactccag ccctttccag ccctcaccct agcagcagaa 6840ccaccgagtc acccccttct ccagggacga ccaccccggg ccacaccacg gccacctcca 6900ggaccacagc cacggccaca cccagcaaga cccgcacctc gaccctgctg cccagcagcc 6960ccacatcggc ccccataacc acggtggtga ccatgggctg tgagccccag tgtgcctggt 7020cagagtggct ggactacagc taccccatgc cggggccctc tggcggggac tttgacacct 7080actccaacat ccgtgcggcc ggaggggccg tctgtgagca gcccctgggc ctcgagtgcc 7140gtgcccaggc ccagcctggt gtccccctgc gggagttggg ccaggtcgtg gaatgcagcc 7200tggactttgg cctggtctgc aggaaccgtg agcaggtggg gaagttcaag atgtgcttca 7260actatgaaat ccgtgtgttc tgctgcaact acggccactg ccccagcacc ccggccacca 7320gctctacggc catgccctcc tccactccgg ggacgacctg gatcctcaca gagctgacca 7380caacagccac tacgactgag tccactggat ccacggccac cccgtcctcc accccaggga 7440ccacctggat cctcacagag ccgagcacta cagccaccgt gacggtgccc accggatcca 7500cggccaccgc ctcctccacc caggcaactg ctggcacccc acatgtgagc accacggcca 7560cgacacccac agtcaccagc tccaaagcca ctcccttctc cagtccaggg actgcaaccg 7620cccttccagc actgagaagc acagccacca cacccacagc taccagcttt acagccatcc 7680cctcctcctc cctgggcacc acctggaccc gcctatcaca gaccaccaca cccacggcca 7740ccatgtccac agccacaccc tcctccactc cagagactgt ccacacctcc acagtgctta 7800ccaccacggc caccacaacc ggggccaccg gctctgtggc caccccctcc tccaccccag 7860gaacagctca cactaccaaa gtgctgacta ccacaaccac gggcttcaca gccaccccct 7920cctccagccc agggacggca cgcacgcttc cagtgtggat cagcacaacc accacaccca 7980caaccagagg ttccacggtg accccctcct ccatcccggg gaccacccac acccccacag 8040tgctgaccac caccaccaca actgtggcca ctggttctat ggcaacaccc tcctctagca 8100cacagaccag tggtactccc ccatcactga ccaccacggc cactacgatc acggccaccg 8160gctccaccac caacccctcc tcaactccag ggacaacacc tatcccccca gtgctgacca 8220ccaccgccac cacacctgca gccaccagca gcacagtgac tccctcctct gccctaggga 8280ccacccacac acccccagtg ccgaacacca cggccaccac acacgggcga tccctgtccc 8340ccagcagtcc ccacacggtg cgcacagcct ggacttcggc cacctcaggc accttgggca 8400ccacccacat cacagagcct tccacgggga cttcccacac cccagcagca accaccggta 8460ccacccagca ctcgactcca gccctgtcca gccctcaccc tagcagcagg accaccgagt 8520cacccccttc tccagggacg accaccccgg gccacaccag ggccacctcc aggaccacgg 8580ccacggccac acccagcaag acccgcacct cgaccctgct gcccagcagc cccacatcgg 8640ccccaataac cacggtggtg accatgggct gtgagcccca gtgtgcctgg tcagagtggc 8700tggactacag ctaccccatg ccggggccct ctggcgggga ctttgacacc tactccaaca 8760tccgtgcggc cggaggggcc gtctgtgagc agcccctggg cctcgagtgc cgtgcccagg 8820cccagcctgg tgtccccctg cgggagttgg gccaggtcgt ggaatgcagc ctggactttg 8880gcctggtctg caggaaccgt gagcaggtgg ggaagttcaa gatgtgcttc aactatgaaa 8940tccgtgtgtt ctgctgcaac tacggccact gccccagcac cccggccacc agctctacgg 9000ccacgccctc ctccactcca gggacgacct ggatcctcac agagcagacc acagcagcca 9060ctacgaccgc aaccactgga tccacggcca tcccgtcctc caccccggga acagctcccc 9120ctcccaaagt gctgaccagc acggccacca cacccacagc caccagttcc aaagccactt 9180cctcctccag tccaaggact gcaaccaccc ttccagtgct gacaagcaca gccaccaaat 9240ccacagctac cagctttaca cccatcccct ccttcaccct tgggaccacc gggaccctcc 9300cagaacagac caccacaccc atggccacca tgtccacaat ccacccctcc tccactccgg 9360agaccaccca cacctccaca gtgctgacca cgaaggccac cacgacaagg gccaccagtt 9420ccatgtccac cccctcctcc actccgggga cgacctggat cctcacagag ctgaccacag 9480cagccactac aactgcagcc actggcccca cggccacccc gtcctccacc ccagggacca 9540cctggatcct cacagagccc agcactacag ccaccgtgac ggtgcccacc ggatccacgg 9600ccaccgcctc ctccacccgg gcaactgctg gcaccctcaa agtgctgacc agcacggcca 9660ccacacccac agtcatcagc tccagagcca ctccctcctc cagtccaggg actgcaaccg 9720cccttccagc actgagaagc acagccacca cacccacagc taccagcgtt acagccatcc 9780cctcttcctc cctgggcacc gcctggaccc gcctatcaca gaccaccaca cccacggcca 9840ccatgtccac agccacaccc tcctctactc cagagactgt ccacacctcc acagtgctta 9900ccaccacgac caccacaacc agggccaccg gctctgtggc caccccctcc tccaccccag 9960gaacagctca cactaccaaa gtgccgacta ccacaaccac gggcttcaca gccaccccct 10020cctccagccc agggacggca ctcacgcctc cagtgtggat cagcacaacc accacaccca 10080caaccagagg ctccacggtg accccctcct ccatcccggg gaccacccac accgccacag 10140tgctgaccac caccaccaca actgtggcca ctggttctat ggcaacaccc tcctctagca 10200cacagaccag tggtactccc ccatcactga ccaccacggc cactacgatc acagccaccg 10260gctccaccac caacccctcc tcaactccag ggacaactcc catcccccca gtgctgacca 10320ccaccgccac cacacctgca gccaccagca gcacagtgac tccctcctct gccctaggga 10380ccacccacac acccccagtg ccgaacacca cggccaccac acacgggcgg tccctgcccc 10440ccagcagtcc ccacacggtg cgcacagcct ggacttcggc cacctcgggc atcttgggca 10500ccacccacat cacagagcct tccacggtga cttcccacac cccagcagca accaccagta 10560ccacccagca ctcgactcca gccctgtcca gccctcaccc tagcagcagg accaccgagt 10620cacccccttc tccagggacg accaccccgg gccacaccag gggcacctcc aggaccacag 10680ccacagccac acccagcaag acccgcacct cgaccctgct gcccagcagc cccacatcgg 10740cccccataac cacggtggtg accacgggct gtgagcccca gtgtgcctgg tcagagtggc 10800tggactacag ctaccccatg ccggggccct ctggcgggga ctttgacacc tactccaaca 10860tccgtgcggc cggaggggca gtctgtgagc agcccctggg cctcgagtgc cgtgcccagg 10920cccagcctgg tgtccccctg cgggagttgg gccaggtcgt ggaatgcagc ctggactttg 10980gcctggtctg caggaaccgt gagcaggtgg ggaagttcaa gatgtgcttc aactatgaaa 11040tccgtgtgtt ctgctgcaac tacggccact gccccagcac cccggccacc agctctacgg 11100ccacgccctc ctcaactccg gggacgacct ggatcctcac aaagctgacc acaacagcca 11160ctacgactga gtccactgga tccacggcca ccccgtcctc caccccaggg accacctgga 11220tcctcacaga gccgagcact acagccaccg tgacggtgcc caccggatcc acggccaccg 11280cctcctccac ccaggcaact gctggcaccc cacatgtgag caccacggcc acgacaccca 11340cagtcaccag ctccaaagcc actcccttct ccagtccagg gactgcaacc gcccttccag 11400cactgagaag cacagccacc acacccacag ctaccagctt tacagccatc ccctcctcct 11460ccctgggcac cacctggacc cgcctatcac agaccaccac acccacggcc accatgtcca 11520cagccacacc ctcctccact ccagagactg cccacacctc cacagtgctt accaccacgg 11580ccaccacaac cagggccacc ggctctgtgg ccaccccctc ttccacccca ggaacagctc 11640acactaccaa agtgccgact accacaacca cgggcttcac agtcaccccc tcctccagcc 11700cagggacggc acgcacgcct ccagtgtgga tcagcacaac caccacaccc acaaccagtg 11760gctccacggt gaccccctcc tccgtcccgg ggaccaccca cacccccaca gtgctgacca 11820ccaccaccac aactgtggcc actggttcta tggcaacacc ctcctctagc acacagacca 11880gtggtactcc cccatcactg atcaccacgg ccactacgat cacggccacc ggctccacca 11940ccaacccctc ctcaactcca gggacaacac ctatcccccc agtgctgacc accaccgcca 12000ccacacctgc agccaccagc agcacagtga ctccctcctc tgccctaggg accacccaca 12060cacccccagt gccgaacacc acggccacca cacacgggcg atccctgtcc cccagcagtc 12120cccacacggt gcgcacagcc tggacttcgg ccacctcagg caccttgggc accacccaca 12180tcacagagcc ttccacgggg acttcccaca ccccagcagc aaccaccggt accacccagc 12240actcgactcc agccctgtcc agccctcacc ctagcagcag gaccaccgag tcaccccctt 12300ccccagggac gaccaccccg ggccacacca cggccacctc caggaccacg gccacggcca 12360cacccagcaa gacccgcacc tcgaccctgc tgcccagcag ccccacatcg gcccccataa 12420ccacggtggt gaccacgggc tgtgagcccc agtgtgcctg gtcagagtgg ctggactaca 12480gctaccccat gccggggccc tctggcgggg actttgacac ctactccaac atccgtgcgg 12540ccggaggggc cgtctgtgag cagcccctgg gcctcgagtg ccgtgcccag gcccagcctg 12600gtgtccccct gggggagttg ggccaggtcg tggaatgcag cctggacttt ggcctggtct 12660gcaggaaccg tgagcaggtg gggaagttca agatgtgctt caactatgaa atccgtgtgt 12720tctgctgcaa ctacggccac tgccccagca ccccggccac cagctctacg gccatgccct 12780cctccactcc ggggacgacc tggatcctca cagagctgac cacaacagcc actacgactg 12840catccactgg atccacggcc accccgtcct ccaccccggg aacagctccc cctcccaaag 12900tgctgaccag cccggccacc acacccacag ccaccagttc caaagccact tcctcctcca 12960gtccaaggac tgcaaccacc cttccagtgc tgacaagcac agccaccaaa tccacagcta 13020ccagcgttac acccatcccc tcctccaccc ttgggaccac cgggaccctc ccagaacaga 13080ccaccacacc cgtggccacc atgtccacaa tccacccctc ctccactccg gagaccaccc 13140acacctccac agtgctgacc acgaaggcca ccacgacaag ggccaccagt tccacgtcca 13200ccccctcctc cactccgggg acgacctgga tcctcacaga gctgaccaca gcagccacta 13260caactgcagc cactggcccc acggccaccc cgtcctccac cccagggacc acctggatcc 13320tcacagagct gaccacaaca gccactacga ctgcgtccac tggatccacg gccaccccgt 13380cctccacccc agggaccacc tggatcctca cagagccgag cactacagcc accgtgacgg 13440tgcccaccgg atccacggcc accgcctcct ccacccaggc aactgctggc accccacatg 13500tgagcaccac ggccacgaca cccacagtca ccagctccaa agccactccc tcctccagtc 13560cagggactgc aactgccctt ccagcactga gaagcacagc caccacaccc acagctacca 13620gctttacagc catcccctcc tcctccctgg gcaccacctg gacccgccta tcacagacca 13680ccacacccac ggccaccatg tccacagcca caccctcctc cactccagag actgtccaca 13740cctccacagt gcttaccgcc acggccacca caaccggggc caccggctct gtggccaccc 13800cctcctccac cccaggaaca gctcacacta ccaaagtgcc gactaccaca accacgggct 13860tcacagccac cccctcctcc agcccaggga cggcactcac gcctccagtg tggatcagca 13920caaccaccac acccacaacc accacaccca caaccagtgg ctccacggtg accccctcct 13980ccatcccggg gaccacccac accgccagag tgctgaccac caccaccaca actgtggcca 14040ctggttctat ggcaacaccc tcctctagca cacagaccag tggtactccc ccatcactga 14100ccaccacggc cactacgatc acggccaccg gctccaccac caacccctcc tcaactccag 14160ggacaacacc catcacccca gtgctgacca gcacggccac cacacccgca gccaccagct 14220ccaaagccac ttcctcctcc agtccaagga ctgcaaccac ccttccagtg ctgacaagca 14280cagccacaaa atccacagct accagcttta cacccatccc ctcctccacc ctgtggacca 14340cgtggaccgt cccagcacag accaccacac ccatgtccac catgtccaca atccacacct 14400cctctactcc agagaccacc cacacctcca cagtgctgac caccacagcc accatgacaa 14460gggccaccaa ttccacggcc acaccctcct ccactctggg gacgacccgg atcctcactg 14520agctgaccac aacagccact acaactgcag ccactggatc cacggccacc ctgtcctcca 14580ccccagggac cacctggatc ctcacagagc cgagcactat agccaccgtg atggtgccca 14640ccggttccac ggccaccgcc tcctccactc tgggaacagc tcacaccccc aaagtggtga 14700ccaccatggc cactatgccc acagccactg cctccacggt tcccagctcg tccaccgtgg 14760ggaccacccg cacccctgca gtgctcccca gcagcctgcc aaccttcagc gtgtccactg 14820tgtcctcctc agtcctcacc accctgagac ccactggctt ccccagctcc cacttctcta 14880ctccctgctt ctgcagggca tttggacagt ttttctcgcc cggggaagtc atctacaata 14940agaccgaccg agccggctgc catttctacg cagtgtgcaa tcagcactgt gacattgacc 15000gcttccaggg cgcctgtccc acctccccac cgccagtgtc ctccgccccg ctgtcctcgc 15060cctcccctgc ccctggctgt gacaatgcca tccctctccg gcaggtgaat gagacctgga 15120ccctggagaa ctgcacggtg gccaggtgcg tgggtgacaa ccgtgtcgtc ctgctggacc 15180caaagcctgt ggccaacgtc acctgcgtga acaagcacct gcccatcaaa gtgtcggacc 15240cgagccagcc ctgtgacttc cactatgagt gcgagtgcat ctgcagcatg tggggcggct 15300cccactattc cacctttgac ggcacctctt acaccttccg gggcaactgc acctatgtcc 15360tcatgagaga gatccatgca cgctttggga atctcagcct ctacctggac aaccactact 15420gcacggcctc tgccactgcc gctgccgccc gctgcccccg cgccctcagc atccactaca 15480agtccatgga tatcgtcctc actgtcacca tggtgcatgg gaaggaggag ggcctgatcc 15540tgtttgacca aattccggtg agcagcggtt tcagcaagaa cggcgtgctt gtgtctgtgc 15600tggggaccac caccatgcgt gtggacattc ctgccctggg cgtgagcgtc accttcaatg 15660gccaagtctt ccaggcccgg ctgccctaca gcctcttcca caacaacacc gagggccagt 15720gcggcacctg caccaacaac cagagggacg actgtctcca gcgggacgga accactgccg 15780ccagttgcaa ggacatggcc aagacgtggc tggtccccga cagcagaaag gatggctgct 15840gggccccgac tggcacaccc cccactgcca gccccgcagc cccggtgtct agcacaccca 15900cccccacccc atgcccacca cagccgctct gtgatctgat gctgagccag gtctttgctg 15960agtgccacaa ccttgtgccc ccgggcccat tcttcaacgc ctgcatcagc gaccactgca 16020ggggccgcct tgaggtgccc tgccagagcc tggaggctta cgcagagctc tgccgcgccc 16080ggggagtgtg cagtgactgg cgaggtgcaa ccggtggcct gtgcgacctc acctgcccac 16140ccaccaaagt gtacaagcca tgcggcccca tacagcctgc cacctgcaac tctaggaacc 16200agagcccaca gctggagggg atggcggagg gctgcttctg ccctgaggac cagatcctct 16260tcaacgcaca catgggcatc tgcgtgcagg cctgcccctg cgtgggaccc gatgggtttc 16320ctaaatttcc cggggagcgg tgggtcagca actgccagtc ctgcgtgtgt gacgagggtt 16380cagtgtcggt gcagtgcaag cccctgccct gtgacgccca gggtcagccc ccgccgtgca 16440accgtcccgg cttcgtaacc gtgaccaggc cccgggccga gaacccctgc tgccccgaga 16500cggtgtgcgt gtgcaacaca accacctgcc cccagagcct gcctgtgtgc ccgccagggc 16560aggagtccat ctgcacccag gaggagggcg actgctgtcc caccttccgc tgcagacctc 16620agctgtgttc gtacaatggc accttctacg gggttggtgc aaccttccca ggcgcccttc 16680cctgccacat gtgtacctgc ctctctgggg acacccagga cccaacggtg caatgtcagg 16740aggatgcctg caacaatact acctgtcccc agggctttga gtacaagaga gtggccgggc 16800agtgctgtgg ggagtgcgtc cagaccgcct gcctcacgcc cgatggccag ccagtccagc 16860tgaatgaaac ctgggtcaac agccatgtgg acaactgcac cgtgtacctc tgtgaggctg 16920agggtggagt ccatttgctg accccacagc ctgcatcctg cccagatgtg tccagctgca 16980gggggagcct caggaaaacc ggctgctgct actcctgtga ggaggactcc tgtcaagtcc 17040gcatcaacac gaccatcctg tggcaccagg gctgcgagac cgaggtcaac atcaccttct 17100gcgagggctc ctgccccgga gcgtccaagt actcagcaga ggcccaggcc atgcagcacc 17160agtgcacctg ctgccaggag aggcgggtcc acgaggagac ggtgcccttg cactgtccta 17220acggctcagc catcctgcac acctacaccc acgtggatga gtgtggctgc acgcccttct 17280gtgtccctgc gcccatggct cccccacaca cccgtggctt cccggcccag gaggccactg 17340ctgtctgaga acgttctgcc tccatcccca tgctctgtcc acctggagcc aggatgtgca 17400ttgtctgatc atgaaaacct tgggcctcct ctgcggagcc ccccggcctg tgtgtggcac 17460cccgcgctcc gtgctcctgc tgcccacccc gtgggtgaaa ccggccccag aagggtgagg 17520ggccagcagg acccctttcg ggagggcgcc actcaggagt cctaccctgg gagagcctgt 17580ggcccacctt ggccttgccc ctccctgatg tcactgggac gccctggaac aaactaagca 17640tgtgcgggcc tatgtgtccc tgccacggcc ggagcgcccg cgcagcacgg attccagctg 17700gccacgtccg gccgctgggg cagacaggct ggtccaggca aggccagctg ctgccaggaa 17760gctgcgacag gcaaggcggc cgcctgtcca tgcctgctgc agggtaactc agggctgagg 17820tcgcaacggc caggtcagag aggggtcagc atcccaaagc cccctctgct caacccagcc 17880cagttttgca aataaaccct gagcattgag tacgtt 17916125762PRTHomo sapiens 12Met Gly Ala Pro Ser Ala Cys Arg Thr Leu Val Leu Ala Leu Ala Ala1 5 10 15Met Leu Val Val Pro Gln Ala Glu Thr Gln Gly Pro Val Glu Pro Ser 20 25 30Trp Glu Asn Ala Gly His Thr Met Asp Gly Gly Ala Pro Thr Ser Ser 35 40 45Pro Thr Arg Arg Val Ser Phe Val Pro Pro Val Thr Val Phe Pro Ser 50 55 60Leu Ser Pro Leu Asn Pro Ala His Asn Gly Arg Val Cys Ser Thr Trp65 70 75 80Gly Asp Phe His Tyr Lys Thr Phe Asp Gly Asp Val Phe Arg Phe Pro 85 90 95Gly Leu Cys Asn Tyr Val Phe Ser Glu His Cys Arg Ala Ala Tyr Glu 100 105 110Asp Phe Asn Val Gln Leu Arg Arg Gly Leu Val Gly Ser Arg Pro Val 115 120 125Val Thr Arg Val Val Ile Lys Ala Gln Gly Leu Val Leu Glu Ala Ser 130 135 140Asn Gly Ser Val Leu Ile Asn Gly Gln Arg Glu Glu Leu Pro Tyr Ser145 150 155 160Arg Thr Gly Leu Leu Val Glu Gln Ser Gly Asp Tyr Ile Lys Val Ser 165 170 175Ile Arg Leu Val Leu Thr Phe Leu Trp Asn Gly Glu Asp Ser Ala Leu 180 185 190Leu Glu Leu Asp Pro Lys Tyr Ala Asn Gln Thr Cys Gly Leu Cys Gly 195 200 205Asp Phe Asn Gly Leu Pro Ala Phe Asn Glu Phe Tyr Ala His Asn Ala 210 215 220Arg Leu Thr Pro Leu Gln Phe Gly Asn Leu Gln Lys Leu Asp Gly Pro225 230 235 240Thr Glu Gln Cys Pro Asp Pro Leu Pro Leu Pro Ala Gly Asn Cys Thr 245 250 255Asp Glu Glu Gly Ile Cys His Arg Thr Leu Leu Gly Pro Ala Phe Ala 260 265 270Glu Cys His Ala Leu Val Asp Ser Thr Ala Tyr Leu Ala Ala Cys Ala 275 280 285Gln Asp Leu Cys Arg Cys Pro Thr Cys Pro Cys Ala Thr Phe Val Glu 290 295 300Tyr Ser Arg Gln Cys Ala His Ala Gly Gly Gln Pro Arg Asn Trp Arg305 310 315 320Cys Pro Glu Leu Cys Pro Arg Thr Cys Pro Leu Asn Met Gln His Gln 325 330 335Glu Cys Gly Ser Pro Cys Thr Asp Thr Cys Ser Asn Pro Gln Arg Ala

340 345 350Gln Leu Cys Glu Asp His Cys Val Asp Gly Cys Phe Cys Pro Pro Gly 355 360 365Thr Val Leu Asp Asp Ile Thr His Ser Gly Cys Leu Pro Leu Gly Gln 370 375 380Cys Pro Cys Thr His Gly Gly Arg Thr Tyr Ser Pro Gly Thr Ser Phe385 390 395 400Asn Thr Thr Cys Ser Ser Cys Thr Cys Ser Gly Gly Leu Trp Gln Cys 405 410 415Gln Asp Leu Pro Cys Pro Gly Thr Cys Ser Val Gln Gly Gly Ala His 420 425 430Ile Ser Thr Tyr Asp Glu Lys Leu Tyr Asp Leu His Gly Asp Cys Ser 435 440 445Tyr Val Leu Ser Lys Lys Cys Ala Asp Ser Ser Phe Thr Val Leu Ala 450 455 460Glu Leu Arg Lys Cys Gly Leu Thr Asp Asn Glu Asn Cys Leu Lys Ala465 470 475 480Val Thr Leu Ser Leu Asp Gly Gly Asp Thr Ala Ile Arg Val Gln Ala 485 490 495Asp Gly Gly Val Phe Leu Asn Ser Ile Tyr Thr Gln Leu Pro Leu Ser 500 505 510Ala Ala Asn Ile Thr Leu Phe Thr Pro Ser Ser Phe Phe Ile Val Val 515 520 525Gln Thr Gly Leu Gly Leu Gln Leu Leu Val Gln Leu Val Pro Leu Met 530 535 540Gln Val Phe Val Arg Leu Asp Pro Ala His Gln Gly Gln Met Cys Gly545 550 555 560Leu Cys Gly Asn Phe Asn Gln Asn Gln Ala Asp Asp Phe Thr Ala Leu 565 570 575Ser Gly Val Val Glu Ala Thr Gly Ala Ala Phe Ala Asn Thr Trp Lys 580 585 590Ala Gln Ala Ala Cys Ala Asn Ala Arg Asn Ser Phe Glu Asp Pro Cys 595 600 605Ser Leu Ser Val Glu Asn Glu Asn Tyr Ala Arg His Trp Cys Ser Arg 610 615 620Leu Thr Asp Pro Asn Ser Ala Phe Ser Arg Cys His Ser Ile Ile Asn625 630 635 640Pro Lys Pro Phe His Ser Asn Cys Met Phe Asp Thr Cys Asn Cys Glu 645 650 655Arg Ser Glu Asp Cys Leu Cys Ala Ala Leu Ser Ser Tyr Val His Ala 660 665 670Cys Ala Ala Lys Gly Val Gln Leu Ser Asp Trp Arg Asp Gly Val Cys 675 680 685Thr Lys Tyr Met Gln Asn Cys Pro Lys Ser Gln Arg Tyr Ala Tyr Val 690 695 700Val Asp Ala Cys Gln Pro Thr Cys Arg Gly Leu Ser Glu Ala Asp Val705 710 715 720Thr Cys Ser Val Ser Phe Val Pro Val Asp Gly Cys Thr Cys Pro Ala 725 730 735Gly Thr Phe Leu Asn Asp Ala Gly Ala Cys Val Pro Ala Gln Glu Cys 740 745 750Pro Cys Tyr Ala His Gly Thr Val Leu Ala Pro Gly Glu Val Val His 755 760 765Asp Glu Gly Ala Val Cys Ser Cys Thr Gly Gly Lys Leu Ser Cys Leu 770 775 780Gly Ala Ser Leu Gln Lys Ser Thr Gly Cys Ala Ala Pro Met Val Tyr785 790 795 800Leu Asp Cys Ser Asn Ser Ser Ala Gly Thr Pro Gly Ala Glu Cys Leu 805 810 815Arg Ser Cys His Thr Leu Asp Val Gly Cys Phe Ser Thr His Cys Val 820 825 830Ser Gly Cys Val Cys Pro Pro Gly Leu Val Ser Asp Gly Ser Gly Gly 835 840 845Cys Ile Ala Glu Glu Asp Cys Pro Cys Val His Asn Glu Ala Thr Tyr 850 855 860Lys Pro Gly Glu Thr Ile Arg Val Asp Cys Asn Thr Cys Thr Cys Arg865 870 875 880Asn Arg Arg Trp Glu Cys Ser His Arg Leu Cys Leu Gly Thr Cys Val 885 890 895Ala Tyr Gly Asp Gly His Phe Ile Thr Phe Asp Gly Asp Arg Tyr Ser 900 905 910Phe Glu Gly Ser Cys Glu Tyr Ile Leu Ala Gln Asp Tyr Cys Gly Asp 915 920 925Asn Thr Thr His Gly Thr Phe Arg Ile Val Thr Glu Asn Ile Pro Cys 930 935 940Gly Thr Thr Gly Thr Thr Cys Ser Lys Ala Ile Lys Leu Phe Val Glu945 950 955 960Ser Tyr Glu Leu Ile Leu Gln Glu Gly Thr Phe Lys Ala Val Ala Arg 965 970 975Gly Pro Gly Gly Asp Pro Pro Tyr Lys Ile Arg Tyr Met Gly Ile Phe 980 985 990Leu Val Ile Glu Thr His Gly Met Ala Val Ser Trp Asp Arg Lys Thr 995 1000 1005Ser Val Phe Ile Arg Leu His Gln Asp Tyr Lys Gly Arg Val Cys 1010 1015 1020Gly Leu Cys Gly Asn Phe Asp Asp Asn Ala Ile Asn Asp Phe Ala 1025 1030 1035Thr Arg Ser Arg Ser Val Val Gly Asp Ala Leu Glu Phe Gly Asn 1040 1045 1050Ser Trp Lys Leu Ser Pro Ser Cys Pro Asp Ala Leu Ala Pro Lys 1055 1060 1065Asp Pro Cys Thr Ala Asn Pro Phe Arg Lys Ser Trp Ala Gln Lys 1070 1075 1080Gln Cys Ser Ile Leu His Gly Pro Thr Phe Ala Ala Cys Arg Ser 1085 1090 1095Gln Val Asp Ser Thr Lys Tyr Tyr Glu Ala Cys Val Asn Asp Ala 1100 1105 1110Cys Ala Cys Asp Ser Gly Gly Asp Cys Glu Cys Phe Cys Thr Ala 1115 1120 1125Val Ala Ala Tyr Ala Gln Ala Cys His Asp Ala Gly Leu Cys Val 1130 1135 1140Ser Trp Arg Thr Pro Asp Thr Cys Pro Leu Phe Cys Asp Phe Tyr 1145 1150 1155Asn Pro His Gly Gly Cys Glu Trp His Tyr Gln Pro Cys Gly Ala 1160 1165 1170Pro Cys Leu Lys Thr Cys Arg Asn Pro Ser Gly His Cys Leu Val 1175 1180 1185Asp Leu Pro Gly Leu Glu Gly Cys Tyr Pro Lys Cys Pro Pro Ser 1190 1195 1200Gln Pro Phe Phe Asn Glu Asp Gln Met Lys Cys Val Ala Gln Cys 1205 1210 1215Gly Cys Tyr Asp Lys Asp Gly Asn Tyr Tyr Asp Val Gly Ala Arg 1220 1225 1230Val Pro Thr Ala Glu Asn Cys Gln Ser Cys Asn Cys Thr Pro Ser 1235 1240 1245Gly Ile Gln Cys Ala His Ser Leu Glu Ala Cys Thr Cys Thr Tyr 1250 1255 1260Glu Asp Arg Thr Tyr Ser Tyr Gln Asp Val Ile Tyr Asn Thr Thr 1265 1270 1275Asp Gly Leu Gly Ala Cys Leu Ile Ala Ile Cys Gly Ser Asn Gly 1280 1285 1290Thr Ile Ile Arg Lys Ala Val Ala Cys Pro Gly Thr Pro Ala Thr 1295 1300 1305Thr Pro Phe Thr Phe Thr Thr Ala Trp Val Pro His Ser Thr Thr 1310 1315 1320Ser Pro Ala Leu Pro Val Ser Thr Val Cys Val Arg Glu Val Cys 1325 1330 1335Arg Trp Ser Ser Trp Tyr Asn Gly His Arg Pro Glu Pro Gly Leu 1340 1345 1350Gly Gly Gly Asp Phe Glu Thr Phe Glu Asn Leu Arg Gln Arg Gly 1355 1360 1365Tyr Gln Val Cys Pro Val Leu Ala Asp Ile Glu Cys Arg Ala Ala 1370 1375 1380Gln Leu Pro Asp Met Pro Leu Glu Glu Leu Gly Gln Gln Val Asp 1385 1390 1395Cys Asp Arg Met Arg Gly Leu Met Cys Ala Asn Ser Gln Gln Ser 1400 1405 1410Pro Pro Leu Cys His Asp Tyr Glu Leu Arg Val Leu Cys Cys Glu 1415 1420 1425Tyr Val Pro Cys Gly Pro Ser Pro Ala Pro Gly Thr Ser Pro Gln 1430 1435 1440Pro Ser Leu Ser Ala Ser Thr Glu Pro Ala Val Pro Thr Pro Thr 1445 1450 1455Gln Thr Thr Ala Thr Glu Lys Thr Thr Leu Trp Val Thr Pro Ser 1460 1465 1470Ile Arg Ser Thr Ala Ala Leu Thr Ser Gln Thr Gly Ser Ser Ser 1475 1480 1485Gly Pro Val Thr Val Thr Pro Ser Ala Pro Gly Thr Thr Thr Cys 1490 1495 1500Gln Pro Arg Cys Gln Trp Thr Glu Trp Phe Asp Glu Asp Tyr Pro 1505 1510 1515Lys Ser Glu Gln Leu Gly Gly Asp Val Glu Ser Tyr Asp Lys Ile 1520 1525 1530Arg Ala Ala Gly Gly His Leu Cys Gln Gln Pro Lys Asp Ile Glu 1535 1540 1545Cys Gln Ala Glu Ser Phe Pro Asn Trp Thr Leu Ala Gln Val Gly 1550 1555 1560Gln Lys Val His Cys Asp Val His Phe Gly Leu Val Cys Arg Asn 1565 1570 1575Trp Glu Gln Glu Gly Val Phe Lys Met Cys Tyr Asn Tyr Arg Ile 1580 1585 1590Arg Val Leu Cys Cys Ser Asp Asp His Cys Arg Gly Arg Ala Thr 1595 1600 1605Thr Pro Pro Pro Thr Thr Glu Leu Glu Thr Ala Thr Thr Thr Thr 1610 1615 1620Thr Gln Ala Leu Phe Ser Thr Pro Gln Pro Thr Ser Ser Pro Gly 1625 1630 1635Leu Thr Arg Ala Pro Pro Ala Ser Thr Thr Ala Val Pro Thr Leu 1640 1645 1650Ser Glu Gly Leu Thr Ser Pro Arg Tyr Thr Ser Thr Leu Gly Thr 1655 1660 1665Ala Thr Thr Gly Gly Pro Thr Thr Pro Ala Gly Ser Thr Glu Pro 1670 1675 1680Thr Val Pro Gly Val Ala Thr Ser Thr Leu Pro Thr Arg Ser Ala 1685 1690 1695Leu Pro Gly Thr Thr Gly Ser Leu Gly Thr Trp Arg Pro Ser Gln 1700 1705 1710Pro Pro Thr Leu Ala Pro Thr Thr Met Ala Thr Ser Arg Ala Arg 1715 1720 1725Pro Thr Gly Thr Ala Ser Thr Ala Ser Lys Glu Pro Leu Thr Thr 1730 1735 1740Ser Leu Ala Pro Thr Leu Thr Ser Glu Leu Ser Thr Ser Gln Ala 1745 1750 1755Glu Thr Ser Thr Pro Arg Thr Glu Thr Thr Met Ser Pro Leu Thr 1760 1765 1770Asn Thr Thr Thr Ser Gln Gly Thr Thr Arg Cys Gln Pro Lys Cys 1775 1780 1785Glu Trp Thr Glu Trp Phe Asp Val Asp Phe Pro Thr Ser Gly Val 1790 1795 1800Ala Gly Gly Asp Met Glu Thr Phe Glu Asn Ile Arg Ala Ala Gly 1805 1810 1815Gly Lys Met Cys Trp Ala Pro Lys Ser Ile Glu Cys Arg Ala Glu 1820 1825 1830Asn Tyr Pro Glu Val Ser Ile Asp Gln Val Gly Gln Val Leu Thr 1835 1840 1845Cys Ser Leu Glu Thr Gly Leu Thr Cys Lys Asn Glu Asp Gln Thr 1850 1855 1860Gly Arg Phe Asn Met Cys Phe Asn Tyr Asn Val Arg Val Leu Cys 1865 1870 1875Cys Asp Asp Tyr Ser His Cys Pro Ser Thr Pro Ala Thr Ser Ser 1880 1885 1890Thr Ala Thr Pro Ser Ser Thr Pro Gly Thr Thr Trp Ile Leu Thr 1895 1900 1905Lys Pro Thr Thr Thr Ala Thr Thr Thr Ala Ser Thr Gly Ser Thr 1910 1915 1920Ala Thr Pro Thr Ser Thr Leu Arg Thr Ala Pro Pro Pro Lys Val 1925 1930 1935Leu Thr Thr Thr Ala Thr Thr Pro Thr Val Thr Ser Ser Lys Ala 1940 1945 1950Thr Pro Ser Ser Ser Pro Gly Thr Ala Thr Ala Leu Pro Ala Leu 1955 1960 1965Arg Ser Thr Ala Thr Thr Pro Thr Ala Thr Ser Val Thr Pro Ile 1970 1975 1980Pro Ser Ser Ser Leu Gly Thr Thr Trp Thr Arg Leu Ser Gln Thr 1985 1990 1995Thr Thr Pro Thr Ala Thr Met Ser Thr Ala Thr Pro Ser Ser Thr 2000 2005 2010Pro Glu Thr Ala His Thr Ser Thr Val Leu Thr Ala Thr Ala Thr 2015 2020 2025Thr Thr Gly Ala Thr Gly Ser Val Ala Thr Pro Ser Ser Thr Pro 2030 2035 2040Gly Thr Ala His Thr Thr Lys Val Pro Thr Thr Thr Thr Thr Gly 2045 2050 2055Phe Thr Ala Thr Pro Ser Ser Ser Pro Gly Thr Ala Leu Thr Pro 2060 2065 2070Pro Val Trp Ile Ser Thr Thr Thr Thr Pro Thr Thr Arg Gly Ser 2075 2080 2085Thr Val Thr Pro Ser Ser Ile Pro Gly Thr Thr His Thr Ala Thr 2090 2095 2100Val Leu Thr Thr Thr Thr Thr Thr Val Ala Thr Gly Ser Met Ala 2105 2110 2115Thr Pro Ser Ser Ser Thr Gln Thr Ser Gly Thr Pro Pro Ser Leu 2120 2125 2130Thr Thr Thr Ala Thr Thr Ile Thr Ala Thr Gly Ser Thr Thr Asn 2135 2140 2145Pro Ser Ser Thr Pro Gly Thr Thr Pro Ile Pro Pro Val Leu Thr 2150 2155 2160Thr Thr Ala Thr Thr Pro Ala Ala Thr Ser Asn Thr Val Thr Pro 2165 2170 2175Ser Ser Ala Leu Gly Thr Thr His Thr Pro Pro Val Pro Asn Thr 2180 2185 2190Met Ala Thr Thr His Gly Arg Ser Leu Pro Pro Ser Ser Pro His 2195 2200 2205Thr Val Arg Thr Ala Trp Thr Ser Ala Thr Ser Gly Ile Leu Gly 2210 2215 2220Thr Thr His Ile Thr Glu Pro Ser Thr Val Thr Ser His Thr Leu 2225 2230 2235Ala Ala Thr Thr Gly Thr Thr Gln His Ser Thr Pro Ala Leu Ser 2240 2245 2250Ser Pro His Pro Ser Ser Arg Thr Thr Glu Ser Pro Pro Ser Pro 2255 2260 2265Gly Thr Thr Thr Pro Gly His Thr Thr Ala Thr Ser Arg Thr Thr 2270 2275 2280Ala Thr Ala Thr Pro Ser Lys Thr Arg Thr Ser Thr Leu Leu Pro 2285 2290 2295Ser Ser Pro Thr Ser Ala Pro Ile Thr Thr Val Val Thr Met Gly 2300 2305 2310Cys Glu Pro Gln Cys Ala Trp Ser Glu Trp Leu Asp Tyr Ser Tyr 2315 2320 2325Pro Met Pro Gly Pro Ser Gly Gly Asp Phe Asp Thr Tyr Ser Asn 2330 2335 2340Ile Arg Ala Ala Gly Gly Ala Val Cys Glu Gln Pro Leu Gly Leu 2345 2350 2355Glu Cys Arg Ala Gln Ala Gln Pro Gly Val Pro Leu Arg Glu Leu 2360 2365 2370Gly Gln Val Val Glu Cys Ser Leu Asp Phe Gly Leu Val Cys Arg 2375 2380 2385Asn Arg Glu Gln Val Gly Lys Phe Lys Met Cys Phe Asn Tyr Glu 2390 2395 2400Ile Arg Val Phe Cys Cys Asn Tyr Gly His Cys Pro Ser Thr Pro 2405 2410 2415Ala Thr Ser Ser Thr Ala Met Pro Ser Ser Thr Pro Gly Thr Thr 2420 2425 2430Trp Ile Leu Thr Glu Leu Thr Thr Thr Ala Thr Thr Thr Glu Ser 2435 2440 2445Thr Gly Ser Thr Ala Thr Pro Ser Ser Thr Pro Gly Thr Thr Trp 2450 2455 2460Ile Leu Thr Glu Pro Ser Thr Thr Ala Thr Val Thr Val Pro Thr 2465 2470 2475Gly Ser Thr Ala Thr Ala Ser Ser Thr Gln Ala Thr Ala Gly Thr 2480 2485 2490Pro His Val Ser Thr Thr Ala Thr Thr Pro Thr Val Thr Ser Ser 2495 2500 2505Lys Ala Thr Pro Phe Ser Ser Pro Gly Thr Ala Thr Ala Leu Pro 2510 2515 2520Ala Leu Arg Ser Thr Ala Thr Thr Pro Thr Ala Thr Ser Phe Thr 2525 2530 2535Ala Ile Pro Ser Ser Ser Leu Gly Thr Thr Trp Thr Arg Leu Ser 2540 2545 2550Gln Thr Thr Thr Pro Thr Ala Thr Met Ser Thr Ala Thr Pro Ser 2555 2560 2565Ser Thr Pro Glu Thr Val His Thr Ser Thr Val Leu Thr Thr Thr 2570 2575 2580Ala Thr Thr Thr Gly Ala Thr Gly Ser Val Ala Thr Pro Ser Ser 2585 2590 2595Thr Pro Gly Thr Ala His Thr Thr Lys Val Leu Thr Thr Thr Thr 2600 2605 2610Thr Gly Phe Thr Ala Thr Pro Ser Ser Ser Pro Gly Thr Ala Arg 2615 2620 2625Thr Leu Pro Val Trp Ile Ser Thr Thr Thr Thr Pro Thr Thr Arg 2630 2635 2640Gly Ser Thr Val Thr Pro Ser Ser Ile Pro Gly Thr Thr His Thr 2645 2650 2655Pro Thr Val Leu Thr Thr Thr Thr Thr Thr Val Ala Thr Gly Ser 2660 2665 2670Met Ala Thr Pro Ser Ser Ser Thr Gln Thr Ser Gly Thr Pro Pro 2675 2680 2685Ser Leu Thr Thr Thr Ala Thr Thr Ile Thr Ala Thr Gly Ser Thr 2690 2695 2700Thr Asn Pro Ser Ser Thr Pro Gly Thr Thr Pro Ile Pro Pro Val 2705 2710 2715Leu Thr Thr Thr Ala Thr Thr Pro Ala Ala Thr Ser Ser Thr Val 2720 2725 2730Thr Pro Ser Ser Ala Leu Gly Thr Thr His Thr Pro Pro Val Pro 2735 2740 2745Asn Thr Thr Ala Thr Thr His Gly Arg Ser Leu Ser Pro Ser Ser 2750 2755 2760Pro His Thr Val Arg Thr Ala Trp Thr Ser Ala Thr Ser Gly Thr 2765 2770 2775Leu Gly Thr Thr His Ile Thr Glu Pro Ser Thr Gly Thr Ser His 2780 2785

2790Thr Pro Ala Ala Thr Thr Gly Thr Thr Gln His Ser Thr Pro Ala 2795 2800 2805Leu Ser Ser Pro His Pro Ser Ser Arg Thr Thr Glu Ser Pro Pro 2810 2815 2820Ser Pro Gly Thr Thr Thr Pro Gly His Thr Arg Ala Thr Ser Arg 2825 2830 2835Thr Thr Ala Thr Ala Thr Pro Ser Lys Thr Arg Thr Ser Thr Leu 2840 2845 2850Leu Pro Ser Ser Pro Thr Ser Ala Pro Ile Thr Thr Val Val Thr 2855 2860 2865Met Gly Cys Glu Pro Gln Cys Ala Trp Ser Glu Trp Leu Asp Tyr 2870 2875 2880Ser Tyr Pro Met Pro Gly Pro Ser Gly Gly Asp Phe Asp Thr Tyr 2885 2890 2895Ser Asn Ile Arg Ala Ala Gly Gly Ala Val Cys Glu Gln Pro Leu 2900 2905 2910Gly Leu Glu Cys Arg Ala Gln Ala Gln Pro Gly Val Pro Leu Arg 2915 2920 2925Glu Leu Gly Gln Val Val Glu Cys Ser Leu Asp Phe Gly Leu Val 2930 2935 2940Cys Arg Asn Arg Glu Gln Val Gly Lys Phe Lys Met Cys Phe Asn 2945 2950 2955Tyr Glu Ile Arg Val Phe Cys Cys Asn Tyr Gly His Cys Pro Ser 2960 2965 2970Thr Pro Ala Thr Ser Ser Thr Ala Thr Pro Ser Ser Thr Pro Gly 2975 2980 2985Thr Thr Trp Ile Leu Thr Glu Gln Thr Thr Ala Ala Thr Thr Thr 2990 2995 3000Ala Thr Thr Gly Ser Thr Ala Ile Pro Ser Ser Thr Pro Gly Thr 3005 3010 3015Ala Pro Pro Pro Lys Val Leu Thr Ser Thr Ala Thr Thr Pro Thr 3020 3025 3030Ala Thr Ser Ser Lys Ala Thr Ser Ser Ser Ser Pro Arg Thr Ala 3035 3040 3045Thr Thr Leu Pro Val Leu Thr Ser Thr Ala Thr Lys Ser Thr Ala 3050 3055 3060Thr Ser Phe Thr Pro Ile Pro Ser Phe Thr Leu Gly Thr Thr Gly 3065 3070 3075Thr Leu Pro Glu Gln Thr Thr Thr Pro Met Ala Thr Met Ser Thr 3080 3085 3090Ile His Pro Ser Ser Thr Pro Glu Thr Thr His Thr Ser Thr Val 3095 3100 3105Leu Thr Thr Lys Ala Thr Thr Thr Arg Ala Thr Ser Ser Met Ser 3110 3115 3120Thr Pro Ser Ser Thr Pro Gly Thr Thr Trp Ile Leu Thr Glu Leu 3125 3130 3135Thr Thr Ala Ala Thr Thr Thr Ala Ala Thr Gly Pro Thr Ala Thr 3140 3145 3150Pro Ser Ser Thr Pro Gly Thr Thr Trp Ile Leu Thr Glu Pro Ser 3155 3160 3165Thr Thr Ala Thr Val Thr Val Pro Thr Gly Ser Thr Ala Thr Ala 3170 3175 3180Ser Ser Thr Arg Ala Thr Ala Gly Thr Leu Lys Val Leu Thr Ser 3185 3190 3195Thr Ala Thr Thr Pro Thr Val Ile Ser Ser Arg Ala Thr Pro Ser 3200 3205 3210Ser Ser Pro Gly Thr Ala Thr Ala Leu Pro Ala Leu Arg Ser Thr 3215 3220 3225Ala Thr Thr Pro Thr Ala Thr Ser Val Thr Ala Ile Pro Ser Ser 3230 3235 3240Ser Leu Gly Thr Ala Trp Thr Arg Leu Ser Gln Thr Thr Thr Pro 3245 3250 3255Thr Ala Thr Met Ser Thr Ala Thr Pro Ser Ser Thr Pro Glu Thr 3260 3265 3270Val His Thr Ser Thr Val Leu Thr Thr Thr Thr Thr Thr Thr Arg 3275 3280 3285Ala Thr Gly Ser Val Ala Thr Pro Ser Ser Thr Pro Gly Thr Ala 3290 3295 3300His Thr Thr Lys Val Pro Thr Thr Thr Thr Thr Gly Phe Thr Ala 3305 3310 3315Thr Pro Ser Ser Ser Pro Gly Thr Ala Leu Thr Pro Pro Val Trp 3320 3325 3330Ile Ser Thr Thr Thr Thr Pro Thr Thr Arg Gly Ser Thr Val Thr 3335 3340 3345Pro Ser Ser Ile Pro Gly Thr Thr His Thr Ala Thr Val Leu Thr 3350 3355 3360Thr Thr Thr Thr Thr Val Ala Thr Gly Ser Met Ala Thr Pro Ser 3365 3370 3375Ser Ser Thr Gln Thr Ser Gly Thr Pro Pro Ser Leu Thr Thr Thr 3380 3385 3390Ala Thr Thr Ile Thr Ala Thr Gly Ser Thr Thr Asn Pro Ser Ser 3395 3400 3405Thr Pro Gly Thr Thr Pro Ile Pro Pro Val Leu Thr Thr Thr Ala 3410 3415 3420Thr Thr Pro Ala Ala Thr Ser Ser Thr Val Thr Pro Ser Ser Ala 3425 3430 3435Leu Gly Thr Thr His Thr Pro Pro Val Pro Asn Thr Thr Ala Thr 3440 3445 3450Thr His Gly Arg Ser Leu Pro Pro Ser Ser Pro His Thr Val Arg 3455 3460 3465Thr Ala Trp Thr Ser Ala Thr Ser Gly Ile Leu Gly Thr Thr His 3470 3475 3480Ile Thr Glu Pro Ser Thr Val Thr Ser His Thr Pro Ala Ala Thr 3485 3490 3495Thr Ser Thr Thr Gln His Ser Thr Pro Ala Leu Ser Ser Pro His 3500 3505 3510Pro Ser Ser Arg Thr Thr Glu Ser Pro Pro Ser Pro Gly Thr Thr 3515 3520 3525Thr Pro Gly His Thr Arg Gly Thr Ser Arg Thr Thr Ala Thr Ala 3530 3535 3540Thr Pro Ser Lys Thr Arg Thr Ser Thr Leu Leu Pro Ser Ser Pro 3545 3550 3555Thr Ser Ala Pro Ile Thr Thr Val Val Thr Thr Gly Cys Glu Pro 3560 3565 3570Gln Cys Ala Trp Ser Glu Trp Leu Asp Tyr Ser Tyr Pro Met Pro 3575 3580 3585Gly Pro Ser Gly Gly Asp Phe Asp Thr Tyr Ser Asn Ile Arg Ala 3590 3595 3600Ala Gly Gly Ala Val Cys Glu Gln Pro Leu Gly Leu Glu Cys Arg 3605 3610 3615Ala Gln Ala Gln Pro Gly Val Pro Leu Arg Glu Leu Gly Gln Val 3620 3625 3630Val Glu Cys Ser Leu Asp Phe Gly Leu Val Cys Arg Asn Arg Glu 3635 3640 3645Gln Val Gly Lys Phe Lys Met Cys Phe Asn Tyr Glu Ile Arg Val 3650 3655 3660Phe Cys Cys Asn Tyr Gly His Cys Pro Ser Thr Pro Ala Thr Ser 3665 3670 3675Ser Thr Ala Thr Pro Ser Ser Thr Pro Gly Thr Thr Trp Ile Leu 3680 3685 3690Thr Lys Leu Thr Thr Thr Ala Thr Thr Thr Glu Ser Thr Gly Ser 3695 3700 3705Thr Ala Thr Pro Ser Ser Thr Pro Gly Thr Thr Trp Ile Leu Thr 3710 3715 3720Glu Pro Ser Thr Thr Ala Thr Val Thr Val Pro Thr Gly Ser Thr 3725 3730 3735Ala Thr Ala Ser Ser Thr Gln Ala Thr Ala Gly Thr Pro His Val 3740 3745 3750Ser Thr Thr Ala Thr Thr Pro Thr Val Thr Ser Ser Lys Ala Thr 3755 3760 3765Pro Phe Ser Ser Pro Gly Thr Ala Thr Ala Leu Pro Ala Leu Arg 3770 3775 3780Ser Thr Ala Thr Thr Pro Thr Ala Thr Ser Phe Thr Ala Ile Pro 3785 3790 3795Ser Ser Ser Leu Gly Thr Thr Trp Thr Arg Leu Ser Gln Thr Thr 3800 3805 3810Thr Pro Thr Ala Thr Met Ser Thr Ala Thr Pro Ser Ser Thr Pro 3815 3820 3825Glu Thr Ala His Thr Ser Thr Val Leu Thr Thr Thr Ala Thr Thr 3830 3835 3840Thr Arg Ala Thr Gly Ser Val Ala Thr Pro Ser Ser Thr Pro Gly 3845 3850 3855Thr Ala His Thr Thr Lys Val Pro Thr Thr Thr Thr Thr Gly Phe 3860 3865 3870Thr Val Thr Pro Ser Ser Ser Pro Gly Thr Ala Arg Thr Pro Pro 3875 3880 3885Val Trp Ile Ser Thr Thr Thr Thr Pro Thr Thr Ser Gly Ser Thr 3890 3895 3900Val Thr Pro Ser Ser Val Pro Gly Thr Thr His Thr Pro Thr Val 3905 3910 3915Leu Thr Thr Thr Thr Thr Thr Val Ala Thr Gly Ser Met Ala Thr 3920 3925 3930Pro Ser Ser Ser Thr Gln Thr Ser Gly Thr Pro Pro Ser Leu Ile 3935 3940 3945Thr Thr Ala Thr Thr Ile Thr Ala Thr Gly Ser Thr Thr Asn Pro 3950 3955 3960Ser Ser Thr Pro Gly Thr Thr Pro Ile Pro Pro Val Leu Thr Thr 3965 3970 3975Thr Ala Thr Thr Pro Ala Ala Thr Ser Ser Thr Val Thr Pro Ser 3980 3985 3990Ser Ala Leu Gly Thr Thr His Thr Pro Pro Val Pro Asn Thr Thr 3995 4000 4005Ala Thr Thr His Gly Arg Ser Leu Ser Pro Ser Ser Pro His Thr 4010 4015 4020Val Arg Thr Ala Trp Thr Ser Ala Thr Ser Gly Thr Leu Gly Thr 4025 4030 4035Thr His Ile Thr Glu Pro Ser Thr Gly Thr Ser His Thr Pro Ala 4040 4045 4050Ala Thr Thr Gly Thr Thr Gln His Ser Thr Pro Ala Leu Ser Ser 4055 4060 4065Pro His Pro Ser Ser Arg Thr Thr Glu Ser Pro Pro Ser Pro Gly 4070 4075 4080Thr Thr Thr Pro Gly His Thr Thr Ala Thr Ser Arg Thr Thr Ala 4085 4090 4095Thr Ala Thr Pro Ser Lys Thr Arg Thr Ser Thr Leu Leu Pro Ser 4100 4105 4110Ser Pro Thr Ser Ala Pro Ile Thr Thr Val Val Thr Thr Gly Cys 4115 4120 4125Glu Pro Gln Cys Ala Trp Ser Glu Trp Leu Asp Tyr Ser Tyr Pro 4130 4135 4140Met Pro Gly Pro Ser Gly Gly Asp Phe Asp Thr Tyr Ser Asn Ile 4145 4150 4155Arg Ala Ala Gly Gly Ala Val Cys Glu Gln Pro Leu Gly Leu Glu 4160 4165 4170Cys Arg Ala Gln Ala Gln Pro Gly Val Pro Leu Gly Glu Leu Gly 4175 4180 4185Gln Val Val Glu Cys Ser Leu Asp Phe Gly Leu Val Cys Arg Asn 4190 4195 4200Arg Glu Gln Val Gly Lys Phe Lys Met Cys Phe Asn Tyr Glu Ile 4205 4210 4215Arg Val Phe Cys Cys Asn Tyr Gly His Cys Pro Ser Thr Pro Ala 4220 4225 4230Thr Ser Ser Thr Ala Met Pro Ser Ser Thr Pro Gly Thr Thr Trp 4235 4240 4245Ile Leu Thr Glu Leu Thr Thr Thr Ala Thr Thr Thr Ala Ser Thr 4250 4255 4260Gly Ser Thr Ala Thr Pro Ser Ser Thr Pro Gly Thr Ala Pro Pro 4265 4270 4275Pro Lys Val Leu Thr Ser Pro Ala Thr Thr Pro Thr Ala Thr Ser 4280 4285 4290Ser Lys Ala Thr Ser Ser Ser Ser Pro Arg Thr Ala Thr Thr Leu 4295 4300 4305Pro Val Leu Thr Ser Thr Ala Thr Lys Ser Thr Ala Thr Ser Val 4310 4315 4320Thr Pro Ile Pro Ser Ser Thr Leu Gly Thr Thr Gly Thr Leu Pro 4325 4330 4335Glu Gln Thr Thr Thr Pro Val Ala Thr Met Ser Thr Ile His Pro 4340 4345 4350Ser Ser Thr Pro Glu Thr Thr His Thr Ser Thr Val Leu Thr Thr 4355 4360 4365Lys Ala Thr Thr Thr Arg Ala Thr Ser Ser Thr Ser Thr Pro Ser 4370 4375 4380Ser Thr Pro Gly Thr Thr Trp Ile Leu Thr Glu Leu Thr Thr Ala 4385 4390 4395Ala Thr Thr Thr Ala Ala Thr Gly Pro Thr Ala Thr Pro Ser Ser 4400 4405 4410Thr Pro Gly Thr Thr Trp Ile Leu Thr Glu Leu Thr Thr Thr Ala 4415 4420 4425Thr Thr Thr Ala Ser Thr Gly Ser Thr Ala Thr Pro Ser Ser Thr 4430 4435 4440Pro Gly Thr Thr Trp Ile Leu Thr Glu Pro Ser Thr Thr Ala Thr 4445 4450 4455Val Thr Val Pro Thr Gly Ser Thr Ala Thr Ala Ser Ser Thr Gln 4460 4465 4470Ala Thr Ala Gly Thr Pro His Val Ser Thr Thr Ala Thr Thr Pro 4475 4480 4485Thr Val Thr Ser Ser Lys Ala Thr Pro Ser Ser Ser Pro Gly Thr 4490 4495 4500Ala Thr Ala Leu Pro Ala Leu Arg Ser Thr Ala Thr Thr Pro Thr 4505 4510 4515Ala Thr Ser Phe Thr Ala Ile Pro Ser Ser Ser Leu Gly Thr Thr 4520 4525 4530Trp Thr Arg Leu Ser Gln Thr Thr Thr Pro Thr Ala Thr Met Ser 4535 4540 4545Thr Ala Thr Pro Ser Ser Thr Pro Glu Thr Val His Thr Ser Thr 4550 4555 4560Val Leu Thr Ala Thr Ala Thr Thr Thr Gly Ala Thr Gly Ser Val 4565 4570 4575Ala Thr Pro Ser Ser Thr Pro Gly Thr Ala His Thr Thr Lys Val 4580 4585 4590Pro Thr Thr Thr Thr Thr Gly Phe Thr Ala Thr Pro Ser Ser Ser 4595 4600 4605Pro Gly Thr Ala Leu Thr Pro Pro Val Trp Ile Ser Thr Thr Thr 4610 4615 4620Thr Pro Thr Thr Thr Thr Pro Thr Thr Ser Gly Ser Thr Val Thr 4625 4630 4635Pro Ser Ser Ile Pro Gly Thr Thr His Thr Ala Arg Val Leu Thr 4640 4645 4650Thr Thr Thr Thr Thr Val Ala Thr Gly Ser Met Ala Thr Pro Ser 4655 4660 4665Ser Ser Thr Gln Thr Ser Gly Thr Pro Pro Ser Leu Thr Thr Thr 4670 4675 4680Ala Thr Thr Ile Thr Ala Thr Gly Ser Thr Thr Asn Pro Ser Ser 4685 4690 4695Thr Pro Gly Thr Thr Pro Ile Thr Pro Val Leu Thr Ser Thr Ala 4700 4705 4710Thr Thr Pro Ala Ala Thr Ser Ser Lys Ala Thr Ser Ser Ser Ser 4715 4720 4725Pro Arg Thr Ala Thr Thr Leu Pro Val Leu Thr Ser Thr Ala Thr 4730 4735 4740Lys Ser Thr Ala Thr Ser Phe Thr Pro Ile Pro Ser Ser Thr Leu 4745 4750 4755Trp Thr Thr Trp Thr Val Pro Ala Gln Thr Thr Thr Pro Met Ser 4760 4765 4770Thr Met Ser Thr Ile His Thr Ser Ser Thr Pro Glu Thr Thr His 4775 4780 4785Thr Ser Thr Val Leu Thr Thr Thr Ala Thr Met Thr Arg Ala Thr 4790 4795 4800Asn Ser Thr Ala Thr Pro Ser Ser Thr Leu Gly Thr Thr Arg Ile 4805 4810 4815Leu Thr Glu Leu Thr Thr Thr Ala Thr Thr Thr Ala Ala Thr Gly 4820 4825 4830Ser Thr Ala Thr Leu Ser Ser Thr Pro Gly Thr Thr Trp Ile Leu 4835 4840 4845Thr Glu Pro Ser Thr Ile Ala Thr Val Met Val Pro Thr Gly Ser 4850 4855 4860Thr Ala Thr Ala Ser Ser Thr Leu Gly Thr Ala His Thr Pro Lys 4865 4870 4875Val Val Thr Thr Met Ala Thr Met Pro Thr Ala Thr Ala Ser Thr 4880 4885 4890Val Pro Ser Ser Ser Thr Val Gly Thr Thr Arg Thr Pro Ala Val 4895 4900 4905Leu Pro Ser Ser Leu Pro Thr Phe Ser Val Ser Thr Val Ser Ser 4910 4915 4920Ser Val Leu Thr Thr Leu Arg Pro Thr Gly Phe Pro Ser Ser His 4925 4930 4935Phe Ser Thr Pro Cys Phe Cys Arg Ala Phe Gly Gln Phe Phe Ser 4940 4945 4950Pro Gly Glu Val Ile Tyr Asn Lys Thr Asp Arg Ala Gly Cys His 4955 4960 4965Phe Tyr Ala Val Cys Asn Gln His Cys Asp Ile Asp Arg Phe Gln 4970 4975 4980Gly Ala Cys Pro Thr Ser Pro Pro Pro Val Ser Ser Ala Pro Leu 4985 4990 4995Ser Ser Pro Ser Pro Ala Pro Gly Cys Asp Asn Ala Ile Pro Leu 5000 5005 5010Arg Gln Val Asn Glu Thr Trp Thr Leu Glu Asn Cys Thr Val Ala 5015 5020 5025Arg Cys Val Gly Asp Asn Arg Val Val Leu Leu Asp Pro Lys Pro 5030 5035 5040Val Ala Asn Val Thr Cys Val Asn Lys His Leu Pro Ile Lys Val 5045 5050 5055Ser Asp Pro Ser Gln Pro Cys Asp Phe His Tyr Glu Cys Glu Cys 5060 5065 5070Ile Cys Ser Met Trp Gly Gly Ser His Tyr Ser Thr Phe Asp Gly 5075 5080 5085Thr Ser Tyr Thr Phe Arg Gly Asn Cys Thr Tyr Val Leu Met Arg 5090 5095 5100Glu Ile His Ala Arg Phe Gly Asn Leu Ser Leu Tyr Leu Asp Asn 5105 5110 5115His Tyr Cys Thr Ala Ser Ala Thr Ala Ala Ala Ala Arg Cys Pro 5120 5125 5130Arg Ala Leu Ser Ile His Tyr Lys Ser Met Asp Ile Val Leu Thr 5135 5140 5145Val Thr Met Val His Gly Lys Glu Glu Gly Leu Ile Leu Phe Asp 5150 5155 5160Gln Ile Pro Val Ser Ser Gly Phe Ser Lys Asn Gly Val Leu Val 5165 5170 5175Ser Val Leu Gly Thr Thr Thr Met Arg Val Asp Ile Pro Ala Leu 5180 5185 5190Gly Val Ser Val Thr Phe Asn Gly Gln Val Phe Gln Ala Arg Leu 5195 5200 5205Pro Tyr Ser Leu Phe His Asn Asn Thr Glu Gly Gln Cys Gly Thr 5210 5215 5220Cys Thr Asn Asn Gln Arg Asp Asp Cys

