Biomarker Specific To Brain/nerve Or Specific To Neuronal Differentiation

Abstract

The invention provides a novel polypeptide and a specific partial peptide thereof, as well as a novel polynucleotide and a specific partial nucleotide thereof, that can be used as a biomarker specific for the brain/nerves or specific for nerve differentiation; an expression vector for such a polynucleotide and a specific partial peptide thereof; a transformant incorporating such an expression vector; an antisense molecule, RNAi-inducing nucleic acid (e.g., siRNA), aptamer, or antibody for such a biomarker, and a composition comprising the same; a mammalian cell or non-human mammal wherein the expression or a function of such a biomarker is regulated; a measuring means (e.g., primer set, nucleic acid probe, antibody, aptamer) for such a biomarker, and a reagent comprising the same and the like.

Description

TECHNICAL FIELD

[0001] The present invention provides a polypeptide and a partial peptide thereof, as well as a polynucleotide and a partial nucleotide thereof, that can be used as biomarkers specific for the brain/nerves or specific for nerve differentiation; an expression vector; a transformant; an antisense molecule, an RNAi-inducing nucleic acid (e.g., siRNA), an aptamer, an antibody, and a composition comprising them; a mammalian cell or a non-human mammal; a measuring means for a biomarker specific for the brain/nerves or specific for nerve differentiation (e.g., primer set, nucleic acid probe, antibody, aptamer), a measuring method and the like.

BACKGROUND ART

[0002] Although there have been remarkable advances in the analysis of human chromosome sequences thanks to the progress in human genome research, this does not mean that all the human genetic functions have been clarified. In humans, gene diversity is significantly associated with changes in gene functions. In fact, it is known that in humans, a plurality of mRNAs are transcribed from a particular region of a chromosome to produce different variants.

[0003] For the series of genes that have been discovered by the present inventors, and that can be used as biomarkers specific for the brain/nerves or specific for nerve differentiation (abbreviated as "brain/nerve-specific genes" or "brain/nerve-specific genes 1 to 10" as required), known variants have been reported. Examples of such known variants include known variants of brain/nerve-specific gene 1 (Genbank accession number: NM.sub.--133460.1; non-patent documents 1 and 2), brain/nerve-specific gene 2 (Genbank accession number: NM.sub.--005163.1; non-patent documents 3 and 4), brain/nerve-specific gene 3 (Genbank accession number: NM.sub.--181784.1; non-patent documents 5 and 6), brain/nerve-specific gene 4 (Genbank accession number: NM.sub.--003930.3; non-patent documents 7 and 8), brain/nerve-specific gene 5 (Genbank accession number: NM.sub.--000898.3; non-patent documents 9 and 10), brain/nerve-specific gene 6 (Genbank accession number: NM.sub.--005079.1; non-patent documents 11 and 12), brain/nerve-specific gene 7% (Genbank accession number: NM.sub.--001679.2; non-patent document 13 and 14), brain/nerve-specific gene 8 (Genbank accession number: NM.sub.--000431.1; non-patent documents 15 and 16), brain/nerve-specific gene 9 (Genbank accession number: NM.sub.--153449.2; non-patent document 17), and brain/nerve-specific gene 10 (Genbank accession number: NM.sub.--015009.1; non-patent documents 18 and 19).

[0004] However, it is not known that the brain/nerve-specific genes 1 to 10 can be useful as biomarkers specific for the brain/nerves or specific for nerve cell differentiation, and that the particular variants discovered by the present inventors exist in the brain/nerve-specific genes 1 to 10. [0005] [Non-patent document 1] Ota, T. et al., Nat. Genet. 36 (1), 40-45 (2004) [0006] [Non-patent document 2] Strausberg, R. L. et al., Proc. Natl. Acad. Sci. U.S.A. 99 (26), 16899-16903 (2002) [0007] [Non-patent document 3] Staal, S. P., Proc. Natl. Acad. Sci. U.S.A. 84 (14), 5034-5037 (1987) [0008] [Non-patent document 4] Staal, S. P. et al., Genomics 2 (1), 96-98 (1988) [0009] [Non-patent document 5] Wakioka, T. et al., Nature 412 (6847), 647-651 (2001) [0010] [Non-patent document 6] Kato, R. et al., Biochem. Biophys. Res. Commun. 302 (4), 767-772 (2003) [0011] [Non-patent document 7] Marie-Cardine, A. et al., FEES Lett. 435 (1), 55-60 (1998) [0012] [Non-patent document 8] Kouroku, Y. et al., Biochem. Biophys. Res. Commun. 252 (3), 738-742 (1998) [0013] [Non-patent document 9] Kochersperger, L. M. et al., J. Neurosci. Res. 16 (4), 601-616 (1986) [0014] [Non-patent document 10] Bach, A. W. et al., Proc. Natl. Acad. Sci. U.S.A. 85 (13), 4934-4938 (1988) [0015] [Non-patent document 11] Chen, S. L. et al., Oncogene 12 (4), 741-751 (1996) [0016] [Non-patent document 12] Byrne, J. A. et al., Genomics 35 (3), 523-532 (1996) [0017] [Non-patent document 13] Lingrel, J. B. et al., Prog. Nucleic Acid Res. Mol. Biol. 38, 37-