Leu Gln Arg Asp Gly Thr 5225 5230 5235Thr Ala Ala Ser Cys Lys Asp Met Ala Lys Thr Trp Leu Val Pro 5240 5245 5250Asp Ser Arg Lys Asp Gly Cys Trp Ala Pro Thr Gly Thr Pro Pro 5255 5260 5265Thr Ala Ser Pro Ala Ala Pro Val Ser Ser Thr Pro Thr Pro Thr 5270 5275 5280Pro Cys Pro Pro Gln Pro Leu Cys Asp Leu Met Leu Ser Gln Val 5285 5290 5295Phe Ala Glu Cys His Asn Leu Val Pro Pro Gly Pro Phe Phe Asn 5300 5305 5310Ala Cys Ile Ser Asp His Cys Arg Gly Arg Leu Glu Val Pro Cys 5315 5320 5325Gln Ser Leu Glu Ala Tyr Ala Glu Leu Cys Arg Ala Arg Gly Val 5330 5335 5340Cys Ser Asp Trp Arg Gly Ala Thr Gly Gly Leu Cys Asp Leu Thr 5345 5350 5355Cys Pro Pro Thr Lys Val Tyr Lys Pro Cys Gly Pro Ile Gln Pro 5360 5365 5370Ala Thr Cys Asn Ser Arg Asn Gln Ser Pro Gln Leu Glu Gly Met 5375 5380 5385Ala Glu Gly Cys Phe Cys Pro Glu Asp Gln Ile Leu Phe Asn Ala 5390 5395 5400His Met Gly Ile Cys Val Gln Ala Cys Pro Cys Val Gly Pro Asp 5405 5410 5415Gly Phe Pro Lys Phe Pro Gly Glu Arg Trp Val Ser Asn Cys Gln 5420 5425 5430Ser Cys Val Cys Asp Glu Gly Ser Val Ser Val Gln Cys Lys Pro 5435 5440 5445Leu Pro Cys Asp Ala Gln Gly Gln Pro Pro Pro Cys Asn Arg Pro 5450 5455 5460Gly Phe Val Thr Val Thr Arg Pro Arg Ala Glu Asn Pro Cys Cys 5465 5470 5475Pro Glu Thr Val Cys Val Cys Asn Thr Thr Thr Cys Pro Gln Ser 5480 5485 5490Leu Pro Val Cys Pro Pro Gly Gln Glu Ser Ile Cys Thr Gln Glu 5495 5500 5505Glu Gly Asp Cys Cys Pro Thr Phe Arg Cys Arg Pro Gln Leu Cys 5510 5515 5520Ser Tyr Asn Gly Thr Phe Tyr Gly Val Gly Ala Thr Phe Pro Gly 5525 5530 5535Ala Leu Pro Cys His Met Cys Thr Cys Leu Ser Gly Asp Thr Gln 5540 5545 5550Asp Pro Thr Val Gln Cys Gln Glu Asp Ala Cys Asn Asn Thr Thr 5555 5560 5565Cys Pro Gln Gly Phe Glu Tyr Lys Arg Val Ala Gly Gln Cys Cys 5570 5575 5580Gly Glu Cys Val Gln Thr Ala Cys Leu Thr Pro Asp Gly Gln Pro 5585 5590 5595Val Gln Leu Asn Glu Thr Trp Val Asn Ser His Val Asp Asn Cys 5600 5605 5610Thr Val Tyr Leu Cys Glu Ala Glu Gly Gly Val His Leu Leu Thr 5615 5620 5625Pro Gln Pro Ala Ser Cys Pro Asp Val Ser Ser Cys Arg Gly Ser 5630 5635 5640Leu Arg Lys Thr Gly Cys Cys Tyr Ser Cys Glu Glu Asp Ser Cys 5645 5650 5655Gln Val Arg Ile Asn Thr Thr Ile Leu Trp His Gln Gly Cys Glu 5660 5665 5670Thr Glu Val Asn Ile Thr Phe Cys Glu Gly Ser Cys Pro Gly Ala 5675 5680 5685Ser Lys Tyr Ser Ala Glu Ala Gln Ala Met Gln His Gln Cys Thr 5690 5695 5700Cys Cys Gln Glu Arg Arg Val His Glu Glu Thr Val Pro Leu His 5705 5710 5715Cys Pro Asn Gly Ser Ala Ile Leu His Thr Tyr Thr His Val Asp 5720 5725 5730Glu Cys Gly Cys Thr Pro Phe Cys Val Pro Ala Pro Met Ala Pro 5735 5740 5745Pro His Thr Arg Gly Phe Pro Ala Gln Glu Ala Thr Ala Val 5750 5755 5760134018DNAHomo sapiens 13caggcagcgc tgcgtcctgc tgcgcacgtg ggaagccctg gccccggcca cccccgcgat 60gccgcgcgct ccccgctgcc gagccgtgcg ctccctgctg cgcagccact accgcgaggt 120gctgccgctg gccacgttcg tgcggcgcct ggggccccag ggctggcggc tggtgcagcg 180cggggacccg gcggctttcc gcgcgctggt ggcccagtgc ctggtgtgcg tgccctggga 240cgcacggccg ccccccgccg ccccctcctt ccgccaggtg tcctgcctga aggagctggt 300ggcccgagtg ctgcagaggc tgtgcgagcg cggcgcgaag aacgtgctgg ccttcggctt 360cgcgctgctg gacggggccc gcgggggccc ccccgaggcc ttcaccacca gcgtgcgcag 420ctacctgccc aacacggtga ccgacgcact gcgggggagc ggggcgtggg ggctgctgct 480gcgccgcgtg ggcgacgacg tgctggttca cctgctggca cgctgcgcgc tctttgtgct 540ggtggctccc agctgcgcct accaggtgtg cgggccgccg ctgtaccagc tcggcgctgc 600cactcaggcc cggcccccgc cacacgctag tggaccccga aggcgtctgg gatgcgaacg 660ggcctggaac catagcgtca gggaggccgg ggtccccctg ggcctgccag ccccgggtgc 720gaggaggcgc gggggcagtg ccagccgaag tctgccgttg cccaagaggc ccaggcgtgg 780cgctgcccct gagccggagc ggacgcccgt tgggcagggg tcctgggccc acccgggcag 840gacgcgtgga ccgagtgacc gtggtttctg tgtggtgtca cctgccagac ccgccgaaga 900agccacctct ttggagggtg cgctctctgg cacgcgccac tcccacccat ccgtgggccg 960ccagcaccac gcgggccccc catccacatc gcggccacca cgtccctggg acacgccttg 1020tcccccggtg tacgccgaga ccaagcactt cctctactcc tcaggcgaca aggagcagct 1080gcggccctcc ttcctactca gctctctgag gcccagcctg actggcgctc ggaggctcgt 1140ggagaccatc tttctgggtt ccaggccctg gatgccaggg actccccgca ggttgccccg 1200cctgccccag cgctactggc aaatgcggcc cctgtttctg gagctgcttg ggaaccacgc 1260gcagtgcccc tacggggtgc tcctcaagac gcactgcccg ctgcgagctg cggtcacccc 1320agcagccggt gtctgtgccc gggagaagcc ccagggctct gtggcggccc ccgaggagga 1380ggacacagac ccccgtcgcc tggtgcagct gctccgccag cacagcagcc cctggcaggt 1440gtacggcttc gtgcgggcct gcctgcgccg gctggtgccc ccaggcctct ggggctccag 1500gcacaacgaa cgccgcttcc tcaggaacac caagaagttc atctccctgg ggaagcatgc 1560caagctctcg ctgcaggagc tgacgtggaa gatgagcgtg cgggactgcg cttggctgcg 1620caggagccca ggggttggct gtgttccggc cgcagagcac cgtctgcgtg aggagatcct 1680ggccaagttc ctgcactggc tgatgagtgt gtacgtcgtc gagctgctca ggtctttctt 1740ttatgtcacg gagaccacgt ttcaaaagaa caggctcttt ttctaccgga agagtgtctg 1800gagcaagttg caaagcattg gaatcagaca gcacttgaag agggtgcagc tgcgggagct 1860gtcggaagca gaggtcaggc agcatcggga agccaggccc gccctgctga cgtccagact 1920ccgcttcatc cccaagcctg acgggctgcg gccgattgtg aacatggact acgtcgtggg 1980agccagaacg ttccgcagag aaaagagggc cgagcgtctc acctcgaggg tgaaggcact 2040gttcagcgtg ctcaactacg agcgggcgcg gcgccccggc ctcctgggcg cctctgtgct 2100gggcctggac gatatccaca gggcctggcg caccttcgtg ctgcgtgtgc gggcccagga 2160cccgccgcct gagctgtact ttgtcaaggt ggatgtgacg ggcgcgtacg acaccatccc 2220ccaggacagg ctcacggagg tcatcgccag catcatcaaa ccccagaaca cgtactgcgt 2280gcgtcggtat gccgtggtcc agaaggccgc ccatgggcac gtccgcaagg ccttcaagag 2340ccacgtctct accttgacag acctccagcc gtacatgcga cagttcgtgg ctcacctgca 2400ggagaccagc ccgctgaggg atgccgtcgt catcgagcag agctcctccc tgaatgaggc 2460cagcagtggc ctcttcgacg tcttcctacg cttcatgtgc caccacgccg tgcgcatcag 2520gggcaagtcc tacgtccagt gccaggggat cccgcagggc tccatcctct ccacgctgct 2580ctgcagcctg tgctacggcg acatggagaa caagctgttt gcggggattc ggcgggacgg 2640gctgctcctg cgtttggtgg atgatttctt gttggtgaca cctcacctca cccacgcgaa 2700aaccttcctc aggaccctgg tccgaggtgt ccctgagtat ggctgcgtgg tgaacttgcg 2760gaagacagtg gtgaacttcc ctgtagaaga cgaggccctg ggtggcacgg cttttgttca 2820gatgccggcc cacggcctat tcccctggtg cggcctgctg ctggataccc ggaccctgga 2880ggtgcagagc gactactcca gctatgcccg gacctccatc agagccagtc tcaccttcaa 2940ccgcggcttc aaggctggga ggaacatgcg tcgcaaactc tttggggtct tgcggctgaa 3000gtgtcacagc ctgtttctgg atttgcaggt gaacagcctc cagacggtgt gcaccaacat 3060ctacaagatc ctcctgctgc aggcgtacag gtttcacgca tgtgtgctgc agctcccatt 3120tcatcagcaa gtttggaaga accccacatt tttcctgcgc gtcatctctg acacggcctc 3180cctctgctac tccatcctga aagccaagaa cgcagggatg tcgctggggg ccaagggcgc 3240cgccggccct ctgccctccg aggccgtgca gtggctgtgc caccaagcat tcctgctcaa 3300gctgactcga caccgtgtca cctacgtgcc actcctgggg tcactcagga cagcccagac 3360gcagctgagt cggaagctcc cggggacgac gctgactgcc ctggaggccg cagccaaccc 3420ggcactgccc tcagacttca agaccatcct ggactgatgg ccacccgccc acagccaggc 3480cgagagcaga caccagcagc cctgtcacgc cgggctctac gtcccaggga gggaggggcg 3540gcccacaccc aggcccgcac cgctgggagt ctgaggcctg agtgagtgtt tggccgaggc 3600ctgcatgtcc ggctgaaggc tgagtgtccg gctgaggcct gagcgagtgt ccagccaagg 3660gctgagtgtc cagcacacct gccgtcttca cttccccaca ggctggcgct cggctccacc 3720ccagggccag cttttcctca ccaggagccc ggcttccact ccccacatag gaatagtcca 3780tccccagatt cgccattgtt cacccctcgc cctgccctcc tttgccttcc acccccacca 3840tccaggtgga gaccctgaga aggaccctgg gagctctggg aatttggagt gaccaaaggt 3900gtgccctgta cacaggcgag gaccctgcac ctggatgggg gtccctgtgg gtcaaattgg 3960ggggaggtgc tgtgggagta aaatactgaa tatatgagtt tttcagtttt gaaaaaaa 4018141132PRTHomo sapiens 14Met Pro Arg Ala Pro Arg Cys Arg Ala Val Arg Ser Leu Leu Arg Ser1 5 10 15His Tyr Arg Glu Val Leu Pro Leu Ala Thr Phe Val Arg Arg Leu Gly 20 25 30Pro Gln Gly Trp Arg Leu Val Gln Arg Gly Asp Pro Ala Ala Phe Arg 35 40 45Ala Leu Val Ala Gln Cys Leu Val Cys Val Pro Trp Asp Ala Arg Pro 50 55 60Pro Pro Ala Ala Pro Ser Phe Arg Gln Val Ser Cys Leu Lys Glu Leu65 70 75 80Val Ala Arg Val Leu Gln Arg Leu Cys Glu Arg Gly Ala Lys Asn Val 85 90 95Leu Ala Phe Gly Phe Ala Leu Leu Asp Gly Ala Arg Gly Gly Pro Pro 100 105 110Glu Ala Phe Thr Thr Ser Val Arg Ser Tyr Leu Pro Asn Thr Val Thr 115 120 125Asp Ala Leu Arg Gly Ser Gly Ala Trp Gly Leu Leu Leu Arg Arg Val 130 135 140Gly Asp Asp Val Leu Val His Leu Leu Ala Arg Cys Ala Leu Phe Val145 150 155 160Leu Val Ala Pro Ser Cys Ala Tyr Gln Val Cys Gly Pro Pro Leu Tyr 165 170 175Gln Leu Gly Ala Ala Thr Gln Ala Arg Pro Pro Pro His Ala Ser Gly 180 185 190Pro Arg Arg Arg Leu Gly Cys Glu Arg Ala Trp Asn His Ser Val Arg 195 200 205Glu Ala Gly Val Pro Leu Gly Leu Pro Ala Pro Gly Ala Arg Arg Arg 210 215 220Gly Gly Ser Ala Ser Arg Ser Leu Pro Leu Pro Lys Arg Pro Arg Arg225 230 235 240Gly Ala Ala Pro Glu Pro Glu Arg Thr Pro Val Gly Gln Gly Ser Trp 245 250 255Ala His Pro Gly Arg Thr Arg Gly Pro Ser Asp Arg Gly Phe Cys Val 260 265 270Val Ser Pro Ala Arg Pro Ala Glu Glu Ala Thr Ser Leu Glu Gly Ala 275 280 285Leu Ser Gly Thr Arg His Ser His Pro Ser Val Gly Arg Gln His His 290 295 300Ala Gly Pro Pro Ser Thr Ser Arg Pro Pro Arg Pro Trp Asp Thr Pro305 310 315 320Cys Pro Pro Val Tyr Ala Glu Thr Lys His Phe Leu Tyr Ser Ser Gly 325 330 335Asp Lys Glu Gln Leu Arg Pro Ser Phe Leu Leu Ser Ser Leu Arg Pro 340 345 350Ser Leu Thr Gly Ala Arg Arg Leu Val Glu Thr Ile Phe Leu Gly Ser 355 360 365Arg Pro Trp Met Pro Gly Thr Pro Arg Arg Leu Pro Arg Leu Pro Gln 370 375 380Arg Tyr Trp Gln Met Arg Pro Leu Phe Leu Glu Leu Leu Gly Asn His385 390 395 400Ala Gln Cys Pro Tyr Gly Val Leu Leu Lys Thr His Cys Pro Leu Arg 405 410 415Ala Ala Val Thr Pro Ala Ala Gly Val Cys Ala Arg Glu Lys Pro Gln 420 425 430Gly Ser Val Ala Ala Pro Glu Glu Glu Asp Thr Asp Pro Arg Arg Leu 435 440 445Val Gln Leu Leu Arg Gln His Ser Ser Pro Trp Gln Val Tyr Gly Phe 450 455 460Val Arg Ala Cys Leu Arg Arg Leu Val Pro Pro Gly Leu Trp Gly Ser465 470 475 480Arg His Asn Glu Arg Arg Phe Leu Arg Asn Thr Lys Lys Phe Ile Ser 485 490 495Leu Gly Lys His Ala Lys Leu Ser Leu Gln Glu Leu Thr Trp Lys Met 500 505 510Ser Val Arg Asp Cys Ala Trp Leu Arg Arg Ser Pro Gly Val Gly Cys 515 520 525Val Pro Ala Ala Glu His Arg Leu Arg Glu Glu Ile Leu Ala Lys Phe 530 535 540Leu His Trp Leu Met Ser Val Tyr Val Val Glu Leu Leu Arg Ser Phe545 550 555 560Phe Tyr Val Thr Glu Thr Thr Phe Gln Lys Asn Arg Leu Phe Phe Tyr 565 570 575Arg Lys Ser Val Trp Ser Lys Leu Gln Ser Ile Gly Ile Arg Gln His 580 585 590Leu Lys Arg Val Gln Leu Arg Glu Leu Ser Glu Ala Glu Val Arg Gln 595 600 605His Arg Glu Ala Arg Pro Ala Leu Leu Thr Ser Arg Leu Arg Phe Ile 610 615 620Pro Lys Pro Asp Gly Leu Arg Pro Ile Val Asn Met Asp Tyr Val Val625 630 635 640Gly Ala Arg Thr Phe Arg Arg Glu Lys Arg Ala Glu Arg Leu Thr Ser 645 650 655Arg Val Lys Ala Leu Phe Ser Val Leu Asn Tyr Glu Arg Ala Arg Arg 660 665 670Pro Gly Leu Leu Gly Ala Ser Val Leu Gly Leu Asp Asp Ile His Arg 675 680 685Ala Trp Arg Thr Phe Val Leu Arg Val Arg Ala Gln Asp Pro Pro Pro 690 695 700Glu Leu Tyr Phe Val Lys Val Asp Val Thr Gly Ala Tyr Asp Thr Ile705 710 715 720Pro Gln Asp Arg Leu Thr Glu Val Ile Ala Ser Ile Ile Lys Pro Gln 725 730 735Asn Thr Tyr Cys Val Arg Arg Tyr Ala Val Val Gln Lys Ala Ala His 740 745 750Gly His Val Arg Lys Ala Phe Lys Ser His Val Ser Thr Leu Thr Asp 755 760 765Leu Gln Pro Tyr Met Arg Gln Phe Val Ala His Leu Gln Glu Thr Ser 770 775 780Pro Leu Arg Asp Ala Val Val Ile Glu Gln Ser Ser Ser Leu Asn Glu785 790 795 800Ala Ser Ser Gly Leu Phe Asp Val Phe Leu Arg Phe Met Cys His His 805 810 815Ala Val Arg Ile Arg Gly Lys Ser Tyr Val Gln Cys Gln Gly Ile Pro 820 825 830Gln Gly Ser Ile Leu Ser Thr Leu Leu Cys Ser Leu Cys Tyr Gly Asp 835 840 845Met Glu Asn Lys Leu Phe Ala Gly Ile Arg Arg Asp Gly Leu Leu Leu 850 855 860Arg Leu Val Asp Asp Phe Leu Leu Val Thr Pro His Leu Thr His Ala865 870 875 880Lys Thr Phe Leu Arg Thr Leu Val Arg Gly Val Pro Glu Tyr Gly Cys 885 890 895Val Val Asn Leu Arg Lys Thr Val Val Asn Phe Pro Val Glu Asp Glu 900 905 910Ala Leu Gly Gly Thr Ala Phe Val Gln Met Pro Ala His Gly Leu Phe 915 920 925Pro Trp Cys Gly Leu Leu Leu Asp Thr Arg Thr Leu Glu Val Gln Ser 930 935 940Asp Tyr Ser Ser Tyr Ala Arg Thr Ser Ile Arg Ala Ser Leu Thr Phe945 950 955 960Asn Arg Gly Phe Lys Ala Gly Arg Asn Met Arg Arg Lys Leu Phe Gly 965 970 975Val Leu Arg Leu Lys Cys His Ser Leu Phe Leu Asp Leu Gln Val Asn 980 985 990Ser Leu Gln Thr Val Cys Thr Asn Ile Tyr Lys Ile Leu Leu Leu Gln 995 1000 1005Ala Tyr Arg Phe His Ala Cys Val Leu Gln Leu Pro Phe His Gln 1010 1015 1020Gln Val Trp Lys Asn Pro Thr Phe Phe Leu Arg Val Ile Ser Asp 1025 1030 1035Thr Ala Ser Leu Cys Tyr Ser Ile Leu Lys Ala Lys Asn Ala Gly 1040 1045 1050Met Ser Leu Gly Ala Lys Gly Ala Ala Gly Pro Leu Pro Ser Glu 1055 1060 1065Ala Val Gln Trp Leu Cys His Gln Ala Phe Leu Leu Lys Leu Thr 1070 1075 1080Arg His Arg Val Thr Tyr Val Pro Leu Leu Gly Ser Leu Arg Thr 1085 1090 1095Ala Gln Thr Gln Leu Ser Arg Lys Leu Pro Gly Thr Thr Leu Thr 1100 1105 1110Ala Leu Glu Ala Ala Ala Asn Pro Ala Leu Pro Ser Asp Phe Lys 1115 1120 1125Thr Ile Leu Asp 1130153829DNAHomo sapiens 15caggcagcgc tgcgtcctgc tgcgcacgtg ggaagccctg gccccggcca cccccgcgat 60gccgcgcgct ccccgctgcc gagccgtgcg ctccctgctg cgcagccact accgcgaggt 120gctgccgctg gccacgttcg tgcggcgcct ggggccccag ggctggcggc tggtgcagcg 180cggggacccg gcggctttcc gcgcgctggt ggcccagtgc ctggtgtgcg tgccctggga 240cgcacggccg ccccccgccg ccccctcctt ccgccaggtg tcctgcctga aggagctggt 300ggcccgagtg ctgcagaggc tgtgcgagcg cggcgcgaag aacgtgctgg ccttcggctt 360cgcgctgctg gacggggccc gcgggggccc ccccgaggcc ttcaccacca gcgtgcgcag 420ctacctgccc aacacggtga ccgacgcact gcgggggagc ggggcgtggg ggctgctgct 480gcgccgcgtg ggcgacgacg tgctggttca cctgctggca cgctgcgcgc tctttgtgct 540ggtggctccc agctgcgcct accaggtgtg cgggccgccg ctgtaccagc tcggcgctgc 600cactcaggcc cggcccccgc cacacgctag tggaccccga aggcgtctgg gatgcgaacg 660ggcctggaac catagcgtca gggaggccgg ggtccccctg ggcctgccag ccccgggtgc 720gaggaggcgc gggggcagtg ccagccgaag tctgccgttg cccaagaggc

ccaggcgtgg 780cgctgcccct gagccggagc ggacgcccgt tgggcagggg tcctgggccc acccgggcag 840gacgcgtgga ccgagtgacc gtggtttctg tgtggtgtca cctgccagac ccgccgaaga 900agccacctct ttggagggtg cgctctctgg cacgcgccac tcccacccat ccgtgggccg 960ccagcaccac gcgggccccc catccacatc gcggccacca cgtccctggg acacgccttg 1020tcccccggtg tacgccgaga ccaagcactt cctctactcc tcaggcgaca aggagcagct 1080gcggccctcc ttcctactca gctctctgag gcccagcctg actggcgctc ggaggctcgt 1140ggagaccatc tttctgggtt ccaggccctg gatgccaggg actccccgca ggttgccccg 1200cctgccccag cgctactggc aaatgcggcc cctgtttctg gagctgcttg ggaaccacgc 1260gcagtgcccc tacggggtgc tcctcaagac gcactgcccg ctgcgagctg cggtcacccc 1320agcagccggt gtctgtgccc gggagaagcc ccagggctct gtggcggccc ccgaggagga 1380ggacacagac ccccgtcgcc tggtgcagct gctccgccag cacagcagcc cctggcaggt 1440gtacggcttc gtgcgggcct gcctgcgccg gctggtgccc ccaggcctct ggggctccag 1500gcacaacgaa cgccgcttcc tcaggaacac caagaagttc atctccctgg ggaagcatgc 1560caagctctcg ctgcaggagc tgacgtggaa gatgagcgtg cgggactgcg cttggctgcg 1620caggagccca ggggttggct gtgttccggc cgcagagcac cgtctgcgtg aggagatcct 1680ggccaagttc ctgcactggc tgatgagtgt gtacgtcgtc gagctgctca ggtctttctt 1740ttatgtcacg gagaccacgt ttcaaaagaa caggctcttt ttctaccgga agagtgtctg 1800gagcaagttg caaagcattg gaatcagaca gcacttgaag agggtgcagc tgcgggagct 1860gtcggaagca gaggtcaggc agcatcggga agccaggccc gccctgctga cgtccagact 1920ccgcttcatc cccaagcctg acgggctgcg gccgattgtg aacatggact acgtcgtggg 1980agccagaacg ttccgcagag aaaagagggc cgagcgtctc acctcgaggg tgaaggcact 2040gttcagcgtg ctcaactacg agcgggcgcg gcgccccggc ctcctgggcg cctctgtgct 2100gggcctggac gatatccaca gggcctggcg caccttcgtg ctgcgtgtgc gggcccagga 2160cccgccgcct gagctgtact ttgtcaaggt ggatgtgacg ggcgcgtacg acaccatccc 2220ccaggacagg ctcacggagg tcatcgccag catcatcaaa ccccagaaca cgtactgcgt 2280gcgtcggtat gccgtggtcc agaaggccgc ccatgggcac gtccgcaagg ccttcaagag 2340ccacgtctct accttgacag acctccagcc gtacatgcga cagttcgtgg ctcacctgca 2400ggagaccagc ccgctgaggg atgccgtcgt catcgagcag agctcctccc tgaatgaggc 2460cagcagtggc ctcttcgacg tcttcctacg cttcatgtgc caccacgccg tgcgcatcag 2520gggcaagtcc tacgtccagt gccaggggat cccgcagggc tccatcctct ccacgctgct 2580ctgcagcctg tgctacggcg acatggagaa caagctgttt gcggggattc ggcgggacgg 2640gctgctcctg cgtttggtgg atgatttctt gttggtgaca cctcacctca cccacgcgaa 2700aaccttcctc agctatgccc ggacctccat cagagccagt ctcaccttca accgcggctt 2760caaggctggg aggaacatgc gtcgcaaact ctttggggtc ttgcggctga agtgtcacag 2820cctgtttctg gatttgcagg tgaacagcct ccagacggtg tgcaccaaca tctacaagat 2880cctcctgctg caggcgtaca ggtttcacgc atgtgtgctg cagctcccat ttcatcagca 2940agtttggaag aaccccacat ttttcctgcg cgtcatctct gacacggcct ccctctgcta 3000ctccatcctg aaagccaaga acgcagggat gtcgctgggg gccaagggcg ccgccggccc 3060tctgccctcc gaggccgtgc agtggctgtg ccaccaagca ttcctgctca agctgactcg 3120acaccgtgtc acctacgtgc cactcctggg gtcactcagg acagcccaga cgcagctgag 3180tcggaagctc ccggggacga cgctgactgc cctggaggcc gcagccaacc cggcactgcc 3240ctcagacttc aagaccatcc tggactgatg gccacccgcc cacagccagg ccgagagcag 3300acaccagcag ccctgtcacg ccgggctcta cgtcccaggg agggaggggc ggcccacacc 3360caggcccgca ccgctgggag tctgaggcct gagtgagtgt ttggccgagg cctgcatgtc 3420cggctgaagg ctgagtgtcc ggctgaggcc tgagcgagtg tccagccaag ggctgagtgt 3480ccagcacacc tgccgtcttc acttccccac aggctggcgc tcggctccac cccagggcca 3540gcttttcctc accaggagcc cggcttccac tccccacata ggaatagtcc atccccagat 3600tcgccattgt tcacccctcg ccctgccctc ctttgccttc cacccccacc atccaggtgg 3660agaccctgag aaggaccctg ggagctctgg gaatttggag tgaccaaagg tgtgccctgt 3720acacaggcga ggaccctgca cctggatggg ggtccctgtg ggtcaaattg gggggaggtg 3780ctgtgggagt aaaatactga atatatgagt ttttcagttt tgaaaaaaa 3829161069PRTHomo sapiens 16Met Pro Arg Ala Pro Arg Cys Arg Ala Val Arg Ser Leu Leu Arg Ser1 5 10 15His Tyr Arg Glu Val Leu Pro Leu Ala Thr Phe Val Arg Arg Leu Gly 20 25 30Pro Gln Gly Trp Arg Leu Val Gln Arg Gly Asp Pro Ala Ala Phe Arg 35 40 45Ala Leu Val Ala Gln Cys Leu Val Cys Val Pro Trp Asp Ala Arg Pro 50 55 60Pro Pro Ala Ala Pro Ser Phe Arg Gln Val Ser Cys Leu Lys Glu Leu65 70 75 80Val Ala Arg Val Leu Gln Arg Leu Cys Glu Arg Gly Ala Lys Asn Val 85 90 95Leu Ala Phe Gly Phe Ala Leu Leu Asp Gly Ala Arg Gly Gly Pro Pro 100 105 110Glu Ala Phe Thr Thr Ser Val Arg Ser Tyr Leu Pro Asn Thr Val Thr 115 120 125Asp Ala Leu Arg Gly Ser Gly Ala Trp Gly Leu Leu Leu Arg Arg Val 130 135 140Gly Asp Asp Val Leu Val His Leu Leu Ala Arg Cys Ala Leu Phe Val145 150 155 160Leu Val Ala Pro Ser Cys Ala Tyr Gln Val Cys Gly Pro Pro Leu Tyr 165 170 175Gln Leu Gly Ala Ala Thr Gln Ala Arg Pro Pro Pro His Ala Ser Gly 180 185 190Pro Arg Arg Arg Leu Gly Cys Glu Arg Ala Trp Asn His Ser Val Arg 195 200 205Glu Ala Gly Val Pro Leu Gly Leu Pro Ala Pro Gly Ala Arg Arg Arg 210 215 220Gly Gly Ser Ala Ser Arg Ser Leu Pro Leu Pro Lys Arg Pro Arg Arg225 230 235 240Gly Ala Ala Pro Glu Pro Glu Arg Thr Pro Val Gly Gln Gly Ser Trp 245 250 255Ala His Pro Gly Arg Thr Arg Gly Pro Ser Asp Arg Gly Phe Cys Val 260 265 270Val Ser Pro Ala Arg Pro Ala Glu Glu Ala Thr Ser Leu Glu Gly Ala 275 280 285Leu Ser Gly Thr Arg His Ser His Pro Ser Val Gly Arg Gln His His 290 295 300Ala Gly Pro Pro Ser Thr Ser Arg Pro Pro Arg Pro Trp Asp Thr Pro305 310 315 320Cys Pro Pro Val Tyr Ala Glu Thr Lys His Phe Leu Tyr Ser Ser Gly 325 330 335Asp Lys Glu Gln Leu Arg Pro Ser Phe Leu Leu Ser Ser Leu Arg Pro 340 345 350Ser Leu Thr Gly Ala Arg Arg Leu Val Glu Thr Ile Phe Leu Gly Ser 355 360 365Arg Pro Trp Met Pro Gly Thr Pro Arg Arg Leu Pro Arg Leu Pro Gln 370 375 380Arg Tyr Trp Gln Met Arg Pro Leu Phe Leu Glu Leu Leu Gly Asn His385 390 395 400Ala Gln Cys Pro Tyr Gly Val Leu Leu Lys Thr His Cys Pro Leu Arg 405 410 415Ala Ala Val Thr Pro Ala Ala Gly Val Cys Ala Arg Glu Lys Pro Gln 420 425 430Gly Ser Val Ala Ala Pro Glu Glu Glu Asp Thr Asp Pro Arg Arg Leu 435 440 445Val Gln Leu Leu Arg Gln His Ser Ser Pro Trp Gln Val Tyr Gly Phe 450 455 460Val Arg Ala Cys Leu Arg Arg Leu Val Pro Pro Gly Leu Trp Gly Ser465 470 475 480Arg His Asn Glu Arg Arg Phe Leu Arg Asn Thr Lys Lys Phe Ile Ser 485 490 495Leu Gly Lys His Ala Lys Leu Ser Leu Gln Glu Leu Thr Trp Lys Met 500 505 510Ser Val Arg Asp Cys Ala Trp Leu Arg Arg Ser Pro Gly Val Gly Cys 515 520 525Val Pro Ala Ala Glu His Arg Leu Arg Glu Glu Ile Leu Ala Lys Phe 530 535 540Leu His Trp Leu Met Ser Val Tyr Val Val Glu Leu Leu Arg Ser Phe545 550 555 560Phe Tyr Val Thr Glu Thr Thr Phe Gln Lys Asn Arg Leu Phe Phe Tyr 565 570 575Arg Lys Ser Val Trp Ser Lys Leu Gln Ser Ile Gly Ile Arg Gln His 580 585 590Leu Lys Arg Val Gln Leu Arg Glu Leu Ser Glu Ala Glu Val Arg Gln 595 600 605His Arg Glu Ala Arg Pro Ala Leu Leu Thr Ser Arg Leu Arg Phe Ile 610 615 620Pro Lys Pro Asp Gly Leu Arg Pro Ile Val Asn Met Asp Tyr Val Val625 630 635 640Gly Ala Arg Thr Phe Arg Arg Glu Lys Arg Ala Glu Arg Leu Thr Ser 645 650 655Arg Val Lys Ala Leu Phe Ser Val Leu Asn Tyr Glu Arg Ala Arg Arg 660 665 670Pro Gly Leu Leu Gly Ala Ser Val Leu Gly Leu Asp Asp Ile His Arg 675 680 685Ala Trp Arg Thr Phe Val Leu Arg Val Arg Ala Gln Asp Pro Pro Pro 690 695 700Glu Leu Tyr Phe Val Lys Val Asp Val Thr Gly Ala Tyr Asp Thr Ile705 710 715 720Pro Gln Asp Arg Leu Thr Glu Val Ile Ala Ser Ile Ile Lys Pro Gln 725 730 735Asn Thr Tyr Cys Val Arg Arg Tyr Ala Val Val Gln Lys Ala Ala His 740 745 750Gly His Val Arg Lys Ala Phe Lys Ser His Val Ser Thr Leu Thr Asp 755 760 765Leu Gln Pro Tyr Met Arg Gln Phe Val Ala His Leu Gln Glu Thr Ser 770 775 780Pro Leu Arg Asp Ala Val Val Ile Glu Gln Ser Ser Ser Leu Asn Glu785 790 795 800Ala Ser Ser Gly Leu Phe Asp Val Phe Leu Arg Phe Met Cys His His 805 810 815Ala Val Arg Ile Arg Gly Lys Ser Tyr Val Gln Cys Gln Gly Ile Pro 820 825 830Gln Gly Ser Ile Leu Ser Thr Leu Leu Cys Ser Leu Cys Tyr Gly Asp 835 840 845Met Glu Asn Lys Leu Phe Ala Gly Ile Arg Arg Asp Gly Leu Leu Leu 850 855 860Arg Leu Val Asp Asp Phe Leu Leu Val Thr Pro His Leu Thr His Ala865 870 875 880Lys Thr Phe Leu Ser Tyr Ala Arg Thr Ser Ile Arg Ala Ser Leu Thr 885 890 895Phe Asn Arg Gly Phe Lys Ala Gly Arg Asn Met Arg Arg Lys Leu Phe 900 905 910Gly Val Leu Arg Leu Lys Cys His Ser Leu Phe Leu Asp Leu Gln Val 915 920 925Asn Ser Leu Gln Thr Val Cys Thr Asn Ile Tyr Lys Ile Leu Leu Leu 930 935 940Gln Ala Tyr Arg Phe His Ala Cys Val Leu Gln Leu Pro Phe His Gln945 950 955 960Gln Val Trp Lys Asn Pro Thr Phe Phe Leu Arg Val Ile Ser Asp Thr 965 970 975Ala Ser Leu Cys Tyr Ser Ile Leu Lys Ala Lys Asn Ala Gly Met Ser 980 985 990Leu Gly Ala Lys Gly Ala Ala Gly Pro Leu Pro Ser Glu Ala Val Gln 995 1000 1005Trp Leu Cys His Gln Ala Phe Leu Leu Lys Leu Thr Arg His Arg 1010 1015 1020Val Thr Tyr Val Pro Leu Leu Gly Ser Leu Arg Thr Ala Gln Thr 1025 1030 1035Gln Leu Ser Arg Lys Leu Pro Gly Thr Thr Leu Thr Ala Leu Glu 1040 1045 1050Ala Ala Ala Asn Pro Ala Leu Pro Ser Asp Phe Lys Thr Ile Leu 1055 1060 1065Asp175030DNAHomo sapiens 17attgaggagc agaaggagta gggtgcgggg gaggaggagg agcgccttta gtgctgcagc 60agctgctgct ctgattggcc cggtggttca gctgcttccc tggaacaaaa ggtcaaagtg 120gactgcagtg taaatgtaga gaagcagccg ataaaatagc attgcctgaa gaagtttgga 180ggctgagagc agcagtagac tggccaactg cagagcaagt tgtttctcca gccgtgcggt 240gcagcctcat gcccccaacc cagcttagcc actgtaagaa gacgttcact gtacagacga 300ccaaacttgc cgtggaagag acagttgtga gattcccttg caaatttaca tacgagaatg 360gcttgtgaaa tcatgcctct gcaaagttca caggaagatg aaagacctct gtcacctttc 420tatttgagtg ctcatgtacc ccaagtcagc aatgtgtctg caaccggaga actcttagaa 480agaaccatcc gatcagctgt agaacaacat ctttttgatg ttaataactc tggaggtcaa 540agttcagagg actcagaatc tggaacacta tcagcatctt ctgccacatc tgccagacag 600cgccgccgcc agtccaagga gcaggatgaa gttcgacatg ggagagacaa gggacttatc 660aacaaagaaa atactccttc tgggttcaac caccttgatg attgtatttt gaatactcag 720gaagtcgaaa aggtacacaa aaatactttt ggttgtgctg gagaaaggag caagcctaaa 780cgtcagaaat ccagtactaa actttctgag cttcatgaca atcaggacgg tcttgtgaat 840atggaaagtc tcaattccac acgatctcat gagagaactg gacctgatga ttttgaatgg 900atgtctgatg aaaggaaagg aaatgaaaaa gatggtggac acactcagca ttttgagagc 960cccacaatga agatccagga gcatcccagc ctatctgaca ccaaacagca gagaaatcaa 1020gatgccggtg accaggagga gagctttgtc tccgaagtgc cccagtcgga cctgactgca 1080ttgtgtgatg aaaagaactg ggaagagcct atccctgctt tctcctcctg gcagcgggag 1140aacagtgact ctgatgaagc ccacctctcg ccgcaggctg ggcgcctgat ccgtcagctg 1200ctggacgaag acagcgaccc catgctctct cctcggttct acgcttatgg gcagagcagg 1260caatacctgg atgacacaga agtgcctcct tccccaccaa actcccattc tttcatgagg 1320cggcgaagct cctctctggg gtcctatgat gatgagcaag aggacctgac acctgcccag 1380ctcacacgaa ggattcagag ccttaaaaag aagatccgga agtttgaaga tagattcgaa 1440gaagagaaga agtacagacc ttcccacagt gacaaagcag ccaatccgga ggttctgaaa 1500tggacaaatg accttgccaa attccggaga caacttaaag aatcaaaact aaagatatct 1560gaagaggacc taactcccag gatgcggcag cgaagcaaca cactccccaa gagttttggt 1620tcccaacttg agaaagaaga tgagaagaag caagagctgg tggataaagc aataaagccc 1680agtgttgaag ccacattgga atctattcag aggaagctcc aggagaagcg agcggaaagc 1740agccgccctg aggacattaa ggatatgacc aaagaccaga ttgctaatga gaaagtggct 1800ctgcagaaag ctctgttata ttatgaaagc attcatggac ggccggtaac aaagaacgaa 1860cggcaggtga tgaagccact atacgacagg taccggctgg tcaaacagat cctctcccga 1920gctaacacca tacccatcat tggttccccc tccagcaagc ggagaagccc tttgctgcag 1980ccaattatcg agggcgaaac tgcttccttc ttcaaggaga taaaggaaga agaggagggg 2040tcagaagacg atagcaatgt gaagccagac ttcatggtca ctctgaaaac cgatttcagt 2100gcacgatgct ttctggacca attcgaagat gacgctgatg gatttatttc cccaatggat 2160gataaaatac catcaaaatg cagccaggac acagggcttt caaatctcca tgctgcctca 2220atacctgaac tcctggaaca cctccaggaa atgagagaag aaaagaaaag gattcgaaag 2280aaacttcggg attttgaaga caactttttc agacagaatg gaagaaatgt ccagaaggaa 2340gaccgcactc ctatggctga agaatacagt gaatataagc acataaaggc gaaactgagg 2400ctcctggagg tgctcatcag caagagagac actgattcca agtccatgtg aggggcatgg 2460ccaagcacag ggggctggca gctgcggtga gagtttactg tccccagaga aagtgcagct 2520ctggaaggca gccttggggc tggccctgca aagcatgcag cccttctgcc tctagaccat 2580ttggcatcgg ctcctgtttc cattgcctgc cttagaaact ggctggaaga agacaatgtg 2640acctgactta ggcattttgt aattggaaag tcaagactgc agtatgtgca catgcgcacg 2700cgcatgcacg cacacacaca cacagtagtg gagctttcct aacactagca gagattaatc 2760actacattag acaacactca tctacagaga atatacactg ttcttccctg gataactgag 2820aaacaagaga ccattctctg tctaactgtg ataaaaacaa gctcaggact ttattctata 2880gagcaaactt gctgtggagg gccatgctct ccttggaccc agttaactgc aaacgtgcat 2940tggagcccta tttgctgccg ctgccattct agtgaccttt ccacagagct gcgccttcct 3000cacgtgtgtg aaaggttttc cccttcagcc ctcaggtaga tggaagctgc atctgcccac 3060gatggcagtg cagtcatcat cttcaggatg tttcttcagg acttcctcag ctgacaagga 3120attttggtcc ctgcctagga ccgggtcatc tgcagaggac agagagatgg taagcagctg 3180tatgaatgct gattttaaaa ccaggtcatg ggagaagagc ctggagattc tttcctgaac 3240actgactgca cttaccagtc tgattttatc gtcaaacacc aagccaggct agcatgctca 3300tggcaatctg tttggggctg ttttgttgtg gcactagcca aacataaagg ggcttaagtc 3360agcctgcata cagaggatcg gggagagaag gggcctgtgt tctcagcctc ctgagtactt 3420accagagttt aattttttta aaaaaaatct gcactaaaat ccccaaactg acaggtaaat 3480gtagccctca gagctcagcc caaggcagaa tctaaatcac actattttcg agatcatgta 3540taaaaagaaa aaaaagaagt catgctgtgt ggccaattat aatttttttc aaagactttg 3600tcacaaaact gtctatatta gacattttgg agggaccagg aaatgtaaga caccaaatcc 3660tccatctctt cagtgtgcct gatgtcacct catgatttgc tgttactttt ttaactcctg 3720cgccaaggac agtgggttct gtgtccacct ttgtgctttg cgaggccgag cccaggcatc 3780tgctcgcctg ccacggctga ccagagaagg tgcttcagga gctctgcctt agacgacgtg 3840ttacagtatg aacacacagc agaggcaccc tcgtatgttt tgaaagttgc cttctgaaag 3900ggcacagttt taaggaaaag aaaaagaatg taaaactata ctgacccgtt ttcagtttta 3960aagggtcgtg agaaactggc tggtccaatg ggatttacag caacattttc cattgctgaa 4020gtgaggtagc agctctcttc tgtcagctga atgttaagga tggggaaaaa gaatgccttt 4080aagtttgctc ttaatcgtat ggaagcttga gctatgtgtt ggaagtgccc tggttttaat 4140ccatacacaa agacggtaca taatcctaca ggtttaaatg tacataaaaa tatagtttgg 4200aattctttgc tctactgttt acattgcaga ttgctataat ttcaaggagt gagattataa 4260ataaaatgat gcactttagg atgtttccta tttttgaaat ctgaacatga atcattcaca 4320tgaccaaaaa ttgtgttttt ttaaaaatac atgtctagtc tgtcctttaa tagctctctt 4380aaataagcta tgatattaat cagatcatta ccagttagct tttaaagcac atttgtttaa 4440gactatgttt ttggaaaaat acgctacaga attttttttt aagctacaaa taaatgagat 4500gctactaatt gttttggaat ctgttgtttc tgccaaaggt aaattaacta aagatttatt 4560caggaatccc catttgaatt tgtatgattc aataaaagaa aacaccaagt aagttatata 4620aaataaattg tgtatgagat gttgtgtttt cctttgtaat ttccactaac taactaacta 4680acttatattc ttcatggaat ggagcccaga agaaatgaga ggaagccctt ttcacactag 4740atcttatttg aagaaatgtt tgttagtcag tcagtcagtg gtttctggct ctgccgaggg 4800agatgtgttc cccagcaacc atttctgcag cccagaatct caaggcacta gaggcggtgt 4860cttaattaat tggcttcaca aagacaaaat gctctggact gggatttttc ctttgctgtg 4920ttgggaatat gtgtttatta attagcacat gccaacaaaa taaatgtcaa gagttatttc 4980ataagtgtaa gtaaacttaa gaattaaaga gtgcagactt ataattttca 503018697PRTHomo sapiens 18Met Ala Cys Glu Ile Met Pro Leu Gln Ser Ser Gln Glu Asp Glu Arg1 5 10 15Pro Leu Ser Pro Phe Tyr Leu Ser Ala His Val Pro Gln Val Ser Asn 20 25 30Val Ser Ala Thr Gly Glu Leu Leu Glu Arg Thr Ile Arg Ser Ala Val 35 40 45Glu Gln His Leu Phe Asp Val Asn Asn Ser Gly Gly Gln Ser Ser Glu 50 55

60Asp Ser Glu Ser Gly Thr Leu Ser Ala Ser Ser Ala Thr Ser Ala Arg65 70 75 80Gln Arg Arg Arg Gln Ser Lys Glu Gln Asp Glu Val Arg His Gly Arg 85 90 95Asp Lys Gly Leu Ile Asn Lys Glu Asn Thr Pro Ser Gly Phe Asn His 100 105 110Leu Asp Asp Cys Ile Leu Asn Thr Gln Glu Val Glu Lys Val His Lys 115 120 125Asn Thr Phe Gly Cys Ala Gly Glu Arg Ser Lys Pro Lys Arg Gln Lys 130 135 140Ser Ser Thr Lys Leu Ser Glu Leu His Asp Asn Gln Asp Gly Leu Val145 150 155 160Asn Met Glu Ser Leu Asn Ser Thr Arg Ser His Glu Arg Thr Gly Pro 165 170 175Asp Asp Phe Glu Trp Met Ser Asp Glu Arg Lys Gly Asn Glu Lys Asp 180 185 190Gly Gly His Thr Gln His Phe Glu Ser Pro Thr Met Lys Ile Gln Glu 195 200 205His Pro Ser Leu Ser Asp Thr Lys Gln Gln Arg Asn Gln Asp Ala Gly 210 215 220Asp Gln Glu Glu Ser Phe Val Ser Glu Val Pro Gln Ser Asp Leu Thr225 230 235 240Ala Leu Cys Asp Glu Lys Asn Trp Glu Glu Pro Ile Pro Ala Phe Ser 245 250 255Ser Trp Gln Arg Glu Asn Ser Asp Ser Asp Glu Ala His Leu Ser Pro 260 265 270Gln Ala Gly Arg Leu Ile Arg Gln Leu Leu Asp Glu Asp Ser Asp Pro 275 280 285Met Leu Ser Pro Arg Phe Tyr Ala Tyr Gly Gln Ser Arg Gln Tyr Leu 290 295 300Asp Asp Thr Glu Val Pro Pro Ser Pro Pro Asn Ser His Ser Phe Met305 310 315 320Arg Arg Arg Ser Ser Ser Leu Gly Ser Tyr Asp Asp Glu Gln Glu Asp 325 330 335Leu Thr Pro Ala Gln Leu Thr Arg Arg Ile Gln Ser Leu Lys Lys Lys 340 345 350Ile Arg Lys Phe Glu Asp Arg Phe Glu Glu Glu Lys Lys Tyr Arg Pro 355 360 365Ser His Ser Asp Lys Ala Ala Asn Pro Glu Val Leu Lys Trp Thr Asn 370 375 380Asp Leu Ala Lys Phe Arg Arg Gln Leu Lys Glu Ser Lys Leu Lys Ile385 390 395 400Ser Glu Glu Asp Leu Thr Pro Arg Met Arg Gln Arg Ser Asn Thr Leu 405 410 415Pro Lys Ser Phe Gly Ser Gln Leu Glu Lys Glu Asp Glu Lys Lys Gln 420 425 430Glu Leu Val Asp Lys Ala Ile Lys Pro Ser Val Glu Ala Thr Leu Glu 435 440 445Ser Ile Gln Arg Lys Leu Gln Glu Lys Arg Ala Glu Ser Ser Arg Pro 450 455 460Glu Asp Ile Lys Asp Met Thr Lys Asp Gln Ile Ala Asn Glu Lys Val465 470 475 480Ala Leu Gln Lys Ala Leu Leu Tyr Tyr Glu Ser Ile His Gly Arg Pro 485 490 495Val Thr Lys Asn Glu Arg Gln Val Met Lys Pro Leu Tyr Asp Arg Tyr 500 505 510Arg Leu Val Lys Gln Ile Leu Ser Arg Ala Asn Thr Ile Pro Ile Ile 515 520 525Gly Ser Pro Ser Ser Lys Arg Arg Ser Pro Leu Leu Gln Pro Ile Ile 530 535 540Glu Gly Glu Thr Ala Ser Phe Phe Lys Glu Ile Lys Glu Glu Glu Glu545 550 555 560Gly Ser Glu Asp Asp Ser Asn Val Lys Pro Asp Phe Met Val Thr Leu 565 570 575Lys Thr Asp Phe Ser Ala Arg Cys Phe Leu Asp Gln Phe Glu Asp Asp 580 585 590Ala Asp Gly Phe Ile Ser Pro Met Asp Asp Lys Ile Pro Ser Lys Cys 595 600 605Ser Gln Asp Thr Gly Leu Ser Asn Leu His Ala Ala Ser Ile Pro Glu 610 615 620Leu Leu Glu His Leu Gln Glu Met Arg Glu Glu Lys Lys Arg Ile Arg625 630 635 640Lys Lys Leu Arg Asp Phe Glu Asp Asn Phe Phe Arg Gln Asn Gly Arg 645 650 655Asn Val Gln Lys Glu Asp Arg Thr Pro Met Ala Glu Glu Tyr Ser Glu 660 665 670Tyr Lys His Ile Lys Ala Lys Leu Arg Leu Leu Glu Val Leu Ile Ser 675 680 685Lys Arg Asp Thr Asp Ser Lys Ser Met 690 695198005DNAHomo sapiens 19aagaaaccgg ccaggtgtgg cctaggcgcc cagtgccagc ggggaggaga ctcgctccgc 60cgccgaccaa caccaacacc cagctccgac gcagctcctc tgcgcccttg ccgccctccg 120agccacagct ttcctcccgc tcctgccccc ggcccgtcgc cgtctccgcg ctcgcagcgg 180cctcgggagg gcccaggtag cgagcagcga cctcgcgagc cttccgcact cccgcccggt 240tccccggccg tccgcctatc cttggccccc tccgctttct ccgcgccggc ccgcctcgct 300tatgcctcgg cgctgagccg ctctcccgat tgcccgccga catgagctgc aacggaggct 360cccacccgcg gatcaacact ctgggccgca tgatccgcgc cgagtctggc ccggacctgc 420gctacgaggt gaccagcggc ggcgggggca ccagcaggat gtactattct cggcgcggcg 480tgatcaccga ccagaactcg gacggctact gtcaaaccgg cacgatgtcc aggcaccaga 540accagaacac catccaggag ctgctgcaga actgctccga ctgcttgatg cgagcagagc 600tcatcgtgca gcctgaattg aagtatggag atggaataca actgactcgg agtcgagaat 660tggatgagtg ttttgcccag gccaatgacc aaatggaaat cctcgacagc ttgatcagag 720agatgcggca gatgggccag ccctgtgatg cttaccagaa aaggcttctt cagctccaag 780agcaaatgcg agccctttat aaagccatca gtgtccctcg agtccgcagg gccagctcca 840agggtggtgg aggctacact tgtcagagtg gctctggctg ggatgagttc accaaacatg 900tcaccagtga atgtttgggg tggatgaggc agcaaagggc ggagatggac atggtggcct 960ggggtgtgga cctggcctca gtggagcagc acattaacag ccaccggggc atccacaact 1020ccatcggcga ctatcgctgg cagctggaca aaatcaaagc cgacctgcgc gagaaatctg 1080cgatctacca gttggaggag gagtatgaaa acctgctgaa agcgtccttt gagaggatgg 1140atcacctgcg acagctgcag aacatcattc aggccacgtc cagggagatc atgtggatca 1200atgactgcga ggaggaggag ctgctgtacg actggagcga caagaacacc aacatcgctc 1260agaaacagga ggccttctcc atacgcatga gtcaactgga agttaaagaa aaagagctca 1320ataagctgaa acaagaaagt gaccaacttg tcctcaatca gcatccagct tcagacaaaa 1380ttgaggccta tatggacact ctgcagacgc agtggagttg gattcttcag atcaccaagt 1440gcattgatgt tcatctgaaa gaaaatgctg cctactttca gttttttgaa gaggcgcagt 1500ctactgaagc atacctgaag gggctccagg actccatcag gaagaagtac ccctgcgaca 1560agaacatgcc cctgcagcac ctgctggaac agatcaagga gctggagaaa gaacgagaga 1620aaatccttga atacaagcgt caggtgcaga acttggtaaa caagtctaag aagattgtac 1680agctgaagcc tcgtaaccca gactacagaa gcaataaacc cattattctc agagctctct 1740gtgactacaa acaagatcag aaaatcgtgc ataaggggga tgagtgtatc ctgaaggaca 1800acaacgagcg cagcaagtgg tacgtgacgg gcccgggagg cgttgacatg cttgttccct 1860ctgtggggct gatcatccct cctccgaacc cactggccgt ggacctctct tgcaagattg 1920agcagtacta cgaagccatc ttggctctgt ggaaccagct ctacatcaac atgaagagcc 1980tggtgtcctg gcactactgc atgattgaca tagagaagat cagggccatg acaatcgcca 2040agctgaaaac aatgcggcag gaagattaca tgaagacgat agccgacctt gagttacatt 2100accaagagtt catcagaaat agccaaggct cagagatgtt tggagatgat gacaagcgga 2160aaatacagtc tcagttcacc gatgcccaga agcattacca gaccctggtc attcagctcc 2220ctggctatcc ccagcaccag acagtgacca caactgaaat cactcatcat ggaacctgcc 2280aagatgtcaa ccataataaa gtaattgaaa ccaacagaga aaatgacaag caagaaacat 2340ggatgctgat ggagctgcag aagattcgca ggcagataga gcactgcgag ggcaggatga 2400ctctcaaaaa cctccctcta gcagaccagg gatcttctca ccacatcaca gtgaaaatta 2460acgagcttaa gagtgtgcag aatgattcac aagcaattgc tgaggttctc aaccagctta 2520aagatatgct tgccaacttc agaggttctg aaaagtactg ctatttacag aatgaagtat 2580ttggactatt tcagaaactg gaaaatatca atggtgttac agatggctac ttaaatagct 2640tatgcacagt aagggcactg ctccaggcta ttctccaaac agaagacatg ttaaaggttt 2700atgaagccag gctcactgag gaggaaactg tctgcctgga cctggataaa gtggaagctt 2760accgctgtgg actgaagaaa ataaaaaatg acttgaactt gaagaagtcg ttgttggcca 2820ctatgaagac agaactacag aaagcccagc agatccactc tcagacttca cagcagtatc 2880cactttatga tctggacttg ggcaagttcg gtgaaaaagt cacacagctg acagaccgct 2940ggcaaaggat agataaacag atcgacttta ggttatggga cctggagaaa caaatcaagc 3000aattgaggaa ttatcgtgat aactatcagg ctttctgcaa gtggctctat gatgctaaac 3060gccgccagga ttccttagaa tccatgaaat ttggagattc caacacagtc atgcggtttt 3120tgaatgagca gaagaacttg cacagtgaaa tatctggcaa acgagacaaa tcagaggaag 3180tacaaaaaat tgctgaactt tgcgccaatt caattaagga ttatgagctc cagctggcct 3240catacacctc aggactggaa actctgctga acatacctat caagaggacc atgattcagt 3300ccccttctgg ggtgattctg caagaggctg cagatgttca tgctcggtac attgaactac 3360ttacaagatc tggagactat tacaggttct taagtgagat gctgaagagt ttggaagatc 3420tgaagctgaa aaataccaag atcgaagttt tggaagagga gctcagactg gcccgagatg 3480ccaactcgga aaactgtaat aagaacaaat tcctggatca gaacctgcag aaataccagg 3540cagagtgttc ccagttcaaa gcgaagcttg cgagcctgga ggagctgaag agacaggctg 3600agctggatgg gaagtcggct aagcaaaatc tagacaagtg ctacggccaa ataaaagaac 3660tcaatgagaa gatcacccga ctgacttatg agattgaaga tgaaaagaga agaagaaaat 3720ctgtggaaga cagatttgac caacagaaga atgactatga ccaactgcag aaagcaaggc 3780aatgtgaaaa ggagaacctt ggttggcaga aattagagtc tgagaaagcc atcaaggaga 3840aggagtacga gattgaaagg ttgagggttc tactgcagga agaaggcacc cggaagagag 3900aatatgaaaa tgagctggca aaggcatcta ataggattca ggaatcaaag aatcagtgta 3960ctcaggtggt acaggaaaga gagagccttc tggtgaaaat caaagtcctg gagcaagaca 4020aggcaaggct gcagaggctg gaggatgagc tgaatcgtgc aaaatcaact ctagaggcag 4080aaaccagggt gaaacagcgc ctggagtgtg agaaacagca aattcagaat gacctgaatc 4140agtggaagac tcaatattcc cgcaaggagg aggctattag gaagatagaa tcggaaagag 4200aaaagagtga gagagagaag aacagtctta ggagtgagat cgaaagactc caagcagaga 4260tcaagagaat tgaagagagg tgcaggcgta agctggagga ttctaccagg gagacacagt 4320cacagttaga aacagaacgc tcccgatatc agagggagat tgataaactc agacagcgcc 4380catatgggtc ccatcgagag acccagactg agtgtgagtg gaccgttgac acctccaagc 4440tggtgtttga tgggctgagg aagaaggtga cagcaatgca gctctatgag tgtcagctga 4500tcgacaaaac aaccttggac aaactattga aggggaagaa gtcagtggaa gaagttgctt 4560ctgaaatcca gccattcctt cggggtgcag gatctatcgc tggagcatct gcttctccta 4620aggaaaaata ctctttggta gaggccaaga gaaagaaatt aatcagccca gaatccacag 4680tcatgcttct ggaggcccag gcagctacag gtggtataat tgatccccat cggaatgaga 4740agctgactgt cgacagtgcc atagctcggg acctcattga cttcgatgac cgtcagcaga 4800tatatgcagc agaaaaagct atcactggtt ttgatgatcc attttcaggc aagacagtat 4860ctgtttcaga agccatcaag aaaaatttga ttgatagaga aaccggaatg cgcctgctgg 4920aagcccagat tgcttcaggg ggtgtagtag accctgtgaa cagtgtcttt ttgccaaaag 4980atgtcgcctt ggcccggggg ctgattgata gagatttgta tcgatccctg aatgatcccc 5040gagatagtca gaaaaacttt gtggatccag tcaccaaaaa gaaggtcagt tacgtgcagc 5100tgaaggaacg gtgcagaatc gaaccacata ctggtctgct cttgctttca gtacagaaga 5160gaagcatgtc cttccaagga atcagacaac ctgtgaccgt cactgagcta gtagattctg 5220gtatattgag accgtccact gtcaatgaac tggaatctgg tcagatttct tatgacgagg 5280ttggtgagag aattaaggac ttcctccagg gttcaagctg catagcaggc atatacaatg 5340agaccacaaa acagaagctt ggcatttatg aggccatgaa aattggctta gtccgacctg 5400gtactgctct ggagttgctg gaagcccaag cagctactgg ctttatagtg gatcctgtta 5460gcaacttgag gttaccagtg gaggaagcct acaagagagg tctggtgggc attgagttca 5520aagagaagct cctgtctgca gaacgagctg tcactgggta taatgatcct gaaacaggaa 5580acatcatctc tttgttccaa gccatgaata aggaactcat cgaaaagggc cacggtattc 5640gcttattaga agcacagatc gcaaccgggg ggatcattga cccaaaggag agccatcgtt 5700taccagttga catagcatat aagaggggct atttcaatga ggaactcagt gagattctct 5760cagatccaag tgatgatacc aaaggatttt ttgaccccaa cactgaagaa aatcttacct 5820atctgcaact aaaagaaaga tgcattaagg atgaggaaac agggctctgt cttctgcctc 5880tgaaagaaaa gaagaaacag gtgcagacat cacaaaagaa taccctcagg aagcgtagag 5940tggtcatagt tgacccagaa accaataaag aaatgtctgt tcaggaggcc tacaagaagg 6000gcctaattga ttatgaaacc ttcaaagaac tgtgtgagca ggaatgtgaa tgggaagaaa 6060taaccatcac gggatcagat ggctccacca gggtggtcct ggtagataga aagacaggca 6120gtcagtatga tattcaagat gctattgaca agggccttgt tgacaggaag ttctttgatc 6180agtaccgatc cggcagcctc agcctcactc aatttgctga catgatctcc ttgaaaaatg 6240gtgtcggcac cagcagcagc atgggcagtg gtgtcagcga tgatgttttt agcagctccc 6300gacatgaatc agtaagtaag atttccacca tatccagcgt caggaattta accataagga 6360gcagctcttt ttcagacacc ctggaagaat cgagccccat tgcagccatc tttgacacag 6420aaaacctgga gaaaatctcc attacagaag gtatagagcg gggcatcgtt gacagcatca 6480cgggtcagag gcttctggag gctcaggcct gcacaggtgg catcatccac ccaaccacgg 6540gccagaagct gtcacttcag gacgcagtct cccagggtgt gattgaccaa gacatggcca 6600ccaggctgaa gcctgctcag aaagccttca taggcttcga gggtgtgaag ggaaagaaga 6660agatgtcagc agcagaggca gtgaaagaaa aatggctccc gtatgaggct ggccagcgct 6720tcctggagtt ccagtacctc acgggaggtc ttgttgaccc ggaagtgcat gggaggataa 6780gcaccgaaga agccatccgg aaggggttca tagatggccg cgccgcacag aggctgcaag 6840acaccagcag ctatgccaaa atcctgacct gccccaaaac caaattaaaa atatcctata 6900aggatgccat aaatcgctcc atggtagaag atatcactgg gctgcgcctt ctggaagccg 6960cctccgtgtc gtccaagggc ttacccagcc cttacaacat gtcttcggct ccggggtccc 7020gctccggctc ccgctcggga tctcgctccg gatctcgctc cgggtcccgc agtgggtccc 7080ggagaggaag ctttgacgcc acagggaatt cttcctactc ttattcctac tcatttagca 7140gtagttctat tgggcactag tagtcagttg ggagtggttg ctataccttg acttcattta 7200tatgaatttc cactttatta aataatagaa aagaaaatcc cggtgcttgc agtagagtga 7260taggacattc tatgcttaca gaaaatatag ccatgattga aatcaaatag taaaggctgt 7320tctggctttt tatcttctta gctcatctta aataagcagt acacttggat gcagtgcgtc 7380tgaagtgcta atcagttgta acaatagcac aaatcgaact taggatttgt ttcttctctt 7440ctgtgtttcg atttttgatc aattctttaa ttttggaagc ctataataca gttttctatt 7500cttggagata aaaattaaat ggatcactga tattttagtc attctgcttc tcatctaaat 7560atttccatat tctgtattag gagaaaatta ccctcccagc accagccccc ctctcaaacc 7620cccaacccaa aaccaagcat tttggaatga gtctccttta gtttcagagt gtggattgta 7680taacccatat actcttcgat gtacttgttt ggtttggtat taatttgact gtgcatgaca 7740gcggcaatct tttctttggt caaagttttc tgtttatttt gcttgtcata ttcgatgtac 7800tttaaggtgt ctttatgaag tttgctattc tggcaataaa cttttagact tttgaagtgt 7860ttgtgtttta atttaatatg tttataagca tgtataaaca tttagcatat ttttatcata 7920ggtctaaaaa tatttgttta ctaaatacct gtgaagaaat accattaaaa aactatttgg 7980ttctgaattc ttactagaaa aaaaa 8005202272PRTHomo sapiens 20Met Ser Cys Asn Gly Gly Ser His Pro Arg Ile Asn Thr Leu Gly Arg1 5 10 15Met Ile Arg Ala Glu Ser Gly Pro Asp Leu Arg Tyr Glu Val Thr Ser 20 25 30Gly Gly Gly Gly Thr Ser Arg Met Tyr Tyr Ser Arg Arg Gly Val Ile 35 40 45Thr Asp Gln Asn Ser Asp Gly Tyr Cys Gln Thr Gly Thr Met Ser Arg 50 55 60His Gln Asn Gln Asn Thr Ile Gln Glu Leu Leu Gln Asn Cys Ser Asp65 70 75 80Cys Leu Met Arg Ala Glu Leu Ile Val Gln Pro Glu Leu Lys Tyr Gly 85 90 95Asp Gly Ile Gln Leu Thr Arg Ser Arg Glu Leu Asp Glu Cys Phe Ala 100 105 110Gln Ala Asn Asp Gln Met Glu Ile Leu Asp Ser Leu Ile Arg Glu Met 115 120 125Arg Gln Met Gly Gln Pro Cys Asp Ala Tyr Gln Lys Arg Leu Leu Gln 130 135 140Leu Gln Glu Gln Met Arg Ala Leu Tyr Lys Ala Ile Ser Val Pro Arg145 150 155 160Val Arg Arg Ala Ser Ser Lys Gly Gly Gly Gly Tyr Thr Cys Gln Ser 165 170 175Gly Ser Gly Trp Asp Glu Phe Thr Lys His Val Thr Ser Glu Cys Leu 180 185 190Gly Trp Met Arg Gln Gln Arg Ala Glu Met Asp Met Val Ala Trp Gly 195 200 205Val Asp Leu Ala Ser Val Glu Gln His Ile Asn Ser His Arg Gly Ile 210 215 220His Asn Ser Ile Gly Asp Tyr Arg Trp Gln Leu Asp Lys Ile Lys Ala225 230 235 240Asp Leu Arg Glu Lys Ser Ala Ile Tyr Gln Leu Glu Glu Glu Tyr Glu 245 250 255Asn Leu Leu Lys Ala Ser Phe Glu Arg Met Asp His Leu Arg Gln Leu 260 265 270Gln Asn Ile Ile Gln Ala Thr Ser Arg Glu Ile Met Trp Ile Asn Asp 275 280 285Cys Glu Glu Glu Glu Leu Leu Tyr Asp Trp Ser Asp Lys Asn Thr Asn 290 295 300Ile Ala Gln Lys Gln Glu Ala Phe Ser Ile Arg Met Ser Gln Leu Glu305 310 315 320Val Lys Glu Lys Glu Leu Asn Lys Leu Lys Gln Glu Ser Asp Gln Leu 325 330 335Val Leu Asn Gln His Pro Ala Ser Asp Lys Ile Glu Ala Tyr Met Asp 340 345 350Thr Leu Gln Thr Gln Trp Ser Trp Ile Leu Gln Ile Thr Lys Cys Ile 355 360 365Asp Val His Leu Lys Glu Asn Ala Ala Tyr Phe Gln Phe Phe Glu Glu 370 375 380Ala Gln Ser Thr Glu Ala Tyr Leu Lys Gly Leu Gln Asp Ser Ile Arg385 390 395 400Lys Lys Tyr Pro Cys Asp Lys Asn Met Pro Leu Gln His Leu Leu Glu 405 410 415Gln Ile Lys Glu Leu Glu Lys Glu Arg Glu Lys Ile Leu Glu Tyr Lys 420 425 430Arg Gln Val Gln Asn Leu Val Asn Lys Ser Lys Lys Ile Val Gln Leu 435 440 445Lys Pro Arg Asn Pro Asp Tyr Arg Ser Asn Lys Pro Ile Ile Leu Arg 450 455 460Ala Leu Cys Asp Tyr Lys Gln Asp Gln Lys Ile Val His Lys Gly Asp465 470 475 480Glu Cys Ile Leu Lys Asp Asn Asn Glu Arg Ser Lys Trp Tyr Val Thr 485 490 495Gly Pro Gly Gly Val Asp Met Leu Val Pro Ser Val Gly Leu Ile Ile 500 505 510Pro

Pro Pro Asn Pro Leu Ala Val Asp Leu Ser Cys Lys Ile Glu Gln 515 520 525Tyr Tyr Glu Ala Ile Leu Ala Leu Trp Asn Gln Leu Tyr Ile Asn Met 530 535 540Lys Ser Leu Val Ser Trp His Tyr Cys Met Ile Asp Ile Glu Lys Ile545 550 555 560Arg Ala Met Thr Ile Ala Lys Leu Lys Thr Met Arg Gln Glu Asp Tyr 565 570 575Met Lys Thr Ile Ala Asp Leu Glu Leu His Tyr Gln Glu Phe Ile Arg 580 585 590Asn Ser Gln Gly Ser Glu Met Phe Gly Asp Asp Asp Lys Arg Lys Ile 595 600 605Gln Ser Gln Phe Thr Asp Ala Gln Lys His Tyr Gln Thr Leu Val Ile 610 615 620Gln Leu Pro Gly Tyr Pro Gln His Gln Thr Val Thr Thr Thr Glu Ile625 630 635 640Thr His His Gly Thr Cys Gln Asp Val Asn His Asn Lys Val Ile Glu 645 650 655Thr Asn Arg Glu Asn Asp Lys Gln Glu Thr Trp Met Leu Met Glu Leu 660 665 670Gln Lys Ile Arg Arg Gln Ile Glu His Cys Glu Gly Arg Met Thr Leu 675 680 685Lys Asn Leu Pro Leu Ala Asp Gln Gly Ser Ser His His Ile Thr Val 690 695 700Lys Ile Asn Glu Leu Lys Ser Val Gln Asn Asp Ser Gln Ala Ile Ala705 710 715 720Glu Val Leu Asn Gln Leu Lys Asp Met Leu Ala Asn Phe Arg Gly Ser 725 730 735Glu Lys Tyr Cys Tyr Leu Gln Asn Glu Val Phe Gly Leu Phe Gln Lys 740 745 750Leu Glu Asn Ile Asn Gly Val Thr Asp Gly Tyr Leu Asn Ser Leu Cys 755 760 765Thr Val Arg Ala Leu Leu Gln Ala Ile Leu Gln Thr Glu Asp Met Leu 770 775 780Lys Val Tyr Glu Ala Arg Leu Thr Glu Glu Glu Thr Val Cys Leu Asp785 790 795 800Leu Asp Lys Val Glu Ala Tyr Arg Cys Gly Leu Lys Lys Ile Lys Asn 805 810 815Asp Leu Asn Leu Lys Lys Ser Leu Leu Ala Thr Met Lys Thr Glu Leu 820 825 830Gln Lys Ala Gln Gln Ile His Ser Gln Thr Ser Gln Gln Tyr Pro Leu 835 840 845Tyr Asp Leu Asp Leu Gly Lys Phe Gly Glu Lys Val Thr Gln Leu Thr 850 855 860Asp Arg Trp Gln Arg Ile Asp Lys Gln Ile Asp Phe Arg Leu Trp Asp865 870 875 880Leu Glu Lys Gln Ile Lys Gln Leu Arg Asn Tyr Arg Asp Asn Tyr Gln 885 890 895Ala Phe Cys Lys Trp Leu Tyr Asp Ala Lys Arg Arg Gln Asp Ser Leu 900 905 910Glu Ser Met Lys Phe Gly Asp Ser Asn Thr Val Met Arg Phe Leu Asn 915 920 925Glu Gln Lys Asn Leu His Ser Glu Ile Ser Gly Lys Arg Asp Lys Ser 930 935 940Glu Glu Val Gln Lys Ile Ala Glu Leu Cys Ala Asn Ser Ile Lys Asp945 950 955 960Tyr Glu Leu Gln Leu Ala Ser Tyr Thr Ser Gly Leu Glu Thr Leu Leu 965 970 975Asn Ile Pro Ile Lys Arg Thr Met Ile Gln Ser Pro Ser Gly Val Ile 980 985 990Leu Gln Glu Ala Ala Asp Val His Ala Arg Tyr Ile Glu Leu Leu Thr 995 1000 1005Arg Ser Gly Asp Tyr Tyr Arg Phe Leu Ser Glu Met Leu Lys Ser 1010 1015 1020Leu Glu Asp Leu Lys Leu Lys Asn Thr Lys Ile Glu Val Leu Glu 1025 1030 1035Glu Glu Leu Arg Leu Ala Arg Asp Ala Asn Ser Glu Asn Cys Asn 1040 1045 1050Lys Asn Lys Phe Leu Asp Gln Asn Leu Gln Lys Tyr Gln Ala Glu 1055 1060 1065Cys Ser Gln Phe Lys Ala Lys Leu Ala Ser Leu Glu Glu Leu Lys 1070 1075 1080Arg Gln Ala Glu Leu Asp Gly Lys Ser Ala Lys Gln Asn Leu Asp 1085 1090 1095Lys Cys Tyr Gly Gln Ile Lys Glu Leu Asn Glu Lys Ile Thr Arg 1100 1105 1110Leu Thr Tyr Glu Ile Glu Asp Glu Lys Arg Arg Arg Lys Ser Val 1115 1120 1125Glu Asp Arg Phe Asp Gln Gln Lys Asn Asp Tyr Asp Gln Leu Gln 1130 1135 1140Lys Ala Arg Gln Cys Glu Lys Glu Asn Leu Gly Trp Gln Lys Leu 1145 1150 1155Glu Ser Glu Lys Ala Ile Lys Glu Lys Glu Tyr Glu Ile Glu Arg 1160 1165 1170Leu Arg Val Leu Leu Gln Glu Glu Gly Thr Arg Lys Arg Glu Tyr 1175 1180 1185Glu Asn Glu Leu Ala Lys Ala Ser Asn Arg Ile Gln Glu Ser Lys 1190 1195 1200Asn Gln Cys Thr Gln Val Val Gln Glu Arg Glu Ser Leu Leu Val 1205 1210 1215Lys Ile Lys Val Leu Glu Gln Asp Lys Ala Arg Leu Gln Arg Leu 1220 1225 1230Glu Asp Glu Leu Asn Arg Ala Lys Ser Thr Leu Glu Ala Glu Thr 1235 1240 1245Arg Val Lys Gln Arg Leu Glu Cys Glu Lys Gln Gln Ile Gln Asn 1250 1255 1260Asp Leu Asn Gln Trp Lys Thr Gln Tyr Ser Arg Lys Glu Glu Ala 1265 1270 1275Ile Arg Lys Ile Glu Ser Glu Arg Glu Lys Ser Glu Arg Glu Lys 1280 1285 1290Asn Ser Leu Arg Ser Glu Ile Glu Arg Leu Gln Ala Glu Ile Lys 1295 1300 1305Arg Ile Glu Glu Arg Cys Arg Arg Lys Leu Glu Asp Ser Thr Arg 1310 1315 1320Glu Thr Gln Ser Gln Leu Glu Thr Glu Arg Ser Arg Tyr Gln Arg 1325 1330 1335Glu Ile Asp Lys Leu Arg Gln Arg Pro Tyr Gly Ser His Arg Glu 1340 1345 1350Thr Gln Thr Glu Cys Glu Trp Thr Val Asp Thr Ser Lys Leu Val 1355 1360 1365Phe Asp Gly Leu Arg Lys Lys Val Thr Ala Met Gln Leu Tyr Glu 1370 1375 1380Cys Gln Leu Ile Asp Lys Thr Thr Leu Asp Lys Leu Leu Lys Gly 1385 1390 1395Lys Lys Ser Val Glu Glu Val Ala Ser Glu Ile Gln Pro Phe Leu 1400 1405 1410Arg Gly Ala Gly Ser Ile Ala Gly Ala Ser Ala Ser Pro Lys Glu 1415 1420 1425Lys Tyr Ser Leu Val Glu Ala Lys Arg Lys Lys Leu Ile Ser Pro 1430 1435 1440Glu Ser Thr Val Met Leu Leu Glu Ala Gln Ala Ala Thr Gly Gly 1445 1450 1455Ile Ile Asp Pro His Arg Asn Glu Lys Leu Thr Val Asp Ser Ala 1460 1465 1470Ile Ala Arg Asp Leu Ile Asp Phe Asp Asp Arg Gln Gln Ile Tyr 1475 1480 1485Ala Ala Glu Lys Ala Ile Thr Gly Phe Asp Asp Pro Phe Ser Gly 1490 1495 1500Lys Thr Val Ser Val Ser Glu Ala Ile Lys Lys Asn Leu Ile Asp 1505 1510 1515Arg Glu Thr Gly Met Arg Leu Leu Glu Ala Gln Ile Ala Ser Gly 1520 1525 1530Gly Val Val Asp Pro Val Asn Ser Val Phe Leu Pro Lys Asp Val 1535 1540 1545Ala Leu Ala Arg Gly Leu Ile Asp Arg Asp Leu Tyr Arg Ser Leu 1550 1555 1560Asn Asp Pro Arg Asp Ser Gln Lys Asn Phe Val Asp Pro Val Thr 1565 1570 1575Lys Lys Lys Val Ser Tyr Val Gln Leu Lys Glu Arg Cys Arg Ile 1580 1585 1590Glu Pro His Thr Gly Leu Leu Leu Leu Ser Val Gln Lys Arg Ser 1595 1600 1605Met Ser Phe Gln Gly Ile Arg Gln Pro Val Thr Val Thr Glu Leu 1610 1615 1620Val Asp Ser Gly Ile Leu Arg Pro Ser Thr Val Asn Glu Leu Glu 1625 1630 1635Ser Gly Gln Ile Ser Tyr Asp Glu Val Gly Glu Arg Ile Lys Asp 1640 1645 1650Phe Leu Gln Gly Ser Ser Cys Ile Ala Gly Ile Tyr Asn Glu Thr 1655 1660 1665Thr Lys Gln Lys Leu Gly Ile Tyr Glu Ala Met Lys Ile Gly Leu 1670 1675 1680Val Arg Pro Gly Thr Ala Leu Glu Leu Leu Glu Ala Gln Ala Ala 1685 1690 1695Thr Gly Phe Ile Val Asp Pro Val Ser Asn Leu Arg Leu Pro Val 1700 1705 1710Glu Glu Ala Tyr Lys Arg Gly Leu Val Gly Ile Glu Phe Lys Glu 1715 1720 1725Lys Leu Leu Ser Ala Glu Arg Ala Val Thr Gly Tyr Asn Asp Pro 1730 1735 1740Glu Thr Gly Asn Ile Ile Ser Leu Phe Gln Ala Met Asn Lys Glu 1745 1750 1755Leu Ile Glu Lys Gly His Gly Ile Arg Leu Leu Glu Ala Gln Ile 1760 1765 1770Ala Thr Gly Gly Ile Ile Asp Pro Lys Glu Ser His Arg Leu Pro 1775 1780 1785Val Asp Ile Ala Tyr Lys Arg Gly Tyr Phe Asn Glu Glu Leu Ser 1790 1795 1800Glu Ile Leu Ser Asp Pro Ser Asp Asp Thr Lys Gly Phe Phe Asp 1805 1810 1815Pro Asn Thr Glu Glu Asn Leu Thr Tyr Leu Gln Leu Lys Glu Arg 1820 1825 1830Cys Ile Lys Asp Glu Glu Thr Gly Leu Cys Leu Leu Pro Leu Lys 1835 1840 1845Glu Lys Lys Lys Gln Val Gln Thr Ser Gln Lys Asn Thr Leu Arg 1850 1855 1860Lys Arg Arg Val Val Ile Val Asp Pro Glu Thr Asn Lys Glu Met 1865 1870 1875Ser Val Gln Glu Ala Tyr Lys Lys Gly Leu Ile Asp Tyr Glu Thr 1880 1885 1890Phe Lys Glu Leu Cys Glu Gln Glu Cys Glu Trp Glu Glu Ile Thr 1895 1900 1905Ile Thr Gly Ser Asp Gly Ser Thr Arg Val Val Leu Val Asp Arg 1910 1915 1920Lys Thr Gly Ser Gln Tyr Asp Ile Gln Asp Ala Ile Asp Lys Gly 1925 1930 1935Leu Val Asp Arg Lys Phe Phe Asp Gln Tyr Arg Ser Gly Ser Leu 1940 1945 1950Ser Leu Thr Gln Phe Ala Asp Met Ile Ser Leu Lys Asn Gly Val 1955 1960 1965Gly Thr Ser Ser Ser Met Gly Ser Gly Val Ser Asp Asp Val Phe 1970 1975 1980Ser Ser Ser Arg His Glu Ser Val Ser Lys Ile Ser Thr Ile Ser 1985 1990 1995Ser Val Arg Asn Leu Thr Ile Arg Ser Ser Ser Phe Ser Asp Thr 2000 2005 2010Leu Glu Glu Ser Ser Pro Ile Ala Ala Ile Phe Asp Thr Glu Asn 2015 2020 2025Leu Glu Lys Ile Ser Ile Thr Glu Gly Ile Glu Arg Gly Ile Val 2030 2035 2040Asp Ser Ile Thr Gly Gln Arg Leu Leu Glu Ala Gln Ala Cys Thr 2045 2050 2055Gly Gly Ile Ile His Pro Thr Thr Gly Gln Lys Leu Ser Leu Gln 2060 2065 2070Asp Ala Val Ser Gln Gly Val Ile Asp Gln Asp Met Ala Thr Arg 2075 2080 2085Leu Lys Pro Ala Gln Lys Ala Phe Ile Gly Phe Glu Gly Val Lys 2090 2095 2100Gly Lys Lys Lys Met Ser Ala Ala Glu Ala Val Lys Glu Lys Trp 2105 2110 2115Leu Pro Tyr Glu Ala Gly Gln Arg Phe Leu Glu Phe Gln Tyr Leu 2120 2125 2130Thr Gly Gly Leu Val Asp Pro Glu Val His Gly Arg Ile Ser Thr 2135 2140 2145Glu Glu Ala Ile Arg Lys Gly Phe Ile Asp Gly Arg Ala Ala Gln 2150 2155 2160Arg Leu Gln Asp Thr Ser Ser Tyr Ala Lys Ile Leu Thr Cys Pro 2165 2170 2175Lys Thr Lys Leu Lys Ile Ser Tyr Lys Asp Ala Ile Asn Arg Ser 2180 2185 2190Met Val Glu Asp Ile Thr Gly Leu Arg Leu Leu Glu Ala Ala Ser 2195 2200 2205Val Ser Ser Lys Gly Leu Pro Ser Pro Tyr Asn Met Ser Ser Ala 2210 2215 2220Pro Gly Ser Arg Ser Gly Ser Arg Ser Gly Ser Arg Ser Gly Ser 2225 2230 2235Arg Ser Gly Ser Arg Ser Gly Ser Arg Arg Gly Ser Phe Asp Ala 2240 2245 2250Thr Gly Asn Ser Ser Tyr Ser Tyr Ser Tyr Ser Phe Ser Ser Ser 2255 2260 2265Ser Ile Gly His 2270211278DNAHomo sapiens 21ccattggcct gtagattcac ctcccctggg cagggcccca ggacccagga taatatctgt 60gcctcctgcc cagaaccctc caagcagaca caatggtaag aatggtgcct gtcctgctgt 120ctctgctgct gcttctgggt cctgctgtcc cccaggagaa ccaagatggt cgttactctc 180tgacctatat ctacactggg ctgtccaagc atgttgaaga cgtccccgcg tttcaggccc 240ttggctcact caatgacctc cagttcttta gatacaacag taaagacagg aagtctcagc 300ccatgggact ctggagacag gtggaaggaa tggaggattg gaagcaggac agccaacttc 360agaaggccag ggaggacatc tttatggaga ccctgaaaga catcgtggag tattacaacg 420acagtaacgg gtctcacgta ttgcagggaa ggtttggttg tgagatcgag aataacagaa 480gcagcggagc attctggaaa tattactatg atggaaagga ctacattgaa ttcaacaaag 540aaatcccagc ctgggtcccc ttcgacccag cagcccagat aaccaagcag aagtgggagg 600cagaaccagt ctacgtgcag cgggccaagg cttacctgga ggaggagtgc cctgcgactc 660tgcggaaata cctgaaatac agcaaaaata tcctggaccg gcaagatcct ccctctgtgg 720tggtcaccag ccaccaggcc ccaggagaaa agaagaaact gaagtgcctg gcctacgact 780tctacccagg gaaaattgat gtgcactgga ctcgggccgg cgaggtgcag gagcctgagt 840tacggggaga tgttcttcac aatggaaatg gcacttacca gtcctgggtg gtggtggcag 900tgcccccgca ggacacagcc ccctactcct gccacgtgca gcacagcagc ctggcccagc 960ccctcgtggt gccctgggag gccagctagg aagcaagggt tggaggcaat gtgggatctc 1020agacccagta gctgcccttc ctgcctgatg tgggagctga accacagaaa tcacagtcaa 1080tggatccaca aggcctgagg agcagtgtgg ggggacagac aggaggtgga tttggagacc 1140gaagactggg atgcctgtct tgagtagact tggacccaaa aaatcatctc accttgagcc 1200cacccccacc ccattgtcta atctgtagaa gctaataaat aatcatccct ccttgcctag 1260cataaaaaaa aaaaaaaa 127822298PRTHomo sapiens 22Met Val Arg Met Val Pro Val Leu Leu Ser Leu Leu Leu Leu Leu Gly1 5 10 15Pro Ala Val Pro Gln Glu Asn Gln Asp Gly Arg Tyr Ser Leu Thr Tyr 20 25 30Ile Tyr Thr Gly Leu Ser Lys His Val Glu Asp Val Pro Ala Phe Gln 35 40 45Ala Leu Gly Ser Leu Asn Asp Leu Gln Phe Phe Arg Tyr Asn Ser Lys 50 55 60Asp Arg Lys Ser Gln Pro Met Gly Leu Trp Arg Gln Val Glu Gly Met65 70 75 80Glu Asp Trp Lys Gln Asp Ser Gln Leu Gln Lys Ala Arg Glu Asp Ile 85 90 95Phe Met Glu Thr Leu Lys Asp Ile Val Glu Tyr Tyr Asn Asp Ser Asn 100 105 110Gly Ser His Val Leu Gln Gly Arg Phe Gly Cys Glu Ile Glu Asn Asn 115 120 125Arg Ser Ser Gly Ala Phe Trp Lys Tyr Tyr Tyr Asp Gly Lys Asp Tyr 130 135 140Ile Glu Phe Asn Lys Glu Ile Pro Ala Trp Val Pro Phe Asp Pro Ala145 150 155 160Ala Gln Ile Thr Lys Gln Lys Trp Glu Ala Glu Pro Val Tyr Val Gln 165 170 175Arg Ala Lys Ala Tyr Leu Glu Glu Glu Cys Pro Ala Thr Leu Arg Lys 180 185 190Tyr Leu Lys Tyr Ser Lys Asn Ile Leu Asp Arg Gln Asp Pro Pro Ser 195 200 205Val Val Val Thr Ser His Gln Ala Pro Gly Glu Lys Lys Lys Leu Lys 210 215 220Cys Leu Ala Tyr Asp Phe Tyr Pro Gly Lys Ile Asp Val His Trp Thr225 230 235 240Arg Ala Gly Glu Val Gln Glu Pro Glu Leu Arg Gly Asp Val Leu His 245 250 255Asn Gly Asn Gly Thr Tyr Gln Ser Trp Val Val Val Ala Val Pro Pro 260 265 270Gln Asp Thr Ala Pro Tyr Ser Cys His Val Gln His Ser Ser Leu Ala 275 280 285Gln Pro Leu Val Val Pro Trp Glu Ala Ser 290 295236483DNAHomo sapiens 23aaatgcgctg gcggggagac cggggttggt ccctggcggg gcagggggcg ggctcaggcc 60ggaactccag agacgacctc agccaactgc tcctgcgccg ggcggggtcg tcgccgccag 120cggctccgag cgccggaagg gccaggtctc agggctcctg gagctgcagg cggcgggagg 180ggctacaaat gcttgactca gtgatgcaga acctttcaga gttagctgga agccacagcc 240ctgcctcttg atgcagcctg gatccagccg gtgtgaagag gagacccctt ccctcttgtg 300gggtttggat cctgtgtttc tagcctttgc aaaactctac atcagggata tcctggacat 360gaaggagtcc cgccaggtgc caggtgtatt tttgtacaat ggacatccaa taaaacaggt 420agatgtcttg ggaactgtca ttggagtgag agaaagagat gctttctaca gttatggagt 480ggatgacagc actggagtta taaactgcat ctgctggaaa aagttgaata ctgagtctgt 540atcagctgct ccaagtgcag caagagagct cagcttaacc tcacaactta agaagctaca 600agagaccatt gagcagaaaa caaagataga gatcggggac acgatccgag tcagaggcag 660tatccgcaca tacagagaag agcgagagat tcatgccacc acttactata aagtggacga 720cccagtgtgg aacattcaaa ttgcaaggat gcttgagctg cccactatct acaggaaagt 780ttatgaccag ccttttcaca gctcagccct agagaaagaa gaggcactaa gcaatccagg 840cgccctggac ctccccagtc tcacgagttt gctgagtgaa aaagccaaag aattcctcat 900ggagaacaga gtgcagagct tttaccagca ggagctggaa atggtggagt ctttgctgtc 960ccttgccaat cagcctgtga ttcacagtgc ctcctccgac caagtgaatt ttaagaagga 1020caccacttcc aaggcaattc atagtatatt taagaatgct

atacaactgc tgcaggaaaa 1080aggacttgtt ttccagaaag atgatggttt tgataaccta tactatgtaa ccagagaaga 1140caaagacctg cacagaaaga tccaccggat cattcagcag gactgccaga aaccaaatca 1200catggagaag ggctgtcact tcctgcacat cttggcctgt gctcgcctga gcatccgccc 1260gggcctgagc gaggctgtgc tgcagcaagt tctggagctc ctggaggacc agagtgacat 1320tgtcagcaca atggagcact actacacagc gttctgagca gagacacgca gaccagctga 1380ggaggacaaa gataaggtgg cattcacccc caggctctga ctttcagcat catgcagggg 1440cttatctgtc tggaggcagt tacctcataa taaactataa aatatagtca tcttgggaat 1500gggatttggc ataaatgttg ttggctccct tctgtccact atgtccttgg tgtacaatga 1560ctttgatctc agccatgaca caacaagaaa accctccctg ttgagctcct ggctggactg 1620tgcgttgttc gcagagcaga atggggagga aacagtgttg gcagcttaac tgatgtgtgt 1680ggttggagtc tcttccatgg caaagggaca ccacagggta gtgaacattc aggaactgag 1740gggcatatgg cctgatcaca cagttctaag cttttcaaaa cttcaggtta tcagagacct 1800tcctgtgggc ctctcttgct ggctaagaac cggtttaggg gagtagttct ccctggatga 1860gtgcttacag tttctgtggc tcagttacca gcagtggggt tgagacctgg gtcgatgctc 1920tttacaggcc tgcccagaga tgggaataaa cagggatcca cagcgtgact atgtgtttgt 1980cattttcctt ttatttcctt gggaatcgaa aggtgtccca gtacatttcc ctgcacttac 2040agaggtgcat gactaaatac attgtccctc gatgcccctg aagatcacgg aggcagtcag 2100ccaattgcct ggcaggtggt agatgttatt ttcagggttg ccgctgagtg tgcaggatgt 2160gctgacacca tccagacaaa gactcggtat gtgcccagac aggtgatgga gtcatgcttt 2220tgctcagaat gacaaggtaa aggaaaaaca tctgaggtat gttgtaggcc tgttctgaca 2280gcaaaatgac aaatccagcc agcaaaaata aagtgtggag aaagatttgg agttaattac 2340agtcatttca cagaaggcac tgccttcgtc tgctgcattt gctcttgatg tgataagctc 2400ttcgtggctc agctggagat cctttaggcc tggagagttg ctcctctctc cgtggaaaca 2460ggacagtctt tatacgcaga agtccgctgc agctcgatac gtcaggctga gagctagaac 2520cagtagattg cctcctgtca tagacttttg taatgatgca aacctttgct gatttctaac 2580agtgattatg tagtggctgc cctgcatctt ctctgtgtac agaagggtcc ctagcataga 2640gtctgcctgg aatgatgtcc tgggcagttc ttccttgagg tcagcagctg ttccacgttg 2700aatgcatctg attagtgggg ctgcccagga aggagttcag aatcagaagg taaaaagggc 2760atacccttgc ctatagcaac tctgctctta ggggtttatc tcaaggagat ggctacacaa 2820gtgtgaaagg atggttgcac aaggtgttca ttgctgtata atctagaatt ctatattggg 2880gaaaatacct atagggaaaa agttaattac ggttcttggg cacaatgaaa tactatgcag 2940ctatgaaaaa aatgatgaaa gcagacagac agtgttgcca tggcacactg tccctagtag 3000atttagtggg aagtagatag agttatagat ctgtttctat agtataacac cattatctac 3060agctccctgt gtgtatgtat atatccgtag agagagtgta tatttctgca tggaggtctt 3120tataaatgta gcacatgtac atatatatat atatacacac acacagtcga ccactccctt 3180ctcctggaag tactttccgc gtttggcttt caggacacca agctctctgg ttgctccttc 3240tcaggttcct ttgttcagtg ctctgcctcc ctgaggactc agtcccagac ctcttttcta 3300tctggcttgc tcactggggt gtctccagca gccacatgga ttataccatc tacatgctgt 3360ctaacacctc agtttaaacc cagaatgggc ctcttccctg aactgcagac ccctatattc 3420agtttgctac tgacatctcc acttaggtct ctaatggaca tctcagattt cacaggccca 3480aagccaggct cccaattact cctgacccca ggcttgctcc tgatagtgac atgaggcagc 3540caaatgccta ggcagagagg ggagggtccc aaatgaaacc ccacgttcaa gcaaagatca 3600gcctgaaggc taaaagacca gattgctggt cctggatgaa acccaccacg cagagtggga 3660acttctgttc ctgtttgccc accctttccc aattgttctt tctgaataac gccttaacca 3720atcgaatgtt gccttttcca gtaataccta cagcctgccc ctccccccat tctgagccca 3780taaaaagacc cagactcccc catattaagg ggactttcct gcctttgggt agggggacca 3840cccccacgtc tcctctctgt tgaaaactgt ttcatcactc aataaaactc ccagctttgc 3900tcactcttcc actgtcagca cattctcatt cttctttggt gctgggcaag aactcaacca 3960gtgtggaagc catacttggc ccaggcgggt gaagtgggcg ggccgtctcc tgcagcaggt 4020agcatggtca agcgaggccc aggtgggccg tcaccagcca gaggtccctg gcttgcaaag 4080tgaccgagaa aaaaatcctg tgccactcct ttggaaaatg tccctgattc aggaagaggt 4140agctccatcc agttgctcaa accaaatcca ttggcttctt tctttctatc atacctcaca 4200tccaatctgt ctgcaagtct tttggctcta ccttcagaat atctccagaa tcttaactgc 4260ttcaccctcc tccccggcct cctcagtcct ctctgcttcc gccctggccc ctcttgggct 4320gttcacagca cagcagctgt tgccaccctg ttaatgctcc cactctccta cagccttcgg 4380tcttgcccca ggtaggagcc tgaggctgca cagaggtcag cacggccccg cttaccctgc 4440cctcccagcc cagccgcacg ggccttgcac acatgcctcg gcatattcct gccttagggc 4500tggtgctcct gctatttcct cttcccaggt aaccatgtga agtgcctccc tctgccctct 4560ttccagcctt tacttgagtg tcaccttctc agtgaggcct gccctcattc ctctttcgct 4620gtttgcaacc catctcctgt cccccttccc agaactccct ttcctacttc gtttttcttc 4680acagtacttg atactgccta acacactcca tggtttctta cttgccctgt ttattatttt 4740cccccaatag acagaatgtt ccatgatggc agaattctct gttttgtttc cttccatgtc 4800cccagcacct agaacagtgc ctgacgcatc tcctaagcaa tacgaccaat aagtatgtgt 4860ctggctgcct tccggctgcc agtgtctgcc tctttcctag gggcagtggt tgcgggggtg 4920ctttctcaca tgtcttagta ggctgtgcag gctggaagtg ctcagaagtc acacccccag 4980ggagcagcct cagccaacag caccttggct gtaaatgccc cagctccctc gccctcaggt 5040aagcattgct gaggcacacg ttccatactc ttttccacag ttcctccgtg ggactgagca 5100ccacccagcc acccacagga gcagctaacc tgataaccac cagcctcacc ctccctgcct 5160tacttccccg ctccccttta ccacatgctg acctcccaga tgcatttctt gctttccggt 5220ctctgtctca ggattggctc ctggatgaac acaaactaac actatgttca caaatatatt 5280tgggaaatgc tggatgaata attatacaca tcagacagat tactagaaat tctcaccaaa 5340gggatgcaca tgttacctct gcatggtgag atctcaggtg ctttttaccc cacatagcta 5400tcctttggca tttttataat tagcaagtgc tcactcttcc actgtcagta cattctcatt 5460cttcttgggc gctggacaag aattcaaccg gtgtgtaagc cagactcggc ccgggcagtc 5520tcaaactcct gactccttat ataatttcta caaaaattat aaagctattt cccactcccc 5580accccacatt catgtaacct gaagcatgag taaaccaaga atgaggtagg cctctgtctt 5640ctaagcaaca tcagaactct aagaacatga gggactctta gaaaactctc tggagctaac 5700cacagctggg tcactgctca tgtactgaag accagccaga gggttcccct gaaaaggagg 5760gaaactgagc aaacattctc cagttctctt agtgtgcaca tgtttcagga ggtgtgaacc 5820ccacatgtag cttgtgtagg caagaagaca aatagtgcta ctgtctggtc aaggatttgt 5880ttgaagagcc atgattatgc ccatatggta agccaccagt gctccccatc cctgtaagac 5940acttctttct cattattttc tcctctgatg gtgtgccagg atgctggcca agagaagcca 6000agtggaaaga aggctgttca gtgacaagga acctaagact tagtgccaag gactgaaacc 6060aagtaaactt gtaattttcc atgatggaaa catctacact ttctcattag tggcctctac 6120agcagttgcc ccaaagaagc gtctcattgt ttttttacta catttatgtg aagcatacag 6180gcaaactcag aaagactgtg ataaggctcg ccagagatgc ctgcacaggt gctgggggaa 6240aagcaggacc atcctgaagg gagatggtgt ctgtggacaa agaactctgc agtggttctt 6300atttgcatga tttctgctgg tggaggctgt aaatgtgagc tcaaactccc acataagtga 6360gttttcattg taatccagaa tgtttttaaa tcaccctact tctattgaac ttgcactatc 6420atctgttaac ctctactgta tttattaaat aaacctgaat aggtaaatca cagtacagca 6480aaa 648324368PRTHomo sapiens 24Met Gln Pro Gly Ser Ser Arg Cys Glu Glu Glu Thr Pro Ser Leu Leu1 5 10 15Trp Gly Leu Asp Pro Val Phe Leu Ala Phe Ala Lys Leu Tyr Ile Arg 20 25 30Asp Ile Leu Asp Met Lys Glu Ser Arg Gln Val Pro Gly Val Phe Leu 35 40 45Tyr Asn Gly His Pro Ile Lys Gln Val Asp Val Leu Gly Thr Val Ile 50 55 60Gly Val Arg Glu Arg Asp Ala Phe Tyr Ser Tyr Gly Val Asp Asp Ser65 70 75 80Thr Gly Val Ile Asn Cys Ile Cys Trp Lys Lys Leu Asn Thr Glu Ser 85 90 95Val Ser Ala Ala Pro Ser Ala Ala Arg Glu Leu Ser Leu Thr Ser Gln 100 105 110Leu Lys Lys Leu Gln Glu Thr Ile Glu Gln Lys Thr Lys Ile Glu Ile 115 120 125Gly Asp Thr Ile Arg Val Arg Gly Ser Ile Arg Thr Tyr Arg Glu Glu 130 135 140Arg Glu Ile His Ala Thr Thr Tyr Tyr Lys Val Asp Asp Pro Val Trp145 150 155 160Asn Ile Gln Ile Ala Arg Met Leu Glu Leu Pro Thr Ile Tyr Arg Lys 165 170 175Val Tyr Asp Gln Pro Phe His Ser Ser Ala Leu Glu Lys Glu Glu Ala 180 185 190Leu Ser Asn Pro Gly Ala Leu Asp Leu Pro Ser Leu Thr Ser Leu Leu 195 200 205Ser Glu Lys Ala Lys Glu Phe Leu Met Glu Asn Arg Val Gln Ser Phe 210 215 220Tyr Gln Gln Glu Leu Glu Met Val Glu Ser Leu Leu Ser Leu Ala Asn225 230 235 240Gln Pro Val Ile His Ser Ala Ser Ser Asp Gln Val Asn Phe Lys Lys 245 250 255Asp Thr Thr Ser Lys Ala Ile His Ser Ile Phe Lys Asn Ala Ile Gln 260 265 270Leu Leu Gln Glu Lys Gly Leu Val Phe Gln Lys Asp Asp Gly Phe Asp 275 280 285Asn Leu Tyr Tyr Val Thr Arg Glu Asp Lys Asp Leu His Arg Lys Ile 290 295 300His Arg Ile Ile Gln Gln Asp Cys Gln Lys Pro Asn His Met Glu Lys305 310 315 320Gly Cys His Phe Leu His Ile Leu Ala Cys Ala Arg Leu Ser Ile Arg 325 330 335Pro Gly Leu Ser Glu Ala Val Leu Gln Gln Val Leu Glu Leu Leu Glu 340 345 350Asp Gln Ser Asp Ile Val Ser Thr Met Glu His Tyr Tyr Thr Ala Phe 355 360 365258795DNAHomo sapiens 25gcggccgcac tagtaccccg gagcccatgg gcgcgccgag ccgggcgcgg gggcgctgaa 60cggcggagcg ggagcggccg gaggagccat ggactgcagc ctcgtgcgga cgctcgtgca 120cagatactgt gcaggagaag agaattgggt ggacagcagg accatctacg tgggacacag 180ggagccacct ccgggcgcag aggcctacat cccacagaga tacccagaca acaggatcgt 240ctcgtccaag tacacatttt ggaactttat acccaagaat ttatttgaac aattcagaag 300agtagccaac ttttatttcc ttatcatatt tctggtgcag ttgattattg atacacccac 360aagtccagtg acaagcggac ttccactctt ctttgtcatt actgtgacgg ctatcaaaca 420gggttatgaa gactggcttc gacataaagc agacaatgcc atgaaccagt gtcctgttca 480tttcattcag cacggcaagc tcgttcggaa acaaagtcga aagctgcgag ttggggacat 540tgtcatggtt aaggaggacg agacctttcc ctgcgacttg atcttccttt ccagcaaccg 600gggagatggg acgtgccacg tcaccaccgc cagcttggat ggagaatcca gccataaaac 660gcattacgcg gtccaggaca ccaaaggctt ccacacagag gaggatatcg gcggacttca 720cgccaccatc gagtgtgagc agccccagcc cgacctctac aagttcgtgg gtcgcatcaa 780cgtttacagt gacctgaatg accccgtggt gaggccctta ggatcggaaa acctgctgct 840tagaggagct acactgaaga acactgagaa aatctttggt gtggctattt acacgggaat 900ggaaaccaag atggcattaa attatcaatc aaaatctcag aagcgatctg ccgtggaaaa 960atcgatgaat gcgttcctca ttgtgtatct ctgcattctg atcagcaaag ccctgataaa 1020cactgtgctg aaatacatgt ggcagagtga gccctttcgg gatgagccgt ggtataatca 1080gaaaacggag tcggaaaggc agaggaatct gttcctcaag gcattcacgg acttcctggc 1140cttcatggtc ctctttaact acatcatccc tgtgtccatg tacgtcacgg tcgagatgca 1200gaagttcctc ggctcttact tcatcacctg ggacgaagac atgtttgacg aggagactgg 1260cgaggggcct ctggtgaaca cgtcggacct caatgaagag ctgggacagg tggagtacat 1320cttcacagac aagaccggca ccctcacgga aaacaacatg gagttcaagg agtgctgcat 1380cgaaggccat gtctacgtgc cccacgtcat ctgcaacggg caggtcctcc cagagtcgtc 1440aggaatcgac atgattgact cgtcccccag cgtcaacggg agggagcgcg aggagctgtt 1500tttccgggcc ctctgtctct gccacaccgt ccaggtgaaa gacgatgaca gcgtagacgg 1560ccccaggaaa tcgccggacg gggggaaatc ctgtgtgtac atctcatcct cgcccgacga 1620ggtggcgctg gtcgaaggtg tccagagact tggctttacc tacctaaggc tgaaggacaa 1680ttacatggag atattaaaca gggagaacca catcgaaagg tttgaattgc tggaaatttt 1740gagttttgac tcagtcagaa ggagaatgag tgtaattgta aaatctgcta caggagaaat 1800ttatctgttt tgcaaaggag cagattcttc gatattcccc cgagtgatag aaggcaaagt 1860tgaccagatc cgagccagag tggagcgtaa cgcagtggag gggctccgaa ctttgtgtgt 1920tgcttataaa aggctgatcc aagaagaata tgaaggcatt tgtaagctgc tgcaggctgc 1980caaagtggcc cttcaagatc gagagaaaaa gttagcagaa gcctatgagc aaatagagaa 2040agatcttact ctgcttggtg ctacagctgt tgaggaccgg ctgcaggaga aagctgcaga 2100caccatcgag gccctgcaga aggccgggat caaagtctgg gttctcacgg gagacaagat 2160ggagacggcc gcggccacgt gctacgcctg caagctcttc cgcaggaaca cgcagctgct 2220ggagctgacc accaagagga tcgaggagca gagcctgcac gacgtcctgt tcgagctgag 2280caagacggtc ctgcgccaca gcgggagcct gaccagagac aacctgtccg gactttcagc 2340agatatgcag gactacggtt taattatcga cggagctgca ctgtctctga taatgaagcc 2400tcgagaagac gggagttccg gcaactacag ggagctcttc ctggaaatct gccggagctg 2460cagcgcggtg ctctgctgcc gcatggcgcc cttgcagaag gctcagattg ttaaattaat 2520caaattttca aaagagcacc caatcacgtt agcaattggc gatggtgcaa atgatgtcag 2580catgattctg gaagcgcacg tgggcatagg tgtcatcggc aaggaaggcc gccaggctgc 2640caggaacagc gactatgcaa tcccaaagtt taagcatttg aagaagatgc tgcttgttca 2700cgggcatttt tattacatta ggatctctga gctcgtgcag tacttcttct ataagaacgt 2760ctgcttcatc ttccctcagt ttttatacca gttcttctgt gggttttcac aacagacttt 2820gtacgacacc gcgtatctga ccctctacaa catcagcttc acctccctcc ccatcctcct 2880gtacagcctc atggagcagc atgttggcat tgacgtgctc aagagagacc cgaccctgta 2940cagggacgtc gccaagaatg ccctgctgcg ctggcgcgtg ttcatctact ggacgctcct 3000gggactgttt gacgcactgg tgttcttctt tggtgcttat ttcgtgtttg aaaatacaac 3060tgtgacaagc aacgggcaga tatttggaaa ctggacgttt ggaacgctgg tattcaccgt 3120gatggtgttc acagttacac taaagcttgc attggacaca cactactgga cttggatcaa 3180ccattttgtc atctgggggt cgctgctgtt ctacgttgtc ttttcgcttc tctggggagg 3240agtgatctgg ccgttcctca actaccagag gatgtactac gtgttcatcc agatgctgtc 3300cagcgggccc gcctggctgg ccatcgtgct gctggtgacc atcagcctcc ttcccgacgt 3360cctcaagaaa gtcctgtgcc ggcagctgtg gccaacagca acagagagag tccagactaa 3420gagccagtgc ctttctgtcg agcagtcaac catctttatg ctttctcaga cttccagcag 3480cctgagtttc tgatggaaca agagcccagg ctaccagagc acctgtccct cggccgcctg 3540gtacagctcc cactctcagc aggtgacact cgcggcctgg aaggagaagg tgtccacgga 3600gcccccaccc atcctcggcg gttcccatca ccactgcagt tccatcccaa gtcacagctg 3660ccctaggtcc cgtgtgggaa tgctcgtgtg atggatggtc ctaagcctgt ggagactgtg 3720cacgtgcctc ttcctggccc ccagcaggca aggagggggg tcacaggcct tgccctcgag 3780catggcaccc tggccgcctg gacccagcac tgtggttgtt gagccacacc agtggcctct 3840gggcattcgg ctcaacgcag gagggacatt ctgctggccc accctgcgcg ctgtcatgca 3900gaggccattc ccccaggcct gtgtcttcac ccacctgcca tcattggcct ttgctgtcac 3960tgggagagaa gagccgtcca gggacccatg gtggcccaca tgtggatgcc acatgctgct 4020gtttcctgct tgcccggcca ccacccatgc cctccatagg gtgaggtgga gccatggtgg 4080tgcgtccttt actcaacaac cctccaatcc ggatgctgtg ggaagggccg ggtcactcgg 4140ataccatcat ccctgcggat gcaccgccgt accctgctca tctgggagtg gtttccctgc 4200ggttacgtcc aagcccgcct gccctgtgtg ttggggctgg ctgagtttcg gtctccccat 4260caccggccgc ctcgtggaga aggcagtgcc acgtgggagg acaaggccac gccggcagct 4320tccagccctg ccgcagaagt gccaggatgt ccatcagcca ctcgccaggg cacggagccg 4380tcagtccact gttacgggag aatgttgatt tcgcgggtgc gagggccggg agacagatac 4440ttggctgtga tgagcagaca tcctctgtcc ccgtggaggg gtcaacacca aggtggtgtt 4500cgtgcaccag aacctgtctc gggctgacgg gggtggcaca caggacacgg gtggatccca 4560acaggcagca ccgcacctct gcccgcctcc cgcactgcag ctccgcccgc cgggctctgc 4620gtccccacgt cccctcgtcc catccccacg tcccctcatc ccgtcacctc gtccccacat 4680ccccttgccc cgtcacctcg tcctcatgtc cccttgtcct gtcacctcgt ccccacgtcc 4740cctcgtctcc tcatccccac gtcctctcgt ccccttgtcc cgtccccaca taccctcgtc 4800cccatgtccc cacgcagggc tctccttcgt cttaggatct gtccagcgct gctctgggtg 4860ggttagcaac cccagggctg ctgtgatagg aagtccctgt tgttctccgt actggcattt 4920ctatttctag aaataatatt tgacatagcc ttaatggtcc ttaaagaaga catttcagtg 4980tgagattcag acttcagacg ctgaaactgc tgcctttcag gaaagcacca ccaacgctgg 5040aggaggagcc ggccctcacg cccgccccgc gccacgctgt ggaacggggc tccggcaagt 5100gaaacccaga gggtgtttcc gaggtgctcg acagtaggta tttttggaag ctcagatttc 5160accatttgat tgtataatct tttacctata aaatatttat ttgaagtaga gggtaaatca 5220gcggtaagaa cagtgaacac agtggttggg ataaaataag gtgacaaaca tcacaccaaa 5280gatgagggta gcgagcaact ggcttgagca gacagaacgg ggaagactcc actctgtccc 5340gaggggccag ccgcaggcgt ccccagggcc accctgccct gaggtccttg tgtggccgcc 5400ctggcttggc agccctgccc acgctgcccc cgcaaacaat ggtgtgtgcg tttttacagc 5460cctttttagg aacccaatat gggcataaat gtaacacctg tagcgggggc agattctctg 5520tatgttcagt taacaaatta tttgtaatgt atttttttag aaatcttaaa attgcctttg 5580cactgaagta ttttcatagc tgtttatatc tcttttattc atttatttaa catactgtct 5640aattttaaaa ataggttttt aaagctttca tttttaagtt tatgaaattt tggccacttt 5700acatttagat tctggtgaga gttttgactg aatgttccaa tctctgatga atgcgaattt 5760tcagatttga ttttattctc tacacacacc tcttcttttc ttggtatttc tggtggcagt 5820gattagttga acagcacatt taaggcacga taatttgcta cactttttct ttacaatttg 5880ttgcaatttc atctgctttc tatgtttcat tgttaattgc catccttcag ccttaaaaat 5940agaagattct cacgtgaagg tttagtaagt tgggtcccag ctctgcctgt gtggagatag 6000tcaccatgta cctctgacaa caagttttag tgtgaaagtc actaaacttt tacacactcc 6060caaacgtctt tttaaaaatt gcttgggaaa ttattaaatg aatgtgcctg atgatttgaa 6120atagacaagg ggcacgagat aaaaaagaaa aggatgagaa gatcctcagt gaatgacgtt 6180gcagggtctt catgcaattt tccacctcgc agtagttagt atttacttgc cttaaactaa 6240ctttgaagca agtaatgtca actttgagca ctttgttgag ttttgaaaaa tcttatttgt 6300tgctgcacag gttaataaat tatcaatttg taattcagca tgttggtcag agacacggtc 6360actgattcac acccagtccc tgccacagac cgtctcagac acgcacagtg ggcctgctgc 6420atgattcaca cccagtccct gccacagacc gtctcagaca cgcacagtgg gcctgctgca 6480tgattcacac ccagtccctg ccacagaccg tctcagacac gcacagtggg cctgctgcat 6540gcgtgttacc tggcttttgg ctccacgctc actcatagcc atgtccacat gggggcttgc 6600acacaggatc actcacatat gtacatgtac ccaccacaaa cgtgcaagct cctgcacaca 6660tgcatgcaca caaacgtgta cacaagtgtg agctcctaca cgcatacaca cacacacgtg 6720tacatgcacc aaagcatgtg tgacctacag acatgcagaa catgcacgtg tacacatacc 6780acagacacgc gtgtgcatgc tcctacacaa tacatatgca catatcatga acagcgtaag 6840ttcctacaca cggacgtgtg atacacacat gcatgtacag gtaagcacac atgtacaagc 6900tcctacaggc ttgctctcac acacgtgtat gcacagcaga gagacgtatg agcttctact 6960gcacacatgc acacacacac gcacacgtac attcactaca aacgtgcagc ctcctgcaca 7020cgtgcacatt catgtgtaca ccacaaatga gttcccagac gtgtaaacac acgtgcacac 7080atcgtacaca tgtgagctcc cacacgtaca cacagatgca catggacaca ccccaaacac 7140gcacaggctc ctacacacat gcacacacgt gtacaccaca aacgagctcc cagacatgta 7200aacacacgtc tcccacacgt gagctcccac acgtacacat gcacatgtac gcaccacaaa 7260cacatgcgca ggctcctgca ggcgtgaata cacacatgca

cacacatata cacacatgtg 7320ccacaaacaa gtgcacactg tcctggtgtc ctgcactgca tcctgcctcc ttgctgaggg 7380gcccctgtga gaggcctctg gatgggcatg ggaagatggg ctccctggcc cccagcccat 7440gcctccctgg gatgaagagt ccccctcctg gcagaatgtc tgggctttgc agagcaggcc 7500ccgggggtga agtcgcagct tcacttacac cagctgctct gtgagcaagg cttggtgccc 7560tggacaaggc ccttcccctt tagggaggtc cagcctcgca agctgaaacc tcccctcggc 7620tcagccctat accaggcggc cacagcagga ctggccacac ccacgccgca cctcatccgt 7680gcacgcgtcg gagcacggcc agccttccgc cacgagccag ctgggaaggg ccgcggccgc 7740ctaaagcccc agtcaaccca gcctgtgtct gagcagacag ggcgaacaag caggccacac 7800cgtctcgagg gaggaggcca gatgcggcca gcgtctccaa cagggtgacc atccgctcgg 7860cttgctgagc gtttaaacaa atgtttagac aggctgtggg gactcccctg agttgagcct 7920tggccagggg tccggtgctg tcgcgggaaa cctccagcct tgttcttcaa accactcagc 7980tcatgtgttt tgcactgact agtactgaat aatacaacca ctcttattta atgttagtat 8040tatttatttg acaactcagt gtctaacagc ttgatatgca ggtccttgca tcctacattt 8100ctttaggaag ttacccattt gtaactttaa aaacaggaaa aatatcagtt ggcaaatgca 8160atcttttttt tttttaagct aaaggtgggt gaactggaat gaaaatcttt ctgatgttgt 8220gtctataagc agccttgatg ggatatgtta gaagtgtcat gaaagtgtga ttctactttt 8280gcagaaaaat ctaaagatca atttatatag ctttattttt tactttatca aagtatacag 8340aattttaata tgcatatatt gtgtctgact taaaattata atgtctgcgt caccatttaa 8400aatgtctgtt cattatgtaa tgtaataaaa gaaggtcttc aaaaatgtat ttaacatgaa 8460tggtatccat agttgtcatc atcataaata ctggagttta tttttaaatt attaaacata 8520gtaggtgcat taacataaat cagtctccac acagtaacat ttaactgata attcattaat 8580cagctttgaa aaattaaatt gttaattaaa ccaatctaac atttcagtaa agtttatttt 8640gtatgcttct gtttttaact tttatttctg tagataaact gactggataa tattatattg 8700gacttttctc tagattatct aagcaggaga cctgaatctg cttgcaataa agaataaaag 8760tctgcttcag tttctttata aagaaactca cacaa 8795261134PRTHomo sapiens 26Met Asp Cys Ser Leu Val Arg Thr Leu Val His Arg Tyr Cys Ala Gly1 5 10 15Glu Glu Asn Trp Val Asp Ser Arg Thr Ile Tyr Val Gly His Arg Glu 20 25 30Pro Pro Pro Gly Ala Glu Ala Tyr Ile Pro Gln Arg Tyr Pro Asp Asn 35 40 45Arg Ile Val Ser Ser Lys Tyr Thr Phe Trp Asn Phe Ile Pro Lys Asn 50 55 60Leu Phe Glu Gln Phe Arg Arg Val Ala Asn Phe Tyr Phe Leu Ile Ile65 70 75 80Phe Leu Val Gln Leu Ile Ile Asp Thr Pro Thr Ser Pro Val Thr Ser 85 90 95Gly Leu Pro Leu Phe Phe Val Ile Thr Val Thr Ala Ile Lys Gln Gly 100 105 110Tyr Glu Asp Trp Leu Arg His Lys Ala Asp Asn Ala Met Asn Gln Cys 115 120 125Pro Val His Phe Ile Gln His Gly Lys Leu Val Arg Lys Gln Ser Arg 130 135 140Lys Leu Arg Val Gly Asp Ile Val Met Val Lys Glu Asp Glu Thr Phe145 150 155 160Pro Cys Asp Leu Ile Phe Leu Ser Ser Asn Arg Gly Asp Gly Thr Cys 165 170 175His Val Thr Thr Ala Ser Leu Asp Gly Glu Ser Ser His Lys Thr His 180 185 190Tyr Ala Val Gln Asp Thr Lys Gly Phe His Thr Glu Glu Asp Ile Gly 195 200 205Gly Leu His Ala Thr Ile Glu Cys Glu Gln Pro Gln Pro Asp Leu Tyr 210 215 220Lys Phe Val Gly Arg Ile Asn Val Tyr Ser Asp Leu Asn Asp Pro Val225 230 235 240Val Arg Pro Leu Gly Ser Glu Asn Leu Leu Leu Arg Gly Ala Thr Leu 245 250 255Lys Asn Thr Glu Lys Ile Phe Gly Val Ala Ile Tyr Thr Gly Met Glu 260 265 270Thr Lys Met Ala Leu Asn Tyr Gln Ser Lys Ser Gln Lys Arg Ser Ala 275 280 285Val Glu Lys Ser Met Asn Ala Phe Leu Ile Val Tyr Leu Cys Ile Leu 290 295 300Ile Ser Lys Ala Leu Ile Asn Thr Val Leu Lys Tyr Met Trp Gln Ser305 310 315 320Glu Pro Phe Arg Asp Glu Pro Trp Tyr Asn Gln Lys Thr Glu Ser Glu 325 330 335Arg Gln Arg Asn Leu Phe Leu Lys Ala Phe Thr Asp Phe Leu Ala Phe 340 345 350Met Val Leu Phe Asn Tyr Ile Ile Pro Val Ser Met Tyr Val Thr Val 355 360 365Glu Met Gln Lys Phe Leu Gly Ser Tyr Phe Ile Thr Trp Asp Glu Asp 370 375 380Met Phe Asp Glu Glu Thr Gly Glu Gly Pro Leu Val Asn Thr Ser Asp385 390 395 400Leu Asn Glu Glu Leu Gly Gln Val Glu Tyr Ile Phe Thr Asp Lys Thr 405 410 415Gly Thr Leu Thr Glu Asn Asn Met Glu Phe Lys Glu Cys Cys Ile Glu 420 425 430Gly His Val Tyr Val Pro His Val Ile Cys Asn Gly Gln Val Leu Pro 435 440 445Glu Ser Ser Gly Ile Asp Met Ile Asp Ser Ser Pro Ser Val Asn Gly 450 455 460Arg Glu Arg Glu Glu Leu Phe Phe Arg Ala Leu Cys Leu Cys His Thr465 470 475 480Val Gln Val Lys Asp Asp Asp Ser Val Asp Gly Pro Arg Lys Ser Pro 485 490 495Asp Gly Gly Lys Ser Cys Val Tyr Ile Ser Ser Ser Pro Asp Glu Val 500 505 510Ala Leu Val Glu Gly Val Gln Arg Leu Gly Phe Thr Tyr Leu Arg Leu 515 520 525Lys Asp Asn Tyr Met Glu Ile Leu Asn Arg Glu Asn His Ile Glu Arg 530 535 540Phe Glu Leu Leu Glu Ile Leu Ser Phe Asp Ser Val Arg Arg Arg Met545 550 555 560Ser Val Ile Val Lys Ser Ala Thr Gly Glu Ile Tyr Leu Phe Cys Lys 565 570 575Gly Ala Asp Ser Ser Ile Phe Pro Arg Val Ile Glu Gly Lys Val Asp 580 585 590Gln Ile Arg Ala Arg Val Glu Arg Asn Ala Val Glu Gly Leu Arg Thr 595 600 605Leu Cys Val Ala Tyr Lys Arg Leu Ile Gln Glu Glu Tyr Glu Gly Ile 610 615 620Cys Lys Leu Leu Gln Ala Ala Lys Val Ala Leu Gln Asp Arg Glu Lys625 630 635 640Lys Leu Ala Glu Ala Tyr Glu Gln Ile Glu Lys Asp Leu Thr Leu Leu 645 650 655Gly Ala Thr Ala Val Glu Asp Arg Leu Gln Glu Lys Ala Ala Asp Thr 660 665 670Ile Glu Ala Leu Gln Lys Ala Gly Ile Lys Val Trp Val Leu Thr Gly 675 680 685Asp Lys Met Glu Thr Ala Ala Ala Thr Cys Tyr Ala Cys Lys Leu Phe 690 695 700Arg Arg Asn Thr Gln Leu Leu Glu Leu Thr Thr Lys Arg Ile Glu Glu705 710 715 720Gln Ser Leu His Asp Val Leu Phe Glu Leu Ser Lys Thr Val Leu Arg 725 730 735His Ser Gly Ser Leu Thr Arg Asp Asn Leu Ser Gly Leu Ser Ala Asp 740 745 750Met Gln Asp Tyr Gly Leu Ile Ile Asp Gly Ala Ala Leu Ser Leu Ile 755 760 765Met Lys Pro Arg Glu Asp Gly Ser Ser Gly Asn Tyr Arg Glu Leu Phe 770 775 780Leu Glu Ile Cys Arg Ser Cys Ser Ala Val Leu Cys Cys Arg Met Ala785 790 795 800Pro Leu Gln Lys Ala Gln Ile Val Lys Leu Ile Lys Phe Ser Lys Glu 805 810 815His Pro Ile Thr Leu Ala Ile Gly Asp Gly Ala Asn Asp Val Ser Met 820 825 830Ile Leu Glu Ala His Val Gly Ile Gly Val Ile Gly Lys Glu Gly Arg 835 840 845Gln Ala Ala Arg Asn Ser Asp Tyr Ala Ile Pro Lys Phe Lys His Leu 850 855 860Lys Lys Met Leu Leu Val His Gly His Phe Tyr Tyr Ile Arg Ile Ser865 870 875 880Glu Leu Val Gln Tyr Phe Phe Tyr Lys Asn Val Cys Phe Ile Phe Pro 885 890 895Gln Phe Leu Tyr Gln Phe Phe Cys Gly Phe Ser Gln Gln Thr Leu Tyr 900 905 910Asp Thr Ala Tyr Leu Thr Leu Tyr Asn Ile Ser Phe Thr Ser Leu Pro 915 920 925Ile Leu Leu Tyr Ser Leu Met Glu Gln His Val Gly Ile Asp Val Leu 930 935 940Lys Arg Asp Pro Thr Leu Tyr Arg Asp Val Ala Lys Asn Ala Leu Leu945 950 955 960Arg Trp Arg Val Phe Ile Tyr Trp Thr Leu Leu Gly Leu Phe Asp Ala 965 970 975Leu Val Phe Phe Phe Gly Ala Tyr Phe Val Phe Glu Asn Thr Thr Val 980 985 990Thr Ser Asn Gly Gln Ile Phe Gly Asn Trp Thr Phe Gly Thr Leu Val 995 1000 1005Phe Thr Val Met Val Phe Thr Val Thr Leu Lys Leu Ala Leu Asp 1010 1015 1020Thr His Tyr Trp Thr Trp Ile Asn His Phe Val Ile Trp Gly Ser 1025 1030 1035Leu Leu Phe Tyr Val Val Phe Ser Leu Leu Trp Gly Gly Val Ile 1040 1045 1050Trp Pro Phe Leu Asn Tyr Gln Arg Met Tyr Tyr Val Phe Ile Gln 1055 1060 1065Met Leu Ser Ser Gly Pro Ala Trp Leu Ala Ile Val Leu Leu Val 1070 1075 1080Thr Ile Ser Leu Leu Pro Asp Val Leu Lys Lys Val Leu Cys Arg 1085 1090 1095Gln Leu Trp Pro Thr Ala Thr Glu Arg Val Gln Thr Lys Ser Gln 1100 1105 1110Cys Leu Ser Val Glu Gln Ser Thr Ile Phe Met Leu Ser Gln Thr 1115 1120 1125Ser Ser Ser Leu Ser Phe 1130274575DNAHomo sapiens 27tttccgcagt taggggctgc tatttcaacg cagggagata aaaagaaaaa aacacttgct 60cttctacccc gctaaaaaca ctcatcctag ggagcacgcc agcatttgca gcgttcgggg 120cagggccact cggcctgcgg ccgttgcact ggctggaagc tggcaggcga tcacggttga 180ttggctcggg tgcggtccaa gggcagcaac gccttcggcg ggccgcctag ggtgattggc 240tgctgcagcc caccccctag ccggtttggt gggcggcgaa gcctggattg gtggagctaa 300gagctggctc agtttcagcg ctggctcttc gtgcatggca gagatggcga ctgcgactcg 360gctgctgggg tggcgtgtgg cgagctggag gctgcggccg ccgcttgccg gcttcgtttc 420ccagcgggcc cactcgcttt tgcccgtgga cgatgcaatc aatgggctaa gcgaggagca 480gaggcaggaa ttttggaagc agctggggaa cctgggcgta ttgggcatca cagcccctgt 540tcagtatggc ggctccggcc tgggctacct ggagcatgtg ctggtgatgg aggagatatc 600ccgagcttcc ggagcagtgg ggctcagtta cggtgcccac tccaacctct gcatcaacca 660gcttgtacgc aatgggaatg aggcccagaa agagaagtat ctcccgaagc tgatcagtgg 720tgagtacatc ggagccctgg ccatgagtga gcccaatgca ggctctgatg ttgtctctat 780gaagctcaaa gcggaaaaga aaggaaatca ctacatcctg aatggcaaca agttctggat 840cactaatggc cctgatgctg acgtcctgat tgtctatgcc aagacagatc tggctgctgt 900gccagcttct cggggcatca cagccttcat tgtggagaag ggtatgcctg gctttagcac 960ctctaagaag ctggacaagc tggggatgag gggctctaac acctgtgagc taatctttga 1020agactgcaag attcctgctg ccaacatcct gggccatgag aataagggtg tctacgtgct 1080gatgagtggg ctggacctgg agcggctggt gctggccggg gggcctcttg ggctcatgca 1140agcggtcctg gaccacacca ttccctacct gcacgtgagg gaagcctttg gccagaagat 1200cggccacttc cagttgatgc aggggaagat ggctgacatg tacacccgcc tcatggcgtg 1260tcggcagtat gtctacaatg tcgccaaggc ctgcgatgag ggccattgca ctgctaagga 1320ctgtgcaggt gtgattcttt actcagctga gtgtgccaca caggtagccc tggacggcat 1380tcagtgtttt ggtggcaatg gctacatcaa tgactttccc atgggccgct ttcttcgaga 1440tgccaagctg tatgagatag gggctgggac cagcgaggtg aggcggctgg tcatcggcag 1500agccttcaat gcagactttc actagtcctg agacccttcg cccccttttc ctgcacctag 1560tggcctttct tgggaagtag agatgtggcg gctttcccac cctgcccaca gcaggccctc 1620ctgcccagct gctcttgtca gccctctggc ctctggatga ggttgagttc tccacaacag 1680ctcccaagca tcatgggcct cgcagccggg cctgtgccac ggctagtgtt gtgtgattta 1740aaatggactc agcaggaagc atattgtctg gggattgttg ggacaggttt tggtgactct 1800gtgcccttgc tctctaactt ctgagcccac ctcccagggt aggcacctgg gggcatgcag 1860gtgcccacct cccagggtag gcacctgggg gcatgcaggt acccacctct ttctcttggg 1920tgaggctctg gcaaggagat ctctctgctc aagcacagca gaatcatggc ccctctccat 1980gaattggaac ttggtacagg ttaagtatcc ctaatcctga aatctgaaac acttgtggtt 2040ccaagcattt tggataaggc aaattcaact ttcagtctct tttctggggg aaaaaaataa 2100taaacctagc ctagccaggc gtggtggctc atgcttgtaa tcccagcact tcaggaggct 2160gagatgggtg gatcacctga ggtcaggagt tcaagaccag cctggccaac atgtggaaac 2220ctcgcctcaa ctaaaaatag aaaaaaatta gttgggcatg gtggtgggca cctgtaatcc 2280cagctacttc aggaggctga ggcaggagaa ttacttgaac ccaggaggcg gacgttgcag 2340tgagccgagc ttgtgccatt gcactccagc ctgggcgaca agagcaaaac tcttcaaaaa 2400acaaaacaaa acaaaaaaac cctggccctt gtttcttcca gtttctagag gtatcagctc 2460ctagcagctt atgaacacat atgcttgctt ggccaggcaa ggtggtgtgt gcctgtaatc 2520ccagcacttt gggaggccaa ggcaggtgga tcacttgcag tcaggagttc aagaccagcc 2580tgtccaacgt ggtgaaaccc catctctact aaaaatacaa aaattagcca ggggtggtgg 2640tgcacgtctg taatcccagc tactcaggag gctgaggcag gagaatcact tgaacccggg 2700aggtggaggt tgcaatgagc caatatgaca ccgctgcagt ccagcctggg ccatagagtg 2760agactctgtc tcaaaaaagg aaagaaaaat aggctgggca cagtgactca tgcctgtaat 2820cccaacactt tgggaggccg aggcaggtgg atcacgaggt caggagttca agaccagcct 2880ggccaagatg gtaaaacctc gtctctacta aaaatacaaa aattagccag gtgtggtggc 2940aggctcctgt aatcccagct actcaggagg ctgaggcaga gaattgcttg aacccgggag 3000gcagagtttg cagtgagcca agatcacacc actgcactcc agcttggacg acagagcgag 3060actctgtctc aaaaaataat aggccaggca tggtggctca acgtctgtaa tcccagcact 3120ttgggaggcc gaggcgggca gatcacaagg tcaggagttc gagaccagcc tgacgaccaa 3180catggtgaaa cctcgtctct actaaaaata caaaaattag ccaggcctgg tggcacgcgc 3240ctgtaatccc agttacacag aagactgagg caggagaatc gcttgaacgc aggaggcaga 3300ggttgcagga gctgagatcg cgccattgca ctccagcctg ggcaacagag tgagactctg 3360tctcaaaaaa taataataaa ataaatgaac acacatgctg ctgagtccgc agggggggca 3420gagcagagga cagcgtgctt ttgtgtactg ttggaagact ggctcctcct gtacagcacc 3480tctgagccct tgtgcaccgc cctgccacgg gcaccatcca gtcctggccg tgtgaccacc 3540cacagctgac tgggcagcag gcacaggccc tacccgagca ggccggagtt ggctcgcatg 3600actccagctg aggctgcctg tgtacatttc tccagatacc ctatggctaa ttttgttata 3660actgcacagt ggctgctgcc attttgtatt aaatatattg tgaaacaaac ctatctgggg 3720agaagcaatc tacttgccgc tgcttcctgt ctggatccag cttgtgtcct tggagagtgg 3780ctggcccagg tcctattcct gtcctccagc ccgttctttc atgagggaca ggaaggtaaa 3840atcagccctt aggagagagg tctcagcctc cctttcccag atctcccagt gagttttaaa 3900ggaagcaggg agcccagagt gctaagttct tacagccaga aggaagctta tagatttctg 3960aaaaccgccc ctttgttttt aaaaagatca acacaatttg actttctcaa ggtcaaaacg 4020aactagaatc cagatctgct catggcaaaa atgggggtgt tctgagaatt ccagctttgg 4080gccgcactgt acagcagtct ggatagagtg tgatctgaga agggaatggg tctgggttgt 4140tccacccctt ccgagttcca aaaagaggga actggttttc ttggttctca gcccagcagc 4200acctatcctg gctcttggtc ctggcctgca gccaagtgct gttcctagcc tgaggcttga 4260gacaggtggg gttggctcct caccaacccc agttccgtcc catcctgagg gcaagatcct 4320gggctcatag gcagtccctt tcacttcctt gtcttgctcc ctgctatgtt ggagatgaat 4380gtgactaaaa gggccatctt gctggcttaa tgtgtggctg gagagaccag cctggagaca 4440atgtggcaaa atggggcgct tcatccagtc tgtctaagcc ctgtcgactt ggggaggtga 4500tttctttcct ggttctatat gtgaagcaaa ataaatgttt taaaattaaa agcaaaaaaa 4560acaaaatgaa ccatg 457528396PRTHomo sapiens 28Met Ala Glu Met Ala Thr Ala Thr Arg Leu Leu Gly Trp Arg Val Ala1 5 10 15Ser Trp Arg Leu Arg Pro Pro Leu Ala Gly Phe Val Ser Gln Arg Ala 20 25 30His Ser Leu Leu Pro Val Asp Asp Ala Ile Asn Gly Leu Ser Glu Glu 35 40 45Gln Arg Gln Glu Phe Trp Lys Gln Leu Gly Asn Leu Gly Val Leu Gly 50 55 60Ile Thr Ala Pro Val Gln Tyr Gly Gly Ser Gly Leu Gly Tyr Leu Glu65 70 75 80His Val Leu Val Met Glu Glu Ile Ser Arg Ala Ser Gly Ala Val Gly 85 90 95Leu Ser Tyr Gly Ala His Ser Asn Leu Cys Ile Asn Gln Leu Val Arg 100 105 110Asn Gly Asn Glu Ala Gln Lys Glu Lys Tyr Leu Pro Lys Leu Ile Ser 115 120 125Gly Glu Tyr Ile Gly Ala Leu Ala Met Ser Glu Pro Asn Ala Gly Ser 130 135 140Asp Val Val Ser Met Lys Leu Lys Ala Glu Lys Lys Gly Asn His Tyr145 150 155 160Ile Leu Asn Gly Asn Lys Phe Trp Ile Thr Asn Gly Pro Asp Ala Asp 165 170 175Val Leu Ile Val Tyr Ala Lys Thr Asp Leu Ala Ala Val Pro Ala Ser 180 185 190Arg Gly Ile Thr Ala Phe Ile Val Glu Lys Gly Met Pro Gly Phe Ser 195 200 205Thr Ser Lys Lys Leu Asp Lys Leu Gly Met Arg Gly Ser Asn Thr Cys 210 215 220Glu Leu Ile Phe Glu Asp Cys Lys Ile Pro Ala Ala Asn Ile Leu Gly225 230 235 240His Glu Asn Lys Gly Val Tyr Val Leu Met Ser Gly Leu Asp Leu Glu 245 250 255Arg Leu Val Leu Ala Gly Gly Pro Leu Gly Leu Met Gln Ala Val Leu 260 265 270Asp His Thr Ile Pro Tyr Leu His Val Arg Glu Ala Phe Gly Gln Lys 275 280 285Ile Gly His Phe Gln Leu Met Gln Gly Lys Met Ala Asp Met Tyr Thr 290 295 300Arg Leu Met Ala Cys Arg Gln Tyr Val Tyr Asn Val Ala Lys Ala Cys305 310 315

320Asp Glu Gly His Cys Thr Ala Lys Asp Cys Ala Gly Val Ile Leu Tyr 325 330 335Ser Ala Glu Cys Ala Thr Gln Val Ala Leu Asp Gly Ile Gln Cys Phe 340 345 350Gly Gly Asn Gly Tyr Ile Asn Asp Phe Pro Met Gly Arg Phe Leu Arg 355 360 365Asp Ala Lys Leu Tyr Glu Ile Gly Ala Gly Thr Ser Glu Val Arg Arg 370 375 380Leu Val Ile Gly Arg Ala Phe Asn Ala Asp Phe His385 390 395294286DNAHomo sapiens 29caacttccgg gtcaaaggtg cctgagccgg cgggtcccct gtgtccgccg cggctgtcgt 60cccccgctcc cgccacttcc ggggtcgcag tcccgggcat ggagccgcga ccgtgaggcg 120ccgctggacc cgggacgacc tgcccagtcc ggccgccgcc ccacgtcccg gtctgtgtcc 180cacgcctgca gctggaatgg aggctctctg gaccctttag aaggcacccc tgccctcctg 240aggtcagctg agcggttaat gcggaaggtt aagaaactgc gcctggacaa ggagaacacc 300ggaagttgga gaagcttctc gctgaattcc gagggggctg agaggatggc caccaccggg 360accccaacgg ccgaccgagg cgacgcagcc gccacagatg acccggccgc ccgcttccag 420gtgcagaagc actcgtggga cgggctccgg agcatcatcc acggcagccg caagtactcg 480ggcctcattg tcaacaaggc gccccacgac ttccagtttg tgcagaagac ggatgagtct 540gggccccact cccaccgcct ctactacctg ggaatgccat atggcagccg agagaactcc 600ctcctctact ctgagattcc caagaaggtc cggaaagagg ctctgctgct cctgtcctgg 660aagcagatgc tggatcattt ccaggccacg ccccaccatg gggtctactc tcgggaggag 720gagctgctga gggagcggaa acgcctgggg gtcttcggca tcacctccta cgacttccac 780agcgagagtg gcctcttcct cttccaggcc agcaacagcc tcttccactg ccgcgacggc 840ggcaagaacg gcttcatggt gtcccctatg aaaccgctgg aaatcaagac ccagtgctca 900gggccccgga tggaccccaa aatctgccct gccgaccctg ccttcttctc cttcatcaat 960aacagcgacc tgtgggtggc caacatcgag acaggcgagg agcggcggct gaccttctgc 1020caccaaggtt tatccaatgt cctggatgac cccaagtctg cgggtgtggc caccttcgtc 1080atacaggaag agttcgaccg cttcactggg tactggtggt gccccacagc ctcctgggaa 1140ggttcagagg gcctcaagac gctgcgaatc ctgtatgagg aagtcgatga gtccgaggtg 1200gaggtcattc acgtcccctc tcctgcgcta gaagaaagga agacggactc gtatcggtac 1260cccaggacag gcagcaagaa tcccaagatt gccttgaaac tggctgagtt ccagactgac 1320agccagggca agatcgtctc gacccaggag aaggagctgg tgcagccctt cagctcgctg 1380ttcccgaagg tggagtacat cgccagggcc gggtggaccc gggatggcaa atacgcctgg 1440gccatgttcc tggaccggcc ccagcagtgg ctccagctcg tcctcctccc cccggccctg 1500ttcatcccga gcacagagaa tgaggagcag cggctagcct ctgccagagc tgtccccagg 1560aatgtccagc cgtatgtggt gtacgaggag gtcaccaacg tctggatcaa tgttcatgac 1620atcttctatc ccttccccca atcagaggga gaggacgagc tctgctttct ccgcgccaat 1680gaatgcaaga ccggcttctg ccatttgtac aaagtcaccg ccgttttaaa atcccagggc 1740tacgattgga gtgagccctt cagccccggg gaagatgaat ttaagtgccc cattaaggaa 1800gagattgctc tgaccagcgg tgaatgggag gttttggcga ggcacggctc caagatctgg 1860gtcaatgagg agaccaagct ggtgtacttc cagggcacca aggacacgcc gctggagcac 1920cacctctacg tggtcagcta tgaggcggcc ggcgagatcg tacgcctcac cacgcccggc 1980ttctcccata gctgctccat gagccagaac ttcgacatgt tcgtcagcca ctacagcagc 2040gtgagcacgc cgccctgcgt gcacgtctac aagctgagcg gccccgacga cgaccccctg 2100cacaagcagc cccgcttctg ggctagcatg atggaggcag ccagctgccc cccggattat 2160gttcctccag agatcttcca tttccacacg cgctcggatg tgcggctcta cggcatgatc 2220tacaagcccc acgccttgca gccagggaag aagcacccca ccgtcctctt tgtatatgga 2280ggcccccagg tgcagctggt gaataactcc ttcaaaggca tcaagtactt gcggctcaac 2340acactggcct ccctgggcta cgccgtggtt gtgattgacg gcaggggctc ctgtcagcga 2400gggcttcggt tcgaaggggc cctgaaaaac caaatgggcc aggtggagat cgaggaccag 2460gtggagggcc tgcagttcgt ggccgagaag tatggcttca tcgacctgag ccgagttgcc 2520atccatggct ggtcctacgg gggcttcctc tcgctcatgg ggctaatcca caagccccag 2580gtgttcaagg tggccatcgc gggtgccccg gtcaccgtct ggatggccta cgacacaggg 2640tacactgagc gctacatgga cgtccctgag aacaaccagc acggctatga ggcgggttcc 2700gtggccctgc acgtggagaa gctgcccaat gagcccaacc gcttgcttat cctccacggc 2760ttcctggacg aaaacgtgca ctttttccac acaaacttcc tcgtctccca actgatccga 2820gcagggaaac cttaccagct ccagatctac cccaacgaga gacacagtat tcgctgcccc 2880gagtcgggcg agcactatga agtcacgttg ctgcactttc tacaggaata cctctgagcc 2940tgcccaccgg gagccgccac atcacagcac aagtggctgc agcctccgcg gggaaccagg 3000cgggagggac tgagtggccc gcgggcccca gtgaggcact ttgtcccgcc cagcgctggc 3060cagccccgag gagccgctgc cttcaccgcc ccgacgcctt ttatcctttt ttaaacgctc 3120ttgggtttta tgtccgctgc ttcttggttg ccgagacaga gagatggtgg tctcgggcca 3180gcccctcctc tccccgcctt ctgggaggag gaggtcacac gctgatgggc actggagagg 3240ccagaagaga ctcagaggag cgggctgcct tccgcctggg gctccctgtg acctctcagt 3300cccctggccc ggccagccac cgtccccagc acccaagcat gcaattgcct gtcccccccg 3360gccagcctcc ccaacttgat gtttgtgttt tgtttggggg gatatttttc ataattattt 3420aaaagacagg ccgggcgcgg tggctcacgt ctgtaatccc agcactttgg gaggctgagg 3480cgggcggatc acctgaggtt gggagttcaa gaccagcctg gccaacatgg ggaaaccccg 3540tctctactaa aaatacaaaa aattagccgg gtgtggtggc gcgtgcctat aatcccagct 3600actcgggagg ctgaggcagg agaatcgctt gaacccggga ggtggaggtt gcggtgagcc 3660aagatcgcac cattgcactc cagcctgggc aacaagagcg aaactctgtc tcaaaataaa 3720taaaaaataa aagacagaaa gcaaggggtg cctaaatcta gacttggggt ccacaccggg 3780cagcggggtt gcaacccagc acctggtagg ctccatttct tcccaagccc gagcagaggg 3840tcatgcgggc cccacaggag aagcggccag ggcccgcggg gggcaccacc tgtggacagc 3900cctcctgtcc ccaagctttc aggcaggcac tgaaacgcac cgaacttcca cgctctgctg 3960gtcagtggcg gctgtcccct ccccagccca gccgcccagc cacatgtgtc tgcctgaccc 4020gtacacacca ggggttccgg ggttgggagc tgaaccatcc ccacctcagg gttatatttc 4080cctctcccct tccctccccg ccaagagctc tgccaggggc gggcaaaaaa aaaagtaaaa 4140agaaaagaaa aaaaaaaaaa agaaacaaac cacctctaca tattatggaa agaaaatatt 4200tttgtcgatt cttattcttt tataattatg cgtggaagaa gtagacacat taaacgattc 4260cagttggaaa aaaaaaaaaa aaaaaa 428630892PRTHomo sapiens 30Met Arg Lys Val Lys Lys Leu Arg Leu Asp Lys Glu Asn Thr Gly Ser1 5 10 15Trp Arg Ser Phe Ser Leu Asn Ser Glu Gly Ala Glu Arg Met Ala Thr 20 25 30Thr Gly Thr Pro Thr Ala Asp Arg Gly Asp Ala Ala Ala Thr Asp Asp 35 40 45Pro Ala Ala Arg Phe Gln Val Gln Lys His Ser Trp Asp Gly Leu Arg 50 55 60Ser Ile Ile His Gly Ser Arg Lys Tyr Ser Gly Leu Ile Val Asn Lys65 70 75 80Ala Pro His Asp Phe Gln Phe Val Gln Lys Thr Asp Glu Ser Gly Pro 85 90 95His Ser His Arg Leu Tyr Tyr Leu Gly Met Pro Tyr Gly Ser Arg Glu 100 105 110Asn Ser Leu Leu Tyr Ser Glu Ile Pro Lys Lys Val Arg Lys Glu Ala 115 120 125Leu Leu Leu Leu Ser Trp Lys Gln Met Leu Asp His Phe Gln Ala Thr 130 135 140Pro His His Gly Val Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg145 150 155 160Lys Arg Leu Gly Val Phe Gly Ile Thr Ser Tyr Asp Phe His Ser Glu 165 170 175Ser Gly Leu Phe Leu Phe Gln Ala Ser Asn Ser Leu Phe His Cys Arg 180 185 190Asp Gly Gly Lys Asn Gly Phe Met Val Ser Pro Met Lys Pro Leu Glu 195 200 205Ile Lys Thr Gln Cys Ser Gly Pro Arg Met Asp Pro Lys Ile Cys Pro 210 215 220Ala Asp Pro Ala Phe Phe Ser Phe Ile Asn Asn Ser Asp Leu Trp Val225 230 235 240Ala Asn Ile Glu Thr Gly Glu Glu Arg Arg Leu Thr Phe Cys His Gln 245 250 255Gly Leu Ser Asn Val Leu Asp Asp Pro Lys Ser Ala Gly Val Ala Thr 260 265 270Phe Val Ile Gln Glu Glu Phe Asp Arg Phe Thr Gly Tyr Trp Trp Cys 275 280 285Pro Thr Ala Ser Trp Glu Gly Ser Glu Gly Leu Lys Thr Leu Arg Ile 290 295 300Leu Tyr Glu Glu Val Asp Glu Ser Glu Val Glu Val Ile His Val Pro305 310 315 320Ser Pro Ala Leu Glu Glu Arg Lys Thr Asp Ser Tyr Arg Tyr Pro Arg 325 330 335Thr Gly Ser Lys Asn Pro Lys Ile Ala Leu Lys Leu Ala Glu Phe Gln 340 345 350Thr Asp Ser Gln Gly Lys Ile Val Ser Thr Gln Glu Lys Glu Leu Val 355 360 365Gln Pro Phe Ser Ser Leu Phe Pro Lys Val Glu Tyr Ile Ala Arg Ala 370 375 380Gly Trp Thr Arg Asp Gly Lys Tyr Ala Trp Ala Met Phe Leu Asp Arg385 390 395 400Pro Gln Gln Trp Leu Gln Leu Val Leu Leu Pro Pro Ala Leu Phe Ile 405 410 415Pro Ser Thr Glu Asn Glu Glu Gln Arg Leu Ala Ser Ala Arg Ala Val 420 425 430Pro Arg Asn Val Gln Pro Tyr Val Val Tyr Glu Glu Val Thr Asn Val 435 440 445Trp Ile Asn Val His Asp Ile Phe Tyr Pro Phe Pro Gln Ser Glu Gly 450 455 460Glu Asp Glu Leu Cys Phe Leu Arg Ala Asn Glu Cys Lys Thr Gly Phe465 470 475 480Cys His Leu Tyr Lys Val Thr Ala Val Leu Lys Ser Gln Gly Tyr Asp 485 490 495Trp Ser Glu Pro Phe Ser Pro Gly Glu Asp Glu Phe Lys Cys Pro Ile 500 505 510Lys Glu Glu Ile Ala Leu Thr Ser Gly Glu Trp Glu Val Leu Ala Arg 515 520 525His Gly Ser Lys Ile Trp Val Asn Glu Glu Thr Lys Leu Val Tyr Phe 530 535 540Gln Gly Thr Lys Asp Thr Pro Leu Glu His His Leu Tyr Val Val Ser545 550 555 560Tyr Glu Ala Ala Gly Glu Ile Val Arg Leu Thr Thr Pro Gly Phe Ser 565 570 575His Ser Cys Ser Met Ser Gln Asn Phe Asp Met Phe Val Ser His Tyr 580 585 590Ser Ser Val Ser Thr Pro Pro Cys Val His Val Tyr Lys Leu Ser Gly 595 600 605Pro Asp Asp Asp Pro Leu His Lys Gln Pro Arg Phe Trp Ala Ser Met 610 615 620Met Glu Ala Ala Ser Cys Pro Pro Asp Tyr Val Pro Pro Glu Ile Phe625 630 635 640His Phe His Thr Arg Ser Asp Val Arg Leu Tyr Gly Met Ile Tyr Lys 645 650 655Pro His Ala Leu Gln Pro Gly Lys Lys His Pro Thr Val Leu Phe Val 660 665 670Tyr Gly Gly Pro Gln Val Gln Leu Val Asn Asn Ser Phe Lys Gly Ile 675 680 685Lys Tyr Leu Arg Leu Asn Thr Leu Ala Ser Leu Gly Tyr Ala Val Val 690 695 700Val Ile Asp Gly Arg Gly Ser Cys Gln Arg Gly Leu Arg Phe Glu Gly705 710 715 720Ala Leu Lys Asn Gln Met Gly Gln Val Glu Ile Glu Asp Gln Val Glu 725 730 735Gly Leu Gln Phe Val Ala Glu Lys Tyr Gly Phe Ile Asp Leu Ser Arg 740 745 750Val Ala Ile His Gly Trp Ser Tyr Gly Gly Phe Leu Ser Leu Met Gly 755 760 765Leu Ile His Lys Pro Gln Val Phe Lys Val Ala Ile Ala Gly Ala Pro 770 775 780Val Thr Val Trp Met Ala Tyr Asp Thr Gly Tyr Thr Glu Arg Tyr Met785 790 795 800Asp Val Pro Glu Asn Asn Gln His Gly Tyr Glu Ala Gly Ser Val Ala 805 810 815Leu His Val Glu Lys Leu Pro Asn Glu Pro Asn Arg Leu Leu Ile Leu 820 825 830His Gly Phe Leu Asp Glu Asn Val His Phe Phe His Thr Asn Phe Leu 835 840 845Val Ser Gln Leu Ile Arg Ala Gly Lys Pro Tyr Gln Leu Gln Ile Tyr 850 855 860Pro Asn Glu Arg His Ser Ile Arg Cys Pro Glu Ser Gly Glu His Tyr865 870 875 880Glu Val Thr Leu Leu His Phe Leu Gln Glu Tyr Leu 885 890312113DNAHomo sapiens 31actcaccctc cggcttcctg tcggggcttt ctcagcccca ccccacgttt ggacatttgg 60agcatttcct tccctgacag ccggacctgg gactgggctg gggccctggc ggatggagac 120atgctgcccc tgctgctgct gcccctgctg tggggggggt ccctgcagga gaagccagtg 180tacgagctgc aagtgcagaa gtcggtgacg gtgcaggagg gcctgtgcgt ccttgtgccc 240tgctccttct cttacccctg gagatcctgg tattcctctc ccccactcta cgtctactgg 300ttccgggacg gggagatccc atactacgct gaggttgtgg ccacaaacaa cccagacaga 360agagtgaagc cagagaccca gggccgattc cgcctccttg gggatgtcca gaagaagaac 420tgctccctga gcatcggaga tgccagaatg gaggacacgg gaagctattt cttccgcgtg 480gagagaggaa gggatgtaaa atatagctac caacagaata agctgaactt ggaggtgaca 540gccctgatag agaaacccga catccacttt ctggagcctc tggagtccgg ccgccccaca 600aggctgagct gcagccttcc aggatcctgt gaagcgggac cacctctcac attctcctgg 660acggggaatg ccctcagccc cctggacccc gagaccaccc gctcctcgga gctcaccctc 720acccccaggc ccgaggacca tggcaccaac ctcacctgtc aggtgaaacg ccaaggagct 780caggtgacca cggagagaac tgtccagctc aatgtctcct atgctccaca gaacctcgcc 840atcagcatct tcttcagaaa tggcacaggc acagccctgc ggatcctgag caatggcatg 900tcggtgccca tccaggaggg ccagtccctg ttcctcgcct gcacagttga cagcaacccc 960cctgcctcac tgagctggtt ccgggaggga aaagccctca atccttccca gacctcaatg 1020tctgggaccc tggagctgcc taacatagga gctagagagg gaggggaatt cacctgccgg 1080gttcagcatc cgctgggctc ccagcacctg tccttcatcc tttctgtgca gagaagctcc 1140tcttcctgca tatgtgtaac tgagaaacag cagggctcct ggcccctcgt cctcaccctg 1200atcagggggg ctctcatggg ggctggcttc ctcctcacct atggcctcac ctggatctac 1260tataccaggt gtggaggccc ccagcagagc agggctgaga ggcctggctg agcccctccc 1320gctcaagaca gaactgaggt gtggacactt agccctgtgg gacacatgca ggacatcact 1380gtcagcttct ttctggaagc tcacatccca ctgactaccc ctcttttcct tcctgcccca 1440taccccttct acttattccc ctctgcttgt gagtcttgcc ccaccacacc tgcatcccca 1500tctgcacccc atcccctctc cacctgccct tctcttccct ctccatccac catctccagc 1560cctgtgaagg gaatgtactt tcggtcttat acccccatta cccattaccc aaaagttacc 1620tttttttttt tttttttttt ttgagacaga gtctcactct gttgcacagg ctggagttca 1680gtggcacaat ctccgttcac tgcaacctcc acctctgggg ttcaagcaat tctcctgcct 1740cagcctccct agtagctggg attacaggtg cctgccacca catccagtta attttttttt 1800tttgtatgtt agtagagatg gggttttacc atgttggcca ggtctcgaac tcctgacctc 1860aagcaatcca ctgcattggc ctcccaaagt gctggcatta caggtatgag ccaccgtgcc 1920tggctgccaa aagttacctt cttaacactt gaatttctgg tctcctcagc ttccctatcc 1980atataggcac agagaggcag catttgtttt ccagttaaaa ctctacctca ttgtgattat 2040tatccaatac aattgttaca aaataagtaa aacttttatg aaacaataca acataactga 2100ttttactctt taa 211332396PRTHomo sapiens 32Met Leu Pro Leu Leu Leu Leu Pro Leu Leu Trp Gly Gly Ser Leu Gln1 5 10 15Glu Lys Pro Val Tyr Glu Leu Gln Val Gln Lys Ser Val Thr Val Gln 20 25 30Glu Gly Leu Cys Val Leu Val Pro Cys Ser Phe Ser Tyr Pro Trp Arg 35 40 45Ser Trp Tyr Ser Ser Pro Pro Leu Tyr Val Tyr Trp Phe Arg Asp Gly 50 55 60Glu Ile Pro Tyr Tyr Ala Glu Val Val Ala Thr Asn Asn Pro Asp Arg65 70 75 80Arg Val Lys Pro Glu Thr Gln Gly Arg Phe Arg Leu Leu Gly Asp Val 85 90 95Gln Lys Lys Asn Cys Ser Leu Ser Ile Gly Asp Ala Arg Met Glu Asp 100 105 110Thr Gly Ser Tyr Phe Phe Arg Val Glu Arg Gly Arg Asp Val Lys Tyr 115 120 125Ser Tyr Gln Gln Asn Lys Leu Asn Leu Glu Val Thr Ala Leu Ile Glu 130 135 140Lys Pro Asp Ile His Phe Leu Glu Pro Leu Glu Ser Gly Arg Pro Thr145 150 155 160Arg Leu Ser Cys Ser Leu Pro Gly Ser Cys Glu Ala Gly Pro Pro Leu 165 170 175Thr Phe Ser Trp Thr Gly Asn Ala Leu Ser Pro Leu Asp Pro Glu Thr 180 185 190Thr Arg Ser Ser Glu Leu Thr Leu Thr Pro Arg Pro Glu Asp His Gly 195 200 205Thr Asn Leu Thr Cys Gln Val Lys Arg Gln Gly Ala Gln Val Thr Thr 210 215 220Glu Arg Thr Val Gln Leu Asn Val Ser Tyr Ala Pro Gln Asn Leu Ala225 230 235 240Ile Ser Ile Phe Phe Arg Asn Gly Thr Gly Thr Ala Leu Arg Ile Leu 245 250 255Ser Asn Gly Met Ser Val Pro Ile Gln Glu Gly Gln Ser Leu Phe Leu 260 265 270Ala Cys Thr Val Asp Ser Asn Pro Pro Ala Ser Leu Ser Trp Phe Arg 275 280 285Glu Gly Lys Ala Leu Asn Pro Ser Gln Thr Ser Met Ser Gly Thr Leu 290 295 300Glu Leu Pro Asn Ile Gly Ala Arg Glu Gly Gly Glu Phe Thr Cys Arg305 310 315 320Val Gln His Pro Leu Gly Ser Gln His Leu Ser Phe Ile Leu Ser Val 325 330 335Gln Arg Ser Ser Ser Ser Cys Ile Cys Val Thr Glu Lys Gln Gln Gly 340 345 350Ser Trp Pro Leu Val Leu Thr Leu Ile Arg Gly Ala Leu Met Gly Ala 355 360 365Gly Phe Leu Leu Thr Tyr Gly Leu Thr Trp Ile Tyr Tyr Thr Arg Cys 370 375 380Gly Gly Pro Gln Gln Ser Arg Ala Glu Arg Pro Gly385 390 395334045DNAHomo sapiens 33cgcccacgcc cggcgccccg accgcggagg actccccgag ccccgcccgc catggcccgg 60atcccgacgg ccgccctggg ttgcatcagc ctcctctgcc tgcagctccc tggctcgctg 120tcccgcagcc tgggcgggga cccgcgaccc gtcaaaccca gggagccccc agcccggagc 180ccttccagca

gcctgcagcc caggcacccc gcaccccgac ctgtggtctg gaagcttcac 240cgggccctcc aggcacagag gggtgccggc ctggcccctg ttatgggtca gcctctccgg 300gatggtggcc gccaacactc gggcccccga agacactcgg gcccccgcag gacccaagcc 360cagctcctgc gagtgggctg tgtgctgggc acctgccagg tgcagaatct cagccaccgc 420ctgtggcaac tcatgggacc ggccggccgg caggactcag ctcctgtgga ccccagcagc 480ccccacagct atggctgagg tggggccggg ccacacccct gcccatccca gccagggtgc 540tgtgcccccg tccagagctg cagctgagcc ccatctgaag cccagtccct cggagctgca 600gacagcaggt cctgcagcaa caatacctgc acggctttgc acacgtaaac ctaggctggt 660ctacacgcag tgctggtacg tcaaggagcc taaacaccct gaaattgtga ccccctgggg 720gacagctgcc agacacagct ggcggcagca ccagatgcta agcgcttcag agaggaggtg 780tctgcccaga gatgtggagc agaagctggg ccctgaacac acggggccat gtctggacga 840gcaggggaga gaggctgaac tggccagaag tggcccctcc gctgctggtc cagtcagact 900gaagcccggc cttgtgcctg ggctgttcct gctctcatgc acaaccagcc cttccacgtg 960cctgcctgtg ggacaggagg gggagcgtgg gatgctgtag cccccggggt tgggcaaggg 1020aaggatggtg gccctccaga ggtcatgaag ggacctctgt ggctccagct gccaaccctg 1080gagcccagac cgaggtggcc atggagactc cacctggatc ccctgtagga ggccagggag 1140gggaactcag cagttcagga gccaccccaa accattctgg gacagggaca cccctttcta 1200ccccagggca gggcagggct gggtggggca agatccccca gcccgactag acccacctca 1260cctgaagggg gtgagaccct tgttggcagc cagacaaggg tggggctcca caggcagcac 1320aggcgcccca ccaccaccca gtttggggac ccagtgggac caggtgcggg ggcagagggt 1380gacttaccaa gagccaggga gggcagccca ggcccaagtg acagcaagaa caagaaccac 1440tgccggcgtg cacagacttg gtgtgtgtcc ttccctgggg ggacggggga ctcacatgtg 1500cctgccactg gagcctctca accgtccagc agaacacggg gttcagaaag ggctccttct 1560gctatttagc gaacactgag catttaattt acaaatgttt gctagggtca ccctctcggc 1620catcccacga gggtcgccat gatcacccca actctagagg ccgcagcaga gctcaggaca 1680ttcccccaca gagcttgccc ctcagttcct acctccaagg gggagggtcc tggaagcgcc 1740cacccaggcg ccgcccctgt gcttgctccc cgagctcagg gattgccgag tccacgtaac 1800tgacctgtac tccacgaggc cctgtgggaa cggtccaggc tggtcctgcc ctgtggaggc 1860ctccgtgcac tgagagatgt actaggattg cagcaaaggt ggtcagggtg atgggccgca 1920cagcgaggca gtcaaggcca gctccctggg agaagcactg ggtcaggtga ggtctgagga 1980cagcaggcct tccctagggg aaggagctgg gagtgccaag gccccaggtg cacaggaggc 2040gtggctgctg agaggctgca gggtggaggg gcctcggcct cagagtcatg tgccctgtga 2100ccactgaagg gtgtcagcag agcacacggc atgaggacag agggaggggc acggggagtg 2160aaggaggggg ccctggggca aggctcgggg gtcaggagct cagcgtccgc tactcagccc 2220agccaaaacc ctcccagacg tctcctctcc tgcctgggca aagtccagct tggcaccccg 2280tctggggcct gcctgtggtc agggccaagt gttccctcct ccaggaaagc ctttaccctc 2340ctcatgccct gtagtcagga ggccgcctgc tgtaaccctc cgtgtcgcct cgggtgcgaa 2400atcagaccca cctgacacca tcacgcggag gcccagcagc acctgcaccc acttccagct 2460gctctggcca aaatctccgc tcggccaggc cccgtggctc acacctgtaa tcctagcaca 2520ttgggaggcc aaggcaggca catcacctga gttcaggagt tcaagaccag cctggccaac 2580atggtgaaat cccgtctcta ctaaaaacag aaaattatcc gggcgtggtg gcacatgact 2640gtaatcccag ctactcagga ggctgaggca ggaggatcac ttgaacctgg gaggcggagg 2700ttgcagtgag ctgagattgc gccattgcac tccagcctgg gcaacaagag caaaattctg 2760cctcaaaaaa aaaaatagta ataatacaaa aattagctgg gcgtggtggc acatgccagt 2820aattccatct actcgggagg ctgaggcagg agaatcgtct aagcccggga ggtggaggtt 2880gcagtgagcc cagatggcgc tgctgcactc aagcttggat gacagagcaa gactccgttt 2940caaaaaaaaa aaacctcctc tcttccttca caccttcctc tgaatcccac ccggtcccac 3000ctcctgaacc tatccagaca ccttctcctg acccaggcac cacctgcttt cggggcgatg 3060gccgtagcct cctcccaggc acctgtctgc atccctctgg ccagtgcatg ctgagcacgt 3120gacctacccg tgttgggaca cgtgaggata cagccttgac ccccaggggc tgacattcta 3180gggggagata gaaggagaca aacgtagaag gtagaataag tgggtggtgg agtggcaggg 3240agtgctgagt gccacaggaa gtcagacaag gaaggagagt gtggggcagg tgccgtttaa 3300atggggggcg ctggggtctc ctcacagttg cttctcagct cagctgtgcc aggatcttgt 3360tgagtcaggt cagctgccca cagccctctt gcctgacccc tgaagcccag aactctgatc 3420ttcacagccc taggtatggc cccagcaccc cactgccctc tctcctgccc cagccgactg 3480ctgttcccag acttccctgg ccacgctcca agacgccagc tctgccgcgg gcactttgtt 3540ctcacggtgt cctccatgcc tgcagggccc atgcatggga agttgcgttg gcggcctggg 3600tgttggcggt tccgtgcctg ctccaactct ccgtgaggcc cctctcccag agcctgacac 3660actctgtggc cgaactctag gcaggtgccc ctgagtcctt tcctcgacga ggcctgaccc 3720catccccatc ctcgctgggc ccgccgaccc cggtgttagc aagaatcctc taaatcagtt 3780tatggagaat tacccaccct cgatatctga tcccattcct catctcccac ccttgatctc 3840atcaccctgc cggcctcctg caagatcctc attgagccac tccagtgaga atccccctac 3900cctcgaaggc cgccctaaca acttcccatc cgctgacccc tccaacgcca tcaatctcca 3960gctgtggttg ttgaactcgg aggtgagctc ctctcaccac tctcttgaat aaagcttttc 4020tcaccatttt aaaaaaaaaa aaaaa 404534148PRTHomo sapiens 34Met Ala Arg Ile Pro Thr Ala Ala Leu Gly Cys Ile Ser Leu Leu Cys1 5 10 15Leu Gln Leu Pro Gly Ser Leu Ser Arg Ser Leu Gly Gly Asp Pro Arg 20 25 30Pro Val Lys Pro Arg Glu Pro Pro Ala Arg Ser Pro Ser Ser Ser Leu 35 40 45Gln Pro Arg His Pro Ala Pro Arg Pro Val Val Trp Lys Leu His Arg 50 55 60Ala Leu Gln Ala Gln Arg Gly Ala Gly Leu Ala Pro Val Met Gly Gln65 70 75 80Pro Leu Arg Asp Gly Gly Arg Gln His Ser Gly Pro Arg Arg His Ser 85 90 95Gly Pro Arg Arg Thr Gln Ala Gln Leu Leu Arg Val Gly Cys Val Leu 100 105 110Gly Thr Cys Gln Val Gln Asn Leu Ser His Arg Leu Trp Gln Leu Met 115 120 125Gly Pro Ala Gly Arg Gln Asp Ser Ala Pro Val Asp Pro Ser Ser Pro 130 135 140His Ser Tyr Gly145353406DNAHomo sapiens 35aggcgggcgg agcgaggggt gggagggcgc gcgcgaacgg gcgggcgagc aagcgagcgg 60cgtctccacc agcatctgcc gcggccgcct ttgcccgaag cccggggacg aaccgacgga 120ccgaccgcct ggcgcacgga cgcgggcgct cgctttgtgt tcggggctag cgtcggcgag 180gcttgagctt gcagcgcgcg gcttccctgc tttctcgcgg ccaccccggc tccggcggcc 240tcggcgcgcg aggggctgga ggtgcgggag ccgctctccg ccggtcggtc cccgcgcggc 300tgagcccagg ccgccagcgc cgcggccccg tgcggtgtcc ctgagctcct gctccccgcc 360gggctgctcc gagcaacggt gcttcggagc tccaaactcg ggctgccggg gcaagtgtct 420tcatgaaccc agaggatgtc cgggaagcac tacaagggtc ctgaagtcag ttgttgcatc 480aaatacttca tatttggctt caatgtcata ttttggtttt tgggaataac atttcttgga 540attggactgt gggcatggaa tgaaaaagga gttctgtcca acatctcttc catcaccgat 600ctcggcggct ttgacccagt ttggctcttc cttgtggtgg gaggagtgat gttcattttg 660ggatttgcag ggtgcattgg agcgctacgg gaaaacactt tccttctcaa gtttttttct 720gtgttcctgg gaattatttt cttcctggag ctcactgccg gagttctagc atttgttttc 780aaagactgga tcaaagacca gctgtatttc tttataaaca acaacatcag agcatatcgg 840gatgacattg atttgcaaaa cctcatagac ttcacccagg aatattggca gtgctgtggg 900gcttttggag ctgatgattg gaacctaaat atttacttca attgcacaga ttccaatgca 960agtcgagagc gatgtggcgt tccattctcc tgctgcacta aagatcccgc agaagatgtc 1020atcaacactc agtgtggcta tgatgccagg caaaaaccag aagttgacca gcagattgta 1080atctacacga aaggctgtgt gccccagttt gagaagtggt tgcaggacaa tttaaccatc 1140gttgctggta ttttcatagg cattgcattg ctgcagatat ttgggatatg cctggcccag 1200aatttggtta gcgatatcga agctgtcagg gcgagctggt agaccccctg caaccgctgc 1260tgcaagacac tggacagacc cagctttcgg gaccctcccg cgtgccgaac tgatcttcga 1320gctgcatgga cctaatcaca gatgcagcct gcagtctcgc ctaatggagc tgccattagg 1380ggagtgtaaa actgggaaat gctgctcact gacagaatta aaaaaaaaaa taaccagtat 1440gaaagtcgtt gcgccgtgaa tctctactgt agccatgaat ttatggacag ttagatgctt 1500accaaaaaag aaaaaaaggg agggtagggg acccagatgt acttgaatgt gcagaaaata 1560cattcttgtc ctcatcttcc gtaattggag ggctgggaga ggcagctttg ctcttcacca 1620caccttggac ggaccacctt ctttctgttc catggcctga aggagtgcat ctcctcaaag 1680actcagcccc tcacctggga gggcagtggt ttgtgggcat ccctccatgt acattttagg 1740aaacacttgc aactctcatc tgaagaagaa aacaactcat ctttgggttc agattttgtg 1800atggtattca gcaagtcact tgggcgagca cacttggtct atcctggaaa gtctccttat 1860aagagaagtt gtgtatttca tgtgcaccga gcaagggcat tggaagacgt catgaggctg 1920tattttagca ggactgatcg tttttctaag tagacctgag ctttgtttat cagtgaaatt 1980caaggagaaa atgaggttaa tgaagaggta tcagttaaat atccccttct tctcaccctg 2040ccaaaattag cagttggatt tttggaaact ctggaatatt ctgggtcatt ttgttttgta 2100tgtttgttgt ttttcgtctt ccaaaggtga aagctatgat acagttccac ttaaatttta 2160gtgttttctt actcagctca agcattaatt tttgattaag tcttaatctg catgacctgt 2220gaatctgaat ccatcatctc cctttcctgc cagcttttct acaaacattg aaatatgtta 2280tttggtcagc acttatttcc taggttcaca gccttgggag gttgtggcat gtcctcccag 2340tctggctggg aagagaccag ctgtaccatc caaatgcttc cctggtcttg atgatctctt 2400ccagagtcga tctgagtggc cttttctgca ccctcccctt ctttctcttt gaatggaatt 2460aaacccaatt tggaaacaac attgacccag tcaaaagctt ctaatggttt ctttttcttc 2520ctccagtttt agtttgcttt tattaaaaaa agaaaatagt gcatggccat agctccttca 2580gttctcttat tgcagactaa ccatcaggat ggtatcaaag cacaaatact ttggagggga 2640atgcgttgaa ctggggcaag tactctgtaa cacaaagtgg gaaaccactt cctggtgctg 2700ccgctcctgc ccccacttta ggtgggaggg acgagttttg ccctctagat tttaatccag 2760ctggtgtcca ccggatgttg ccctcctggg gagcagatat cagtctgtgg aactctggga 2820aaaccacagg cacatttttc ggtgcggaca gatttgccag cacataactg ggcagccagc 2880tagaatactt tgtggaaatt aagcgaggtt ttccatttca gccccatggt gcatggtggt 2940ggccgatgaa tgtgtcagtc tgctcagaga aaggacaaaa aggaaattat tttcaaaact 3000gtgttcactg tttgggtgtg tgtatggctc tgcatgtgtg tgtttttgtc tctgtatagg 3060tagaggtatt cacatcttac tccgactgta aggttgtctt acttcatctc tgcccccacc 3120acagttgcca ttttgtaatg tccttccaac atggagaaga cacgagctct ctccagttgg 3180catcatttgt cttttttgtt gattgcctca ttctccagtg aactccatct ggccaattga 3240ttcagaatca ggcaagatcc ctgccctttg gcacatccac tgaaaggcca aacagcaagt 3300ccgagtgagt tttaaatatt aattaatcac cctttatttt ttacacttga gagtgattgt 3360aataaaggct gtcattaata aacttggttc taccttaaaa aaaaaa 3406365882DNAHomo sapiens 36atcaaatttc aactccaggc agtccttcca gccatgtggg ttcagcggaa agagaagcaa 60aaccactctt cctaaaatgt tagaagctgc tcttcgctta ccttggggcc tttgcattgg 120gagctgtttt tcacatcaaa gaatatgtgc tgaatggaat tttagtattt tgctgtcgtt 180ttaatatttt cgtctggtct tcctcagttc ttccagacgc tttctgagag aatgggggca 240ggagctctag ccatctgtca aagtaaagca gcggttcggc tgaaagaaga catgaaaaag 300atagtggcag tgccattaaa tgaacagaag gattttacct atcagaagtt atttggagtc 360agtctccaag aacttgaacg gcaggggctc accgagaatg gcattccagc agtagtgtgg 420aatatagtgg aatatttgac gcagcatgga cttacccaag aaggtctttt tagggtgaat 480ggtaacgtga aggtggtgga acaacttcga ctgaagttcg agagtggagt gcccgtggag 540ctcgggaagg acggtgatgt ctgctcagca gccagtctgt tgaagctgtt tctgagggag 600ctgcctgaca gtctgatcac ctcagcgttg cagcctcgat tcattcaact ctttcaggat 660ggcagaaatg atgttcagga gagtagctta agagacttaa taaaagagct gccagacacc 720cactactgcc tcctcaagta cctttgccag ttcttgacaa aagtagccaa gcatcatgtg 780cagaatcgca tgaatgttca caatctcgcc actgtatttg ggccaaattg ctttcatgtg 840ccacctgggc ttgaaggcat gaaggaacag gacctgtgca acaagataat ggctaaaatt 900ctagaaaatt acaataccct gtttgaagta gagtatacag aaaatgatca tctgagatgt 960gaaaacctgg ctaggcttat catagtaaaa gaggtctatt ataagaactc cctgcccatc 1020cttttaacaa gaggcttaga aagagacatg ccaaaaccac ctccaaaaac caagatccca 1080aaatccagga gtgagggatc tattcaggcc cacagagtac tgcaaccaga gctatctgat 1140ggcattcctc agctcagctt gcggctaagt tatagaaaag cctgcttgga agacatgaat 1200tcagcagagg gtgctattag tgccaagttg gtacccagtt cacaggaaga tgaaagacct 1260ctgtcacctt tctatttgag tgctcatgta ccccaagtca gcaatgtgtc tgcaaccgga 1320gaactcttag aaagaaccat ccgatcagct gtagaacaac atctttttga tgttaataac 1380tctggaggtc aaagttcaga ggactcagaa tctggaacac tatcagcatc ttctgccaca 1440tctgccagac agcgccgccg ccagtccaag gagcaggatg aagttcgaca tgggagagac 1500aagggactta tcaacaaaga aaatactcct tctgggttca accaccttga tgattgtatt 1560ttgaatactc aggaagtcga aaaggtacac aaaaatactt ttggttgtgc tggagaaagg 1620agcaagccta aacgtcagaa atccagtact aaactttctg agcttcatga caatcaggac 1680ggtcttgtga atatggaaag tctcaattcc acacgatctc atgagagaac tggacctgat 1740gattttgaat ggatgtctga tgaaaggaaa ggaaatgaaa aagatggtgg acacactcag 1800cattttgaga gccccacaat gaagatccag gagcatccca gcctatctga caccaaacag 1860cagagaaatc aagatgccgg tgaccaggag gagagctttg tctccgaagt gccccagtcg 1920gacctgactg cattgtgtga tgaaaagaac tgggaagagc ctatccctgc tttctcctcc 1980tggcagcggg agaacagtga ctctgatgaa gcccacctct cgccgcaggc tgggcgcctg 2040atccgtcagc tgctggacga agacagcgac cccatgctct ctcctcggtt ctacgcttat 2100gggcagagca ggcaatacct ggatgacaca gaagtgcctc cttccccacc aaactcccat 2160tctttcatga ggcggcgaag ctcctctctg gggtcctatg atgatgagca agaggacctg 2220acacctgccc agctcacacg aaggattcag agccttaaaa agaagatccg gaagtttgaa 2280gatagattcg aagaagagaa gaagtacaga ccttcccaca gtgacaaagc agccaatccg 2340gaggttctga aatggacaaa tgaccttgcc aaattccgga gacaacttaa agaatcaaaa 2400ctaaagatat ctgaagagga cctaactccc aggatgcggc agcgaagcaa cacactcccc 2460aagagttttg gttcccaact tgagaaagaa gatgagaaga agcaagagct ggtggataaa 2520gcaataaagc ccagtgttga agccacattg gaatctattc agaggaagct ccaggagaag 2580cgagcggaaa gcagccgccc tgaggacatt aaggatatga ccaaagacca gattgctaat 2640gagaaagtgg ctctgcagaa agctctgtta tattatgaaa gcattcatgg acggccggta 2700acaaagaacg aacggcaggt gatgaagcca ctatacgaca ggtaccggct ggtcaaacag 2760atcctctccc gagctaacac catacccatc attggttccc cctccagcaa gcggagaagc 2820cctttgctgc agccaattat cgagggcgaa actgcttcct tcttcaagga gataaaggaa 2880gaagaggagg ggtcagaaga cgatagcaat gtgaagccag acttcatggt cactctgaaa 2940accgatttca gtgcacgatg ctttctggac caattcgaag atgacgctga tggatttatt 3000tccccaatgg atgataaaat accatcaaaa tgcagccagg acacagggct ttcaaatctc 3060catgctgcct caatacctga actcctggaa cacctccagg aaatgagaga agaaaagaaa 3120aggattcgaa agaaacttcg ggattttgaa gacaactttt tcagacagaa tggaagaaat 3180gtccagaagg aagaccgcac tcctatggct gaagaataca gtgaatataa gcacataaag 3240gcgaaactga ggctcctgga ggtgctcatc agcaagagag acactgattc caagtccatg 3300tgaggggcat ggccaagcac agggggctgg cagctgcggt gagagtttac tgtccccaga 3360gaaagtgcag ctctggaagg cagccttggg gctggccctg caaagcatgc agcccttctg 3420cctctagacc atttggcatc ggctcctgtt tccattgcct gccttagaaa ctggctggaa 3480gaagacaatg tgacctgact taggcatttt gtaattggaa agtcaagact gcagtatgtg 3540cacatgcgca cgcgcatgca cgcacacaca cacacagtag tggagctttc ctaacactag 3600cagagattaa tcactacatt agacaacact catctacaga gaatatacac tgttcttccc 3660tggataactg agaaacaaga gaccattctc tgtctaactg tgataaaaac aagctcagga 3720ctttattcta tagagcaaac ttgctgtgga gggccatgct ctccttggac ccagttaact 3780gcaaacgtgc attggagccc tatttgctgc cgctgccatt ctagtgacct ttccacagag 3840ctgcgccttc ctcacgtgtg tgaaaggttt tccccttcag ccctcaggta gatggaagct 3900gcatctgccc acgatggcag tgcagtcatc atcttcagga tgtttcttca ggacttcctc 3960agctgacaag gaattttggt ccctgcctag gaccgggtca tctgcagagg acagagagat 4020ggtaagcagc tgtatgaatg ctgattttaa aaccaggtca tgggagaaga gcctggagat 4080tctttcctga acactgactg cacttaccag tctgatttta tcgtcaaaca ccaagccagg 4140ctagcatgct catggcaatc tgtttggggc tgttttgttg tggcactagc caaacataaa 4200ggggcttaag tcagcctgca tacagaggat cggggagaga aggggcctgt gttctcagcc 4260tcctgagtac ttaccagagt ttaatttttt taaaaaaaat ctgcactaaa atccccaaac 4320tgacaggtaa atgtagccct cagagctcag cccaaggcag aatctaaatc acactatttt 4380cgagatcatg tataaaaaga aaaaaaagaa gtcatgctgt gtggccaatt ataatttttt 4440tcaaagactt tgtcacaaaa ctgtctatat tagacatttt ggagggacca ggaaatgtaa 4500gacaccaaat cctccatctc ttcagtgtgc ctgatgtcac ctcatgattt gctgttactt 4560ttttaactcc tgcgccaagg acagtgggtt ctgtgtccac ctttgtgctt tgcgaggccg 4620agcccaggca tctgctcgcc tgccacggct gaccagagaa ggtgcttcag gagctctgcc 4680ttagacgacg tgttacagta tgaacacaca gcagaggcac cctcgtatgt tttgaaagtt 4740gccttctgaa agggcacagt tttaaggaaa agaaaaagaa tgtaaaacta tactgacccg 4800ttttcagttt taaagggtcg tgagaaactg gctggtccaa tgggatttac agcaacattt 4860tccattgctg aagtgaggta gcagctctct tctgtcagct gaatgttaag gatggggaaa 4920aagaatgcct ttaagtttgc tcttaatcgt atggaagctt gagctatgtg ttggaagtgc 4980cctggtttta atccatacac aaagacggta cataatccta caggtttaaa tgtacataaa 5040aatatagttt ggaattcttt gctctactgt ttacattgca gattgctata atttcaagga 5100gtgagattat aaataaaatg atgcacttta ggatgtttcc tatttttgaa atctgaacat 5160gaatcattca catgaccaaa aattgtgttt ttttaaaaat acatgtctag tctgtccttt 5220aatagctctc ttaaataagc tatgatatta atcagatcat taccagttag cttttaaagc 5280acatttgttt aagactatgt ttttggaaaa atacgctaca gaattttttt ttaagctaca 5340aataaatgag atgctactaa ttgttttgga atctgttgtt tctgccaaag gtaaattaac 5400taaagattta ttcaggaatc cccatttgaa tttgtatgat tcaataaaag aaaacaccaa 5460gtaagttata taaaataaat tgtgtatgag atgttgtgtt ttcctttgta atttccacta 5520actaactaac taacttatat tcttcatgga atggagccca gaagaaatga gaggaagccc 5580ttttcacact agatcttatt tgaagaaatg tttgttagtc agtcagtcag tggtttctgg 5640ctctgccgag ggagatgtgt tccccagcaa ccatttctgc agcccagaat ctcaaggcac 5700tagaggcggt gtcttaatta attggcttca caaagacaaa atgctctgga ctgggatttt 5760tcctttgctg tgttgggaat atgtgtttat taattagcac atgccaacaa aataaatgtc 5820aagagttatt tcataagtgt aagtaaactt aagaattaaa gagtgcagac ttataatttt 5880ca 5882371023PRTHomo sapiens 37Met Gly Ala Gly Ala Leu Ala Ile Cys Gln Ser Lys Ala Ala Val Arg1 5 10 15Leu Lys Glu Asp Met Lys Lys Ile Val Ala Val Pro Leu Asn Glu Gln 20 25 30Lys Asp Phe Thr Tyr Gln Lys Leu Phe Gly Val Ser Leu Gln Glu Leu 35 40 45Glu Arg Gln Gly Leu Thr Glu Asn Gly Ile Pro Ala Val Val Trp Asn 50 55 60Ile Val Glu Tyr Leu Thr Gln His Gly Leu Thr Gln Glu Gly Leu Phe65 70 75 80Arg Val Asn Gly Asn Val Lys Val Val Glu Gln Leu Arg Leu Lys Phe 85 90 95Glu Ser Gly Val Pro Val Glu Leu Gly Lys Asp Gly Asp Val Cys Ser 100 105 110Ala Ala Ser Leu Leu Lys Leu Phe Leu Arg Glu Leu Pro Asp Ser Leu 115 120 125Ile Thr Ser Ala Leu Gln Pro Arg Phe Ile Gln Leu Phe Gln Asp Gly 130

135 140Arg Asn Asp Val Gln Glu Ser Ser Leu Arg Asp Leu Ile Lys Glu Leu145 150 155 160Pro Asp Thr His Tyr Cys Leu Leu Lys Tyr Leu Cys Gln Phe Leu Thr 165 170 175Lys Val Ala Lys His His Val Gln Asn Arg Met Asn Val His Asn Leu 180 185 190Ala Thr Val Phe Gly Pro Asn Cys Phe His Val Pro Pro Gly Leu Glu 195 200 205Gly Met Lys Glu Gln Asp Leu Cys Asn Lys Ile Met Ala Lys Ile Leu 210 215 220Glu Asn Tyr Asn Thr Leu Phe Glu Val Glu Tyr Thr Glu Asn Asp His225 230 235 240Leu Arg Cys Glu Asn Leu Ala Arg Leu Ile Ile Val Lys Glu Val Tyr 245 250 255Tyr Lys Asn Ser Leu Pro Ile Leu Leu Thr Arg Gly Leu Glu Arg Asp 260 265 270Met Pro Lys Pro Pro Pro Lys Thr Lys Ile Pro Lys Ser Arg Ser Glu 275 280 285Gly Ser Ile Gln Ala His Arg Val Leu Gln Pro Glu Leu Ser Asp Gly 290 295 300Ile Pro Gln Leu Ser Leu Arg Leu Ser Tyr Arg Lys Ala Cys Leu Glu305 310 315 320Asp Met Asn Ser Ala Glu Gly Ala Ile Ser Ala Lys Leu Val Pro Ser 325 330 335Ser Gln Glu Asp Glu Arg Pro Leu Ser Pro Phe Tyr Leu Ser Ala His 340 345 350Val Pro Gln Val Ser Asn Val Ser Ala Thr Gly Glu Leu Leu Glu Arg 355 360 365Thr Ile Arg Ser Ala Val Glu Gln His Leu Phe Asp Val Asn Asn Ser 370 375 380Gly Gly Gln Ser Ser Glu Asp Ser Glu Ser Gly Thr Leu Ser Ala Ser385 390 395 400Ser Ala Thr Ser Ala Arg Gln Arg Arg Arg Gln Ser Lys Glu Gln Asp 405 410 415Glu Val Arg His Gly Arg Asp Lys Gly Leu Ile Asn Lys Glu Asn Thr 420 425 430Pro Ser Gly Phe Asn His Leu Asp Asp Cys Ile Leu Asn Thr Gln Glu 435 440 445Val Glu Lys Val His Lys Asn Thr Phe Gly Cys Ala Gly Glu Arg Ser 450 455 460Lys Pro Lys Arg Gln Lys Ser Ser Thr Lys Leu Ser Glu Leu His Asp465 470 475 480Asn Gln Asp Gly Leu Val Asn Met Glu Ser Leu Asn Ser Thr Arg Ser 485 490 495His Glu Arg Thr Gly Pro Asp Asp Phe Glu Trp Met Ser Asp Glu Arg 500 505 510Lys Gly Asn Glu Lys Asp Gly Gly His Thr Gln His Phe Glu Ser Pro 515 520 525Thr Met Lys Ile Gln Glu His Pro Ser Leu Ser Asp Thr Lys Gln Gln 530 535 540Arg Asn Gln Asp Ala Gly Asp Gln Glu Glu Ser Phe Val Ser Glu Val545 550 555 560Pro Gln Ser Asp Leu Thr Ala Leu Cys Asp Glu Lys Asn Trp Glu Glu 565 570 575Pro Ile Pro Ala Phe Ser Ser Trp Gln Arg Glu Asn Ser Asp Ser Asp 580 585 590Glu Ala His Leu Ser Pro Gln Ala Gly Arg Leu Ile Arg Gln Leu Leu 595 600 605Asp Glu Asp Ser Asp Pro Met Leu Ser Pro Arg Phe Tyr Ala Tyr Gly 610 615 620Gln Ser Arg Gln Tyr Leu Asp Asp Thr Glu Val Pro Pro Ser Pro Pro625 630 635 640Asn Ser His Ser Phe Met Arg Arg Arg Ser Ser Ser Leu Gly Ser Tyr 645 650 655Asp Asp Glu Gln Glu Asp Leu Thr Pro Ala Gln Leu Thr Arg Arg Ile 660 665 670Gln Ser Leu Lys Lys Lys Ile Arg Lys Phe Glu Asp Arg Phe Glu Glu 675 680 685Glu Lys Lys Tyr Arg Pro Ser His Ser Asp Lys Ala Ala Asn Pro Glu 690 695 700Val Leu Lys Trp Thr Asn Asp Leu Ala Lys Phe Arg Arg Gln Leu Lys705 710 715 720Glu Ser Lys Leu Lys Ile Ser Glu Glu Asp Leu Thr Pro Arg Met Arg 725 730 735Gln Arg Ser Asn Thr Leu Pro Lys Ser Phe Gly Ser Gln Leu Glu Lys 740 745 750Glu Asp Glu Lys Lys Gln Glu Leu Val Asp Lys Ala Ile Lys Pro Ser 755 760 765Val Glu Ala Thr Leu Glu Ser Ile Gln Arg Lys Leu Gln Glu Lys Arg 770 775 780Ala Glu Ser Ser Arg Pro Glu Asp Ile Lys Asp Met Thr Lys Asp Gln785 790 795 800Ile Ala Asn Glu Lys Val Ala Leu Gln Lys Ala Leu Leu Tyr Tyr Glu 805 810 815Ser Ile His Gly Arg Pro Val Thr Lys Asn Glu Arg Gln Val Met Lys 820 825 830Pro Leu Tyr Asp Arg Tyr Arg Leu Val Lys Gln Ile Leu Ser Arg Ala 835 840 845Asn Thr Ile Pro Ile Ile Gly Ser Pro Ser Ser Lys Arg Arg Ser Pro 850 855 860Leu Leu Gln Pro Ile Ile Glu Gly Glu Thr Ala Ser Phe Phe Lys Glu865 870 875 880Ile Lys Glu Glu Glu Glu Gly Ser Glu Asp Asp Ser Asn Val Lys Pro 885 890 895Asp Phe Met Val Thr Leu Lys Thr Asp Phe Ser Ala Arg Cys Phe Leu 900 905 910Asp Gln Phe Glu Asp Asp Ala Asp Gly Phe Ile Ser Pro Met Asp Asp 915 920 925Lys Ile Pro Ser Lys Cys Ser Gln Asp Thr Gly Leu Ser Asn Leu His 930 935 940Ala Ala Ser Ile Pro Glu Leu Leu Glu His Leu Gln Glu Met Arg Glu945 950 955 960Glu Lys Lys Arg Ile Arg Lys Lys Leu Arg Asp Phe Glu Asp Asn Phe 965 970 975Phe Arg Gln Asn Gly Arg Asn Val Gln Lys Glu Asp Arg Thr Pro Met 980 985 990Ala Glu Glu Tyr Ser Glu Tyr Lys His Ile Lys Ala Lys Leu Arg Leu 995 1000 1005Leu Glu Val Leu Ile Ser Lys Arg Asp Thr Asp Ser Lys Ser Met 1010 1015 1020384988DNAHomo sapiens 38attgaggagc agaaggagta gggtgcgggg gaggaggagg agcgccttta gtgctgcagc 60agctgctgct ctgattggcc cggtggttca gctgcttccc tggaacaaaa ggtcaaagtg 120gactgcagtg taaatgtaga gaagcagccg ataaaatagc attgcctgaa gaagtttgga 180ggctgagagc agcagtagac tggccaactg cagagcaagt tgtttctcca gccgtgcggt 240gcagcctcat gcccccaacc cagcttagcc actgtaagaa gacgttcact gtacagacga 300ccaaacttgc cgtggaagag acagttgtga gattcccttg caaatttaca tacgagaatg 360gcttgtgaaa tcatgcctct gcaaagtgct catgtacccc aagtcagcaa tgtgtctgca 420accggagaac tcttagaaag aaccatccga tcagctgtag aacaacatct ttttgatgtt 480aataactctg gaggtcaaag ttcagaggac tcagaatctg gaacactatc agcatcttct 540gccacatctg ccagacagcg ccgccgccag tccaaggagc aggatgaagt tcgacatggg 600agagacaagg gacttatcaa caaagaaaat actccttctg ggttcaacca ccttgatgat 660tgtattttga atactcagga agtcgaaaag gtacacaaaa atacttttgg ttgtgctgga 720gaaaggagca agcctaaacg tcagaaatcc agtactaaac tttctgagct tcatgacaat 780caggacggtc ttgtgaatat ggaaagtctc aattccacac gatctcatga gagaactgga 840cctgatgatt ttgaatggat gtctgatgaa aggaaaggaa atgaaaaaga tggtggacac 900actcagcatt ttgagagccc cacaatgaag atccaggagc atcccagcct atctgacacc 960aaacagcaga gaaatcaaga tgccggtgac caggaggaga gctttgtctc cgaagtgccc 1020cagtcggacc tgactgcatt gtgtgatgaa aagaactggg aagagcctat ccctgctttc 1080tcctcctggc agcgggagaa cagtgactct gatgaagccc acctctcgcc gcaggctggg 1140cgcctgatcc gtcagctgct ggacgaagac agcgacccca tgctctctcc tcggttctac 1200gcttatgggc agagcaggca atacctggat gacacagaag tgcctccttc cccaccaaac 1260tcccattctt tcatgaggcg gcgaagctcc tctctggggt cctatgatga tgagcaagag 1320gacctgacac ctgcccagct cacacgaagg attcagagcc ttaaaaagaa gatccggaag 1380tttgaagata gattcgaaga agagaagaag tacagacctt cccacagtga caaagcagcc 1440aatccggagg ttctgaaatg gacaaatgac cttgccaaat tccggagaca acttaaagaa 1500tcaaaactaa agatatctga agaggaccta actcccagga tgcggcagcg aagcaacaca 1560ctccccaaga gttttggttc ccaacttgag aaagaagatg agaagaagca agagctggtg 1620gataaagcaa taaagcccag tgttgaagcc acattggaat ctattcagag gaagctccag 1680gagaagcgag cggaaagcag ccgccctgag gacattaagg atatgaccaa agaccagatt 1740gctaatgaga aagtggctct gcagaaagct ctgttatatt atgaaagcat tcatggacgg 1800ccggtaacaa agaacgaacg gcaggtgatg aagccactat acgacaggta ccggctggtc 1860aaacagatcc tctcccgagc taacaccata cccatcattg gttccccctc cagcaagcgg 1920agaagccctt tgctgcagcc aattatcgag ggcgaaactg cttccttctt caaggagata 1980aaggaagaag aggaggggtc agaagacgat agcaatgtga agccagactt catggtcact 2040ctgaaaaccg atttcagtgc acgatgcttt ctggaccaat tcgaagatga cgctgatgga 2100tttatttccc caatggatga taaaatacca tcaaaatgca gccaggacac agggctttca 2160aatctccatg ctgcctcaat acctgaactc ctggaacacc tccaggaaat gagagaagaa 2220aagaaaagga ttcgaaagaa acttcgggat tttgaagaca actttttcag acagaatgga 2280agaaatgtcc agaaggaaga ccgcactcct atggctgaag aatacagtga atataagcac 2340ataaaggcga aactgaggct cctggaggtg ctcatcagca agagagacac tgattccaag 2400tccatgtgag gggcatggcc aagcacaggg ggctggcagc tgcggtgaga gtttactgtc 2460cccagagaaa gtgcagctct ggaaggcagc cttggggctg gccctgcaaa gcatgcagcc 2520cttctgcctc tagaccattt ggcatcggct cctgtttcca ttgcctgcct tagaaactgg 2580ctggaagaag acaatgtgac ctgacttagg cattttgtaa ttggaaagtc aagactgcag 2640tatgtgcaca tgcgcacgcg catgcacgca cacacacaca cagtagtgga gctttcctaa 2700cactagcaga gattaatcac tacattagac aacactcatc tacagagaat atacactgtt 2760cttccctgga taactgagaa acaagagacc attctctgtc taactgtgat aaaaacaagc 2820tcaggacttt attctataga gcaaacttgc tgtggagggc catgctctcc ttggacccag 2880ttaactgcaa acgtgcattg gagccctatt tgctgccgct gccattctag tgacctttcc 2940acagagctgc gccttcctca cgtgtgtgaa aggttttccc cttcagccct caggtagatg 3000gaagctgcat ctgcccacga tggcagtgca gtcatcatct tcaggatgtt tcttcaggac 3060ttcctcagct gacaaggaat tttggtccct gcctaggacc gggtcatctg cagaggacag 3120agagatggta agcagctgta tgaatgctga ttttaaaacc aggtcatggg agaagagcct 3180ggagattctt tcctgaacac tgactgcact taccagtctg attttatcgt caaacaccaa 3240gccaggctag catgctcatg gcaatctgtt tggggctgtt ttgttgtggc actagccaaa 3300cataaagggg cttaagtcag cctgcataca gaggatcggg gagagaaggg gcctgtgttc 3360tcagcctcct gagtacttac cagagtttaa tttttttaaa aaaaatctgc actaaaatcc 3420ccaaactgac aggtaaatgt agccctcaga gctcagccca aggcagaatc taaatcacac 3480tattttcgag atcatgtata aaaagaaaaa aaagaagtca tgctgtgtgg ccaattataa 3540tttttttcaa agactttgtc acaaaactgt ctatattaga cattttggag ggaccaggaa 3600atgtaagaca ccaaatcctc catctcttca gtgtgcctga tgtcacctca tgatttgctg 3660ttactttttt aactcctgcg ccaaggacag tgggttctgt gtccaccttt gtgctttgcg 3720aggccgagcc caggcatctg ctcgcctgcc acggctgacc agagaaggtg cttcaggagc 3780tctgccttag acgacgtgtt acagtatgaa cacacagcag aggcaccctc gtatgttttg 3840aaagttgcct tctgaaaggg cacagtttta aggaaaagaa aaagaatgta aaactatact 3900gacccgtttt cagttttaaa gggtcgtgag aaactggctg gtccaatggg atttacagca 3960acattttcca ttgctgaagt gaggtagcag ctctcttctg tcagctgaat gttaaggatg 4020gggaaaaaga atgcctttaa gtttgctctt aatcgtatgg aagcttgagc tatgtgttgg 4080aagtgccctg gttttaatcc atacacaaag acggtacata atcctacagg tttaaatgta 4140cataaaaata tagtttggaa ttctttgctc tactgtttac attgcagatt gctataattt 4200caaggagtga gattataaat aaaatgatgc actttaggat gtttcctatt tttgaaatct 4260gaacatgaat cattcacatg accaaaaatt gtgttttttt aaaaatacat gtctagtctg 4320tcctttaata gctctcttaa ataagctatg atattaatca gatcattacc agttagcttt 4380taaagcacat ttgtttaaga ctatgttttt ggaaaaatac gctacagaat ttttttttaa 4440gctacaaata aatgagatgc tactaattgt tttggaatct gttgtttctg ccaaaggtaa 4500attaactaaa gatttattca ggaatcccca tttgaatttg tatgattcaa taaaagaaaa 4560caccaagtaa gttatataaa ataaattgtg tatgagatgt tgtgttttcc tttgtaattt 4620ccactaacta actaactaac ttatattctt catggaatgg agcccagaag aaatgagagg 4680aagccctttt cacactagat cttatttgaa gaaatgtttg ttagtcagtc agtcagtggt 4740ttctggctct gccgagggag atgtgttccc cagcaaccat ttctgcagcc cagaatctca 4800aggcactaga ggcggtgtct taattaattg gcttcacaaa gacaaaatgc tctggactgg 4860gatttttcct ttgctgtgtt gggaatatgt gtttattaat tagcacatgc caacaaaata 4920aatgtcaaga gttatttcat aagtgtaagt aaacttaaga attaaagagt gcagacttat 4980aattttca 498839683PRTHomo sapiens 39Met Ala Cys Glu Ile Met Pro Leu Gln Ser Ala His Val Pro Gln Val1 5 10 15Ser Asn Val Ser Ala Thr Gly Glu Leu Leu Glu Arg Thr Ile Arg Ser 20 25 30Ala Val Glu Gln His Leu Phe Asp Val Asn Asn Ser Gly Gly Gln Ser 35 40 45Ser Glu Asp Ser Glu Ser Gly Thr Leu Ser Ala Ser Ser Ala Thr Ser 50 55 60Ala Arg Gln Arg Arg Arg Gln Ser Lys Glu Gln Asp Glu Val Arg His65 70 75 80Gly Arg Asp Lys Gly Leu Ile Asn Lys Glu Asn Thr Pro Ser Gly Phe 85 90 95Asn His Leu Asp Asp Cys Ile Leu Asn Thr Gln Glu Val Glu Lys Val 100 105 110His Lys Asn Thr Phe Gly Cys Ala Gly Glu Arg Ser Lys Pro Lys Arg 115 120 125Gln Lys Ser Ser Thr Lys Leu Ser Glu Leu His Asp Asn Gln Asp Gly 130 135 140Leu Val Asn Met Glu Ser Leu Asn Ser Thr Arg Ser His Glu Arg Thr145 150 155 160Gly Pro Asp Asp Phe Glu Trp Met Ser Asp Glu Arg Lys Gly Asn Glu 165 170 175Lys Asp Gly Gly His Thr Gln His Phe Glu Ser Pro Thr Met Lys Ile 180 185 190Gln Glu His Pro Ser Leu Ser Asp Thr Lys Gln Gln Arg Asn Gln Asp 195 200 205Ala Gly Asp Gln Glu Glu Ser Phe Val Ser Glu Val Pro Gln Ser Asp 210 215 220Leu Thr Ala Leu Cys Asp Glu Lys Asn Trp Glu Glu Pro Ile Pro Ala225 230 235 240Phe Ser Ser Trp Gln Arg Glu Asn Ser Asp Ser Asp Glu Ala His Leu 245 250 255Ser Pro Gln Ala Gly Arg Leu Ile Arg Gln Leu Leu Asp Glu Asp Ser 260 265 270Asp Pro Met Leu Ser Pro Arg Phe Tyr Ala Tyr Gly Gln Ser Arg Gln 275 280 285Tyr Leu Asp Asp Thr Glu Val Pro Pro Ser Pro Pro Asn Ser His Ser 290 295 300Phe Met Arg Arg Arg Ser Ser Ser Leu Gly Ser Tyr Asp Asp Glu Gln305 310 315 320Glu Asp Leu Thr Pro Ala Gln Leu Thr Arg Arg Ile Gln Ser Leu Lys 325 330 335Lys Lys Ile Arg Lys Phe Glu Asp Arg Phe Glu Glu Glu Lys Lys Tyr 340 345 350Arg Pro Ser His Ser Asp Lys Ala Ala Asn Pro Glu Val Leu Lys Trp 355 360 365Thr Asn Asp Leu Ala Lys Phe Arg Arg Gln Leu Lys Glu Ser Lys Leu 370 375 380Lys Ile Ser Glu Glu Asp Leu Thr Pro Arg Met Arg Gln Arg Ser Asn385 390 395 400Thr Leu Pro Lys Ser Phe Gly Ser Gln Leu Glu Lys Glu Asp Glu Lys 405 410 415Lys Gln Glu Leu Val Asp Lys Ala Ile Lys Pro Ser Val Glu Ala Thr 420 425 430Leu Glu Ser Ile Gln Arg Lys Leu Gln Glu Lys Arg Ala Glu Ser Ser 435 440 445Arg Pro Glu Asp Ile Lys Asp Met Thr Lys Asp Gln Ile Ala Asn Glu 450 455 460Lys Val Ala Leu Gln Lys Ala Leu Leu Tyr Tyr Glu Ser Ile His Gly465 470 475 480Arg Pro Val Thr Lys Asn Glu Arg Gln Val Met Lys Pro Leu Tyr Asp 485 490 495Arg Tyr Arg Leu Val Lys Gln Ile Leu Ser Arg Ala Asn Thr Ile Pro 500 505 510Ile Ile Gly Ser Pro Ser Ser Lys Arg Arg Ser Pro Leu Leu Gln Pro 515 520 525Ile Ile Glu Gly Glu Thr Ala Ser Phe Phe Lys Glu Ile Lys Glu Glu 530 535 540Glu Glu Gly Ser Glu Asp Asp Ser Asn Val Lys Pro Asp Phe Met Val545 550 555 560Thr Leu Lys Thr Asp Phe Ser Ala Arg Cys Phe Leu Asp Gln Phe Glu 565 570 575Asp Asp Ala Asp Gly Phe Ile Ser Pro Met Asp Asp Lys Ile Pro Ser 580 585 590Lys Cys Ser Gln Asp Thr Gly Leu Ser Asn Leu His Ala Ala Ser Ile 595 600 605Pro Glu Leu Leu Glu His Leu Gln Glu Met Arg Glu Glu Lys Lys Arg 610 615 620Ile Arg Lys Lys Leu Arg Asp Phe Glu Asp Asn Phe Phe Arg Gln Asn625 630 635 640Gly Arg Asn Val Gln Lys Glu Asp Arg Thr Pro Met Ala Glu Glu Tyr 645 650 655Ser Glu Tyr Lys His Ile Lys Ala Lys Leu Arg Leu Leu Glu Val Leu 660 665 670Ile Ser Lys Arg Asp Thr Asp Ser Lys Ser Met 675 680404946DNAHomo sapiens 40attgaggagc agaaggagta gggtgcgggg gaggaggagg agcgccttta gtgctgcagc 60agctgctgct ctgattggcc cggtggttca gctgcttccc tggaacaaaa ggtcaaagtg 120gactgcagtg taaatgtaga gaagcagccg ataaaatagc attgcctgaa gaagtttgga 180ggctgagagc agcagtagac tggccaactg cagagcaagt tgtttctcca gccgtgcggt 240gcagcctcat gcccccaacc cagcttagcc actgtaagaa gacgttcact gtacagacga 300ccaaacttgc cgtggaagag acagttgtga gattcccttg caaatttaca tacgagaatg 360gcttgtgaaa tcatgcctct gcaaagttca caggaagatg

aaagacctct gtcacctttc 420tatttgagtg ctcatgtacc ccaagtcagc aatgtgtctg caaccggaga actcttagaa 480agaaccatcc gatcagctgt agaacaacat ctttttgatg ttaataactc tggaggtcaa 540agttcagagg actcagaatc tggaacacta tcagcatctt ctgccacatc tgccagacag 600cgccgccgcc agtccaagga gcaggatgaa gttcgacatg ggagagacaa gggacttatc 660aacaaagaaa atactccttc tgggttcaac caccttgatg attgtatttt gaatactcag 720gaagtcgaaa aggtacacaa aaatactttt ggttgtgctg gagaaaggag caagcctaaa 780cgtcagaaat ccagtactaa actttctgag cttcatgaca atcaggacgg tcttgtgaat 840atggaaagtc tcaattccac acgatctcat gagagaactg gacctgatga ttttgaatgg 900atgtctgatg aaaggaaagg aaatgaaaaa gatggtggac acactcagca ttttgagagc 960cccacaatga agatccagga gcatcccagc ctatctgaca ccaaacagca gagaaatcaa 1020gatgccggtg accaggagga gagctttgtc tccgaagtgc cccagtcgga cctgactgca 1080ttgtgtgatg aaaagaactg ggaagagcct atccctgctt tctcctcctg gcagcgggag 1140aacagtgact ctgatgaagc ccacctctcg ccgcaggctg ggcgcctgat ccgtcagctg 1200ctggacgaag acagcgaccc catgctctct cctcggttct acgcttatgg gcagagcagg 1260caatacctgg atgacacaga agtgcctcct tccccaccaa actcccattc tttcatgagg 1320cggcgaagct cctctctggg gtcctatgat gatgagcaag aggacctgac acctgcccag 1380ctcacacgaa ggattcagag ccttaaaaag aagatccgga agtttgaaga tagattcgaa 1440gaagagaaga agtacagacc ttcccacagt gacaaagcag ccaatccgga ggttctgaaa 1500tggacaaatg accttgccaa attccggaga caacttaaag aatcaaaact aaagatatct 1560gaagaggacc taactcccag gatgcggcag cgaagcaaca cactccccaa gagttttggt 1620tcccaacttg agaaagaaga tgagaagaag caagagctgg tggataaagc aataaagccc 1680agtgttgaag ccacattgga atctattcag aggaagctcc aggagaagcg agcggaaagc 1740agccgccctg aggacattaa ggatatgacc aaagaccaga ttgctaatga gaaagtggct 1800ctgcagaaag ctctgttata ttatgaaagc attcatggac ggccggtaac aaagaacgaa 1860cggcaggtga tgaagccact atacgacagg taccggctgg tcaaacagat cctctcccga 1920gctaacacca tacccatcat tgaagaagag gaggggtcag aagacgatag caatgtgaag 1980ccagacttca tggtcactct gaaaaccgat ttcagtgcac gatgctttct ggaccaattc 2040gaagatgacg ctgatggatt tatttcccca atggatgata aaataccatc aaaatgcagc 2100caggacacag ggctttcaaa tctccatgct gcctcaatac ctgaactcct ggaacacctc 2160caggaaatga gagaagaaaa gaaaaggatt cgaaagaaac ttcgggattt tgaagacaac 2220tttttcagac agaatggaag aaatgtccag aaggaagacc gcactcctat ggctgaagaa 2280tacagtgaat ataagcacat aaaggcgaaa ctgaggctcc tggaggtgct catcagcaag 2340agagacactg attccaagtc catgtgaggg gcatggccaa gcacaggggg ctggcagctg 2400cggtgagagt ttactgtccc cagagaaagt gcagctctgg aaggcagcct tggggctggc 2460cctgcaaagc atgcagccct tctgcctcta gaccatttgg catcggctcc tgtttccatt 2520gcctgcctta gaaactggct ggaagaagac aatgtgacct gacttaggca ttttgtaatt 2580ggaaagtcaa gactgcagta tgtgcacatg cgcacgcgca tgcacgcaca cacacacaca 2640gtagtggagc tttcctaaca ctagcagaga ttaatcacta cattagacaa cactcatcta 2700cagagaatat acactgttct tccctggata actgagaaac aagagaccat tctctgtcta 2760actgtgataa aaacaagctc aggactttat tctatagagc aaacttgctg tggagggcca 2820tgctctcctt ggacccagtt aactgcaaac gtgcattgga gccctatttg ctgccgctgc 2880cattctagtg acctttccac agagctgcgc cttcctcacg tgtgtgaaag gttttcccct 2940tcagccctca ggtagatgga agctgcatct gcccacgatg gcagtgcagt catcatcttc 3000aggatgtttc ttcaggactt cctcagctga caaggaattt tggtccctgc ctaggaccgg 3060gtcatctgca gaggacagag agatggtaag cagctgtatg aatgctgatt ttaaaaccag 3120gtcatgggag aagagcctgg agattctttc ctgaacactg actgcactta ccagtctgat 3180tttatcgtca aacaccaagc caggctagca tgctcatggc aatctgtttg gggctgtttt 3240gttgtggcac tagccaaaca taaaggggct taagtcagcc tgcatacaga ggatcgggga 3300gagaaggggc ctgtgttctc agcctcctga gtacttacca gagtttaatt tttttaaaaa 3360aaatctgcac taaaatcccc aaactgacag gtaaatgtag ccctcagagc tcagcccaag 3420gcagaatcta aatcacacta ttttcgagat catgtataaa aagaaaaaaa agaagtcatg 3480ctgtgtggcc aattataatt tttttcaaag actttgtcac aaaactgtct atattagaca 3540ttttggaggg accaggaaat gtaagacacc aaatcctcca tctcttcagt gtgcctgatg 3600tcacctcatg atttgctgtt acttttttaa ctcctgcgcc aaggacagtg ggttctgtgt 3660ccacctttgt gctttgcgag gccgagccca ggcatctgct cgcctgccac ggctgaccag 3720agaaggtgct tcaggagctc tgccttagac gacgtgttac agtatgaaca cacagcagag 3780gcaccctcgt atgttttgaa agttgccttc tgaaagggca cagttttaag gaaaagaaaa 3840agaatgtaaa actatactga cccgttttca gttttaaagg gtcgtgagaa actggctggt 3900ccaatgggat ttacagcaac attttccatt gctgaagtga ggtagcagct ctcttctgtc 3960agctgaatgt taaggatggg gaaaaagaat gcctttaagt ttgctcttaa tcgtatggaa 4020gcttgagcta tgtgttggaa gtgccctggt tttaatccat acacaaagac ggtacataat 4080cctacaggtt taaatgtaca taaaaatata gtttggaatt ctttgctcta ctgtttacat 4140tgcagattgc tataatttca aggagtgaga ttataaataa aatgatgcac tttaggatgt 4200ttcctatttt tgaaatctga acatgaatca ttcacatgac caaaaattgt gtttttttaa 4260aaatacatgt ctagtctgtc ctttaatagc tctcttaaat aagctatgat attaatcaga 4320tcattaccag ttagctttta aagcacattt gtttaagact atgtttttgg aaaaatacgc 4380tacagaattt ttttttaagc tacaaataaa tgagatgcta ctaattgttt tggaatctgt 4440tgtttctgcc aaaggtaaat taactaaaga tttattcagg aatccccatt tgaatttgta 4500tgattcaata aaagaaaaca ccaagtaagt tatataaaat aaattgtgta tgagatgttg 4560tgttttcctt tgtaatttcc actaactaac taactaactt atattcttca tggaatggag 4620cccagaagaa atgagaggaa gcccttttca cactagatct tatttgaaga aatgtttgtt 4680agtcagtcag tcagtggttt ctggctctgc cgagggagat gtgttcccca gcaaccattt 4740ctgcagccca gaatctcaag gcactagagg cggtgtctta attaattggc ttcacaaaga 4800caaaatgctc tggactggga tttttccttt gctgtgttgg gaatatgtgt ttattaatta 4860gcacatgcca acaaaataaa tgtcaagagt tatttcataa gtgtaagtaa acttaagaat 4920taaagagtgc agacttataa ttttca 494641669PRTHomo sapiens 41Met Ala Cys Glu Ile Met Pro Leu Gln Ser Ser Gln Glu Asp Glu Arg1 5 10 15Pro Leu Ser Pro Phe Tyr Leu Ser Ala His Val Pro Gln Val Ser Asn 20 25 30Val Ser Ala Thr Gly Glu Leu Leu Glu Arg Thr Ile Arg Ser Ala Val 35 40 45Glu Gln His Leu Phe Asp Val Asn Asn Ser Gly Gly Gln Ser Ser Glu 50 55 60Asp Ser Glu Ser Gly Thr Leu Ser Ala Ser Ser Ala Thr Ser Ala Arg65 70 75 80Gln Arg Arg Arg Gln Ser Lys Glu Gln Asp Glu Val Arg His Gly Arg 85 90 95Asp Lys Gly Leu Ile Asn Lys Glu Asn Thr Pro Ser Gly Phe Asn His 100 105 110Leu Asp Asp Cys Ile Leu Asn Thr Gln Glu Val Glu Lys Val His Lys 115 120 125Asn Thr Phe Gly Cys Ala Gly Glu Arg Ser Lys Pro Lys Arg Gln Lys 130 135 140Ser Ser Thr Lys Leu Ser Glu Leu His Asp Asn Gln Asp Gly Leu Val145 150 155 160Asn Met Glu Ser Leu Asn Ser Thr Arg Ser His Glu Arg Thr Gly Pro 165 170 175Asp Asp Phe Glu Trp Met Ser Asp Glu Arg Lys Gly Asn Glu Lys Asp 180 185 190Gly Gly His Thr Gln His Phe Glu Ser Pro Thr Met Lys Ile Gln Glu 195 200 205His Pro Ser Leu Ser Asp Thr Lys Gln Gln Arg Asn Gln Asp Ala Gly 210 215 220Asp Gln Glu Glu Ser Phe Val Ser Glu Val Pro Gln Ser Asp Leu Thr225 230 235 240Ala Leu Cys Asp Glu Lys Asn Trp Glu Glu Pro Ile Pro Ala Phe Ser 245 250 255Ser Trp Gln Arg Glu Asn Ser Asp Ser Asp Glu Ala His Leu Ser Pro 260 265 270Gln Ala Gly Arg Leu Ile Arg Gln Leu Leu Asp Glu Asp Ser Asp Pro 275 280 285Met Leu Ser Pro Arg Phe Tyr Ala Tyr Gly Gln Ser Arg Gln Tyr Leu 290 295 300Asp Asp Thr Glu Val Pro Pro Ser Pro Pro Asn Ser His Ser Phe Met305 310 315 320Arg Arg Arg Ser Ser Ser Leu Gly Ser Tyr Asp Asp Glu Gln Glu Asp 325 330 335Leu Thr Pro Ala Gln Leu Thr Arg Arg Ile Gln Ser Leu Lys Lys Lys 340 345 350Ile Arg Lys Phe Glu Asp Arg Phe Glu Glu Glu Lys Lys Tyr Arg Pro 355 360 365Ser His Ser Asp Lys Ala Ala Asn Pro Glu Val Leu Lys Trp Thr Asn 370 375 380Asp Leu Ala Lys Phe Arg Arg Gln Leu Lys Glu Ser Lys Leu Lys Ile385 390 395 400Ser Glu Glu Asp Leu Thr Pro Arg Met Arg Gln Arg Ser Asn Thr Leu 405 410 415Pro Lys Ser Phe Gly Ser Gln Leu Glu Lys Glu Asp Glu Lys Lys Gln 420 425 430Glu Leu Val Asp Lys Ala Ile Lys Pro Ser Val Glu Ala Thr Leu Glu 435 440 445Ser Ile Gln Arg Lys Leu Gln Glu Lys Arg Ala Glu Ser Ser Arg Pro 450 455 460Glu Asp Ile Lys Asp Met Thr Lys Asp Gln Ile Ala Asn Glu Lys Val465 470 475 480Ala Leu Gln Lys Ala Leu Leu Tyr Tyr Glu Ser Ile His Gly Arg Pro 485 490 495Val Thr Lys Asn Glu Arg Gln Val Met Lys Pro Leu Tyr Asp Arg Tyr 500 505 510Arg Leu Val Lys Gln Ile Leu Ser Arg Ala Asn Thr Ile Pro Ile Ile 515 520 525Glu Glu Glu Glu Gly Ser Glu Asp Asp Ser Asn Val Lys Pro Asp Phe 530 535 540Met Val Thr Leu Lys Thr Asp Phe Ser Ala Arg Cys Phe Leu Asp Gln545 550 555 560Phe Glu Asp Asp Ala Asp Gly Phe Ile Ser Pro Met Asp Asp Lys Ile 565 570 575Pro Ser Lys Cys Ser Gln Asp Thr Gly Leu Ser Asn Leu His Ala Ala 580 585 590Ser Ile Pro Glu Leu Leu Glu His Leu Gln Glu Met Arg Glu Glu Lys 595 600 605Lys Arg Ile Arg Lys Lys Leu Arg Asp Phe Glu Asp Asn Phe Phe Arg 610 615 620Gln Asn Gly Arg Asn Val Gln Lys Glu Asp Arg Thr Pro Met Ala Glu625 630 635 640Glu Tyr Ser Glu Tyr Lys His Ile Lys Ala Lys Leu Arg Leu Leu Glu 645 650 655Val Leu Ile Ser Lys Arg Asp Thr Asp Ser Lys Ser Met 660 665424946DNAHomo sapiens 42attgaggagc agaaggagta gggtgcgggg gaggaggagg agcgccttta gtgctgcagc 60agctgctgct ctgattggcc cggtggttca gctgcttccc tggaacaaaa ggtcaaagtg 120gactgcagtg taaatgtaga gaagcagccg ataaaatagc attgcctgaa gaagtttgga 180ggctgagagc agcagtagac tggccaactg cagagcaagt tgtttctcca gccgtgcggt 240gcagcctcat gcccccaacc cagcttagcc actgtaagaa gacgttcact gtacagacga 300ccaaacttgc cgtggaagag acagttgtga gattcccttg caaatttaca tacgagaatg 360gcttgtgaaa tcatgcctct gcaaagactc ttagaaagaa ccatccgatc agctgtagaa 420caacatcttt ttgatgttaa taactctgga ggtcaaagtt cagaggactc agaatctgga 480acactatcag catcttctgc cacatctgcc agacagcgcc gccgccagtc caaggagcag 540gatgaagttc gacatgggag agacaaggga cttatcaaca aagaaaatac tccttctggg 600ttcaaccacc ttgatgattg tattttgaat actcaggaag tcgaaaaggt acacaaaaat 660acttttggtt gtgctggaga aaggagcaag cctaaacgtc agaaatccag tactaaactt 720tctgagcttc atgacaatca ggacggtctt gtgaatatgg aaagtctcaa ttccacacga 780tctcatgaga gaactggacc tgatgatttt gaatggatgt ctgatgaaag gaaaggaaat 840gaaaaagatg gtggacacac tcagcatttt gagagcccca caatgaagat ccaggagcat 900cccagcctat ctgacaccaa acagcagaga aatcaagatg ccggtgacca ggaggagagc 960tttgtctccg aagtgcccca gtcggacctg actgcattgt gtgatgaaaa gaactgggaa 1020gagcctatcc ctgctttctc ctcctggcag cgggagaaca gtgactctga tgaagcccac 1080ctctcgccgc aggctgggcg cctgatccgt cagctgctgg acgaagacag cgaccccatg 1140ctctctcctc ggttctacgc ttatgggcag agcaggcaat acctggatga cacagaagtg 1200cctccttccc caccaaactc ccattctttc atgaggcggc gaagctcctc tctggggtcc 1260tatgatgatg agcaagagga cctgacacct gcccagctca cacgaaggat tcagagcctt 1320aaaaagaaga tccggaagtt tgaagataga ttcgaagaag agaagaagta cagaccttcc 1380cacagtgaca aagcagccaa tccggaggtt ctgaaatgga caaatgacct tgccaaattc 1440cggagacaac ttaaagaatc aaaactaaag atatctgaag aggacctaac tcccaggatg 1500cggcagcgaa gcaacacact ccccaagagt tttggttccc aacttgagaa agaagatgag 1560aagaagcaag agctggtgga taaagcaata aagcccagtg ttgaagccac attggaatct 1620attcagagga agctccagga gaagcgagcg gaaagcagcc gccctgagga cattaaggat 1680atgaccaaag accagattgc taatgagaaa gtggctctgc agaaagctct gttatattat 1740gaaagcattc atggacggcc ggtaacaaag aacgaacggc aggtgatgaa gccactatac 1800gacaggtacc ggctggtcaa acagatcctc tcccgagcta acaccatacc catcattggt 1860tccccctcca gcaagcggag aagccctttg ctgcagccaa ttatcgaggg cgaaactgct 1920tccttcttca aggagataaa ggaagaagag gaggggtcag aagacgatag caatgtgaag 1980ccagacttca tggtcactct gaaaaccgat ttcagtgcac gatgctttct ggaccaattc 2040gaagatgacg ctgatggatt tatttcccca atggatgata aaataccatc aaaatgcagc 2100caggacacag ggctttcaaa tctccatgct gcctcaatac ctgaactcct ggaacacctc 2160caggaaatga gagaagaaaa gaaaaggatt cgaaagaaac ttcgggattt tgaagacaac 2220tttttcagac agaatggaag aaatgtccag aaggaagacc gcactcctat ggctgaagaa 2280tacagtgaat ataagcacat aaaggcgaaa ctgaggctcc tggaggtgct catcagcaag 2340agagacactg attccaagtc catgtgaggg gcatggccaa gcacaggggg ctggcagctg 2400cggtgagagt ttactgtccc cagagaaagt gcagctctgg aaggcagcct tggggctggc 2460cctgcaaagc atgcagccct tctgcctcta gaccatttgg catcggctcc tgtttccatt 2520gcctgcctta gaaactggct ggaagaagac aatgtgacct gacttaggca ttttgtaatt 2580ggaaagtcaa gactgcagta tgtgcacatg cgcacgcgca tgcacgcaca cacacacaca 2640gtagtggagc tttcctaaca ctagcagaga ttaatcacta cattagacaa cactcatcta 2700cagagaatat acactgttct tccctggata actgagaaac aagagaccat tctctgtcta 2760actgtgataa aaacaagctc aggactttat tctatagagc aaacttgctg tggagggcca 2820tgctctcctt ggacccagtt aactgcaaac gtgcattgga gccctatttg ctgccgctgc 2880cattctagtg acctttccac agagctgcgc cttcctcacg tgtgtgaaag gttttcccct 2940tcagccctca ggtagatgga agctgcatct gcccacgatg gcagtgcagt catcatcttc 3000aggatgtttc ttcaggactt cctcagctga caaggaattt tggtccctgc ctaggaccgg 3060gtcatctgca gaggacagag agatggtaag cagctgtatg aatgctgatt ttaaaaccag 3120gtcatgggag aagagcctgg agattctttc ctgaacactg actgcactta ccagtctgat 3180tttatcgtca aacaccaagc caggctagca tgctcatggc aatctgtttg gggctgtttt 3240gttgtggcac tagccaaaca taaaggggct taagtcagcc tgcatacaga ggatcgggga 3300gagaaggggc ctgtgttctc agcctcctga gtacttacca gagtttaatt tttttaaaaa 3360aaatctgcac taaaatcccc aaactgacag gtaaatgtag ccctcagagc tcagcccaag 3420gcagaatcta aatcacacta ttttcgagat catgtataaa aagaaaaaaa agaagtcatg 3480ctgtgtggcc aattataatt tttttcaaag actttgtcac aaaactgtct atattagaca 3540ttttggaggg accaggaaat gtaagacacc aaatcctcca tctcttcagt gtgcctgatg 3600tcacctcatg atttgctgtt acttttttaa ctcctgcgcc aaggacagtg ggttctgtgt 3660ccacctttgt gctttgcgag gccgagccca ggcatctgct cgcctgccac ggctgaccag 3720agaaggtgct tcaggagctc tgccttagac gacgtgttac agtatgaaca cacagcagag 3780gcaccctcgt atgttttgaa agttgccttc tgaaagggca cagttttaag gaaaagaaaa 3840agaatgtaaa actatactga cccgttttca gttttaaagg gtcgtgagaa actggctggt 3900ccaatgggat ttacagcaac attttccatt gctgaagtga ggtagcagct ctcttctgtc 3960agctgaatgt taaggatggg gaaaaagaat gcctttaagt ttgctcttaa tcgtatggaa 4020gcttgagcta tgtgttggaa gtgccctggt tttaatccat acacaaagac ggtacataat 4080cctacaggtt taaatgtaca taaaaatata gtttggaatt ctttgctcta ctgtttacat 4140tgcagattgc tataatttca aggagtgaga ttataaataa aatgatgcac tttaggatgt 4200ttcctatttt tgaaatctga acatgaatca ttcacatgac caaaaattgt gtttttttaa 4260aaatacatgt ctagtctgtc ctttaatagc tctcttaaat aagctatgat attaatcaga 4320tcattaccag ttagctttta aagcacattt gtttaagact atgtttttgg aaaaatacgc 4380tacagaattt ttttttaagc tacaaataaa tgagatgcta ctaattgttt tggaatctgt 4440tgtttctgcc aaaggtaaat taactaaaga tttattcagg aatccccatt tgaatttgta 4500tgattcaata aaagaaaaca ccaagtaagt tatataaaat aaattgtgta tgagatgttg 4560tgttttcctt tgtaatttcc actaactaac taactaactt atattcttca tggaatggag 4620cccagaagaa atgagaggaa gcccttttca cactagatct tatttgaaga aatgtttgtt 4680agtcagtcag tcagtggttt ctggctctgc cgagggagat gtgttcccca gcaaccattt 4740ctgcagccca gaatctcaag gcactagagg cggtgtctta attaattggc ttcacaaaga 4800caaaatgctc tggactggga tttttccttt gctgtgttgg gaatatgtgt ttattaatta 4860gcacatgcca acaaaataaa tgtcaagagt tatttcataa gtgtaagtaa acttaagaat 4920taaagagtgc agacttataa ttttca 494643669PRTHomo sapiens 43Met Ala Cys Glu Ile Met Pro Leu Gln Arg Leu Leu Glu Arg Thr Ile1 5 10 15Arg Ser Ala Val Glu Gln His Leu Phe Asp Val Asn Asn Ser Gly Gly 20 25 30Gln Ser Ser Glu Asp Ser Glu Ser Gly Thr Leu Ser Ala Ser Ser Ala 35 40 45Thr Ser Ala Arg Gln Arg Arg Arg Gln Ser Lys Glu Gln Asp Glu Val 50 55 60Arg His Gly Arg Asp Lys Gly Leu Ile Asn Lys Glu Asn Thr Pro Ser65 70 75 80Gly Phe Asn His Leu Asp Asp Cys Ile Leu Asn Thr Gln Glu Val Glu 85 90 95Lys Val His Lys Asn Thr Phe Gly Cys Ala Gly Glu Arg Ser Lys Pro 100 105 110Lys Arg Gln Lys Ser Ser Thr Lys Leu Ser Glu Leu His Asp Asn Gln 115 120 125Asp Gly Leu Val Asn Met Glu Ser Leu Asn Ser Thr Arg Ser His Glu 130 135 140Arg Thr Gly Pro Asp Asp Phe Glu Trp Met Ser Asp Glu Arg Lys Gly145 150 155 160Asn Glu Lys Asp Gly Gly His Thr Gln His Phe Glu Ser Pro Thr Met 165 170 175Lys Ile Gln Glu His Pro Ser Leu Ser Asp Thr Lys Gln Gln Arg Asn 180 185 190Gln Asp Ala Gly Asp Gln Glu Glu Ser Phe Val Ser Glu Val Pro Gln 195 200 205Ser Asp Leu Thr Ala Leu Cys Asp Glu Lys Asn Trp Glu Glu Pro Ile 210 215 220Pro Ala Phe Ser Ser

Trp Gln Arg Glu Asn Ser Asp Ser Asp Glu Ala225 230 235 240His Leu Ser Pro Gln Ala Gly Arg Leu Ile Arg Gln Leu Leu Asp Glu 245 250 255Asp Ser Asp Pro Met Leu Ser Pro Arg Phe Tyr Ala Tyr Gly Gln Ser 260 265 270Arg Gln Tyr Leu Asp Asp Thr Glu Val Pro Pro Ser Pro Pro Asn Ser 275 280 285His Ser Phe Met Arg Arg Arg Ser Ser Ser Leu Gly Ser Tyr Asp Asp 290 295 300Glu Gln Glu Asp Leu Thr Pro Ala Gln Leu Thr Arg Arg Ile Gln Ser305 310 315 320Leu Lys Lys Lys Ile Arg Lys Phe Glu Asp Arg Phe Glu Glu Glu Lys 325 330 335Lys Tyr Arg Pro Ser His Ser Asp Lys Ala Ala Asn Pro Glu Val Leu 340 345 350Lys Trp Thr Asn Asp Leu Ala Lys Phe Arg Arg Gln Leu Lys Glu Ser 355 360 365Lys Leu Lys Ile Ser Glu Glu Asp Leu Thr Pro Arg Met Arg Gln Arg 370 375 380Ser Asn Thr Leu Pro Lys Ser Phe Gly Ser Gln Leu Glu Lys Glu Asp385 390 395 400Glu Lys Lys Gln Glu Leu Val Asp Lys Ala Ile Lys Pro Ser Val Glu 405 410 415Ala Thr Leu Glu Ser Ile Gln Arg Lys Leu Gln Glu Lys Arg Ala Glu 420 425 430Ser Ser Arg Pro Glu Asp Ile Lys Asp Met Thr Lys Asp Gln Ile Ala 435 440 445Asn Glu Lys Val Ala Leu Gln Lys Ala Leu Leu Tyr Tyr Glu Ser Ile 450 455 460His Gly Arg Pro Val Thr Lys Asn Glu Arg Gln Val Met Lys Pro Leu465 470 475 480Tyr Asp Arg Tyr Arg Leu Val Lys Gln Ile Leu Ser Arg Ala Asn Thr 485 490 495Ile Pro Ile Ile Gly Ser Pro Ser Ser Lys Arg Arg Ser Pro Leu Leu 500 505 510Gln Pro Ile Ile Glu Gly Glu Thr Ala Ser Phe Phe Lys Glu Ile Lys 515 520 525Glu Glu Glu Glu Gly Ser Glu Asp Asp Ser Asn Val Lys Pro Asp Phe 530 535 540Met Val Thr Leu Lys Thr Asp Phe Ser Ala Arg Cys Phe Leu Asp Gln545 550 555 560Phe Glu Asp Asp Ala Asp Gly Phe Ile Ser Pro Met Asp Asp Lys Ile 565 570 575Pro Ser Lys Cys Ser Gln Asp Thr Gly Leu Ser Asn Leu His Ala Ala 580 585 590Ser Ile Pro Glu Leu Leu Glu His Leu Gln Glu Met Arg Glu Glu Lys 595 600 605Lys Arg Ile Arg Lys Lys Leu Arg Asp Phe Glu Asp Asn Phe Phe Arg 610 615 620Gln Asn Gly Arg Asn Val Gln Lys Glu Asp Arg Thr Pro Met Ala Glu625 630 635 640Glu Tyr Ser Glu Tyr Lys His Ile Lys Ala Lys Leu Arg Leu Leu Glu 645 650 655Val Leu Ile Ser Lys Arg Asp Thr Asp Ser Lys Ser Met 660 665449802DNAHomo sapiens 44aagaaaccgg ccaggtgtgg cctaggcgcc cagtgccagc ggggaggaga ctcgctccgc 60cgccgaccaa caccaacacc cagctccgac gcagctcctc tgcgcccttg ccgccctccg 120agccacagct ttcctcccgc tcctgccccc ggcccgtcgc cgtctccgcg ctcgcagcgg 180cctcgggagg gcccaggtag cgagcagcga cctcgcgagc cttccgcact cccgcccggt 240tccccggccg tccgcctatc cttggccccc tccgctttct ccgcgccggc ccgcctcgct 300tatgcctcgg cgctgagccg ctctcccgat tgcccgccga catgagctgc aacggaggct 360cccacccgcg gatcaacact ctgggccgca tgatccgcgc cgagtctggc ccggacctgc 420gctacgaggt gaccagcggc ggcgggggca ccagcaggat gtactattct cggcgcggcg 480tgatcaccga ccagaactcg gacggctact gtcaaaccgg cacgatgtcc aggcaccaga 540accagaacac catccaggag ctgctgcaga actgctccga ctgcttgatg cgagcagagc 600tcatcgtgca gcctgaattg aagtatggag atggaataca actgactcgg agtcgagaat 660tggatgagtg ttttgcccag gccaatgacc aaatggaaat cctcgacagc ttgatcagag 720agatgcggca gatgggccag ccctgtgatg cttaccagaa aaggcttctt cagctccaag 780agcaaatgcg agccctttat aaagccatca gtgtccctcg agtccgcagg gccagctcca 840agggtggtgg aggctacact tgtcagagtg gctctggctg ggatgagttc accaaacatg 900tcaccagtga atgtttgggg tggatgaggc agcaaagggc ggagatggac atggtggcct 960ggggtgtgga cctggcctca gtggagcagc acattaacag ccaccggggc atccacaact 1020ccatcggcga ctatcgctgg cagctggaca aaatcaaagc cgacctgcgc gagaaatctg 1080cgatctacca gttggaggag gagtatgaaa acctgctgaa agcgtccttt gagaggatgg 1140atcacctgcg acagctgcag aacatcattc aggccacgtc cagggagatc atgtggatca 1200atgactgcga ggaggaggag ctgctgtacg actggagcga caagaacacc aacatcgctc 1260agaaacagga ggccttctcc atacgcatga gtcaactgga agttaaagaa aaagagctca 1320ataagctgaa acaagaaagt gaccaacttg tcctcaatca gcatccagct tcagacaaaa 1380ttgaggccta tatggacact ctgcagacgc agtggagttg gattcttcag atcaccaagt 1440gcattgatgt tcatctgaaa gaaaatgctg cctactttca gttttttgaa gaggcgcagt 1500ctactgaagc atacctgaag gggctccagg actccatcag gaagaagtac ccctgcgaca 1560agaacatgcc cctgcagcac ctgctggaac agatcaagga gctggagaaa gaacgagaga 1620aaatccttga atacaagcgt caggtgcaga acttggtaaa caagtctaag aagattgtac 1680agctgaagcc tcgtaaccca gactacagaa gcaataaacc cattattctc agagctctct 1740gtgactacaa acaagatcag aaaatcgtgc ataaggggga tgagtgtatc ctgaaggaca 1800acaacgagcg cagcaagtgg tacgtgacgg gcccgggagg cgttgacatg cttgttccct 1860ctgtggggct gatcatccct cctccgaacc cactggccgt ggacctctct tgcaagattg 1920agcagtacta cgaagccatc ttggctctgt ggaaccagct ctacatcaac atgaagagcc 1980tggtgtcctg gcactactgc atgattgaca tagagaagat cagggccatg acaatcgcca 2040agctgaaaac aatgcggcag gaagattaca tgaagacgat agccgacctt gagttacatt 2100accaagagtt catcagaaat agccaaggct cagagatgtt tggagatgat gacaagcgga 2160aaatacagtc tcagttcacc gatgcccaga agcattacca gaccctggtc attcagctcc 2220ctggctatcc ccagcaccag acagtgacca caactgaaat cactcatcat ggaacctgcc 2280aagatgtcaa ccataataaa gtaattgaaa ccaacagaga aaatgacaag caagaaacat 2340ggatgctgat ggagctgcag aagattcgca ggcagataga gcactgcgag ggcaggatga 2400ctctcaaaaa cctccctcta gcagaccagg gatcttctca ccacatcaca gtgaaaatta 2460acgagcttaa gagtgtgcag aatgattcac aagcaattgc tgaggttctc aaccagctta 2520aagatatgct tgccaacttc agaggttctg aaaagtactg ctatttacag aatgaagtat 2580ttggactatt tcagaaactg gaaaatatca atggtgttac agatggctac ttaaatagct 2640tatgcacagt aagggcactg ctccaggcta ttctccaaac agaagacatg ttaaaggttt 2700atgaagccag gctcactgag gaggaaactg tctgcctgga cctggataaa gtggaagctt 2760accgctgtgg actgaagaaa ataaaaaatg acttgaactt gaagaagtcg ttgttggcca 2820ctatgaagac agaactacag aaagcccagc agatccactc tcagacttca cagcagtatc 2880cactttatga tctggacttg ggcaagttcg gtgaaaaagt cacacagctg acagaccgct 2940ggcaaaggat agataaacag atcgacttta ggttatggga cctggagaaa caaatcaagc 3000aattgaggaa ttatcgtgat aactatcagg ctttctgcaa gtggctctat gatgctaaac 3060gccgccagga ttccttagaa tccatgaaat ttggagattc caacacagtc atgcggtttt 3120tgaatgagca gaagaacttg cacagtgaaa tatctggcaa acgagacaaa tcagaggaag 3180tacaaaaaat tgctgaactt tgcgccaatt caattaagga ttatgagctc cagctggcct 3240catacacctc aggactggaa actctgctga acatacctat caagaggacc atgattcagt 3300ccccttctgg ggtgattctg caagaggctg cagatgttca tgctcggtac attgaactac 3360ttacaagatc tggagactat tacaggttct taagtgagat gctgaagagt ttggaagatc 3420tgaagctgaa aaataccaag atcgaagttt tggaagagga gctcagactg gcccgagatg 3480ccaactcgga aaactgtaat aagaacaaat tcctggatca gaacctgcag aaataccagg 3540cagagtgttc ccagttcaaa gcgaagcttg cgagcctgga ggagctgaag agacaggctg 3600agctggatgg gaagtcggct aagcaaaatc tagacaagtg ctacggccaa ataaaagaac 3660tcaatgagaa gatcacccga ctgacttatg agattgaaga tgaaaagaga agaagaaaat 3720ctgtggaaga cagatttgac caacagaaga atgactatga ccaactgcag aaagcaaggc 3780aatgtgaaaa ggagaacctt ggttggcaga aattagagtc tgagaaagcc atcaaggaga 3840aggagtacga gattgaaagg ttgagggttc tactgcagga agaaggcacc cggaagagag 3900aatatgaaaa tgagctggca aaggtaagaa accactataa tgaggagatg agtaatttaa 3960ggaacaagta tgaaacagag attaacatta cgaagaccac catcaaggag atatccatgc 4020aaaaagagga tgattccaaa aatcttagaa accagcttga tagactttca agggaaaatc 4080gagatctgaa ggatgaaatt gtcaggctca atgacagcat cttgcaggcc actgagcagc 4140gaaggcgagc tgaagaaaac gcccttcagc aaaaggcctg tggctctgag ataatgcaga 4200agaagcagca tctggagata gaactgaagc aggtcatgca gcagcgctct gaggacaatg 4260cccggcacaa gcagtccctg gaggaggctg ccaagaccat tcaggacaaa aataaggaga 4320tcgagagact caaagctgag tttcaggagg aggccaagcg ccgctgggaa tatgaaaatg 4380aactgagtaa ggtaagaaac aattatgatg aggagatcat tagcttaaaa aatcagtttg 4440agaccgagat caacatcacc aagaccacca tccaccagct caccatgcag aaggaagagg 4500ataccagtgg ctaccgggct cagatagaca atctcacccg agaaaacagg agcttatctg 4560aagaaataaa gaggctgaag aacactctaa cccagaccac agagaatctc aggagggtgg 4620aagaagacat ccaacagcaa aaggccactg gctctgaggt gtctcagagg aaacagcagc 4680tggaggttga gctgagacaa gtcactcaga tgcgaacaga ggagagcgta agatataagc 4740aatctcttga tgatgctgcc aaaaccatcc aggataaaaa caaggagata gaaaggttaa 4800aacaactgat cgacaaagaa acaaatgacc ggaaatgcct ggaagatgaa aacgcgagat 4860tacaaagggt ccagtatgac ctgcagaaag caaacagtag tgcgacggag acaataaaca 4920aactgaaggt tcaggagcaa gaactgacac gcctgaggat cgactatgaa agggtttccc 4980aggagaggac tgtgaaggac caggatatca cgcggttcca gaactctctg aaagagctgc 5040agctgcagaa gcagaaggtg gaagaggagc tgaatcggct gaagaggacc gcgtcagaag 5100actcctgcaa gaggaagaag ctggaggaag agctggaagg catgaggagg tcgctgaagg 5160agcaagccat caaaatcacc aacctgaccc agcagctgga gcaggcatcc attgttaaga 5220agaggagtga ggatgacctc cggcagcaga gggacgtgct ggatggccac ctgagggaaa 5280agcagaggac ccaggaagag ctgaggaggc tctcttctga ggtcgaggcc ctgaggcggc 5340agttactcca ggaacaggaa agtgtcaaac aagctcactt gaggaatgag catttccaga 5400aggcgataga agataaaagc agaagcttaa atgaaagcaa aatagaaatt gagaggctgc 5460agtctctcac agagaacctg accaaggagc acttgatgtt agaagaagaa ctgcggaacc 5520tgaggctgga gtacgatgac ctgaggagag gacgaagcga agcggacagt gataaaaatg 5580caaccatctt ggaactaagg agccagctgc agatcagcaa caaccggacc ctggaactgc 5640aggggctgat taatgattta cagagagaga gggaaaattt gagacaggaa attgagaaat 5700tccaaaagca ggctttagag gcatctaata ggattcagga atcaaagaat cagtgtactc 5760aggtggtaca ggaaagagag agccttctgg tgaaaatcaa agtcctggag caagacaagg 5820caaggctgca gaggctggag gatgagctga atcgtgcaaa atcaactcta gaggcagaaa 5880ccagggtgaa acagcgcctg gagtgtgaga aacagcaaat tcagaatgac ctgaatcagt 5940ggaagactca atattcccgc aaggaggagg ctattaggaa gatagaatcg gaaagagaaa 6000agagtgagag agagaagaac agtcttagga gtgagatcga aagactccaa gcagagatca 6060agagaattga agagaggtgc aggcgtaagc tggaggattc taccagggag acacagtcac 6120agttagaaac agaacgctcc cgatatcaga gggagattga taaactcaga cagcgcccat 6180atgggtccca tcgagagacc cagactgagt gtgagtggac cgttgacacc tccaagctgg 6240tgtttgatgg gctgaggaag aaggtgacag caatgcagct ctatgagtgt cagctgatcg 6300acaaaacaac cttggacaaa ctattgaagg ggaagaagtc agtggaagaa gttgcttctg 6360aaatccagcc attccttcgg ggtgcaggat ctatcgctgg agcatctgct tctcctaagg 6420aaaaatactc tttggtagag gccaagagaa agaaattaat cagcccagaa tccacagtca 6480tgcttctgga ggcccaggca gctacaggtg gtataattga tccccatcgg aatgagaagc 6540tgactgtcga cagtgccata gctcgggacc tcattgactt cgatgaccgt cagcagatat 6600atgcagcaga aaaagctatc actggttttg atgatccatt ttcaggcaag acagtatctg 6660tttcagaagc catcaagaaa aatttgattg atagagaaac cggaatgcgc ctgctggaag 6720cccagattgc ttcagggggt gtagtagacc ctgtgaacag tgtctttttg ccaaaagatg 6780tcgccttggc ccgggggctg attgatagag atttgtatcg atccctgaat gatccccgag 6840atagtcagaa aaactttgtg gatccagtca ccaaaaagaa ggtcagttac gtgcagctga 6900aggaacggtg cagaatcgaa ccacatactg gtctgctctt gctttcagta cagaagagaa 6960gcatgtcctt ccaaggaatc agacaacctg tgaccgtcac tgagctagta gattctggta 7020tattgagacc gtccactgtc aatgaactgg aatctggtca gatttcttat gacgaggttg 7080gtgagagaat taaggacttc ctccagggtt caagctgcat agcaggcata tacaatgaga 7140ccacaaaaca gaagcttggc atttatgagg ccatgaaaat tggcttagtc cgacctggta 7200ctgctctgga gttgctggaa gcccaagcag ctactggctt tatagtggat cctgttagca 7260acttgaggtt accagtggag gaagcctaca agagaggtct ggtgggcatt gagttcaaag 7320agaagctcct gtctgcagaa cgagctgtca ctgggtataa tgatcctgaa acaggaaaca 7380tcatctcttt gttccaagcc atgaataagg aactcatcga aaagggccac ggtattcgct 7440tattagaagc acagatcgca accgggggga tcattgaccc aaaggagagc catcgtttac 7500cagttgacat agcatataag aggggctatt tcaatgagga actcagtgag attctctcag 7560atccaagtga tgataccaaa ggattttttg accccaacac tgaagaaaat cttacctatc 7620tgcaactaaa agaaagatgc attaaggatg aggaaacagg gctctgtctt ctgcctctga 7680aagaaaagaa gaaacaggtg cagacatcac aaaagaatac cctcaggaag cgtagagtgg 7740tcatagttga cccagaaacc aataaagaaa tgtctgttca ggaggcctac aagaagggcc 7800taattgatta tgaaaccttc aaagaactgt gtgagcagga atgtgaatgg gaagaaataa 7860ccatcacggg atcagatggc tccaccaggg tggtcctggt agatagaaag acaggcagtc 7920agtatgatat tcaagatgct attgacaagg gccttgttga caggaagttc tttgatcagt 7980accgatccgg cagcctcagc ctcactcaat ttgctgacat gatctccttg aaaaatggtg 8040tcggcaccag cagcagcatg ggcagtggtg tcagcgatga tgtttttagc agctcccgac 8100atgaatcagt aagtaagatt tccaccatat ccagcgtcag gaatttaacc ataaggagca 8160gctctttttc agacaccctg gaagaatcga gccccattgc agccatcttt gacacagaaa 8220acctggagaa aatctccatt acagaaggta tagagcgggg catcgttgac agcatcacgg 8280gtcagaggct tctggaggct caggcctgca caggtggcat catccaccca accacgggcc 8340agaagctgtc acttcaggac gcagtctccc agggtgtgat tgaccaagac atggccacca 8400ggctgaagcc tgctcagaaa gccttcatag gcttcgaggg tgtgaaggga aagaagaaga 8460tgtcagcagc agaggcagtg aaagaaaaat ggctcccgta tgaggctggc cagcgcttcc 8520tggagttcca gtacctcacg ggaggtcttg ttgacccgga agtgcatggg aggataagca 8580ccgaagaagc catccggaag gggttcatag atggccgcgc cgcacagagg ctgcaagaca 8640ccagcagcta tgccaaaatc ctgacctgcc ccaaaaccaa attaaaaata tcctataagg 8700atgccataaa tcgctccatg gtagaagata tcactgggct gcgccttctg gaagccgcct 8760ccgtgtcgtc caagggctta cccagccctt acaacatgtc ttcggctccg gggtcccgct 8820ccggctcccg ctcgggatct cgctccggat ctcgctccgg gtcccgcagt gggtcccgga 8880gaggaagctt tgacgccaca gggaattctt cctactctta ttcctactca tttagcagta 8940gttctattgg gcactagtag tcagttggga gtggttgcta taccttgact tcatttatat 9000gaatttccac tttattaaat aatagaaaag aaaatcccgg tgcttgcagt agagtgatag 9060gacattctat gcttacagaa aatatagcca tgattgaaat caaatagtaa aggctgttct 9120ggctttttat cttcttagct catcttaaat aagcagtaca cttggatgca gtgcgtctga 9180agtgctaatc agttgtaaca atagcacaaa tcgaacttag gatttgtttc ttctcttctg 9240tgtttcgatt tttgatcaat tctttaattt tggaagccta taatacagtt ttctattctt 9300ggagataaaa attaaatgga tcactgatat tttagtcatt ctgcttctca tctaaatatt 9360tccatattct gtattaggag aaaattaccc tcccagcacc agcccccctc tcaaaccccc 9420aacccaaaac caagcatttt ggaatgagtc tcctttagtt tcagagtgtg gattgtataa 9480cccatatact cttcgatgta cttgtttggt ttggtattaa tttgactgtg catgacagcg 9540gcaatctttt ctttggtcaa agttttctgt ttattttgct tgtcatattc gatgtacttt 9600aaggtgtctt tatgaagttt gctattctgg caataaactt ttagactttt gaagtgtttg 9660tgttttaatt taatatgttt ataagcatgt ataaacattt agcatatttt tatcataggt 9720ctaaaaatat ttgtttacta aatacctgtg aagaaatacc attaaaaaac tatttggttc 9780tgaattctta ctagaaaaaa aa 9802452871PRTHomo sapiens 45Met Ser Cys Asn Gly Gly Ser His Pro Arg Ile Asn Thr Leu Gly Arg1 5 10 15Met Ile Arg Ala Glu Ser Gly Pro Asp Leu Arg Tyr Glu Val Thr Ser 20 25 30Gly Gly Gly Gly Thr Ser Arg Met Tyr Tyr Ser Arg Arg Gly Val Ile 35 40 45Thr Asp Gln Asn Ser Asp Gly Tyr Cys Gln Thr Gly Thr Met Ser Arg 50 55 60His Gln Asn Gln Asn Thr Ile Gln Glu Leu Leu Gln Asn Cys Ser Asp65 70 75 80Cys Leu Met Arg Ala Glu Leu Ile Val Gln Pro Glu Leu Lys Tyr Gly 85 90 95Asp Gly Ile Gln Leu Thr Arg Ser Arg Glu Leu Asp Glu Cys Phe Ala 100 105 110Gln Ala Asn Asp Gln Met Glu Ile Leu Asp Ser Leu Ile Arg Glu Met 115 120 125Arg Gln Met Gly Gln Pro Cys Asp Ala Tyr Gln Lys Arg Leu Leu Gln 130 135 140Leu Gln Glu Gln Met Arg Ala Leu Tyr Lys Ala Ile Ser Val Pro Arg145 150 155 160Val Arg Arg Ala Ser Ser Lys Gly Gly Gly Gly Tyr Thr Cys Gln Ser 165 170 175Gly Ser Gly Trp Asp Glu Phe Thr Lys His Val Thr Ser Glu Cys Leu 180 185 190Gly Trp Met Arg Gln Gln Arg Ala Glu Met Asp Met Val Ala Trp Gly 195 200 205Val Asp Leu Ala Ser Val Glu Gln His Ile Asn Ser His Arg Gly Ile 210 215 220His Asn Ser Ile Gly Asp Tyr Arg Trp Gln Leu Asp Lys Ile Lys Ala225 230 235 240Asp Leu Arg Glu Lys Ser Ala Ile Tyr Gln Leu Glu Glu Glu Tyr Glu 245 250 255Asn Leu Leu Lys Ala Ser Phe Glu Arg Met Asp His Leu Arg Gln Leu 260 265 270Gln Asn Ile Ile Gln Ala Thr Ser Arg Glu Ile Met Trp Ile Asn Asp 275 280 285Cys Glu Glu Glu Glu Leu Leu Tyr Asp Trp Ser Asp Lys Asn Thr Asn 290 295 300Ile Ala Gln Lys Gln Glu Ala Phe Ser Ile Arg Met Ser Gln Leu Glu305 310 315 320Val Lys Glu Lys Glu Leu Asn Lys Leu Lys Gln Glu Ser Asp Gln Leu 325 330 335Val Leu Asn Gln His Pro Ala Ser Asp Lys Ile Glu Ala Tyr Met Asp 340 345 350Thr Leu Gln Thr Gln Trp Ser Trp Ile Leu Gln Ile Thr Lys Cys Ile 355 360 365Asp Val His Leu Lys Glu Asn Ala Ala Tyr Phe Gln Phe Phe Glu Glu 370 375 380Ala Gln Ser Thr Glu Ala Tyr Leu Lys Gly Leu Gln Asp Ser Ile Arg385 390 395 400Lys Lys Tyr Pro Cys Asp Lys Asn Met Pro Leu Gln His Leu Leu

Glu 405 410 415Gln Ile Lys Glu Leu Glu Lys Glu Arg Glu Lys Ile Leu Glu Tyr Lys 420 425 430Arg Gln Val Gln Asn Leu Val Asn Lys Ser Lys Lys Ile Val Gln Leu 435 440 445Lys Pro Arg Asn Pro Asp Tyr Arg Ser Asn Lys Pro Ile Ile Leu Arg 450 455 460Ala Leu Cys Asp Tyr Lys Gln Asp Gln Lys Ile Val His Lys Gly Asp465 470 475 480Glu Cys Ile Leu Lys Asp Asn Asn Glu Arg Ser Lys Trp Tyr Val Thr 485 490 495Gly Pro Gly Gly Val Asp Met Leu Val Pro Ser Val Gly Leu Ile Ile 500 505 510Pro Pro Pro Asn Pro Leu Ala Val Asp Leu Ser Cys Lys Ile Glu Gln 515 520 525Tyr Tyr Glu Ala Ile Leu Ala Leu Trp Asn Gln Leu Tyr Ile Asn Met 530 535 540Lys Ser Leu Val Ser Trp His Tyr Cys Met Ile Asp Ile Glu Lys Ile545 550 555 560Arg Ala Met Thr Ile Ala Lys Leu Lys Thr Met Arg Gln Glu Asp Tyr 565 570 575Met Lys Thr Ile Ala Asp Leu Glu Leu His Tyr Gln Glu Phe Ile Arg 580 585 590Asn Ser Gln Gly Ser Glu Met Phe Gly Asp Asp Asp Lys Arg Lys Ile 595 600 605Gln Ser Gln Phe Thr Asp Ala Gln Lys His Tyr Gln Thr Leu Val Ile 610 615 620Gln Leu Pro Gly Tyr Pro Gln His Gln Thr Val Thr Thr Thr Glu Ile625 630 635 640Thr His His Gly Thr Cys Gln Asp Val Asn His Asn Lys Val Ile Glu 645 650 655Thr Asn Arg Glu Asn Asp Lys Gln Glu Thr Trp Met Leu Met Glu Leu 660 665 670Gln Lys Ile Arg Arg Gln Ile Glu His Cys Glu Gly Arg Met Thr Leu 675 680 685Lys Asn Leu Pro Leu Ala Asp Gln Gly Ser Ser His His Ile Thr Val 690 695 700Lys Ile Asn Glu Leu Lys Ser Val Gln Asn Asp Ser Gln Ala Ile Ala705 710 715 720Glu Val Leu Asn Gln Leu Lys Asp Met Leu Ala Asn Phe Arg Gly Ser 725 730 735Glu Lys Tyr Cys Tyr Leu Gln Asn Glu Val Phe Gly Leu Phe Gln Lys 740 745 750Leu Glu Asn Ile Asn Gly Val Thr Asp Gly Tyr Leu Asn Ser Leu Cys 755 760 765Thr Val Arg Ala Leu Leu Gln Ala Ile Leu Gln Thr Glu Asp Met Leu 770 775 780Lys Val Tyr Glu Ala Arg Leu Thr Glu Glu Glu Thr Val Cys Leu Asp785 790 795 800Leu Asp Lys Val Glu Ala Tyr Arg Cys Gly Leu Lys Lys Ile Lys Asn 805 810 815Asp Leu Asn Leu Lys Lys Ser Leu Leu Ala Thr Met Lys Thr Glu Leu 820 825 830Gln Lys Ala Gln Gln Ile His Ser Gln Thr Ser Gln Gln Tyr Pro Leu 835 840 845Tyr Asp Leu Asp Leu Gly Lys Phe Gly Glu Lys Val Thr Gln Leu Thr 850 855 860Asp Arg Trp Gln Arg Ile Asp Lys Gln Ile Asp Phe Arg Leu Trp Asp865 870 875 880Leu Glu Lys Gln Ile Lys Gln Leu Arg Asn Tyr Arg Asp Asn Tyr Gln 885 890 895Ala Phe Cys Lys Trp Leu Tyr Asp Ala Lys Arg Arg Gln Asp Ser Leu 900 905 910Glu Ser Met Lys Phe Gly Asp Ser Asn Thr Val Met Arg Phe Leu Asn 915 920 925Glu Gln Lys Asn Leu His Ser Glu Ile Ser Gly Lys Arg Asp Lys Ser 930 935 940Glu Glu Val Gln Lys Ile Ala Glu Leu Cys Ala Asn Ser Ile Lys Asp945 950 955 960Tyr Glu Leu Gln Leu Ala Ser Tyr Thr Ser Gly Leu Glu Thr Leu Leu 965 970 975Asn Ile Pro Ile Lys Arg Thr Met Ile Gln Ser Pro Ser Gly Val Ile 980 985 990Leu Gln Glu Ala Ala Asp Val His Ala Arg Tyr Ile Glu Leu Leu Thr 995 1000 1005Arg Ser Gly Asp Tyr Tyr Arg Phe Leu Ser Glu Met Leu Lys Ser 1010 1015 1020Leu Glu Asp Leu Lys Leu Lys Asn Thr Lys Ile Glu Val Leu Glu 1025 1030 1035Glu Glu Leu Arg Leu Ala Arg Asp Ala Asn Ser Glu Asn Cys Asn 1040 1045 1050Lys Asn Lys Phe Leu Asp Gln Asn Leu Gln Lys Tyr Gln Ala Glu 1055 1060 1065Cys Ser Gln Phe Lys Ala Lys Leu Ala Ser Leu Glu Glu Leu Lys 1070 1075 1080Arg Gln Ala Glu Leu Asp Gly Lys Ser Ala Lys Gln Asn Leu Asp 1085 1090 1095Lys Cys Tyr Gly Gln Ile Lys Glu Leu Asn Glu Lys Ile Thr Arg 1100 1105 1110Leu Thr Tyr Glu Ile Glu Asp Glu Lys Arg Arg Arg Lys Ser Val 1115 1120 1125Glu Asp Arg Phe Asp Gln Gln Lys Asn Asp Tyr Asp Gln Leu Gln 1130 1135 1140Lys Ala Arg Gln Cys Glu Lys Glu Asn Leu Gly Trp Gln Lys Leu 1145 1150 1155Glu Ser Glu Lys Ala Ile Lys Glu Lys Glu Tyr Glu Ile Glu Arg 1160 1165 1170Leu Arg Val Leu Leu Gln Glu Glu Gly Thr Arg Lys Arg Glu Tyr 1175 1180 1185Glu Asn Glu Leu Ala Lys Val Arg Asn His Tyr Asn Glu Glu Met 1190 1195 1200Ser Asn Leu Arg Asn Lys Tyr Glu Thr Glu Ile Asn Ile Thr Lys 1205 1210 1215Thr Thr Ile Lys Glu Ile Ser Met Gln Lys Glu Asp Asp Ser Lys 1220 1225 1230Asn Leu Arg Asn Gln Leu Asp Arg Leu Ser Arg Glu Asn Arg Asp 1235 1240 1245Leu Lys Asp Glu Ile Val Arg Leu Asn Asp Ser Ile Leu Gln Ala 1250 1255 1260Thr Glu Gln Arg Arg Arg Ala Glu Glu Asn Ala Leu Gln Gln Lys 1265 1270 1275Ala Cys Gly Ser Glu Ile Met Gln Lys Lys Gln His Leu Glu Ile 1280 1285 1290Glu Leu Lys Gln Val Met Gln Gln Arg Ser Glu Asp Asn Ala Arg 1295 1300 1305His Lys Gln Ser Leu Glu Glu Ala Ala Lys Thr Ile Gln Asp Lys 1310 1315 1320Asn Lys Glu Ile Glu Arg Leu Lys Ala Glu Phe Gln Glu Glu Ala 1325 1330 1335Lys Arg Arg Trp Glu Tyr Glu Asn Glu Leu Ser Lys Val Arg Asn 1340 1345 1350Asn Tyr Asp Glu Glu Ile Ile Ser Leu Lys Asn Gln Phe Glu Thr 1355 1360 1365Glu Ile Asn Ile Thr Lys Thr Thr Ile His Gln Leu Thr Met Gln 1370 1375 1380Lys Glu Glu Asp Thr Ser Gly Tyr Arg Ala Gln Ile Asp Asn Leu 1385 1390 1395Thr Arg Glu Asn Arg Ser Leu Ser Glu Glu Ile Lys Arg Leu Lys 1400 1405 1410Asn Thr Leu Thr Gln Thr Thr Glu Asn Leu Arg Arg Val Glu Glu 1415 1420 1425Asp Ile Gln Gln Gln Lys Ala Thr Gly Ser Glu Val Ser Gln Arg 1430 1435 1440Lys Gln Gln Leu Glu Val Glu Leu Arg Gln Val Thr Gln Met Arg 1445 1450 1455Thr Glu Glu Ser Val Arg Tyr Lys Gln Ser Leu Asp Asp Ala Ala 1460 1465 1470Lys Thr Ile Gln Asp Lys Asn Lys Glu Ile Glu Arg Leu Lys Gln 1475 1480 1485Leu Ile Asp Lys Glu Thr Asn Asp Arg Lys Cys Leu Glu Asp Glu 1490 1495 1500Asn Ala Arg Leu Gln Arg Val Gln Tyr Asp Leu Gln Lys Ala Asn 1505 1510 1515Ser Ser Ala Thr Glu Thr Ile Asn Lys Leu Lys Val Gln Glu Gln 1520 1525 1530Glu Leu Thr Arg Leu Arg Ile Asp Tyr Glu Arg Val Ser Gln Glu 1535 1540 1545Arg Thr Val Lys Asp Gln Asp Ile Thr Arg Phe Gln Asn Ser Leu 1550 1555 1560Lys Glu Leu Gln Leu Gln Lys Gln Lys Val Glu Glu Glu Leu Asn 1565 1570 1575Arg Leu Lys Arg Thr Ala Ser Glu Asp Ser Cys Lys Arg Lys Lys 1580 1585 1590Leu Glu Glu Glu Leu Glu Gly Met Arg Arg Ser Leu Lys Glu Gln 1595 1600 1605Ala Ile Lys Ile Thr Asn Leu Thr Gln Gln Leu Glu Gln Ala Ser 1610 1615 1620Ile Val Lys Lys Arg Ser Glu Asp Asp Leu Arg Gln Gln Arg Asp 1625 1630 1635Val Leu Asp Gly His Leu Arg Glu Lys Gln Arg Thr Gln Glu Glu 1640 1645 1650Leu Arg Arg Leu Ser Ser Glu Val Glu Ala Leu Arg Arg Gln Leu 1655 1660 1665Leu Gln Glu Gln Glu Ser Val Lys Gln Ala His Leu Arg Asn Glu 1670 1675 1680His Phe Gln Lys Ala Ile Glu Asp Lys Ser Arg Ser Leu Asn Glu 1685 1690 1695Ser Lys Ile Glu Ile Glu Arg Leu Gln Ser Leu Thr Glu Asn Leu 1700 1705 1710Thr Lys Glu His Leu Met Leu Glu Glu Glu Leu Arg Asn Leu Arg 1715 1720 1725Leu Glu Tyr Asp Asp Leu Arg Arg Gly Arg Ser Glu Ala Asp Ser 1730 1735 1740Asp Lys Asn Ala Thr Ile Leu Glu Leu Arg Ser Gln Leu Gln Ile 1745 1750 1755Ser Asn Asn Arg Thr Leu Glu Leu Gln Gly Leu Ile Asn Asp Leu 1760 1765 1770Gln Arg Glu Arg Glu Asn Leu Arg Gln Glu Ile Glu Lys Phe Gln 1775 1780 1785Lys Gln Ala Leu Glu Ala Ser Asn Arg Ile Gln Glu Ser Lys Asn 1790 1795 1800Gln Cys Thr Gln Val Val Gln Glu Arg Glu Ser Leu Leu Val Lys 1805 1810 1815Ile Lys Val Leu Glu Gln Asp Lys Ala Arg Leu Gln Arg Leu Glu 1820 1825 1830Asp Glu Leu Asn Arg Ala Lys Ser Thr Leu Glu Ala Glu Thr Arg 1835 1840 1845Val Lys Gln Arg Leu Glu Cys Glu Lys Gln Gln Ile Gln Asn Asp 1850 1855 1860Leu Asn Gln Trp Lys Thr Gln Tyr Ser Arg Lys Glu Glu Ala Ile 1865 1870 1875Arg Lys Ile Glu Ser Glu Arg Glu Lys Ser Glu Arg Glu Lys Asn 1880 1885 1890Ser Leu Arg Ser Glu Ile Glu Arg Leu Gln Ala Glu Ile Lys Arg 1895 1900 1905Ile Glu Glu Arg Cys Arg Arg Lys Leu Glu Asp Ser Thr Arg Glu 1910 1915 1920Thr Gln Ser Gln Leu Glu Thr Glu Arg Ser Arg Tyr Gln Arg Glu 1925 1930 1935Ile Asp Lys Leu Arg Gln Arg Pro Tyr Gly Ser His Arg Glu Thr 1940 1945 1950Gln Thr Glu Cys Glu Trp Thr Val Asp Thr Ser Lys Leu Val Phe 1955 1960 1965Asp Gly Leu Arg Lys Lys Val Thr Ala Met Gln Leu Tyr Glu Cys 1970 1975 1980Gln Leu Ile Asp Lys Thr Thr Leu Asp Lys Leu Leu Lys Gly Lys 1985 1990 1995Lys Ser Val Glu Glu Val Ala Ser Glu Ile Gln Pro Phe Leu Arg 2000 2005 2010Gly Ala Gly Ser Ile Ala Gly Ala Ser Ala Ser Pro Lys Glu Lys 2015 2020 2025Tyr Ser Leu Val Glu Ala Lys Arg Lys Lys Leu Ile Ser Pro Glu 2030 2035 2040Ser Thr Val Met Leu Leu Glu Ala Gln Ala Ala Thr Gly Gly Ile 2045 2050 2055Ile Asp Pro His Arg Asn Glu Lys Leu Thr Val Asp Ser Ala Ile 2060 2065 2070Ala Arg Asp Leu Ile Asp Phe Asp Asp Arg Gln Gln Ile Tyr Ala 2075 2080 2085Ala Glu Lys Ala Ile Thr Gly Phe Asp Asp Pro Phe Ser Gly Lys 2090 2095 2100Thr Val Ser Val Ser Glu Ala Ile Lys Lys Asn Leu Ile Asp Arg 2105 2110 2115Glu Thr Gly Met Arg Leu Leu Glu Ala Gln Ile Ala Ser Gly Gly 2120 2125 2130Val Val Asp Pro Val Asn Ser Val Phe Leu Pro Lys Asp Val Ala 2135 2140 2145Leu Ala Arg Gly Leu Ile Asp Arg Asp Leu Tyr Arg Ser Leu Asn 2150 2155 2160Asp Pro Arg Asp Ser Gln Lys Asn Phe Val Asp Pro Val Thr Lys 2165 2170 2175Lys Lys Val Ser Tyr Val Gln Leu Lys Glu Arg Cys Arg Ile Glu 2180 2185 2190Pro His Thr Gly Leu Leu Leu Leu Ser Val Gln Lys Arg Ser Met 2195 2200 2205Ser Phe Gln Gly Ile Arg Gln Pro Val Thr Val Thr Glu Leu Val 2210 2215 2220Asp Ser Gly Ile Leu Arg Pro Ser Thr Val Asn Glu Leu Glu Ser 2225 2230 2235Gly Gln Ile Ser Tyr Asp Glu Val Gly Glu Arg Ile Lys Asp Phe 2240 2245 2250Leu Gln Gly Ser Ser Cys Ile Ala Gly Ile Tyr Asn Glu Thr Thr 2255 2260 2265Lys Gln Lys Leu Gly Ile Tyr Glu Ala Met Lys Ile Gly Leu Val 2270 2275 2280Arg Pro Gly Thr Ala Leu Glu Leu Leu Glu Ala Gln Ala Ala Thr 2285 2290 2295Gly Phe Ile Val Asp Pro Val Ser Asn Leu Arg Leu Pro Val Glu 2300 2305 2310Glu Ala Tyr Lys Arg Gly Leu Val Gly Ile Glu Phe Lys Glu Lys 2315 2320 2325Leu Leu Ser Ala Glu Arg Ala Val Thr Gly Tyr Asn Asp Pro Glu 2330 2335 2340Thr Gly Asn Ile Ile Ser Leu Phe Gln Ala Met Asn Lys Glu Leu 2345 2350 2355Ile Glu Lys Gly His Gly Ile Arg Leu Leu Glu Ala Gln Ile Ala 2360 2365 2370Thr Gly Gly Ile Ile Asp Pro Lys Glu Ser His Arg Leu Pro Val 2375 2380 2385Asp Ile Ala Tyr Lys Arg Gly Tyr Phe Asn Glu Glu Leu Ser Glu 2390 2395 2400Ile Leu Ser Asp Pro Ser Asp Asp Thr Lys Gly Phe Phe Asp Pro 2405 2410 2415Asn Thr Glu Glu Asn Leu Thr Tyr Leu Gln Leu Lys Glu Arg Cys 2420 2425 2430Ile Lys Asp Glu Glu Thr Gly Leu Cys Leu Leu Pro Leu Lys Glu 2435 2440 2445Lys Lys Lys Gln Val Gln Thr Ser Gln Lys Asn Thr Leu Arg Lys 2450 2455 2460Arg Arg Val Val Ile Val Asp Pro Glu Thr Asn Lys Glu Met Ser 2465 2470 2475Val Gln Glu Ala Tyr Lys Lys Gly Leu Ile Asp Tyr Glu Thr Phe 2480 2485 2490Lys Glu Leu Cys Glu Gln Glu Cys Glu Trp Glu Glu Ile Thr Ile 2495 2500 2505Thr Gly Ser Asp Gly Ser Thr Arg Val Val Leu Val Asp Arg Lys 2510 2515 2520Thr Gly Ser Gln Tyr Asp Ile Gln Asp Ala Ile Asp Lys Gly Leu 2525 2530 2535Val Asp Arg Lys Phe Phe Asp Gln Tyr Arg Ser Gly Ser Leu Ser 2540 2545 2550Leu Thr Gln Phe Ala Asp Met Ile Ser Leu Lys Asn Gly Val Gly 2555 2560 2565Thr Ser Ser Ser Met Gly Ser Gly Val Ser Asp Asp Val Phe Ser 2570 2575 2580Ser Ser Arg His Glu Ser Val Ser Lys Ile Ser Thr Ile Ser Ser 2585 2590 2595Val Arg Asn Leu Thr Ile Arg Ser Ser Ser Phe Ser Asp Thr Leu 2600 2605 2610Glu Glu Ser Ser Pro Ile Ala Ala Ile Phe Asp Thr Glu Asn Leu 2615 2620 2625Glu Lys Ile Ser Ile Thr Glu Gly Ile Glu Arg Gly Ile Val Asp 2630 2635 2640Ser Ile Thr Gly Gln Arg Leu Leu Glu Ala Gln Ala Cys Thr Gly 2645 2650 2655Gly Ile Ile His Pro Thr Thr Gly Gln Lys Leu Ser Leu Gln Asp 2660 2665 2670Ala Val Ser Gln Gly Val Ile Asp Gln Asp Met Ala Thr Arg Leu 2675 2680 2685Lys Pro Ala Gln Lys Ala Phe Ile Gly Phe Glu Gly Val Lys Gly 2690 2695 2700Lys Lys Lys Met Ser Ala Ala Glu Ala Val Lys Glu Lys Trp Leu 2705 2710 2715Pro Tyr Glu Ala Gly Gln Arg Phe Leu Glu Phe Gln Tyr Leu Thr 2720 2725 2730Gly Gly Leu Val Asp Pro Glu Val His Gly Arg Ile Ser Thr Glu 2735 2740 2745Glu Ala Ile Arg Lys Gly Phe Ile Asp Gly Arg Ala Ala Gln Arg 2750 2755 2760Leu Gln Asp Thr Ser Ser Tyr Ala Lys Ile Leu Thr Cys Pro Lys 2765 2770 2775Thr Lys Leu Lys Ile Ser Tyr Lys Asp Ala Ile Asn Arg Ser Met 2780 2785 2790Val Glu Asp Ile Thr Gly Leu Arg Leu Leu Glu Ala Ala Ser Val 2795 2800 2805Ser Ser Lys Gly Leu Pro Ser Pro Tyr Asn Met Ser Ser Ala Pro 2810 2815 2820Gly Ser Arg Ser Gly Ser Arg Ser Gly Ser Arg Ser Gly Ser Arg 2825 2830 2835Ser Gly Ser Arg Ser Gly Ser Arg Arg Gly Ser Phe Asp Ala Thr 2840 2845

2850Gly Asn Ser Ser Tyr Ser Tyr Ser Tyr Ser Phe Ser Ser Ser Ser 2855 2860 2865Ile Gly His 2870468473DNAHomo sapiens 46aagaaaccgg ccaggtgtgg cctaggcgcc cagtgccagc ggggaggaga ctcgctccgc 60cgccgaccaa caccaacacc cagctccgac gcagctcctc tgcgcccttg ccgccctccg 120agccacagct ttcctcccgc tcctgccccc ggcccgtcgc cgtctccgcg ctcgcagcgg 180cctcgggagg gcccaggtag cgagcagcga cctcgcgagc cttccgcact cccgcccggt 240tccccggccg tccgcctatc cttggccccc tccgctttct ccgcgccggc ccgcctcgct 300tatgcctcgg cgctgagccg ctctcccgat tgcccgccga catgagctgc aacggaggct 360cccacccgcg gatcaacact ctgggccgca tgatccgcgc cgagtctggc ccggacctgc 420gctacgaggt gaccagcggc ggcgggggca ccagcaggat gtactattct cggcgcggcg 480tgatcaccga ccagaactcg gacggctact gtcaaaccgg cacgatgtcc aggcaccaga 540accagaacac catccaggag ctgctgcaga actgctccga ctgcttgatg cgagcagagc 600tcatcgtgca gcctgaattg aagtatggag atggaataca actgactcgg agtcgagaat 660tggatgagtg ttttgcccag gccaatgacc aaatggaaat cctcgacagc ttgatcagag 720agatgcggca gatgggccag ccctgtgatg cttaccagaa aaggcttctt cagctccaag 780agcaaatgcg agccctttat aaagccatca gtgtccctcg agtccgcagg gccagctcca 840agggtggtgg aggctacact tgtcagagtg gctctggctg ggatgagttc accaaacatg 900tcaccagtga atgtttgggg tggatgaggc agcaaagggc ggagatggac atggtggcct 960ggggtgtgga cctggcctca gtggagcagc acattaacag ccaccggggc atccacaact 1020ccatcggcga ctatcgctgg cagctggaca aaatcaaagc cgacctgcgc gagaaatctg 1080cgatctacca gttggaggag gagtatgaaa acctgctgaa agcgtccttt gagaggatgg 1140atcacctgcg acagctgcag aacatcattc aggccacgtc cagggagatc atgtggatca 1200atgactgcga ggaggaggag ctgctgtacg actggagcga caagaacacc aacatcgctc 1260agaaacagga ggccttctcc atacgcatga gtcaactgga agttaaagaa aaagagctca 1320ataagctgaa acaagaaagt gaccaacttg tcctcaatca gcatccagct tcagacaaaa 1380ttgaggccta tatggacact ctgcagacgc agtggagttg gattcttcag atcaccaagt 1440gcattgatgt tcatctgaaa gaaaatgctg cctactttca gttttttgaa gaggcgcagt 1500ctactgaagc atacctgaag gggctccagg actccatcag gaagaagtac ccctgcgaca 1560agaacatgcc cctgcagcac ctgctggaac agatcaagga gctggagaaa gaacgagaga 1620aaatccttga atacaagcgt caggtgcaga acttggtaaa caagtctaag aagattgtac 1680agctgaagcc tcgtaaccca gactacagaa gcaataaacc cattattctc agagctctct 1740gtgactacaa acaagatcag aaaatcgtgc ataaggggga tgagtgtatc ctgaaggaca 1800acaacgagcg cagcaagtgg tacgtgacgg gcccgggagg cgttgacatg cttgttccct 1860ctgtggggct gatcatccct cctccgaacc cactggccgt ggacctctct tgcaagattg 1920agcagtacta cgaagccatc ttggctctgt ggaaccagct ctacatcaac atgaagagcc 1980tggtgtcctg gcactactgc atgattgaca tagagaagat cagggccatg acaatcgcca 2040agctgaaaac aatgcggcag gaagattaca tgaagacgat agccgacctt gagttacatt 2100accaagagtt catcagaaat agccaaggct cagagatgtt tggagatgat gacaagcgga 2160aaatacagtc tcagttcacc gatgcccaga agcattacca gaccctggtc attcagctcc 2220ctggctatcc ccagcaccag acagtgacca caactgaaat cactcatcat ggaacctgcc 2280aagatgtcaa ccataataaa gtaattgaaa ccaacagaga aaatgacaag caagaaacat 2340ggatgctgat ggagctgcag aagattcgca ggcagataga gcactgcgag ggcaggatga 2400ctctcaaaaa cctccctcta gcagaccagg gatcttctca ccacatcaca gtgaaaatta 2460acgagcttaa gagtgtgcag aatgattcac aagcaattgc tgaggttctc aaccagctta 2520aagatatgct tgccaacttc agaggttctg aaaagtactg ctatttacag aatgaagtat 2580ttggactatt tcagaaactg gaaaatatca atggtgttac agatggctac ttaaatagct 2640tatgcacagt aagggcactg ctccaggcta ttctccaaac agaagacatg ttaaaggttt 2700atgaagccag gctcactgag gaggaaactg tctgcctgga cctggataaa gtggaagctt 2760accgctgtgg actgaagaaa ataaaaaatg acttgaactt gaagaagtcg ttgttggcca 2820ctatgaagac agaactacag aaagcccagc agatccactc tcagacttca cagcagtatc 2880cactttatga tctggacttg ggcaagttcg gtgaaaaagt cacacagctg acagaccgct 2940ggcaaaggat agataaacag atcgacttta ggttatggga cctggagaaa caaatcaagc 3000aattgaggaa ttatcgtgat aactatcagg ctttctgcaa gtggctctat gatgctaaac 3060gccgccagga ttccttagaa tccatgaaat ttggagattc caacacagtc atgcggtttt 3120tgaatgagca gaagaacttg cacagtgaaa tatctggcaa acgagacaaa tcagaggaag 3180tacaaaaaat tgctgaactt tgcgccaatt caattaagga ttatgagctc cagctggcct 3240catacacctc aggactggaa actctgctga acatacctat caagaggacc atgattcagt 3300ccccttctgg ggtgattctg caagaggctg cagatgttca tgctcggtac attgaactac 3360ttacaagatc tggagactat tacaggttct taagtgagat gctgaagagt ttggaagatc 3420tgaagctgaa aaataccaag atcgaagttt tggaagagga gctcagactg gcccgagatg 3480ccaactcgga aaactgtaat aagaacaaat tcctggatca gaacctgcag aaataccagg 3540cagagtgttc ccagttcaaa gcgaagcttg cgagcctgga ggagctgaag agacaggctg 3600agctggatgg gaagtcggct aagcaaaatc tagacaagtg ctacggccaa ataaaagaac 3660tcaatgagaa gatcacccga ctgacttatg agattgaaga tgaaaagaga agaagaaaat 3720ctgtggaaga cagatttgac caacagaaga atgactatga ccaactgcag aaagcaaggc 3780aatgtgaaaa ggagaacctt ggttggcaga aattagagtc tgagaaagcc atcaaggaga 3840aggagtacga gattgaaagg ttgagggttc tactgcagga agaaggcacc cggaagagag 3900aatatgaaaa tgagctggca aaggtaagaa accactataa tgaggagatg agtaatttaa 3960ggaacaagta tgaaacagag attaacatta cgaagaccac catcaaggag atatccatgc 4020aaaaagagga tgattccaaa aatcttagaa accagcttga tagactttca agggaaaatc 4080gagatctgaa ggatgaaatt gtcaggctca atgacagcat cttgcaggcc actgagcagc 4140gaaggcgagc tgaagaaaac gcccttcagc aaaaggcctg tggctctgag ataatgcaga 4200agaagcagca tctggagata gaactgaagc aggtcatgca gcagcgctct gaggacaatg 4260cccggcacaa gcagtccctg gaggaggctg ccaagaccat tcaggacaaa aataaggaga 4320tcgagagact caaagctgag tttcaggagg aggccaagcg ccgctgggaa tatgaaaatg 4380aactgagtaa ggcatctaat aggattcagg aatcaaagaa tcagtgtact caggtggtac 4440aggaaagaga gagccttctg gtgaaaatca aagtcctgga gcaagacaag gcaaggctgc 4500agaggctgga ggatgagctg aatcgtgcaa aatcaactct agaggcagaa accagggtga 4560aacagcgcct ggagtgtgag aaacagcaaa ttcagaatga cctgaatcag tggaagactc 4620aatattcccg caaggaggag gctattagga agatagaatc ggaaagagaa aagagtgaga 4680gagagaagaa cagtcttagg agtgagatcg aaagactcca agcagagatc aagagaattg 4740aagagaggtg caggcgtaag ctggaggatt ctaccaggga gacacagtca cagttagaaa 4800cagaacgctc ccgatatcag agggagattg ataaactcag acagcgccca tatgggtccc 4860atcgagagac ccagactgag tgtgagtgga ccgttgacac ctccaagctg gtgtttgatg 4920ggctgaggaa gaaggtgaca gcaatgcagc tctatgagtg tcagctgatc gacaaaacaa 4980ccttggacaa actattgaag gggaagaagt cagtggaaga agttgcttct gaaatccagc 5040cattccttcg gggtgcagga tctatcgctg gagcatctgc ttctcctaag gaaaaatact 5100ctttggtaga ggccaagaga aagaaattaa tcagcccaga atccacagtc atgcttctgg 5160aggcccaggc agctacaggt ggtataattg atccccatcg gaatgagaag ctgactgtcg 5220acagtgccat agctcgggac ctcattgact tcgatgaccg tcagcagata tatgcagcag 5280aaaaagctat cactggtttt gatgatccat tttcaggcaa gacagtatct gtttcagaag 5340ccatcaagaa aaatttgatt gatagagaaa ccggaatgcg cctgctggaa gcccagattg 5400cttcaggggg tgtagtagac cctgtgaaca gtgtcttttt gccaaaagat gtcgccttgg 5460cccgggggct gattgataga gatttgtatc gatccctgaa tgatccccga gatagtcaga 5520aaaactttgt ggatccagtc accaaaaaga aggtcagtta cgtgcagctg aaggaacggt 5580gcagaatcga accacatact ggtctgctct tgctttcagt acagaagaga agcatgtcct 5640tccaaggaat cagacaacct gtgaccgtca ctgagctagt agattctggt atattgagac 5700cgtccactgt caatgaactg gaatctggtc agatttctta tgacgaggtt ggtgagagaa 5760ttaaggactt cctccagggt tcaagctgca tagcaggcat atacaatgag accacaaaac 5820agaagcttgg catttatgag gccatgaaaa ttggcttagt ccgacctggt actgctctgg 5880agttgctgga agcccaagca gctactggct ttatagtgga tcctgttagc aacttgaggt 5940taccagtgga ggaagcctac aagagaggtc tggtgggcat tgagttcaaa gagaagctcc 6000tgtctgcaga acgagctgtc actgggtata atgatcctga aacaggaaac atcatctctt 6060tgttccaagc catgaataag gaactcatcg aaaagggcca cggtattcgc ttattagaag 6120cacagatcgc aaccgggggg atcattgacc caaaggagag ccatcgttta ccagttgaca 6180tagcatataa gaggggctat ttcaatgagg aactcagtga gattctctca gatccaagtg 6240atgataccaa aggatttttt gaccccaaca ctgaagaaaa tcttacctat ctgcaactaa 6300aagaaagatg cattaaggat gaggaaacag ggctctgtct tctgcctctg aaagaaaaga 6360agaaacaggt gcagacatca caaaagaata ccctcaggaa gcgtagagtg gtcatagttg 6420acccagaaac caataaagaa atgtctgttc aggaggccta caagaagggc ctaattgatt 6480atgaaacctt caaagaactg tgtgagcagg aatgtgaatg ggaagaaata accatcacgg 6540gatcagatgg ctccaccagg gtggtcctgg tagatagaaa gacaggcagt cagtatgata 6600ttcaagatgc tattgacaag ggccttgttg acaggaagtt ctttgatcag taccgatccg 6660gcagcctcag cctcactcaa tttgctgaca tgatctcctt gaaaaatggt gtcggcacca 6720gcagcagcat gggcagtggt gtcagcgatg atgtttttag cagctcccga catgaatcag 6780taagtaagat ttccaccata tccagcgtca ggaatttaac cataaggagc agctcttttt 6840cagacaccct ggaagaatcg agccccattg cagccatctt tgacacagaa aacctggaga 6900aaatctccat tacagaaggt atagagcggg gcatcgttga cagcatcacg ggtcagaggc 6960ttctggaggc tcaggcctgc acaggtggca tcatccaccc aaccacgggc cagaagctgt 7020cacttcagga cgcagtctcc cagggtgtga ttgaccaaga catggccacc aggctgaagc 7080ctgctcagaa agccttcata ggcttcgagg gtgtgaaggg aaagaagaag atgtcagcag 7140cagaggcagt gaaagaaaaa tggctcccgt atgaggctgg ccagcgcttc ctggagttcc 7200agtacctcac gggaggtctt gttgacccgg aagtgcatgg gaggataagc accgaagaag 7260ccatccggaa ggggttcata gatggccgcg ccgcacagag gctgcaagac accagcagct 7320atgccaaaat cctgacctgc cccaaaacca aattaaaaat atcctataag gatgccataa 7380atcgctccat ggtagaagat atcactgggc tgcgccttct ggaagccgcc tccgtgtcgt 7440ccaagggctt acccagccct tacaacatgt cttcggctcc ggggtcccgc tccggctccc 7500gctcgggatc tcgctccgga tctcgctccg ggtcccgcag tgggtcccgg agaggaagct 7560ttgacgccac agggaattct tcctactctt attcctactc atttagcagt agttctattg 7620ggcactagta gtcagttggg agtggttgct ataccttgac ttcatttata tgaatttcca 7680ctttattaaa taatagaaaa gaaaatcccg gtgcttgcag tagagtgata ggacattcta 7740tgcttacaga aaatatagcc atgattgaaa tcaaatagta aaggctgttc tggcttttta 7800tcttcttagc tcatcttaaa taagcagtac acttggatgc agtgcgtctg aagtgctaat 7860cagttgtaac aatagcacaa atcgaactta ggatttgttt cttctcttct gtgtttcgat 7920ttttgatcaa ttctttaatt ttggaagcct ataatacagt tttctattct tggagataaa 7980aattaaatgg atcactgata ttttagtcat tctgcttctc atctaaatat ttccatattc 8040tgtattagga gaaaattacc ctcccagcac cagcccccct ctcaaacccc caacccaaaa 8100ccaagcattt tggaatgagt ctcctttagt ttcagagtgt ggattgtata acccatatac 8160tcttcgatgt acttgtttgg tttggtatta atttgactgt gcatgacagc ggcaatcttt 8220tctttggtca aagttttctg tttattttgc ttgtcatatt cgatgtactt taaggtgtct 8280ttatgaagtt tgctattctg gcaataaact tttagacttt tgaagtgttt gtgttttaat 8340ttaatatgtt tataagcatg tataaacatt tagcatattt ttatcatagg tctaaaaata 8400tttgtttact aaatacctgt gaagaaatac cattaaaaaa ctatttggtt ctgaattctt 8460actagaaaaa aaa 8473472428PRTHomo sapiens 47Met Ser Cys Asn Gly Gly Ser His Pro Arg Ile Asn Thr Leu Gly Arg1 5 10 15Met Ile Arg Ala Glu Ser Gly Pro Asp Leu Arg Tyr Glu Val Thr Ser 20 25 30Gly Gly Gly Gly Thr Ser Arg Met Tyr Tyr Ser Arg Arg Gly Val Ile 35 40 45Thr Asp Gln Asn Ser Asp Gly Tyr Cys Gln Thr Gly Thr Met Ser Arg 50 55 60His Gln Asn Gln Asn Thr Ile Gln Glu Leu Leu Gln Asn Cys Ser Asp65 70 75 80Cys Leu Met Arg Ala Glu Leu Ile Val Gln Pro Glu Leu Lys Tyr Gly 85 90 95Asp Gly Ile Gln Leu Thr Arg Ser Arg Glu Leu Asp Glu Cys Phe Ala 100 105 110Gln Ala Asn Asp Gln Met Glu Ile Leu Asp Ser Leu Ile Arg Glu Met 115 120 125Arg Gln Met Gly Gln Pro Cys Asp Ala Tyr Gln Lys Arg Leu Leu Gln 130 135 140Leu Gln Glu Gln Met Arg Ala Leu Tyr Lys Ala Ile Ser Val Pro Arg145 150 155 160Val Arg Arg Ala Ser Ser Lys Gly Gly Gly Gly Tyr Thr Cys Gln Ser 165 170 175Gly Ser Gly Trp Asp Glu Phe Thr Lys His Val Thr Ser Glu Cys Leu 180 185 190Gly Trp Met Arg Gln Gln Arg Ala Glu Met Asp Met Val Ala Trp Gly 195 200 205Val Asp Leu Ala Ser Val Glu Gln His Ile Asn Ser His Arg Gly Ile 210 215 220His Asn Ser Ile Gly Asp Tyr Arg Trp Gln Leu Asp Lys Ile Lys Ala225 230 235 240Asp Leu Arg Glu Lys Ser Ala Ile Tyr Gln Leu Glu Glu Glu Tyr Glu 245 250 255Asn Leu Leu Lys Ala Ser Phe Glu Arg Met Asp His Leu Arg Gln Leu 260 265 270Gln Asn Ile Ile Gln Ala Thr Ser Arg Glu Ile Met Trp Ile Asn Asp 275 280 285Cys Glu Glu Glu Glu Leu Leu Tyr Asp Trp Ser Asp Lys Asn Thr Asn 290 295 300Ile Ala Gln Lys Gln Glu Ala Phe Ser Ile Arg Met Ser Gln Leu Glu305 310 315 320Val Lys Glu Lys Glu Leu Asn Lys Leu Lys Gln Glu Ser Asp Gln Leu 325 330 335Val Leu Asn Gln His Pro Ala Ser Asp Lys Ile Glu Ala Tyr Met Asp 340 345 350Thr Leu Gln Thr Gln Trp Ser Trp Ile Leu Gln Ile Thr Lys Cys Ile 355 360 365Asp Val His Leu Lys Glu Asn Ala Ala Tyr Phe Gln Phe Phe Glu Glu 370 375 380Ala Gln Ser Thr Glu Ala Tyr Leu Lys Gly Leu Gln Asp Ser Ile Arg385 390 395 400Lys Lys Tyr Pro Cys Asp Lys Asn Met Pro Leu Gln His Leu Leu Glu 405 410 415Gln Ile Lys Glu Leu Glu Lys Glu Arg Glu Lys Ile Leu Glu Tyr Lys 420 425 430Arg Gln Val Gln Asn Leu Val Asn Lys Ser Lys Lys Ile Val Gln Leu 435 440 445Lys Pro Arg Asn Pro Asp Tyr Arg Ser Asn Lys Pro Ile Ile Leu Arg 450 455 460Ala Leu Cys Asp Tyr Lys Gln Asp Gln Lys Ile Val His Lys Gly Asp465 470 475 480Glu Cys Ile Leu Lys Asp Asn Asn Glu Arg Ser Lys Trp Tyr Val Thr 485 490 495Gly Pro Gly Gly Val Asp Met Leu Val Pro Ser Val Gly Leu Ile Ile 500 505 510Pro Pro Pro Asn Pro Leu Ala Val Asp Leu Ser Cys Lys Ile Glu Gln 515 520 525Tyr Tyr Glu Ala Ile Leu Ala Leu Trp Asn Gln Leu Tyr Ile Asn Met 530 535 540Lys Ser Leu Val Ser Trp His Tyr Cys Met Ile Asp Ile Glu Lys Ile545 550 555 560Arg Ala Met Thr Ile Ala Lys Leu Lys Thr Met Arg Gln Glu Asp Tyr 565 570 575Met Lys Thr Ile Ala Asp Leu Glu Leu His Tyr Gln Glu Phe Ile Arg 580 585 590Asn Ser Gln Gly Ser Glu Met Phe Gly Asp Asp Asp Lys Arg Lys Ile 595 600 605Gln Ser Gln Phe Thr Asp Ala Gln Lys His Tyr Gln Thr Leu Val Ile 610 615 620Gln Leu Pro Gly Tyr Pro Gln His Gln Thr Val Thr Thr Thr Glu Ile625 630 635 640Thr His His Gly Thr Cys Gln Asp Val Asn His Asn Lys Val Ile Glu 645 650 655Thr Asn Arg Glu Asn Asp Lys Gln Glu Thr Trp Met Leu Met Glu Leu 660 665 670Gln Lys Ile Arg Arg Gln Ile Glu His Cys Glu Gly Arg Met Thr Leu 675 680 685Lys Asn Leu Pro Leu Ala Asp Gln Gly Ser Ser His His Ile Thr Val 690 695 700Lys Ile Asn Glu Leu Lys Ser Val Gln Asn Asp Ser Gln Ala Ile Ala705 710 715 720Glu Val Leu Asn Gln Leu Lys Asp Met Leu Ala Asn Phe Arg Gly Ser 725 730 735Glu Lys Tyr Cys Tyr Leu Gln Asn Glu Val Phe Gly Leu Phe Gln Lys 740 745 750Leu Glu Asn Ile Asn Gly Val Thr Asp Gly Tyr Leu Asn Ser Leu Cys 755 760 765Thr Val Arg Ala Leu Leu Gln Ala Ile Leu Gln Thr Glu Asp Met Leu 770 775 780Lys Val Tyr Glu Ala Arg Leu Thr Glu Glu Glu Thr Val Cys Leu Asp785 790 795 800Leu Asp Lys Val Glu Ala Tyr Arg Cys Gly Leu Lys Lys Ile Lys Asn 805 810 815Asp Leu Asn Leu Lys Lys Ser Leu Leu Ala Thr Met Lys Thr Glu Leu 820 825 830Gln Lys Ala Gln Gln Ile His Ser Gln Thr Ser Gln Gln Tyr Pro Leu 835 840 845Tyr Asp Leu Asp Leu Gly Lys Phe Gly Glu Lys Val Thr Gln Leu Thr 850 855 860Asp Arg Trp Gln Arg Ile Asp Lys Gln Ile Asp Phe Arg Leu Trp Asp865 870 875 880Leu Glu Lys Gln Ile Lys Gln Leu Arg Asn Tyr Arg Asp Asn Tyr Gln 885 890 895Ala Phe Cys Lys Trp Leu Tyr Asp Ala Lys Arg Arg Gln Asp Ser Leu 900 905 910Glu Ser Met Lys Phe Gly Asp Ser Asn Thr Val Met Arg Phe Leu Asn 915 920 925Glu Gln Lys Asn Leu His Ser Glu Ile Ser Gly Lys Arg Asp Lys Ser 930 935 940Glu Glu Val Gln Lys Ile Ala Glu Leu Cys Ala Asn Ser Ile Lys Asp945 950 955 960Tyr Glu Leu Gln Leu Ala Ser Tyr Thr Ser Gly Leu Glu Thr Leu Leu 965 970 975Asn Ile Pro Ile Lys Arg Thr Met Ile Gln Ser Pro Ser Gly Val Ile 980 985 990Leu Gln Glu Ala Ala Asp Val His Ala Arg Tyr Ile Glu Leu Leu Thr 995 1000 1005Arg Ser Gly Asp Tyr Tyr Arg Phe Leu Ser Glu Met Leu Lys Ser 1010 1015 1020Leu Glu Asp Leu Lys Leu Lys Asn Thr Lys Ile Glu Val Leu Glu 1025 1030 1035Glu Glu Leu Arg Leu Ala Arg Asp Ala Asn Ser Glu Asn Cys

Asn 1040 1045 1050Lys Asn Lys Phe Leu Asp Gln Asn Leu Gln Lys Tyr Gln Ala Glu 1055 1060 1065Cys Ser Gln Phe Lys Ala Lys Leu Ala Ser Leu Glu Glu Leu Lys 1070 1075 1080Arg Gln Ala Glu Leu Asp Gly Lys Ser Ala Lys Gln Asn Leu Asp 1085 1090 1095Lys Cys Tyr Gly Gln Ile Lys Glu Leu Asn Glu Lys Ile Thr Arg 1100 1105 1110Leu Thr Tyr Glu Ile Glu Asp Glu Lys Arg Arg Arg Lys Ser Val 1115 1120 1125Glu Asp Arg Phe Asp Gln Gln Lys Asn Asp Tyr Asp Gln Leu Gln 1130 1135 1140Lys Ala Arg Gln Cys Glu Lys Glu Asn Leu Gly Trp Gln Lys Leu 1145 1150 1155Glu Ser Glu Lys Ala Ile Lys Glu Lys Glu Tyr Glu Ile Glu Arg 1160 1165 1170Leu Arg Val Leu Leu Gln Glu Glu Gly Thr Arg Lys Arg Glu Tyr 1175 1180 1185Glu Asn Glu Leu Ala Lys Val Arg Asn His Tyr Asn Glu Glu Met 1190 1195 1200Ser Asn Leu Arg Asn Lys Tyr Glu Thr Glu Ile Asn Ile Thr Lys 1205 1210 1215Thr Thr Ile Lys Glu Ile Ser Met Gln Lys Glu Asp Asp Ser Lys 1220 1225 1230Asn Leu Arg Asn Gln Leu Asp Arg Leu Ser Arg Glu Asn Arg Asp 1235 1240 1245Leu Lys Asp Glu Ile Val Arg Leu Asn Asp Ser Ile Leu Gln Ala 1250 1255 1260Thr Glu Gln Arg Arg Arg Ala Glu Glu Asn Ala Leu Gln Gln Lys 1265 1270 1275Ala Cys Gly Ser Glu Ile Met Gln Lys Lys Gln His Leu Glu Ile 1280 1285 1290Glu Leu Lys Gln Val Met Gln Gln Arg Ser Glu Asp Asn Ala Arg 1295 1300 1305His Lys Gln Ser Leu Glu Glu Ala Ala Lys Thr Ile Gln Asp Lys 1310 1315 1320Asn Lys Glu Ile Glu Arg Leu Lys Ala Glu Phe Gln Glu Glu Ala 1325 1330 1335Lys Arg Arg Trp Glu Tyr Glu Asn Glu Leu Ser Lys Ala Ser Asn 1340 1345 1350Arg Ile Gln Glu Ser Lys Asn Gln Cys Thr Gln Val Val Gln Glu 1355 1360 1365Arg Glu Ser Leu Leu Val Lys Ile Lys Val Leu Glu Gln Asp Lys 1370 1375 1380Ala Arg Leu Gln Arg Leu Glu Asp Glu Leu Asn Arg Ala Lys Ser 1385 1390 1395Thr Leu Glu Ala Glu Thr Arg Val Lys Gln Arg Leu Glu Cys Glu 1400 1405 1410Lys Gln Gln Ile Gln Asn Asp Leu Asn Gln Trp Lys Thr Gln Tyr 1415 1420 1425Ser Arg Lys Glu Glu Ala Ile Arg Lys Ile Glu Ser Glu Arg Glu 1430 1435 1440Lys Ser Glu Arg Glu Lys Asn Ser Leu Arg Ser Glu Ile Glu Arg 1445 1450 1455Leu Gln Ala Glu Ile Lys Arg Ile Glu Glu Arg Cys Arg Arg Lys 1460 1465 1470Leu Glu Asp Ser Thr Arg Glu Thr Gln Ser Gln Leu Glu Thr Glu 1475 1480 1485Arg Ser Arg Tyr Gln Arg Glu Ile Asp Lys Leu Arg Gln Arg Pro 1490 1495 1500Tyr Gly Ser His Arg Glu Thr Gln Thr Glu Cys Glu Trp Thr Val 1505 1510 1515Asp Thr Ser Lys Leu Val Phe Asp Gly Leu Arg Lys Lys Val Thr 1520 1525 1530Ala Met Gln Leu Tyr Glu Cys Gln Leu Ile Asp Lys Thr Thr Leu 1535 1540 1545Asp Lys Leu Leu Lys Gly Lys Lys Ser Val Glu Glu Val Ala Ser 1550 1555 1560Glu Ile Gln Pro Phe Leu Arg Gly Ala Gly Ser Ile Ala Gly Ala 1565 1570 1575Ser Ala Ser Pro Lys Glu Lys Tyr Ser Leu Val Glu Ala Lys Arg 1580 1585 1590Lys Lys Leu Ile Ser Pro Glu Ser Thr Val Met Leu Leu Glu Ala 1595 1600 1605Gln Ala Ala Thr Gly Gly Ile Ile Asp Pro His Arg Asn Glu Lys 1610 1615 1620Leu Thr Val Asp Ser Ala Ile Ala Arg Asp Leu Ile Asp Phe Asp 1625 1630 1635Asp Arg Gln Gln Ile Tyr Ala Ala Glu Lys Ala Ile Thr Gly Phe 1640 1645 1650Asp Asp Pro Phe Ser Gly Lys Thr Val Ser Val Ser Glu Ala Ile 1655 1660 1665Lys Lys Asn Leu Ile Asp Arg Glu Thr Gly Met Arg Leu Leu Glu 1670 1675 1680Ala Gln Ile Ala Ser Gly Gly Val Val Asp Pro Val Asn Ser Val 1685 1690 1695Phe Leu Pro Lys Asp Val Ala Leu Ala Arg Gly Leu Ile Asp Arg 1700 1705 1710Asp Leu Tyr Arg Ser Leu Asn Asp Pro Arg Asp Ser Gln Lys Asn 1715 1720 1725Phe Val Asp Pro Val Thr Lys Lys Lys Val Ser Tyr Val Gln Leu 1730 1735 1740Lys Glu Arg Cys Arg Ile Glu Pro His Thr Gly Leu Leu Leu Leu 1745 1750 1755Ser Val Gln Lys Arg Ser Met Ser Phe Gln Gly Ile Arg Gln Pro 1760 1765 1770Val Thr Val Thr Glu Leu Val Asp Ser Gly Ile Leu Arg Pro Ser 1775 1780 1785Thr Val Asn Glu Leu Glu Ser Gly Gln Ile Ser Tyr Asp Glu Val 1790 1795 1800Gly Glu Arg Ile Lys Asp Phe Leu Gln Gly Ser Ser Cys Ile Ala 1805 1810 1815Gly Ile Tyr Asn Glu Thr Thr Lys Gln Lys Leu Gly Ile Tyr Glu 1820 1825 1830Ala Met Lys Ile Gly Leu Val Arg Pro Gly Thr Ala Leu Glu Leu 1835 1840 1845Leu Glu Ala Gln Ala Ala Thr Gly Phe Ile Val Asp Pro Val Ser 1850 1855 1860Asn Leu Arg Leu Pro Val Glu Glu Ala Tyr Lys Arg Gly Leu Val 1865 1870 1875Gly Ile Glu Phe Lys Glu Lys Leu Leu Ser Ala Glu Arg Ala Val 1880 1885 1890Thr Gly Tyr Asn Asp Pro Glu Thr Gly Asn Ile Ile Ser Leu Phe 1895 1900 1905Gln Ala Met Asn Lys Glu Leu Ile Glu Lys Gly His Gly Ile Arg 1910 1915 1920Leu Leu Glu Ala Gln Ile Ala Thr Gly Gly Ile Ile Asp Pro Lys 1925 1930 1935Glu Ser His Arg Leu Pro Val Asp Ile Ala Tyr Lys Arg Gly Tyr 1940 1945 1950Phe Asn Glu Glu Leu Ser Glu Ile Leu Ser Asp Pro Ser Asp Asp 1955 1960 1965Thr Lys Gly Phe Phe Asp Pro Asn Thr Glu Glu Asn Leu Thr Tyr 1970 1975 1980Leu Gln Leu Lys Glu Arg Cys Ile Lys Asp Glu Glu Thr Gly Leu 1985 1990 1995Cys Leu Leu Pro Leu Lys Glu Lys Lys Lys Gln Val Gln Thr Ser 2000 2005 2010Gln Lys Asn Thr Leu Arg Lys Arg Arg Val Val Ile Val Asp Pro 2015 2020 2025Glu Thr Asn Lys Glu Met Ser Val Gln Glu Ala Tyr Lys Lys Gly 2030 2035 2040Leu Ile Asp Tyr Glu Thr Phe Lys Glu Leu Cys Glu Gln Glu Cys 2045 2050 2055Glu Trp Glu Glu Ile Thr Ile Thr Gly Ser Asp Gly Ser Thr Arg 2060 2065 2070Val Val Leu Val Asp Arg Lys Thr Gly Ser Gln Tyr Asp Ile Gln 2075 2080 2085Asp Ala Ile Asp Lys Gly Leu Val Asp Arg Lys Phe Phe Asp Gln 2090 2095 2100Tyr Arg Ser Gly Ser Leu Ser Leu Thr Gln Phe Ala Asp Met Ile 2105 2110 2115Ser Leu Lys Asn Gly Val Gly Thr Ser Ser Ser Met Gly Ser Gly 2120 2125 2130Val Ser Asp Asp Val Phe Ser Ser Ser Arg His Glu Ser Val Ser 2135 2140 2145Lys Ile Ser Thr Ile Ser Ser Val Arg Asn Leu Thr Ile Arg Ser 2150 2155 2160Ser Ser Phe Ser Asp Thr Leu Glu Glu Ser Ser Pro Ile Ala Ala 2165 2170 2175Ile Phe Asp Thr Glu Asn Leu Glu Lys Ile Ser Ile Thr Glu Gly 2180 2185 2190Ile Glu Arg Gly Ile Val Asp Ser Ile Thr Gly Gln Arg Leu Leu 2195 2200 2205Glu Ala Gln Ala Cys Thr Gly Gly Ile Ile His Pro Thr Thr Gly 2210 2215 2220Gln Lys Leu Ser Leu Gln Asp Ala Val Ser Gln Gly Val Ile Asp 2225 2230 2235Gln Asp Met Ala Thr Arg Leu Lys Pro Ala Gln Lys Ala Phe Ile 2240 2245 2250Gly Phe Glu Gly Val Lys Gly Lys Lys Lys Met Ser Ala Ala Glu 2255 2260 2265Ala Val Lys Glu Lys Trp Leu Pro Tyr Glu Ala Gly Gln Arg Phe 2270 2275 2280Leu Glu Phe Gln Tyr Leu Thr Gly Gly Leu Val Asp Pro Glu Val 2285 2290 2295His Gly Arg Ile Ser Thr Glu Glu Ala Ile Arg Lys Gly Phe Ile 2300 2305 2310Asp Gly Arg Ala Ala Gln Arg Leu Gln Asp Thr Ser Ser Tyr Ala 2315 2320 2325Lys Ile Leu Thr Cys Pro Lys Thr Lys Leu Lys Ile Ser Tyr Lys 2330 2335 2340Asp Ala Ile Asn Arg Ser Met Val Glu Asp Ile Thr Gly Leu Arg 2345 2350 2355Leu Leu Glu Ala Ala Ser Val Ser Ser Lys Gly Leu Pro Ser Pro 2360 2365 2370Tyr Asn Met Ser Ser Ala Pro Gly Ser Arg Ser Gly Ser Arg Ser 2375 2380 2385Gly Ser Arg Ser Gly Ser Arg Ser Gly Ser Arg Ser Gly Ser Arg 2390 2395 2400Arg Gly Ser Phe Asp Ala Thr Gly Asn Ser Ser Tyr Ser Tyr Ser 2405 2410 2415Tyr Ser Phe Ser Ser Ser Ser Ile Gly His 2420 2425488768DNAHomo sapiens 48gcggccgcac tagtaccccg gagcccatgg gcgcgccgag ccgggcgcgg gggcgctgaa 60cggcggagcg ggagcggccg gaggagccat ggactgcagc ctcgtgcgga cgctcgtgca 120cagatactgt gcaggagaag agaattgggt ggacagcagg accatctacg tgggacacag 180ggagccacct ccgggcgcag aggcctacat cccacagaga tacccagaca acaggatcgt 240ctcgtccaag tacacatttt ggaactttat acccaagaat ttatttgaac aattcagaag 300agtagccaac ttttatttcc ttatcatatt tctggtgcag ttgattattg atacacccac 360aagtccagtg acaagcggac ttccactctt ctttgtcatt actgtgacgg ctatcaaaca 420gggttatgaa gactggcttc gacataaagc agacaatgcc atgaaccagt gtcctgttca 480tttcattcag cacggcaagc tcgttcggaa acaaagtcga aagctgcgag ttggggacat 540tgtcatggtt aaggaggacg agacctttcc ctgcgacttg atcttccttt ccagcaaccg 600gggagatggg acgtgccacg tcaccaccgc cagcttggat ggagaatcca gccataaaac 660gcattacgcg gtccaggaca ccaaaggctt ccacacagag gaggatatcg gcggacttca 720cgccaccatc gagtgtgagc agccccagcc cgacctctac aagttcgtgg gtcgcatcaa 780cgtttacagt gacctgaatg accccgtggt gaggccctta ggatcggaaa acctgctgct 840tagaggagct acactgaaga acactgagaa aatctttggt gtggctattt acacgggaat 900ggaaaccaag atggcattaa attatcaatc aaaatctcag aagcgatctg ccgtggaaaa 960atcgatgaat gcgttcctca ttgtgtatct ctgcattctg atcagcaaag ccctgataaa 1020cactgtgctg aaatacatgt ggcagagtga gccctttcgg gatgagccgt ggtataatca 1080gaaaacggag tcggaaaggc agaggaatct gttcctcaag gcattcacgg acttcctggc 1140cttcatggtc ctctttaact acatcatccc tgtgtccatg tacgtcacgg tcgagatgca 1200gaagttcctc ggctcttact tcatcacctg ggacgaagac atgtttgacg aggagactgg 1260cgaggggcct ctggtgaaca cgtcggacct caatgaagag ctgggacagg tggagtacat 1320cttcacagac aagaccggca ccctcacgga aaacaacatg gagttcaagg agtgctgcat 1380cgaaggccat gtctacgtgc cccacgtcat ctgcaacggg caggtcctcc cagagtcgtc 1440aggaatcgac atgattgact cgtcccccag cgtcaacggg agggagcgcg aggagctgtt 1500tttccgggcc ctctgtctct gccacaccgt ccaggtgaaa gacgatgaca gcgtagacgg 1560ccccaggaaa tcgccggacg gggggaaatc ctgtgtgtac atctcatcct cgcccgacga 1620ggtggcgctg gtcgaaggtg tccagagact tggctttacc tacctaaggc tgaaggacaa 1680ttacatggag atattaaaca gggagaacca catcgaaagg tttgaattgc tggaaatttt 1740gagttttgac tcagtcagaa ggagaatgag tgtaattgta aaatctgcta caggagaaat 1800ttatctgttt tgcaaaggag cagattcttc gatattcccc cgagtgatag aaggcaaagt 1860tgaccagatc cgagccagag tggagcgtaa cgcagtggag gggctccgaa ctttgtgtgt 1920tgcttataaa aggctgatcc aagaagaata tgaaggcatt tgtaagctgc tgcaggctgc 1980caaagtggcc cttcaagatc gagagaaaaa gttagcagaa gcctatgagc aaatagagaa 2040agatcttact ctgcttggtg ctacagctgt tgaggaccgg ctgcaggaga aagctgcaga 2100caccatcgag gccctgcaga aggccgggat caaagtctgg gttctcacgg gagacaagat 2160ggagacggcc gcggccacgt gctacgcctg caagctcttc cgcaggaaca cgcagctgct 2220ggagctgacc accaagagga tcgaggagca gagcctgcac gacgtcctgt tcgagctgag 2280caagacggtc ctgcgccaca gcgggagcct gaccagagac aacctgtccg gactttcagc 2340agatatgcag gactacggtt taattatcga cggagctgca ctgtctctga taatgaagcc 2400tcgagaagac gggagttccg gcaactacag ggagctcttc ctggaaatct gccggagctg 2460cagcgcggtg ctctgctgcc gcatggcgcc cttgcagaag gctcagattg ttaaattaat 2520caaattttca aaagagcacc caatcacgtt agcaattggc gatggtgcaa atgatgtcag 2580catgattctg gaagcgcacg tgggcatagg tgtcatcggc aaggaaggcc gccaggctgc 2640caggaacagc gactatgcaa tcccaaagtt taagcatttg aagaagatgc tgcttgttca 2700cgggcatttt tattacatta ggatctctga gctcgtgcag tacttcttct ataagaacgt 2760ctgcttcatc ttccctcagt ttttatacca gttcttctgt gggttttcac aacagacttt 2820gtacgacacc gcgtatctga ccctctacaa catcagcttc acctccctcc ccatcctcct 2880gtacagcctc atggagcagc atgttggcat tgacgtgctc aagagagacc cgaccctgta 2940cagggacgtc gccaagaatg ccctgctgcg ctggcgcgtg ttcatctact ggacgctcct 3000gggactgttt gacgcactgg tgttcttctt tggtgcttat ttcgtgtttg aaaatacaac 3060tgtgacaagc aacgggcaga tatttggaaa ctggacgttt ggaacgctgg tattcaccgt 3120gatggtgttc acagttacac taaagcttgc attggacaca cactactgga cttggatcaa 3180ccattttgtc atctgggggt cgctgctgtt ctacgttgtc ttttcgcttc tctggggagg 3240agtgatctgg ccgttcctca actaccagag gatgtactac gtgttcatcc agatgctgtc 3300cagcgggccc gcctggctgg ccatcgtgct gctggtgacc atcagcctcc ttcccgacgt 3360cctcaagaaa gtcctgtgcc ggcagctgtg gccaacagca acagagagag tccagaatgg 3420gtgcgcacag cctcgggacc gcgactcaga attcacccct cttgcctctc tgcagagccc 3480aggctaccag agcacctgtc cctcggccgc ctggtacagc tcccactctc agcaggtgac 3540actcgcggcc tggaaggaga aggtgtccac ggagccccca cccatcctcg gcggttccca 3600tcaccactgc agttccatcc caagtcacag ctgccctagg tcccgtgtgg gaatgctcgt 3660gtgatggatg gtcctaagcc tgtggagact gtgcacgtgc ctcttcctgg cccccagcag 3720gcaaggaggg gggtcacagg ccttgccctc gagcatggca ccctggccgc ctggacccag 3780cactgtggtt gttgagccac accagtggcc tctgggcatt cggctcaacg caggagggac 3840attctgctgg cccaccctgc gcgctgtcat gcagaggcca ttcccccagg cctgtgtctt 3900cacccacctg ccatcattgg cctttgctgt cactgggaga gaagagccgt ccagggaccc 3960atggtggccc acatgtggat gccacatgct gctgtttcct gcttgcccgg ccaccaccca 4020tgccctccat agggtgaggt ggagccatgg tggtgcgtcc tttactcaac aaccctccaa 4080tccggatgct gtgggaaggg ccgggtcact cggataccat catccctgcg gatgcaccgc 4140cgtaccctgc tcatctggga gtggtttccc tgcggttacg tccaagcccg cctgccctgt 4200gtgttggggc tggctgagtt tcggtctccc catcaccggc cgcctcgtgg agaaggcagt 4260gccacgtggg aggacaaggc cacgccggca gcttccagcc ctgccgcaga agtgccagga 4320tgtccatcag ccactcgcca gggcacggag ccgtcagtcc actgttacgg gagaatgttg 4380atttcgcggg tgcgagggcc gggagacaga tacttggctg tgatgagcag acatcctctg 4440tccccgtgga ggggtcaaca ccaaggtggt gttcgtgcac cagaacctgt ctcgggctga 4500cgggggtggc acacaggaca cgggtggatc ccaacaggca gcaccgcacc tctgcccgcc 4560tcccgcactg cagctccgcc cgccgggctc tgcgtcccca cgtcccctcg tcccatcccc 4620acgtcccctc atcccgtcac ctcgtcccca catccccttg ccccgtcacc tcgtcctcat 4680gtccccttgt cctgtcacct cgtccccacg tcccctcgtc tcctcatccc cacgtcctct 4740cgtccccttg tcccgtcccc acataccctc gtccccatgt ccccacgcag ggctctcctt 4800cgtcttagga tctgtccagc gctgctctgg gtgggttagc aaccccaggg ctgctgtgat 4860aggaagtccc tgttgttctc cgtactggca tttctatttc tagaaataat atttgacata 4920gccttaatgg tccttaaaga agacatttca gtgtgagatt cagacttcag acgctgaaac 4980tgctgccttt caggaaagca ccaccaacgc tggaggagga gccggccctc acgcccgccc 5040cgcgccacgc tgtggaacgg ggctccggca agtgaaaccc agagggtgtt tccgaggtgc 5100tcgacagtag gtatttttgg aagctcagat ttcaccattt gattgtataa tcttttacct 5160ataaaatatt tatttgaagt agagggtaaa tcagcggtaa gaacagtgaa cacagtggtt 5220gggataaaat aaggtgacaa acatcacacc aaagatgagg gtagcgagca actggcttga 5280gcagacagaa cggggaagac tccactctgt cccgaggggc cagccgcagg cgtccccagg 5340gccaccctgc cctgaggtcc ttgtgtggcc gccctggctt ggcagccctg cccacgctgc 5400ccccgcaaac aatggtgtgt gcgtttttac agcccttttt aggaacccaa tatgggcata 5460aatgtaacac ctgtagcggg ggcagattct ctgtatgttc agttaacaaa ttatttgtaa 5520tgtatttttt tagaaatctt aaaattgcct ttgcactgaa gtattttcat agctgtttat 5580atctctttta ttcatttatt taacatactg tctaatttta aaaataggtt tttaaagctt 5640tcatttttaa gtttatgaaa ttttggccac tttacattta gattctggtg agagttttga 5700ctgaatgttc caatctctga tgaatgcgaa ttttcagatt tgattttatt ctctacacac 5760acctcttctt ttcttggtat ttctggtggc agtgattagt tgaacagcac atttaaggca 5820cgataatttg ctacactttt tctttacaat ttgttgcaat ttcatctgct ttctatgttt 5880cattgttaat tgccatcctt cagccttaaa aatagaagat tctcacgtga aggtttagta 5940agttgggtcc cagctctgcc tgtgtggaga tagtcaccat gtacctctga caacaagttt 6000tagtgtgaaa gtcactaaac ttttacacac tcccaaacgt ctttttaaaa attgcttggg 6060aaattattaa atgaatgtgc ctgatgattt gaaatagaca aggggcacga gataaaaaag 6120aaaaggatga gaagatcctc agtgaatgac gttgcagggt cttcatgcaa ttttccacct 6180cgcagtagtt agtatttact tgccttaaac taactttgaa gcaagtaatg tcaactttga 6240gcactttgtt gagttttgaa aaatcttatt tgttgctgca caggttaata aattatcaat 6300ttgtaattca gcatgttggt cagagacacg gtcactgatt cacacccagt ccctgccaca 6360gaccgtctca gacacgcaca gtgggcctgc tgcatgattc acacccagtc cctgccacag 6420accgtctcag acacgcacag tgggcctgct gcatgattca cacccagtcc ctgccacaga 6480ccgtctcaga cacgcacagt

gggcctgctg catgcgtgtt acctggcttt tggctccacg 6540ctcactcata gccatgtcca catgggggct tgcacacagg atcactcaca tatgtacatg 6600tacccaccac aaacgtgcaa gctcctgcac acatgcatgc acacaaacgt gtacacaagt 6660gtgagctcct acacgcatac acacacacac gtgtacatgc accaaagcat gtgtgaccta 6720cagacatgca gaacatgcac gtgtacacat accacagaca cgcgtgtgca tgctcctaca 6780caatacatat gcacatatca tgaacagcgt aagttcctac acacggacgt gtgatacaca 6840catgcatgta caggtaagca cacatgtaca agctcctaca ggcttgctct cacacacgtg 6900tatgcacagc agagagacgt atgagcttct actgcacaca tgcacacaca cacgcacacg 6960tacattcact acaaacgtgc agcctcctgc acacgtgcac attcatgtgt acaccacaaa 7020tgagttccca gacgtgtaaa cacacgtgca cacatcgtac acatgtgagc tcccacacgt 7080acacacagat gcacatggac acaccccaaa cacgcacagg ctcctacaca catgcacaca 7140cgtgtacacc acaaacgagc tcccagacat gtaaacacac gtctcccaca cgtgagctcc 7200cacacgtaca catgcacatg tacgcaccac aaacacatgc gcaggctcct gcaggcgtga 7260atacacacat gcacacacat atacacacat gtgccacaaa caagtgcaca ctgtcctggt 7320gtcctgcact gcatcctgcc tccttgctga ggggcccctg tgagaggcct ctggatgggc 7380atgggaagat gggctccctg gcccccagcc catgcctccc tgggatgaag agtccccctc 7440ctggcagaat gtctgggctt tgcagagcag gccccggggg tgaagtcgca gcttcactta 7500caccagctgc tctgtgagca aggcttggtg ccctggacaa ggcccttccc ctttagggag 7560gtccagcctc gcaagctgaa acctcccctc ggctcagccc tataccaggc ggccacagca 7620ggactggcca cacccacgcc gcacctcatc cgtgcacgcg tcggagcacg gccagccttc 7680cgccacgagc cagctgggaa gggccgcggc cgcctaaagc cccagtcaac ccagcctgtg 7740tctgagcaga cagggcgaac aagcaggcca caccgtctcg agggaggagg ccagatgcgg 7800ccagcgtctc caacagggtg accatccgct cggcttgctg agcgtttaaa caaatgttta 7860gacaggctgt ggggactccc ctgagttgag ccttggccag gggtccggtg ctgtcgcggg 7920aaacctccag ccttgttctt caaaccactc agctcatgtg ttttgcactg actagtactg 7980aataatacaa ccactcttat ttaatgttag tattatttat ttgacaactc agtgtctaac 8040agcttgatat gcaggtcctt gcatcctaca tttctttagg aagttaccca tttgtaactt 8100taaaaacagg aaaaatatca gttggcaaat gcaatctttt ttttttttaa gctaaaggtg 8160ggtgaactgg aatgaaaatc tttctgatgt tgtgtctata agcagccttg atgggatatg 8220ttagaagtgt catgaaagtg tgattctact tttgcagaaa aatctaaaga tcaatttata 8280tagctttatt ttttacttta tcaaagtata cagaatttta atatgcatat attgtgtctg 8340acttaaaatt ataatgtctg cgtcaccatt taaaatgtct gttcattatg taatgtaata 8400aaagaaggtc ttcaaaaatg tatttaacat gaatggtatc catagttgtc atcatcataa 8460atactggagt ttatttttaa attattaaac atagtaggtg cattaacata aatcagtctc 8520cacacagtaa catttaactg ataattcatt aatcagcttt gaaaaattaa attgttaatt 8580aaaccaatct aacatttcag taaagtttat tttgtatgct tctgttttta acttttattt 8640ctgtagataa actgactgga taatattata ttggactttt ctctagatta tctaagcagg 8700agacctgaat ctgcttgcaa taaagaataa aagtctgctt cagtttcttt ataaagaaac 8760tcacacaa 8768491191PRTHomo sapiens 49Met Asp Cys Ser Leu Val Arg Thr Leu Val His Arg Tyr Cys Ala Gly1 5 10 15Glu Glu Asn Trp Val Asp Ser Arg Thr Ile Tyr Val Gly His Arg Glu 20 25 30Pro Pro Pro Gly Ala Glu Ala Tyr Ile Pro Gln Arg Tyr Pro Asp Asn 35 40 45Arg Ile Val Ser Ser Lys Tyr Thr Phe Trp Asn Phe Ile Pro Lys Asn 50 55 60Leu Phe Glu Gln Phe Arg Arg Val Ala Asn Phe Tyr Phe Leu Ile Ile65 70 75 80Phe Leu Val Gln Leu Ile Ile Asp Thr Pro Thr Ser Pro Val Thr Ser 85 90 95Gly Leu Pro Leu Phe Phe Val Ile Thr Val Thr Ala Ile Lys Gln Gly 100 105 110Tyr Glu Asp Trp Leu Arg His Lys Ala Asp Asn Ala Met Asn Gln Cys 115 120 125Pro Val His Phe Ile Gln His Gly Lys Leu Val Arg Lys Gln Ser Arg 130 135 140Lys Leu Arg Val Gly Asp Ile Val Met Val Lys Glu Asp Glu Thr Phe145 150 155 160Pro Cys Asp Leu Ile Phe Leu Ser Ser Asn Arg Gly Asp Gly Thr Cys 165 170 175His Val Thr Thr Ala Ser Leu Asp Gly Glu Ser Ser His Lys Thr His 180 185 190Tyr Ala Val Gln Asp Thr Lys Gly Phe His Thr Glu Glu Asp Ile Gly 195 200 205Gly Leu His Ala Thr Ile Glu Cys Glu Gln Pro Gln Pro Asp Leu Tyr 210 215 220Lys Phe Val Gly Arg Ile Asn Val Tyr Ser Asp Leu Asn Asp Pro Val225 230 235 240Val Arg Pro Leu Gly Ser Glu Asn Leu Leu Leu Arg Gly Ala Thr Leu 245 250 255Lys Asn Thr Glu Lys Ile Phe Gly Val Ala Ile Tyr Thr Gly Met Glu 260 265 270Thr Lys Met Ala Leu Asn Tyr Gln Ser Lys Ser Gln Lys Arg Ser Ala 275 280 285Val Glu Lys Ser Met Asn Ala Phe Leu Ile Val Tyr Leu Cys Ile Leu 290 295 300Ile Ser Lys Ala Leu Ile Asn Thr Val Leu Lys Tyr Met Trp Gln Ser305 310 315 320Glu Pro Phe Arg Asp Glu Pro Trp Tyr Asn Gln Lys Thr Glu Ser Glu 325 330 335Arg Gln Arg Asn Leu Phe Leu Lys Ala Phe Thr Asp Phe Leu Ala Phe 340 345 350Met Val Leu Phe Asn Tyr Ile Ile Pro Val Ser Met Tyr Val Thr Val 355 360 365Glu Met Gln Lys Phe Leu Gly Ser Tyr Phe Ile Thr Trp Asp Glu Asp 370 375 380Met Phe Asp Glu Glu Thr Gly Glu Gly Pro Leu Val Asn Thr Ser Asp385 390 395 400Leu Asn Glu Glu Leu Gly Gln Val Glu Tyr Ile Phe Thr Asp Lys Thr 405 410 415Gly Thr Leu Thr Glu Asn Asn Met Glu Phe Lys Glu Cys Cys Ile Glu 420 425 430Gly His Val Tyr Val Pro His Val Ile Cys Asn Gly Gln Val Leu Pro 435 440 445Glu Ser Ser Gly Ile Asp Met Ile Asp Ser Ser Pro Ser Val Asn Gly 450 455 460Arg Glu Arg Glu Glu Leu Phe Phe Arg Ala Leu Cys Leu Cys His Thr465 470 475 480Val Gln Val Lys Asp Asp Asp Ser Val Asp Gly Pro Arg Lys Ser Pro 485 490 495Asp Gly Gly Lys Ser Cys Val Tyr Ile Ser Ser Ser Pro Asp Glu Val 500 505 510Ala Leu Val Glu Gly Val Gln Arg Leu Gly Phe Thr Tyr Leu Arg Leu 515 520 525Lys Asp Asn Tyr Met Glu Ile Leu Asn Arg Glu Asn His Ile Glu Arg 530 535 540Phe Glu Leu Leu Glu Ile Leu Ser Phe Asp Ser Val Arg Arg Arg Met545 550 555 560Ser Val Ile Val Lys Ser Ala Thr Gly Glu Ile Tyr Leu Phe Cys Lys 565 570 575Gly Ala Asp Ser Ser Ile Phe Pro Arg Val Ile Glu Gly Lys Val Asp 580 585 590Gln Ile Arg Ala Arg Val Glu Arg Asn Ala Val Glu Gly Leu Arg Thr 595 600 605Leu Cys Val Ala Tyr Lys Arg Leu Ile Gln Glu Glu Tyr Glu Gly Ile 610 615 620Cys Lys Leu Leu Gln Ala Ala Lys Val Ala Leu Gln Asp Arg Glu Lys625 630 635 640Lys Leu Ala Glu Ala Tyr Glu Gln Ile Glu Lys Asp Leu Thr Leu Leu 645 650 655Gly Ala Thr Ala Val Glu Asp Arg Leu Gln Glu Lys Ala Ala Asp Thr 660 665 670Ile Glu Ala Leu Gln Lys Ala Gly Ile Lys Val Trp Val Leu Thr Gly 675 680 685Asp Lys Met Glu Thr Ala Ala Ala Thr Cys Tyr Ala Cys Lys Leu Phe 690 695 700Arg Arg Asn Thr Gln Leu Leu Glu Leu Thr Thr Lys Arg Ile Glu Glu705 710 715 720Gln Ser Leu His Asp Val Leu Phe Glu Leu Ser Lys Thr Val Leu Arg 725 730 735His Ser Gly Ser Leu Thr Arg Asp Asn Leu Ser Gly Leu Ser Ala Asp 740 745 750Met Gln Asp Tyr Gly Leu Ile Ile Asp Gly Ala Ala Leu Ser Leu Ile 755 760 765Met Lys Pro Arg Glu Asp Gly Ser Ser Gly Asn Tyr Arg Glu Leu Phe 770 775 780Leu Glu Ile Cys Arg Ser Cys Ser Ala Val Leu Cys Cys Arg Met Ala785 790 795 800Pro Leu Gln Lys Ala Gln Ile Val Lys Leu Ile Lys Phe Ser Lys Glu 805 810 815His Pro Ile Thr Leu Ala Ile Gly Asp Gly Ala Asn Asp Val Ser Met 820 825 830Ile Leu Glu Ala His Val Gly Ile Gly Val Ile Gly Lys Glu Gly Arg 835 840 845Gln Ala Ala Arg Asn Ser Asp Tyr Ala Ile Pro Lys Phe Lys His Leu 850 855 860Lys Lys Met Leu Leu Val His Gly His Phe Tyr Tyr Ile Arg Ile Ser865 870 875 880Glu Leu Val Gln Tyr Phe Phe Tyr Lys Asn Val Cys Phe Ile Phe Pro 885 890 895Gln Phe Leu Tyr Gln Phe Phe Cys Gly Phe Ser Gln Gln Thr Leu Tyr 900 905 910Asp Thr Ala Tyr Leu Thr Leu Tyr Asn Ile Ser Phe Thr Ser Leu Pro 915 920 925Ile Leu Leu Tyr Ser Leu Met Glu Gln His Val Gly Ile Asp Val Leu 930 935 940Lys Arg Asp Pro Thr Leu Tyr Arg Asp Val Ala Lys Asn Ala Leu Leu945 950 955 960Arg Trp Arg Val Phe Ile Tyr Trp Thr Leu Leu Gly Leu Phe Asp Ala 965 970 975Leu Val Phe Phe Phe Gly Ala Tyr Phe Val Phe Glu Asn Thr Thr Val 980 985 990Thr Ser Asn Gly Gln Ile Phe Gly Asn Trp Thr Phe Gly Thr Leu Val 995 1000 1005Phe Thr Val Met Val Phe Thr Val Thr Leu Lys Leu Ala Leu Asp 1010 1015 1020Thr His Tyr Trp Thr Trp Ile Asn His Phe Val Ile Trp Gly Ser 1025 1030 1035Leu Leu Phe Tyr Val Val Phe Ser Leu Leu Trp Gly Gly Val Ile 1040 1045 1050Trp Pro Phe Leu Asn Tyr Gln Arg Met Tyr Tyr Val Phe Ile Gln 1055 1060 1065Met Leu Ser Ser Gly Pro Ala Trp Leu Ala Ile Val Leu Leu Val 1070 1075 1080Thr Ile Ser Leu Leu Pro Asp Val Leu Lys Lys Val Leu Cys Arg 1085 1090 1095Gln Leu Trp Pro Thr Ala Thr Glu Arg Val Gln Asn Gly Cys Ala 1100 1105 1110Gln Pro Arg Asp Arg Asp Ser Glu Phe Thr Pro Leu Ala Ser Leu 1115 1120 1125Gln Ser Pro Gly Tyr Gln Ser Thr Cys Pro Ser Ala Ala Trp Tyr 1130 1135 1140Ser Ser His Ser Gln Gln Val Thr Leu Ala Ala Trp Lys Glu Lys 1145 1150 1155Val Ser Thr Glu Pro Pro Pro Ile Leu Gly Gly Ser His His His 1160 1165 1170Cys Ser Ser Ile Pro Ser His Ser Cys Pro Arg Ser Arg Val Gly 1175 1180 1185Met Leu Val 1190504673DNAHomo sapiens 50tttccgcagt taggggctgc tatttcaacg cagggagata aaaagaaaaa aacacttgct 60cttctacccc gctaaaaaca ctcatcctag ggagcacgcc agcatttgca gcgttcgggg 120cagggccact cggcctgcgg ccgttgcact ggctggaagc tggcaggcga tcacggttga 180ttggctcggg tgcggtccaa gggcagcaac gccttcggcg ggccgcctag ggtgattggc 240tgctgcagcc caccccctag ccggtttggt gggcggcgaa gcctggattg gtggagctaa 300gagctggctc agtttcagcg ctggctcttc gtgcatggca gagatggcga ctgcgactcg 360gctgctgggg tggcgtgtgg cgagctggag gctgcggccg ccgcttgccg gcttcgtttc 420ccagcgggcc cactcgcttt tgcccgtgga cgatgcaatc aatgggctaa gcgaggagca 480gaggcagctt cgtcagacca tggctaagtt ccttcaggag cacctggccc ccaaggccca 540ggagatcgat cgcagcaatg agttcaagaa cctgcgagaa ttttggaagc agctggggaa 600cctgggcgta ttgggcatca cagcccctgt tcagtatggc ggctccggcc tgggctacct 660ggagcatgtg ctggtgatgg aggagatatc ccgagcttcc ggagcagtgg ggctcagtta 720cggtgcccac tccaacctct gcatcaacca gcttgtacgc aatgggaatg aggcccagaa 780agagaagtat ctcccgaagc tgatcagtgg tgagtacatc ggagccctgg ccatgagtga 840gcccaatgca ggctctgatg ttgtctctat gaagctcaaa gcggaaaaga aaggaaatca 900ctacatcctg aatggcaaca agttctggat cactaatggc cctgatgctg acgtcctgat 960tgtctatgcc aagacagatc tggctgctgt gccagcttct cggggcatca cagccttcat 1020tgtggagaag ggtatgcctg gctttagcac ctctaagaag ctggacaagc tggggatgag 1080gggctctaac acctgtgagc taatctttga agactgcaag attcctgctg ccaacatcct 1140gggccatgag aataagggtg tctacgtgct gatgagtggg ctggacctgg agcggctggt 1200gctggccggg gggcctcttg ggctcatgca agcggtcctg gaccacacca ttccctacct 1260gcacgtgagg gaagcctttg gccagaagat cggccacttc cagttgatgc aggggaagat 1320ggctgacatg tacacccgcc tcatggcgtg tcggcagtat gtctacaatg tcgccaaggc 1380ctgcgatgag ggccattgca ctgctaagga ctgtgcaggt gtgattcttt actcagctga 1440gtgtgccaca caggtagccc tggacggcat tcagtgtttt ggtggcaatg gctacatcaa 1500tgactttccc atgggccgct ttcttcgaga tgccaagctg tatgagatag gggctgggac 1560cagcgaggtg aggcggctgg tcatcggcag agccttcaat gcagactttc actagtcctg 1620agacccttcg cccccttttc ctgcacctag tggcctttct tgggaagtag agatgtggcg 1680gctttcccac cctgcccaca gcaggccctc ctgcccagct gctcttgtca gccctctggc 1740ctctggatga ggttgagttc tccacaacag ctcccaagca tcatgggcct cgcagccggg 1800cctgtgccac ggctagtgtt gtgtgattta aaatggactc agcaggaagc atattgtctg 1860gggattgttg ggacaggttt tggtgactct gtgcccttgc tctctaactt ctgagcccac 1920ctcccagggt aggcacctgg gggcatgcag gtgcccacct cccagggtag gcacctgggg 1980gcatgcaggt acccacctct ttctcttggg tgaggctctg gcaaggagat ctctctgctc 2040aagcacagca gaatcatggc ccctctccat gaattggaac ttggtacagg ttaagtatcc 2100ctaatcctga aatctgaaac acttgtggtt ccaagcattt tggataaggc aaattcaact 2160ttcagtctct tttctggggg aaaaaaataa taaacctagc ctagccaggc gtggtggctc 2220atgcttgtaa tcccagcact tcaggaggct gagatgggtg gatcacctga ggtcaggagt 2280tcaagaccag cctggccaac atgtggaaac ctcgcctcaa ctaaaaatag aaaaaaatta 2340gttgggcatg gtggtgggca cctgtaatcc cagctacttc aggaggctga ggcaggagaa 2400ttacttgaac ccaggaggcg gacgttgcag tgagccgagc ttgtgccatt gcactccagc 2460ctgggcgaca agagcaaaac tcttcaaaaa acaaaacaaa acaaaaaaac cctggccctt 2520gtttcttcca gtttctagag gtatcagctc ctagcagctt atgaacacat atgcttgctt 2580ggccaggcaa ggtggtgtgt gcctgtaatc ccagcacttt gggaggccaa ggcaggtgga 2640tcacttgcag tcaggagttc aagaccagcc tgtccaacgt ggtgaaaccc catctctact 2700aaaaatacaa aaattagcca ggggtggtgg tgcacgtctg taatcccagc tactcaggag 2760gctgaggcag gagaatcact tgaacccggg aggtggaggt tgcaatgagc caatatgaca 2820ccgctgcagt ccagcctggg ccatagagtg agactctgtc tcaaaaaagg aaagaaaaat 2880aggctgggca cagtgactca tgcctgtaat cccaacactt tgggaggccg aggcaggtgg 2940atcacgaggt caggagttca agaccagcct ggccaagatg gtaaaacctc gtctctacta 3000aaaatacaaa aattagccag gtgtggtggc aggctcctgt aatcccagct actcaggagg 3060ctgaggcaga gaattgcttg aacccgggag gcagagtttg cagtgagcca agatcacacc 3120actgcactcc agcttggacg acagagcgag actctgtctc aaaaaataat aggccaggca 3180tggtggctca acgtctgtaa tcccagcact ttgggaggcc gaggcgggca gatcacaagg 3240tcaggagttc gagaccagcc tgacgaccaa catggtgaaa cctcgtctct actaaaaata 3300caaaaattag ccaggcctgg tggcacgcgc ctgtaatccc agttacacag aagactgagg 3360caggagaatc gcttgaacgc aggaggcaga ggttgcagga gctgagatcg cgccattgca 3420ctccagcctg ggcaacagag tgagactctg tctcaaaaaa taataataaa ataaatgaac 3480acacatgctg ctgagtccgc agggggggca gagcagagga cagcgtgctt ttgtgtactg 3540ttggaagact ggctcctcct gtacagcacc tctgagccct tgtgcaccgc cctgccacgg 3600gcaccatcca gtcctggccg tgtgaccacc cacagctgac tgggcagcag gcacaggccc 3660tacccgagca ggccggagtt ggctcgcatg actccagctg aggctgcctg tgtacatttc 3720tccagatacc ctatggctaa ttttgttata actgcacagt ggctgctgcc attttgtatt 3780aaatatattg tgaaacaaac ctatctgggg agaagcaatc tacttgccgc tgcttcctgt 3840ctggatccag cttgtgtcct tggagagtgg ctggcccagg tcctattcct gtcctccagc 3900ccgttctttc atgagggaca ggaaggtaaa atcagccctt aggagagagg tctcagcctc 3960cctttcccag atctcccagt gagttttaaa ggaagcaggg agcccagagt gctaagttct 4020tacagccaga aggaagctta tagatttctg aaaaccgccc ctttgttttt aaaaagatca 4080acacaatttg actttctcaa ggtcaaaacg aactagaatc cagatctgct catggcaaaa 4140atgggggtgt tctgagaatt ccagctttgg gccgcactgt acagcagtct ggatagagtg 4200tgatctgaga agggaatggg tctgggttgt tccacccctt ccgagttcca aaaagaggga 4260actggttttc ttggttctca gcccagcagc acctatcctg gctcttggtc ctggcctgca 4320gccaagtgct gttcctagcc tgaggcttga gacaggtggg gttggctcct caccaacccc 4380agttccgtcc catcctgagg gcaagatcct gggctcatag gcagtccctt tcacttcctt 4440gtcttgctcc ctgctatgtt ggagatgaat gtgactaaaa gggccatctt gctggcttaa 4500tgtgtggctg gagagaccag cctggagaca atgtggcaaa atggggcgct tcatccagtc 4560tgtctaagcc ctgtcgactt ggggaggtga tttctttcct ggttctatat gtgaagcaaa 4620ataaatgttt taaaattaaa agcaaaaaaa acaaaatgaa ccatgaaaaa aaa 467351426PRTHomo sapiens 51Met Ala Glu Met Ala Thr Ala Thr Arg Leu Leu Gly Trp Arg Val Ala1 5 10 15Ser Trp Arg Leu Arg Pro Pro Leu Ala Gly Phe Val Ser Gln Arg Ala 20 25 30His Ser Leu Leu Pro Val Asp Asp Ala Ile Asn Gly Leu Ser Glu Glu 35 40 45Gln Arg Gln Leu Arg Gln Thr Met Ala Lys Phe Leu Gln Glu His Leu 50 55 60Ala Pro Lys Ala Gln Glu Ile Asp Arg Ser Asn Glu Phe Lys Asn Leu65 70 75 80Arg Glu Phe Trp Lys Gln Leu Gly Asn Leu Gly Val Leu Gly Ile Thr 85 90 95Ala Pro Val Gln Tyr Gly Gly Ser Gly Leu Gly Tyr Leu Glu His Val 100 105 110Leu Val Met Glu Glu Ile Ser Arg Ala Ser Gly Ala Val Gly Leu Ser

115 120 125Tyr Gly Ala His Ser Asn Leu Cys Ile Asn Gln Leu Val Arg Asn Gly 130 135 140Asn Glu Ala Gln Lys Glu Lys Tyr Leu Pro Lys Leu Ile Ser Gly Glu145 150 155 160Tyr Ile Gly Ala Leu Ala Met Ser Glu Pro Asn Ala Gly Ser Asp Val 165 170 175Val Ser Met Lys Leu Lys Ala Glu Lys Lys Gly Asn His Tyr Ile Leu 180 185 190Asn Gly Asn Lys Phe Trp Ile Thr Asn Gly Pro Asp Ala Asp Val Leu 195 200 205Ile Val Tyr Ala Lys Thr Asp Leu Ala Ala Val Pro Ala Ser Arg Gly 210 215 220Ile Thr Ala Phe Ile Val Glu Lys Gly Met Pro Gly Phe Ser Thr Ser225 230 235 240Lys Lys Leu Asp Lys Leu Gly Met Arg Gly Ser Asn Thr Cys Glu Leu 245 250 255Ile Phe Glu Asp Cys Lys Ile Pro Ala Ala Asn Ile Leu Gly His Glu 260 265 270Asn Lys Gly Val Tyr Val Leu Met Ser Gly Leu Asp Leu Glu Arg Leu 275 280 285Val Leu Ala Gly Gly Pro Leu Gly Leu Met Gln Ala Val Leu Asp His 290 295 300Thr Ile Pro Tyr Leu His Val Arg Glu Ala Phe Gly Gln Lys Ile Gly305 310 315 320His Phe Gln Leu Met Gln Gly Lys Met Ala Asp Met Tyr Thr Arg Leu 325 330 335Met Ala Cys Arg Gln Tyr Val Tyr Asn Val Ala Lys Ala Cys Asp Glu 340 345 350Gly His Cys Thr Ala Lys Asp Cys Ala Gly Val Ile Leu Tyr Ser Ala 355 360 365Glu Cys Ala Thr Gln Val Ala Leu Asp Gly Ile Gln Cys Phe Gly Gly 370 375 380Asn Gly Tyr Ile Asn Asp Phe Pro Met Gly Arg Phe Leu Arg Asp Ala385 390 395 400Lys Leu Tyr Glu Ile Gly Ala Gly Thr Ser Glu Val Arg Arg Leu Val 405 410 415Ile Gly Arg Ala Phe Asn Ala Asp Phe His 420 42552268PRTHomo sapiens 52Met Ser Gly Lys His Tyr Lys Gly Pro Glu Val Ser Cys Cys Ile Lys1 5 10 15Tyr Phe Ile Phe Gly Phe Asn Val Ile Phe Trp Phe Leu Gly Ile Thr 20 25 30Phe Leu Gly Ile Gly Leu Trp Ala Trp Asn Glu Lys Gly Val Leu Ser 35 40 45Asn Ile Ser Ser Ile Thr Asp Leu Gly Gly Phe Asp Pro Val Trp Leu 50 55 60Phe Leu Val Val Gly Gly Val Met Phe Ile Leu Gly Phe Ala Gly Cys65 70 75 80Ile Gly Ala Leu Arg Glu Asn Thr Phe Leu Leu Lys Phe Phe Ser Val 85 90 95Phe Leu Gly Ile Ile Phe Phe Leu Glu Leu Thr Ala Gly Val Leu Ala 100 105 110Phe Val Phe Lys Asp Trp Ile Lys Asp Gln Leu Tyr Phe Phe Ile Asn 115 120 125Asn Asn Ile Arg Ala Tyr Arg Asp Asp Ile Asp Leu Gln Asn Leu Ile 130 135 140Asp Phe Thr Gln Glu Tyr Trp Gln Cys Cys Gly Ala Phe Gly Ala Asp145 150 155 160Asp Trp Asn Leu Asn Ile Tyr Phe Asn Cys Thr Asp Ser Asn Ala Ser 165 170 175Arg Glu Arg Cys Gly Val Pro Phe Ser Cys Cys Thr Lys Asp Pro Ala 180 185 190Glu Asp Val Ile Asn Thr Gln Cys Gly Tyr Asp Ala Arg Gln Lys Pro 195 200 205Glu Val Asp Gln Gln Ile Val Ile Tyr Thr Lys Gly Cys Val Pro Gln 210 215 220Phe Glu Lys Trp Leu Gln Asp Asn Leu Thr Ile Val Ala Gly Ile Phe225 230 235 240Ile Gly Ile Ala Leu Leu Gln Ile Phe Gly Ile Cys Leu Ala Gln Asn 245 250 255Leu Val Ser Asp Ile Glu Ala Val Arg Ala Ser Trp 260 265533583DNAHomo sapiens 53ctgggcccca gcgaggcggt ggggcggggc ggggcggggc ggggcgcgca gcaggagcga 60gtggggccgc ccgccgggcc gcggacactg tcgcccggcg cccaggttcc caacaaggct 120acgcagaaga acccccttga ctgaagcaat ggaggggggt ccagctgtct gctgccagga 180tcctcgggca gagctggtag aacgggtggc agccatcgat gtgactcact tggaggaggc 240agatggtggc ccagagccta ctagaaacgg tgtggacccc ccaccacggg ccagagctgc 300ctctgtgatc cctggcagta cttcaagact gctcccagcc cggcctagcc tctcagccag 360gaagctttcc ctacaggagc ggccagcagg aagctatctg gaggcgcagg ctgggcctta 420tgccacgggg cctgccagcc acatctcccc ccgggcctgg cggaggccca ccatcgagtc 480ccaccacgtg gccatctcag atgcagagga ctgcgtgcag ctgaaccagt acaagctgca 540gagtgagatt ggcaagggtg cctacggtgt ggtgaggctg gcctacaacg aaagtgaaga 600cagacactat gcaatgaaag tcctttccaa aaagaagtta ctgaagcagt atggctttcc 660acgtcgccct cccccgagag ggtcccaggc tgcccaggga ggaccagcca agcagctgct 720gcccctggag cgggtgtacc aggagattgc catcctgaag aagctggacc acgtgaatgt 780ggtcaaactg atcgaggtcc tggatgaccc agctgaggac aacctctatt tggtgtttga 840cctcctgaga aaggggcccg tcatggaagt gccctgtgac aagcccttct cggaggagca 900agctcgcctc tacctgcggg acgtcatcct gggcctcgag tacttgcact gccagaagat 960cgtccacagg gacatcaagc catccaacct gctcctgggg gatgatgggc acgtgaagat 1020cgccgacttt ggcgtcagca accagtttga ggggaacgac gctcagctgt ccagcacggc 1080gggaacccca gcattcatgg cccccgaggc catttctgat tccggccaga gcttcagtgg 1140gaaggccttg gatgtatggg ccactggcgt cacgttgtac tgctttgtct atgggaagtg 1200cccattcatc gacgatttca tcctggccct ccacaggaag atcaagaatg agcccgtggt 1260gtttcctgag gagccagaaa tcagcgagga gctcaaggac ctgatcctga agatgttaga 1320caagaatccc gagacgagaa ttggggtgcc agacatcaag ttgcaccctt gggtgaccaa 1380gaacggggag gagccccttc cttcggagga ggagcactgc agcgtggtgg aggtgacaga 1440ggaggaggtt aagaactcag tcaggctcat ccccagctgg accacggtga tcctggtgaa 1500gtccatgctg aggaagcgtt cctttgggaa cccgtttgag ccccaagcac ggagggaaga 1560gcgatccatg tctgctccag gaaacctact ggtgaaagaa gggtttggtg aagggggcaa 1620gagcccagag ctccccggcg tccaggaaga cgaggctgca tcctgagccc ctgcatgcac 1680ccagggccac ccggcagcac actcatcccg cgcctccaga ggcccacccc tcatgcaaca 1740gccgcccccg caggcagggg gctggggact gcagccccac tcccgcccct cccccatcgt 1800gctgcatgac ctccacgcac gcacgtccag ggacagactg gaatgtatgt catttggggt 1860cttgggggca gggctcccac gaggccatcc tcctcttctt ggacctcctt ggcctgaccc 1920attctgtggg gaaaccgggt gcccatggag cctcagaaat gccacccggc tggttggcat 1980ggcctggggc aggaggcaga ggcaggagac caagatggca ggtggaggcc aggcttacca 2040caacggaaga gacctcccgc tggggccggg caggcctggc tcagctgcca caggcatatg 2100gtggagaggg gggtaccctg cccaccttgg ggtggtggca ccagagctct tgtctattca 2160gacgctggta tgggggctcg gacccctcac tggggacagg gccagtgttg gagaattctg 2220attccttttt tgttgtcttt tacttttgtt tttaacctgg gggttcgggg agaggccctg 2280cttgggaaca tctcacgagc tttcctacat cttccgtggt tcccagcaca gcccaagatt 2340atttggcagc caagtggatg gaactaactt tcctggactg tgtttcgcat tcggcgttat 2400ctggaaagtg gactgaacgg aatcaagctc tgagcagagg cctgaagcgg aagcaccaca 2460tcgtccctgc ccatctcact ctctcccttg atgatgcccc tagagctgag gctggagaag 2520acaccagggc tgactttgac cgagggccat ggacgcgaca ggcctgtggc cctgcgcatg 2580ctgaaataac tggaacccag cctctcctcc tacaccggcc tacccatctg ggcccaagag 2640ctgcactcac actcctacaa cgaaggacaa actgtccagg tcggagggat cacgagacac 2700agaacctgga ggggtgtgca cgctggcagg tggcctctgc ggcaattgcc tcaccctgag 2760gacatcagca gtcagcctgc tcagagcggg ggtgctggag cgcgtgcaga cacagctctt 2820ccggagcagc cttcaccttc tctctgggat cagtgtccgg ctggccgacg tggcatttgc 2880tgaccgaatg ctcatagagg ttgaccccca cagggtcacg caggactcgg acactgccct 2940ggaaacatgg atggacaagg gcttttggcc acaggtgtgg gtgtcctgtt ggaggagggc 3000ttgtttggag aagggaggct ggctggggga gaaacccgga tcccgctgca tctccgcgcc 3060tgtgggtgca tgtcgcgtgc tcatctgttg cacacagctc actcgtatgt cctgcactgg 3120tacatgcatc tgtaatacag tttctacgtc tatttaaggc taggagccga atgtgcccca 3180ttgtcagtgg gtccacgttt ctccccggct cctctgggct aaggcagtgt ggcccgaagc 3240ttaaaaagtt actcggtact gtttttaaga acacttttat agagttagtg gaaggcaagt 3300taagagccaa tcactgatcc ccaagtgttt cttgagcatc tggtctgggg ggaccacttt 3360gatcggaccc acccttggaa agctcagggg taggcccagg tgggatgctc accctgtcac 3420tgagggtttt ggttggcatc gttgtttttg aatgtagcac aagcgatgag caaactctat 3480aagagtgttt taaaaattaa cttcccagga agtgagttaa aaacaataaa agccctttct 3540tgagttaaaa agaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaa 358354505PRTHomo sapiens 54Met Glu Gly Gly Pro Ala Val Cys Cys Gln Asp Pro Arg Ala Glu Leu1 5 10 15Val Glu Arg Val Ala Ala Ile Asp Val Thr His Leu Glu Glu Ala Asp 20 25 30Gly Gly Pro Glu Pro Thr Arg Asn Gly Val Asp Pro Pro Pro Arg Ala 35 40 45Arg Ala Ala Ser Val Ile Pro Gly Ser Thr Ser Arg Leu Leu Pro Ala 50 55 60Arg Pro Ser Leu Ser Ala Arg Lys Leu Ser Leu Gln Glu Arg Pro Ala65 70 75 80Gly Ser Tyr Leu Glu Ala Gln Ala Gly Pro Tyr Ala Thr Gly Pro Ala 85 90 95Ser His Ile Ser Pro Arg Ala Trp Arg Arg Pro Thr Ile Glu Ser His 100 105 110His Val Ala Ile Ser Asp Ala Glu Asp Cys Val Gln Leu Asn Gln Tyr 115 120 125Lys Leu Gln Ser Glu Ile Gly Lys Gly Ala Tyr Gly Val Val Arg Leu 130 135 140Ala Tyr Asn Glu Ser Glu Asp Arg His Tyr Ala Met Lys Val Leu Ser145 150 155 160Lys Lys Lys Leu Leu Lys Gln Tyr Gly Phe Pro Arg Arg Pro Pro Pro 165 170 175Arg Gly Ser Gln Ala Ala Gln Gly Gly Pro Ala Lys Gln Leu Leu Pro 180 185 190Leu Glu Arg Val Tyr Gln Glu Ile Ala Ile Leu Lys Lys Leu Asp His 195 200 205Val Asn Val Val Lys Leu Ile Glu Val Leu Asp Asp Pro Ala Glu Asp 210 215 220Asn Leu Tyr Leu Val Phe Asp Leu Leu Arg Lys Gly Pro Val Met Glu225 230 235 240Val Pro Cys Asp Lys Pro Phe Ser Glu Glu Gln Ala Arg Leu Tyr Leu 245 250 255Arg Asp Val Ile Leu Gly Leu Glu Tyr Leu His Cys Gln Lys Ile Val 260 265 270His Arg Asp Ile Lys Pro Ser Asn Leu Leu Leu Gly Asp Asp Gly His 275 280 285Val Lys Ile Ala Asp Phe Gly Val Ser Asn Gln Phe Glu Gly Asn Asp 290 295 300Ala Gln Leu Ser Ser Thr Ala Gly Thr Pro Ala Phe Met Ala Pro Glu305 310 315 320Ala Ile Ser Asp Ser Gly Gln Ser Phe Ser Gly Lys Ala Leu Asp Val 325 330 335Trp Ala Thr Gly Val Thr Leu Tyr Cys Phe Val Tyr Gly Lys Cys Pro 340 345 350Phe Ile Asp Asp Phe Ile Leu Ala Leu His Arg Lys Ile Lys Asn Glu 355 360 365Pro Val Val Phe Pro Glu Glu Pro Glu Ile Ser Glu Glu Leu Lys Asp 370 375 380Leu Ile Leu Lys Met Leu Asp Lys Asn Pro Glu Thr Arg Ile Gly Val385 390 395 400Pro Asp Ile Lys Leu His Pro Trp Val Thr Lys Asn Gly Glu Glu Pro 405 410 415Leu Pro Ser Glu Glu Glu His Cys Ser Val Val Glu Val Thr Glu Glu 420 425 430Glu Val Lys Asn Ser Val Arg Leu Ile Pro Ser Trp Thr Thr Val Ile 435 440 445Leu Val Lys Ser Met Leu Arg Lys Arg Ser Phe Gly Asn Pro Phe Glu 450 455 460Pro Gln Ala Arg Arg Glu Glu Arg Ser Met Ser Ala Pro Gly Asn Leu465 470 475 480Leu Val Lys Glu Gly Phe Gly Glu Gly Gly Lys Ser Pro Glu Leu Pro 485 490 495Gly Val Gln Glu Asp Glu Ala Ala Ser 500 505553529DNAHomo sapiens 55agcagaacag agtatgcaat ttgggaagct gtggtgtggc tgcagtggag agttcccaac 60aaggctacgc agaagaaccc ccttgactga agcaatggag gggggtccag ctgtctgctg 120ccaggatcct cgggcagagc tggtagaacg ggtggcagcc atcgatgtga ctcacttgga 180ggaggcagat ggtggcccag agcctactag aaacggtgtg gaccccccac cacgggccag 240agctgcctct gtgatccctg gcagtacttc aagactgctc ccagcccggc ctagcctctc 300agccaggaag ctttccctac aggagcggcc agcaggaagc tatctggagg cgcaggctgg 360gccttatgcc acggggcctg ccagccacat ctccccccgg gcctggcgga ggcccaccat 420cgagtcccac cacgtggcca tctcagatgc agaggactgc gtgcagctga accagtacaa 480gctgcagagt gagattggca agggtgccta cggtgtggtg aggctggcct acaacgaaag 540tgaagacaga cactatgcaa tgaaagtcct ttccaaaaag aagttactga agcagtatgg 600ctttccacgt cgccctcccc cgagagggtc ccaggctgcc cagggaggac cagccaagca 660gctgctgccc ctggagcggg tgtaccagga gattgccatc ctgaagaagc tggaccacgt 720gaatgtggtc aaactgatcg aggtcctgga tgacccagct gaggacaacc tctatttggt 780gtttgacctc ctgagaaagg ggcccgtcat ggaagtgccc tgtgacaagc ccttctcgga 840ggagcaagct cgcctctacc tgcgggacgt catcctgggc ctcgagtact tgcactgcca 900gaagatcgtc cacagggaca tcaagccatc caacctgctc ctgggggatg atgggcacgt 960gaagatcgcc gactttggcg tcagcaacca gtttgagggg aacgacgctc agctgtccag 1020cacggcggga accccagcat tcatggcccc cgaggccatt tctgattccg gccagagctt 1080cagtgggaag gccttggatg tatgggccac tggcgtcacg ttgtactgct ttgtctatgg 1140gaagtgccca ttcatcgacg atttcatcct ggccctccac aggaagatca agaatgagcc 1200cgtggtgttt cctgaggagc cagaaatcag cgaggagctc aaggacctga tcctgaagat 1260gttagacaag aatcccgaga cgagaattgg ggtgccagac atcaagttgc acccttgggt 1320gaccaagaac ggggaggagc cccttccttc ggaggaggag cactgcagcg tggtggaggt 1380gacagaggag gaggttaaga actcagtcag gctcatcccc agctggacca cggtgatcct 1440ggtgaagtcc atgctgagga agcgttcctt tgggaacccg tttgagcccc aagcacggag 1500ggaagagcga tccatgtctg ctccaggaaa cctactggtg aaagaagggt ttggtgaagg 1560gggcaagagc ccagagctcc ccggcgtcca ggaagacgag gctgcatcct gagcccctgc 1620atgcacccag ggccacccgg cagcacactc atcccgcgcc tccagaggcc cacccctcat 1680gcaacagccg cccccgcagg cagggggctg gggactgcag ccccactccc gcccctcccc 1740catcgtgctg catgacctcc acgcacgcac gtccagggac agactggaat gtatgtcatt 1800tggggtcttg ggggcagggc tcccacgagg ccatcctcct cttcttggac ctccttggcc 1860tgacccattc tgtggggaaa ccgggtgccc atggagcctc agaaatgcca cccggctggt 1920tggcatggcc tggggcagga ggcagaggca ggagaccaag atggcaggtg gaggccaggc 1980ttaccacaac ggaagagacc tcccgctggg gccgggcagg cctggctcag ctgccacagg 2040catatggtgg agaggggggt accctgccca ccttggggtg gtggcaccag agctcttgtc 2100tattcagacg ctggtatggg ggctcggacc cctcactggg gacagggcca gtgttggaga 2160attctgattc cttttttgtt gtcttttact tttgttttta acctgggggt tcggggagag 2220gccctgcttg ggaacatctc acgagctttc ctacatcttc cgtggttccc agcacagccc 2280aagattattt ggcagccaag tggatggaac taactttcct ggactgtgtt tcgcattcgg 2340cgttatctgg aaagtggact gaacggaatc aagctctgag cagaggcctg aagcggaagc 2400accacatcgt ccctgcccat ctcactctct cccttgatga tgcccctaga gctgaggctg 2460gagaagacac cagggctgac tttgaccgag ggccatggac gcgacaggcc tgtggccctg 2520cgcatgctga aataactgga acccagcctc tcctcctaca ccggcctacc catctgggcc 2580caagagctgc actcacactc ctacaacgaa ggacaaactg tccaggtcgg agggatcacg 2640agacacagaa cctggagggg tgtgcacgct ggcaggtggc ctctgcggca attgcctcac 2700cctgaggaca tcagcagtca gcctgctcag agcgggggtg ctggagcgcg tgcagacaca 2760gctcttccgg agcagccttc accttctctc tgggatcagt gtccggctgg ccgacgtggc 2820atttgctgac cgaatgctca tagaggttga cccccacagg gtcacgcagg actcggacac 2880tgccctggaa acatggatgg acaagggctt ttggccacag gtgtgggtgt cctgttggag 2940gagggcttgt ttggagaagg gaggctggct gggggagaaa cccggatccc gctgcatctc 3000cgcgcctgtg ggtgcatgtc gcgtgctcat ctgttgcaca cagctcactc gtatgtcctg 3060cactggtaca tgcatctgta atacagtttc tacgtctatt taaggctagg agccgaatgt 3120gccccattgt cagtgggtcc acgtttctcc ccggctcctc tgggctaagg cagtgtggcc 3180cgaagcttaa aaagttactc ggtactgttt ttaagaacac ttttatagag ttagtggaag 3240gcaagttaag agccaatcac tgatccccaa gtgtttcttg agcatctggt ctggggggac 3300cactttgatc ggacccaccc ttggaaagct caggggtagg cccaggtggg atgctcaccc 3360tgtcactgag ggttttggtt ggcatcgttg tttttgaatg tagcacaagc gatgagcaaa 3420ctctataaga gtgttttaaa aattaacttc ccaggaagtg agttaaaaac aataaaagcc 3480ctttcttgag ttaaaaagaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaa 352956532PRTHomo sapiens 56Met Gln Phe Gly Lys Leu Trp Cys Gly Cys Ser Gly Glu Phe Pro Thr1 5 10 15Arg Leu Arg Arg Arg Thr Pro Leu Thr Glu Ala Met Glu Gly Gly Pro 20 25 30Ala Val Cys Cys Gln Asp Pro Arg Ala Glu Leu Val Glu Arg Val Ala 35 40 45Ala Ile Asp Val Thr His Leu Glu Glu Ala Asp Gly Gly Pro Glu Pro 50 55 60Thr Arg Asn Gly Val Asp Pro Pro Pro Arg Ala Arg Ala Ala Ser Val65 70 75 80Ile Pro Gly Ser Thr Ser Arg Leu Leu Pro Ala Arg Pro Ser Leu Ser 85 90 95Ala Arg Lys Leu Ser Leu Gln Glu Arg Pro Ala Gly Ser Tyr Leu Glu 100 105 110Ala Gln Ala Gly Pro Tyr Ala Thr Gly Pro Ala Ser His Ile Ser Pro 115 120 125Arg Ala Trp Arg Arg Pro Thr Ile Glu Ser His His Val Ala Ile Ser 130 135 140Asp Ala Glu Asp Cys Val Gln Leu Asn Gln Tyr Lys Leu Gln Ser Glu145 150 155 160Ile Gly Lys Gly Ala Tyr Gly Val Val Arg Leu Ala Tyr Asn Glu Ser 165 170 175Glu Asp Arg His Tyr Ala Met Lys Val Leu Ser Lys Lys Lys Leu Leu 180 185 190Lys Gln Tyr Gly Phe Pro Arg Arg Pro Pro Pro Arg Gly Ser Gln Ala 195

200 205Ala Gln Gly Gly Pro Ala Lys Gln Leu Leu Pro Leu Glu Arg Val Tyr 210 215 220Gln Glu Ile Ala Ile Leu Lys Lys Leu Asp His Val Asn Val Val Lys225 230 235 240Leu Ile Glu Val Leu Asp Asp Pro Ala Glu Asp Asn Leu Tyr Leu Val 245 250 255Phe Asp Leu Leu Arg Lys Gly Pro Val Met Glu Val Pro Cys Asp Lys 260 265 270Pro Phe Ser Glu Glu Gln Ala Arg Leu Tyr Leu Arg Asp Val Ile Leu 275 280 285Gly Leu Glu Tyr Leu His Cys Gln Lys Ile Val His Arg Asp Ile Lys 290 295 300Pro Ser Asn Leu Leu Leu Gly Asp Asp Gly His Val Lys Ile Ala Asp305 310 315 320Phe Gly Val Ser Asn Gln Phe Glu Gly Asn Asp Ala Gln Leu Ser Ser 325 330 335Thr Ala Gly Thr Pro Ala Phe Met Ala Pro Glu Ala Ile Ser Asp Ser 340 345 350Gly Gln Ser Phe Ser Gly Lys Ala Leu Asp Val Trp Ala Thr Gly Val 355 360 365Thr Leu Tyr Cys Phe Val Tyr Gly Lys Cys Pro Phe Ile Asp Asp Phe 370 375 380Ile Leu Ala Leu His Arg Lys Ile Lys Asn Glu Pro Val Val Phe Pro385 390 395 400Glu Glu Pro Glu Ile Ser Glu Glu Leu Lys Asp Leu Ile Leu Lys Met 405 410 415Leu Asp Lys Asn Pro Glu Thr Arg Ile Gly Val Pro Asp Ile Lys Leu 420 425 430His Pro Trp Val Thr Lys Asn Gly Glu Glu Pro Leu Pro Ser Glu Glu 435 440 445Glu His Cys Ser Val Val Glu Val Thr Glu Glu Glu Val Lys Asn Ser 450 455 460Val Arg Leu Ile Pro Ser Trp Thr Thr Val Ile Leu Val Lys Ser Met465 470 475 480Leu Arg Lys Arg Ser Phe Gly Asn Pro Phe Glu Pro Gln Ala Arg Arg 485 490 495Glu Glu Arg Ser Met Ser Ala Pro Gly Asn Leu Leu Val Lys Glu Gly 500 505 510Phe Gly Glu Gly Gly Lys Ser Pro Glu Leu Pro Gly Val Gln Glu Asp 515 520 525Glu Ala Ala Ser 530572535DNAHomo sapiens 57ctgggcccca gcgaggcggt ggggcggggc ggggcggggc ggggcgcgca gcaggagcga 60gtggggccgc ccgccgggcc gcggacactg tcgcccggcg cccaggttcc caacaaggct 120acgcagaaga acccccttga ctgaagcaat ggaggggggt ccagctgtct gctgccagga 180tcctcgggca gagctggtag aacgggtggc agccatcgat gtgactcact tggaggaggc 240agatggtggc ccagagccta ctagaaacgg tgtggacccc ccaccacggg ccagagctgc 300ctctgtgatc cctggcagta cttcaagact gctcccagcc cggcctagcc tctcagccag 360gaagctttcc ctacaggagc ggccagcagg aagctatctg gaggcgcagg ctgggcctta 420tgccacgggg cctgccagcc acatctcccc ccgggcctgg cggaggccca ccatcgagtc 480ccaccacgtg gccatctcag atgcagagga ctgcgtgcag ctgaaccagt acaagctgca 540gagtgagatt ggcaagggtg cctacggtgt ggtgaggctg gcctacaacg aaagtgaaga 600cagacactat gcaatgaaag tcctttccaa aaagaagtta ctgaagcagt atggctttcc 660acgtcgccct cccccgagag ggtcccaggc tgcccaggga ggaccagcca agcagctgct 720gcccctggag cgggtgtacc aggagattgc catcctgaag aagctggacc acgtgaatgt 780ggtcaaactg atcgaggtcc tggatgaccc agctgaggac aacctctatt tggccctgca 840gaaccaggcc cagaatatcc agttagattc aacaaatatc gccaagcccc actccctgct 900tccctctgag cagcaagaca gtggatccac gtgggctgcg cgctcagtgt ttgacctcct 960gagaaagggg cccgtcatgg aagtgccctg tgacaagccc ttctcggagg agcaagctcg 1020cctctacctg cgggacgtca tcctgggcct cgagtacttg cactgccaga agatcgtcca 1080cagggacatc aagccatcca acctgctcct gggggatgat gggcacgtga agatcgccga 1140ctttggcgtc agcaaccagt ttgaggggaa cgacgctcag ctgtccagca cggcgggaac 1200cccagcattc atggcccccg aggccatttc tgattccggc cagagcttca gtgggaaggc 1260cttggatgta tgggccactg gcgtcacgtt gtactgcttt gtctatggga agtgcccatt 1320catcgacgat ttcatcctgg ccctccacag gaagatcaag aatgagcccg tggtgtttcc 1380tgaggagcca gaaatcagcg aggagctcaa ggacctgatc ctgaagatgt tagacaagaa 1440tcccgagacg agaattgggg tgccagacat caagttgcac ccttgggtga ccaagaacgg 1500ggaggagccc cttccttcgg aggaggagca ctgcagcgtg gtggaggtga cagaggagga 1560ggttaagaac tcagtcaggc tcatccccag ctggaccacg gtgatcctgg tgaagtccat 1620gctgaggaag cgttcctttg ggaacccgtt tgagccccaa gcacggaggg aagagcgatc 1680catgtctgct ccaggaaacc tactggtgta agtactggtg ggccagggac tgccgggcac 1740tccctggagt tgggtgggga ggtctgaggc ccatcctccc actctcactg tcgttgggcc 1800aaggccagag cctggggact tggccaggtc tcggtgttgg ccccatttgc atctctgtcc 1860ccaaggttag tcggggctag aagggacctt ttgggcccag ctcttgcttc attcctgggg 1920ccagcatccc tcacacacac acttccaggg atgaggagct cacgcagccc ctccatggga 1980caggaagacc cttcttccat gcagcttgat gtcactctct cactgggtcc agcccctctg 2040gggcttcaaa tctgtggccc cctcagccct tggcagcctg gcagaggttt gcagacaggc 2100tgatgttggc ttcctgtagg aggctggcgg gctgtagagg aggggtgctg gcccctctgc 2160ctggccctgg ggactgttgg ctgctctccc aagtggccca ggctgcctgc agccattgct 2220ggggctctgt gcccagtcag cactttgtga gtgcttgttc agtgagtaag cagggacagg 2280ctggccggtg gaccacggga gaggaacccg cattggccga gggctcccta tggtgagcca 2340cgcctgtggg ttcaccacct cctaggaggg tccagaaaag cagctcccca agcctgtgcg 2400cctcgtcctc agcagatcca ccttcttcac tataataaaa gccagtctgg gatgctaaaa 2460aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2520aaaaaaaaaa aaaaa 253558520PRTHomo sapiens 58Met Glu Gly Gly Pro Ala Val Cys Cys Gln Asp Pro Arg Ala Glu Leu1 5 10 15Val Glu Arg Val Ala Ala Ile Asp Val Thr His Leu Glu Glu Ala Asp 20 25 30Gly Gly Pro Glu Pro Thr Arg Asn Gly Val Asp Pro Pro Pro Arg Ala 35 40 45Arg Ala Ala Ser Val Ile Pro Gly Ser Thr Ser Arg Leu Leu Pro Ala 50 55 60Arg Pro Ser Leu Ser Ala Arg Lys Leu Ser Leu Gln Glu Arg Pro Ala65 70 75 80Gly Ser Tyr Leu Glu Ala Gln Ala Gly Pro Tyr Ala Thr Gly Pro Ala 85 90 95Ser His Ile Ser Pro Arg Ala Trp Arg Arg Pro Thr Ile Glu Ser His 100 105 110His Val Ala Ile Ser Asp Ala Glu Asp Cys Val Gln Leu Asn Gln Tyr 115 120 125Lys Leu Gln Ser Glu Ile Gly Lys Gly Ala Tyr Gly Val Val Arg Leu 130 135 140Ala Tyr Asn Glu Ser Glu Asp Arg His Tyr Ala Met Lys Val Leu Ser145 150 155 160Lys Lys Lys Leu Leu Lys Gln Tyr Gly Phe Pro Arg Arg Pro Pro Pro 165 170 175Arg Gly Ser Gln Ala Ala Gln Gly Gly Pro Ala Lys Gln Leu Leu Pro 180 185 190Leu Glu Arg Val Tyr Gln Glu Ile Ala Ile Leu Lys Lys Leu Asp His 195 200 205Val Asn Val Val Lys Leu Ile Glu Val Leu Asp Asp Pro Ala Glu Asp 210 215 220Asn Leu Tyr Leu Ala Leu Gln Asn Gln Ala Gln Asn Ile Gln Leu Asp225 230 235 240Ser Thr Asn Ile Ala Lys Pro His Ser Leu Leu Pro Ser Glu Gln Gln 245 250 255Asp Ser Gly Ser Thr Trp Ala Ala Arg Ser Val Phe Asp Leu Leu Arg 260 265 270Lys Gly Pro Val Met Glu Val Pro Cys Asp Lys Pro Phe Ser Glu Glu 275 280 285Gln Ala Arg Leu Tyr Leu Arg Asp Val Ile Leu Gly Leu Glu Tyr Leu 290 295 300His Cys Gln Lys Ile Val His Arg Asp Ile Lys Pro Ser Asn Leu Leu305 310 315 320Leu Gly Asp Asp Gly His Val Lys Ile Ala Asp Phe Gly Val Ser Asn 325 330 335Gln Phe Glu Gly Asn Asp Ala Gln Leu Ser Ser Thr Ala Gly Thr Pro 340 345 350Ala Phe Met Ala Pro Glu Ala Ile Ser Asp Ser Gly Gln Ser Phe Ser 355 360 365Gly Lys Ala Leu Asp Val Trp Ala Thr Gly Val Thr Leu Tyr Cys Phe 370 375 380Val Tyr Gly Lys Cys Pro Phe Ile Asp Asp Phe Ile Leu Ala Leu His385 390 395 400Arg Lys Ile Lys Asn Glu Pro Val Val Phe Pro Glu Glu Pro Glu Ile 405 410 415Ser Glu Glu Leu Lys Asp Leu Ile Leu Lys Met Leu Asp Lys Asn Pro 420 425 430Glu Thr Arg Ile Gly Val Pro Asp Ile Lys Leu His Pro Trp Val Thr 435 440 445Lys Asn Gly Glu Glu Pro Leu Pro Ser Glu Glu Glu His Cys Ser Val 450 455 460Val Glu Val Thr Glu Glu Glu Val Lys Asn Ser Val Arg Leu Ile Pro465 470 475 480Ser Trp Thr Thr Val Ile Leu Val Lys Ser Met Leu Arg Lys Arg Ser 485 490 495Phe Gly Asn Pro Phe Glu Pro Gln Ala Arg Arg Glu Glu Arg Ser Met 500 505 510Ser Ala Pro Gly Asn Leu Leu Val 515 520591153DNAHomo sapiens 59gaaaacacca aatcaaccat aggtccaaga acaattgtct ctggacggca gctatgcgac 60tcaccgtgct gtgtgctgtg tgcctgctgc ctggcagcct ggccctgccg ctgcctcagg 120aggcgggagg catgagtgag ctacagtggg aacaggctca ggactatctc aagagatttt 180atctctatga ctcagaaaca aaaaatgcca acagtttaga agccaaactc aaggagatgc 240aaaaattctt tggcctacct ataactggaa tgttaaactc ccgcgtcata gaaataatgc 300agaagcccag atgtggagtg ccagatgttg cagaatactc actatttcca aatagcccaa 360aatggacttc caaagtggtc acctacagga tcgtatcata tactcgagac ttaccgcata 420ttacagtgga tcgattagtg tcaaaggctt taaacatgtg gggcaaagag atccccctgc 480atttcaggaa agttgtatgg ggaactgctg acatcatgat tggctttgcg cgaggagctc 540atggggactc ctacccattt gatgggccag gaaacacgct ggctcatgcc tttgcgcctg 600ggacaggtct cggaggagat gctcacttcg atgaggatga acgctggacg gatggtagca 660gtctagggat taacttcctg tatgctgcaa ctcatgaact tggccattct ttgggtatgg 720gacattcctc tgatcctaat gcagtgatgt atccaaccta tggaaatgga gatccccaaa 780attttaaact ttcccaggat gatattaaag gcattcagaa actatatgga aagagaagta 840attcaagaaa gaaatagaaa cttcaggcag aacatccatt cattcattca ttggattgta 900tatcattgtt gcacaatcag aattgataag cactgttcct ccactccatt tagcaattat 960gtcacccttt tttattgcag ttggtttttg aatgtctttc actcctttta aggataaact 1020cctttatggt gtgactgtgt cttattcatc tatacttgca gtgggtagat gtcaataaat 1080gttacataca caaataaata aaatgtttat tccatggtaa atttaaaaaa aaaaaaaaaa 1140aaaaaaaaaa aaa 115360267PRTHomo sapiens 60Met Arg Leu Thr Val Leu Cys Ala Val Cys Leu Leu Pro Gly Ser Leu1 5 10 15Ala Leu Pro Leu Pro Gln Glu Ala Gly Gly Met Ser Glu Leu Gln Trp 20 25 30Glu Gln Ala Gln Asp Tyr Leu Lys Arg Phe Tyr Leu Tyr Asp Ser Glu 35 40 45Thr Lys Asn Ala Asn Ser Leu Glu Ala Lys Leu Lys Glu Met Gln Lys 50 55 60Phe Phe Gly Leu Pro Ile Thr Gly Met Leu Asn Ser Arg Val Ile Glu65 70 75 80Ile Met Gln Lys Pro Arg Cys Gly Val Pro Asp Val Ala Glu Tyr Ser 85 90 95Leu Phe Pro Asn Ser Pro Lys Trp Thr Ser Lys Val Val Thr Tyr Arg 100 105 110Ile Val Ser Tyr Thr Arg Asp Leu Pro His Ile Thr Val Asp Arg Leu 115 120 125Val Ser Lys Ala Leu Asn Met Trp Gly Lys Glu Ile Pro Leu His Phe 130 135 140Arg Lys Val Val Trp Gly Thr Ala Asp Ile Met Ile Gly Phe Ala Arg145 150 155 160Gly Ala His Gly Asp Ser Tyr Pro Phe Asp Gly Pro Gly Asn Thr Leu 165 170 175Ala His Ala Phe Ala Pro Gly Thr Gly Leu Gly Gly Asp Ala His Phe 180 185 190Asp Glu Asp Glu Arg Trp Thr Asp Gly Ser Ser Leu Gly Ile Asn Phe 195 200 205Leu Tyr Ala Ala Thr His Glu Leu Gly His Ser Leu Gly Met Gly His 210 215 220Ser Ser Asp Pro Asn Ala Val Met Tyr Pro Thr Tyr Gly Asn Gly Asp225 230 235 240Pro Gln Asn Phe Lys Leu Ser Gln Asp Asp Ile Lys Gly Ile Gln Lys 245 250 255Leu Tyr Gly Lys Arg Ser Asn Ser Arg Lys Lys 260 26561451DNAHomo sapiens 61gggttgcgga gggtgggcct gggaggggtg gtggccattt tttgtctaac cctaactgag 60aagggcgtag gcgccgtgct tttgctcccc gcgcgctgtt tttctcgctg actttcagcg 120ggcggaaaag cctcggcctg ccgccttcca ccgttcattc tagagcaaac aaaaaatgtc 180agctgctggc ccgttcgccc ctcccgggga cctgcggcgg gtcgcctgcc cagcccccga 240accccgcctg gaggccgcgg tcggcccggg gcttctccgg aggcacccac tgccaccgcg 300aagagttggg ctctgtcagc cgcgggtctc tcgggggcga gggcgaggtt caggcctttc 360aggccgcagg aagaggaacg gagcgagtcc ccgcgcgcgg cgcgattccc tgagctgtgg 420gacgtgcacc caggactcgg ctcacacatg c 451

Claims

1. A method of treating a fibrotic lung disease in a subject comprising administering to the subject an effective amount of a therapeutic agent, wherein the subject is asymptomatic and wherein the subject is at risk of developing the fibrotic lung disease.

2. The method of claim 1, wherein the subject presents radiographic Usual Interstitial Pneumonia (UIP).

3. The method of claim 1 or 2, wherein the subject has fibrotic interstitial lung disease (FILD).

4. The method of claim 1 or 2, wherein the subject has an interstitial lung disease (ILD).

5. The method of claim 4, where in the subject has rheumatoid arthritis-associated interstitial lung disease (RA-ILD).

6. The method of any one of claims 1-3, wherein the subject has a blood relative with familial interstitial pneumonia (FIP).

7. The method of claim 6, wherein the blood relative is a sibling.

8. The method of any one of claims 1-7, wherein the subject has a mutation in a sequence encoding Mucin 5B (MUC5B), Telomerase RNA Component (TERC), Family with sequence similarity 13 member A (FAM13A), Telomerase Reverse Transcriptase (TERT), Desmoplakin (DSP), Zinc-alpha 2-Glycoprotein 1 (AZGP1), Oligonucleotide/oligosaccharide-binding Fold Containing 1 (OBFC1), ATPase Phospholipid Transporting 11A (ATP11A), Isovaleryl-CoA dehydrogenase (IVD)/Dispatched RND Transporter Family Member 2 (DISP2), Dipeptidyl Peptidase 9 (DPP9), Sialic Acid Binding Ig-Like Lectin 14 (SIGLEC14), Adrenomedullin 2 (ADM2), Tetraspanin 5 (TSPAN5), Calcium/Calmodulin-Dependent Protein Kinase Kinase 1 (CAMKK1), zinc figner with KRAB and SCAN domains 1 (ZKSCAN1), isovaleryl-CoA dehydrogenase (IVD), ATPase phospholipid transporting 11A (AK025511) or Matrix Metalloprotease-7 (MMP-7).

9. The method of claim 8, wherein the mutation comprises a polymorphism in a sequence encoding a MUC5B promoter.

10. The method of claim 9, wherein the polymorphism is rs35705950.

11. The method of claim 8, wherein the mutation comprises a polymorphism in a sequence encoding a TERC 3' untranslated region (UTR).

12. The method of claim 11, wherein the polymorphism is rs2293607.

13. The method of claim 8, wherein the mutation comprises a polymorphism in a sequence encoding intronic FAM13A.

14. The method of claim 13, wherein the polymorphism is rs2609260.

15. The method of claim 8, wherein the mutation comprises a polymorphism in a sequence encoding intronic TERT.

16. The method of claim 15, wherein the polymorphism is rs4449583.

17. The method of claim 8, wherein the mutation comprises a polymorphism in a sequence encoding intronic DSP.

18. The method of claim 17, wherein the polymorphism is rs2076295.

19. The method of claim 8, wherein the mutation comprises a polymorphism in a sequence encoding intronic ZKSCAN1.

20. The method of claim 19, wherein the polymorphism is rs6963345.

21. The method of claim 8, wherein the mutation comprises a polymorphism in a sequence encoding intronic OBFC1.

22. The method of claim 21, wherein the polymorphism is rs2488000.

23. The method of claim 8, wherein the mutation comprises a polymorphism in a sequence encoding an AK025511 3' UTR.

24. The method of claim 23, wherein the polymorphism is rs1278769.

25. The method of claim 8, wherein the mutation comprises a polymorphism in a sequence encoding IVD.

26. The method of claim 25, wherein the polymorphism is rs35700143.

27. The method of claim 8, wherein the mutation comprises a polymorphism in a sequence encoding intronic DPP9.

28. The method of claim 27, wherein the polymorphism is rs12610495.

29. The method of any one of claims 1-28, wherein the fibrotic lung disease is pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), an interstitial lung abnormality (ILA), an asymptomatic ILA, interstitial lung disease (ILD) or rheumatoid arthritis-associated interstitial lung disease (RA-ILD).

30. The method of any one of claims 1-28, wherein the fibrotic lung disease is ILD or RA-ILD.

31. The method of any one of claims 1-28, wherein the fibrotic lung disease is pulmonary fibrosis or IPF.

32. The method of any one of claims 1-28, wherein the fibrotic lung disease is IPF.

33. The method of any one of claims 1-32, wherein the therapeutic agent comprises a N-acetylcysteine, pirfenidone, and nintedanib.

34. The method of any one of claims 1-32, wherein the therapeutic agent comprises pirfenidone.

35. The method of claim 34, wherein the effective dosage is about 2400 mg/day.

36. The method of claim 35, wherein the effective dosage is administered orally as a capsule or a tablet.

37. The method of claim 35 or 36, wherein the effective dosage is administered three times per day.

38. The method of any one of claims 35-37, wherein the effective dosage is administered according to an escalating dosage regimen.

39. The method of claim 39, wherein the escalating dosage regimen comprises (a) administering to the subject about 800 mg of pirfenidone per day for a first week; (b) administering to the subject about 1600 mg of pirfenidone per day for a second week; and (c) administering to the subject about 2400 mg of pirfenidone per day for the remainder of the treatment.

40. The method of claim 38, wherein the escalating dosage regimen comprises (a) administering to the subject a capsule or tablet comprising about 250 mg of pirfenidone three times a day for a first week; (b) administering to the subject two capsules or tablets comprising about 250 mg of pirfenidone three times a day for a second week; and (c) administering to the subject three capsules or tablets comprising about 250 mg of pirfenidone three times a day for the remainder of the treatment.

41. The method of claim 40, wherein the capsule or tablet comprises 267 mg of pirfenidone.

42. The method of any one of claims 1-32, wherein the therapeutic agent comprises nintedanib.

43. The method of claim 42, wherein the effective dosage is administered orally as a capsule or a tablet.

44. The method of claim 43, wherein the effective dosage is about 300 mg/day.

45. The method of claim 42 or 43, wherein the effective dosage is about 150 mg administered twice per day, wherein the daily doses are administered about 12 hours apart from one another.

46. The method of claim 43, wherein the effective dosage is about 200 mg/day.

47. The method of claim 43 or 46, wherein the effective dosage is about 100 mg administered twice per day, wherein the daily doses are administered about 12 hours apart from one another.

48. The method of any one of claims 42-47, wherein the effective dosage is administered according to a modified or interrupted dosage regimen.

49. The method of claim 48, wherein the modified or interrupted dosage regimen comprises (a) administering to the subject about 300 mg of nintedanib per day until the subject presents an elevated level of liver enzymes compared to a control level of liver enzymes; (b) administering to the subject about 200 mg of nintedanib per day until the subject presents the control level of liver enzymes; and (c) administering to the subject about 300 mg of nintedanib per day for the remainder of the treatment; wherein the control level of liver enzymes is a level detected in the subject prior to an initiation of the treatment.

50. The method of claim 48, wherein the modified or interrupted regimen comprises (a) administering to the subject a capsule or tablet comprising about 150 mg of nintedanib twice per day until the subject presents an elevated level of liver enzymes compared to a control level of liver enzymes; (b) administering to the subject two capsules or tablets comprising about 100 mg twice per day until the subject presents an elevated level of liver enzymes compared to a control level of liver enzymes; and (c) administering to the subject a capsule or tablet comprising about 150 mg of nintedanib twice per day for the remainder of the treatment; wherein the control level of liver enzymes is a level detected in the subject prior to an initiation of the treatment.

51. The method of any one of claims 1-50, wherein the therapeutic agent prevents the onset or development of a sign or symptom of the fibrotic lung disease.

52. The method of any one of claims 1-50, wherein the therapeutic agent delays the onset or development of a sign or symptom of the fibrotic lung disease when compared to the expected onset of the a sign or symptom in the absence of treatment with the therapeutic agent.

53. The method of any one of claims 1-50, wherein the therapeutic agent reduces the severity of a sign or symptom of the fibrotic lung disease when compared to the expected severity of the a sign or symptom in the absence of treatment with the therapeutic agent.

54. The method of any one of claims 51-53, wherein at least one sign of the fibrotic lung disease is detectable before the subject presents a symptom of the fibrotic lung disease.

55. The method of claim 54, wherein the at least one sign comprises gradual or unintended weight loss, clubbing of the fingers or toes, rapid and shallow breathing, fibrotic lesions in one or both lungs detectable by radiography, or a cough.

56. The method of claim 54, wherein the symptom comprises shortness of breath during exercise, shortness of breath at rest, a dry and hacking cough, repeated bouts of coughing, and uncontrollable bouts of coughing.

57. The method of any one of claims 1-56, wherein the method prevents the onset of a secondary condition associated with a severe form of the fibrotic lung disease.

58. The method of claim 57, wherein secondary condition comprises a collapsed lung, an infected lung, a blood clot in a lung, lung cancer, respiratory failure, pulmonary hypertension, heart failure or death.

59. A method of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease, comprising administering to a non-human subject a dose of a composition that modifies transcription or translation of a sequence encoding Mucin 5B (MUC5B), Telomerase RNA Component (TERC), Family with sequence similarity 13 member A (FAM13A), Telomerase Reverse Transcriptase (TERT), Desmoplakin (DSP), Zinc-alpha 2-Glycoprotein 1 (AZGP1), Oligonucleotide/oligosaccharide-binding Fold Containing 1 (OBFC1), ATPase Phospholipid Transporting 11A (ATP11A), Isovaleryl-CoA dehydrogenase (IVD)/Dispatched RND Transporter Family Member 2 (DISP2), Dipeptidyl Peptidase 9 (DPP9), Sialic Acid Binding Ig-Like Lectin 14 (SIGLEC14), Adrenomedullin 2 (ADM2), Tetraspanin 5 (TSPAN5), Calcium/Calmodulin-Dependent Protein Kinase Kinase 1 (CAMKK1) or Matrix Metalloprotease-7 (MMP-7), wherein the dose of the composition is tolerable to the non-human subject and wherein the dose of the composition is therapeutically effective.

60. A method of identifying a therapeutic agent or target thereof for the treatment of a fibrotic lung disease, comprising administering to a non-human subject a composition that modifies an activity of a product of a sequence encoding MUC5B, TERC, FAM13A, TERT, DSP, AZGP1, OBFC1, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7, wherein the dose of the composition is tolerable to the non-human subject and wherein the dose of the composition is therapeutically effective.

61. The method of claim 59, wherein the composition that modifies transcription or translation decreases or inhibits transcription or translation.

62. The method of claim 61, wherein the composition decreases or inhibits transcription or translation of a sequence encoding a gene selected from the group consisting of Leukotriene A4 Hydrolase (LTA4H), Surfactant Protein B (SFTPB), Breast Cancer Anti-Estrogen Resistance 3 (BCAR3), C-X-C motif Chemokine Ligand 13 (CXCL13), EPH Receptor A2 (EPHA2), Serum Amyloid A1 (SAA1), Phospholipase A2 Group IIA (PLA2G2A), Insulin-Like Growth Factor Binding Protein 3 (IGFBP3), C-C Motif Chemokine Ligand 28 (CCL28), S100 Calcium Binding Protein A12 (S100A12), Thromboxane A Synthase 1 (TBXAS1), Leukocyte Cell Derived Chemotaxin 1 (LECT1), Complement C3 (C3), Gastrin Releasing Peptide (GRP), C-Reactive Protein (CRP), Vitrin (VIT), Insulin-Like Growth Factor Binding Protein 1 (IGFBP1), Family with Sequence Similarity 173 Member A (FAM173A), Natriuretic Peptide A (NPPA), Secreted Frizzled Related Protein 1 (SFRP1), Ezrin (EZR), Inter-Alpha-Trypsin Inhibitor Heavy Chain Family Member 5 (ITIH5), Pleckstrin and Sec7 Domain Containing 2 (PSD2), Galectin 3 Binding Protein (LGALS3BP), Catenin Beta 1 (CTNNB1), Chromodomain Y Like 2 (CDYL2), Matrix Metallopeptidase 7 (MMPI), Apolipoprotein B (APOB), Proline and Arginine Rich End Leucine Rich Repeat Protein (PRELP), Eukaryotic Translation Initiation Factor 1A, X-linked (EIF1AX), Mesencephalic Astrocyte Derived Neurotrophic Factor (MANF), TNF Receptor Superfamily Member 13C (TNFRSF13C), Deformed Epidermal Autoregulatory Factor 1 transcription factor (DEAF1), Tumor Protein Translationally-Controlled 1 (TPT1), Unc-5 Netrin Receptor B (UNCSB), Phosphatidylethanolamine Binding Protein 1 (PEBP1), Syntaxin 8 (STX8), Polymeric Immunoglobulin Receptor (PIGR), Adenine Phosphoribosyltransferase (APRT), Matrix Metallopeptidase 3 (MMP3), Galectin 7 (LGALS7), Bruton Tyrosine Kinase (BTK), NSFL1 Cofactor (NSFL1C), FER Tyrosine Kinase (FER), Regenerating Family Member 1 Beta (REG1B), SMAD Family Member 2 (SMAD2), Interleukin 1 Receptor Like 1 (IL1RL1), C-C Motif Chemokine Ligand 18 (CCL18), Acid Phosphatase 2 Lysosomal (ACP2), Eukaryotic Translation Initiation Factor 4E Family Member 2 (EIF4E2), Neurexin 3 (NRXN3), IGF Like Family Member 1 (IGFL1), NME/NM23 Nucleoside Diphosphate Kinase 1 (NME1), Potassium Voltage-Gated Channel Isk-Related Family Member 1-Like (KCNE1L) or Neurexophilin 2 (NXPH2).

63. The method of claim 59, wherein the composition that modifies transcription or translation increases or activates transcription or translation.

64. The method of claim 63, wherein the composition increases or activates transcription or translation of a sequence encoding a gene selected from the group consisting of Surfactant Protein D (SFTPD), Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH), Histone Cluster 1 H1 Family Member C (HIST1H1C), YTH Domain Containing 1 (YTHDC1), Plexin A1 (PLXNA1), Serine Peptidase Inhibitor Kazal Type 6 (SPINK6), LDL Receptor Related Protein Associated Protein 1 (LRPAP1), Secretoglobin Family 3A Member 1 (SCGB3A1), H2A Histone Family Member Z (H2AFZ) or Chromosome 1 Open Reading Frame 162 (C1 orf162).

65. The method of claim 60, wherein the composition that modifies an activity decreases or inhibits the activity.

66. The method of claim 65, wherein the composition decreases or inhibits the activity of a sequence encoding a gene selected from Leukotriene A4 Hydrolase (LTA4H), Surfactant Protein B (SFTPB), Breast Cancer Anti-Estrogen Resistance 3 (BCAR3), C-X-C motif Chemokine Ligand 13 (CXCL13), EPH Receptor A2 (EPHA2), Serum Amyloid A1 (SAA1), Phospholipase A2 Group IIA (PLA2G2A), Insulin-Like Growth Factor Binding Protein 3 (IGFBP3), C-C Motif Chemokine Ligand 28 (CCL28), 5100 Calcium Binding Protein A12 (S100A12), Thromboxane A Synthase 1 (TBXAS1), Leukocyte Cell Derived Chemotaxin 1 (LECT1), Complement C3 (C3), Gastrin Releasing Peptide (GRP), C-Reactive Protein (CRP), Vitrin (VIT), Insulin-Like Growth Factor Binding Protein 1 (IGFBP1), Family with Sequence Similarity 173 Member A (FAM173A), Natriuretic Peptide A (NPPA), Secreted Frizzled Related Protein 1 (SFRP1), Ezrin (EZR), Inter-Alpha-Trypsin Inhibitor Heavy Chain Family Member 5 (ITIH5), Pleckstrin and Sec7 Domain Containing 2 (PSD2), Galectin 3 Binding Protein (LGALS3BP), Catenin Beta 1 (CTNNB1), Chromodomain Y Like 2 (CDYL2), Matrix Metallopeptidase 7 (MMPI), Apolipoprotein B (APOB), Proline and Arginine Rich End Leucine Rich Repeat Protein (PRELP), Eukaryotic Translation Initiation Factor 1A, X-linked (EIF1AX), Mesencephalic Astrocyte Derived Neurotrophic Factor (MANF), TNF Receptor Superfamily Member 13C (TNFRSF13C), Deformed Epidermal Autoregulatory Factor 1 transcription factor (DEAF1), Tumor Protein Translationally-Controlled 1 (TPT1), Unc-5 Netrin Receptor B (UNCSB), Phosphatidylethanolamine Binding Protein 1 (PEBP1), Syntaxin 8 (STX8), Polymeric Immunoglobulin Receptor (PIGR), Adenine Phosphoribosyltransferase (APRT), Matrix Metallopeptidase 3 (MMP3), Galectin 7 (LGALS7), Bruton Tyrosine Kinase (BTK), NSFL1 Cofactor (NSFL1C), FER Tyrosine Kinase (FER), Regenerating Family Member 1 Beta (REG1B), SMAD Family Member 2 (SMAD2), Interleukin 1 Receptor Like 1 (IL1RL1), C-C Motif Chemokine Ligand 18 (CCL18), Acid Phosphatase 2 Lysosomal (ACP2), Eukaryotic Translation Initiation Factor 4E Family Member 2 (EIF4E2), Neurexin 3 (NRXN3), IGF Like Family Member 1 (IGFL1), NME/NM23 Nucleoside Diphosphate Kinase 1 (NME1), Potassium Voltage-Gated Channel Isk-Related Family Member 1-Like (KCNE1L) or Neurexophilin 2 (NXPH2).

67. The method of claim 60, wherein the composition that modifies an activity increases or activates the activity.

68. The method of claim 67, wherein the composition increases or activates the activity of a sequence encoding Surfactant Protein D (SFTPD), Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH), Histone Cluster 1 H1 Family Member C (HIST1H1C), YTH Domain Containing 1 (YTHDC1), Plexin A1 (PLXNA1), Serine Peptidase Inhibitor Kazal Type 6 (SPINK6), LDL Receptor Related Protein Associated Protein 1 (LRPAP1), Secretoglobin Family 3A Member 1 (SCGB3A1), H2A Histone Family Member Z (H2AFZ) or Chromosome 1 Open Reading Frame 162 (Clorf162).

69. The method of any one of claims 60-68, wherein the non-human subject is a mammal.

70. The method of any one of claims 60-69, wherein the mammal is genetically-modified.

71. The method of claim 70, wherein the genetically-modified mammal is a model organism for the fibrotic lung disease.

72. The method of any one of claims 60-71, wherein the fibrotic lung disease is pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), an interstitial lung abnormality (ILA), or an asymptomatic ILA.

73. The method of any one of claims 60-71, wherein the fibrotic lung disease is pulmonary fibrosis or IPF.

74. The method of any one of claims 60-71, wherein the fibrotic lung disease is IPF.

75. The method of any one of claims 60-74, wherein the non-human subject carries a mutation in a sequence encoding MUC5B.

76. The method of claim 75, wherein the mutation comprises a polymorphism in a sequence encoding a MUC5B promoter.

77. The method of claim 76, wherein the polymorphism is rs35705950.

78. The method of any one of claims 60-77, wherein the non-human subject carries a mutation in a sequence encoding TERC, FAM13A, TERT, DSP, AZGP1, OBFC1, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7.

79. The method of any one of claims 60-78, wherein the composition prevents the onset or development of a sign or symptom of the fibrotic lung disease.

80. The method of any one of claims 60-78, wherein the composition delays the onset or development of a sign or symptom of the fibrotic lung disease when compared to the expected onset of the a sign or symptom in the absence of treatment with the composition.

81. The method of claim 80, wherein the composition delays the onset or development of a sign or symptom of the fibrotic lung disease when compared to the expected onset of the sign or symptom when treated using a standard therapeutic intervention.

82. The method of any one of claims 60-78, wherein the composition reduces the severity of a sign or symptom of the fibrotic lung disease when compared to the expected severity of the sign or symptom in the absence of treatment with the composition.

83. The method of claim 24, wherein the composition reduces the severity of a sign or symptom of the fibrotic lung disease when compared to the expected severity of the sign or symptom when treated using a standard therapeutic intervention.

84. The method of claim 81 or 83, wherein the standard therapeutic intervention comprises a N-acetylcysteine, pirfenidone, and nintedanib.

85. The method of claim 81 or 83, wherein the standard therapeutic intervention comprises pirfenidone.

86. The method of claim 85, wherein an effective dosage of pirfenidone is about 2400 mg/day.

87. The method of claim 86, wherein the effective dosage is administered orally as a capsule or a tablet.

88. The method of claim 86 or 87, wherein the effective dosage is administered three times per day.

89. The method of any one of claims 85-88, wherein the effective dosage is administered according to an escalating dosage regimen.

90. The method of claim 85, 86 or 89, wherein the escalating dosage regimen comprises (a) administering to the non-human subject about 800 mg of pirfenidone per day for a first week; (b) administering to the non-human subject about 1600 mg of pirfenidone per day for a second week; and (c) administering to the non-human subject about 2400 mg of pirfenidone per day for the remainder of the treatment.

91. The method of claim 85, 86 or 89, wherein the escalating dosage regimen comprises (a) administering to the non-human subject a capsule or tablet comprising about 250 mg of pirfenidone three times a day for a first week; (b) administering to the non-human subject two capsules or tablets comprising about 250 mg of pirfenidone three times a day for a second week; and (c) administering to the non-human subject three capsules or tablets comprising about 250 mg of pirfenidone three times a day for the remainder of the treatment.

92. The method of claim 91, wherein the capsule or tablet comprises 267 mg of pirfenidone.

93. The method of claim 81 or 83, wherein the standard therapeutic intervention comprises nintedanib.

94. The method of claim 93, wherein an effective dosage of nintedanib is administered orally as a capsule or a tablet.

95. The method of claim 94, wherein the effective dosage is about 300 mg/day.

96. The method of claim 94 or 95, wherein the effective dosage is about 150 mg administered twice per day, wherein the daily doses are administered about 12 hours apart from one another.

97. The method of claim 94, wherein the effective dosage is about 200 mg/day.

98. The method of claim 94 or 95, wherein the effective dosage is about 100 mg administered twice per day, wherein the daily doses are administered about 12 hours apart from one another.

99. The method of any one of claims 79-98, wherein the non-human subject presents at least one sign of the fibrotic lung disease.

100. The method of claim 99, wherein the at least one sign comprises gradual or unintended weight loss, clubbing of the fingers or toes, rapid and shallow breathing, fibrotic lesions in one or both lungs detectable by radiography, or a cough.

101. The method of any one of claims 60-100, wherein the compound prevents the onset of a secondary condition associated with a severe form of the fibrotic lung disease.

102. The method of claim 100, wherein the compound prevents the onset for at 1 year, 2 years, 3 years, 4 years, 5 years or any whole or fractional number of years in between.

103. The method of claim 101 or 102, wherein secondary condition comprises a collapsed lung, an infected lung, a blood clot in a lung, lung cancer, respiratory failure, pulmonary hypertension, heart failure or death.

104. A composition for the treatment of a fibrotic lung disease identified by the method of any one of claims 60-103.

105. A method of treating a fibrotic lung disease in a human subject comprising administering to the subject the composition of claim 104, wherein the subject is asymptomatic and wherein the subject is at risk of developing the fibrotic lung disease.

106. The method of claim 105, wherein the human subject presents radiographic Usual Interstitial Pneumonia (UIP).

107. The method of claim 105 or 106, wherein the human subject has fibrotic interstitial lung disease (FILD).

108. The method of any one of claims 105-107, wherein the human subject has a blood relative with familial interstitial pneumonia (FIP).

109. The method of claim 108, wherein the blood relative is a sibling.

110. The method of any one of claims 105-109, wherein the human subject has a mutation in a sequence encoding MUC5B, TERC, FAM13A, TERT, DSP, AZGP1, OBFC1, ATP11A, IVD/DISP2, DPP9, SIGLEC14, ADM2, TSPAN5, CAMKK1 or MMP-7.

111. The method of claim 110, wherein the mutation comprises a polymorphism in a sequence encoding a MUC5B promoter.

112. The method of claim 111, wherein the polymorphism is rs35705950.

113. The method of any one of claims 105-112, wherein the fibrotic lung disease is pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), an interstitial lung abnormality (ILA), or an asymptomatic ILA.

114. The method of any one of claims 105-112, wherein the fibrotic lung disease is pulmonary fibrosis or IPF.

115. The method of any one of claims 105-112, wherein the fibrotic lung disease is IPF.

116. The method of any one of claims 105-112, wherein the method prevents the onset of a secondary condition associated with a severe form of the fibrotic lung disease.

117. The method of claim 116, wherein secondary condition comprises a collapsed lung, an infected lung, a blood clot in a lung, lung cancer, respiratory failure, pulmonary hypertension, heart failure or death.

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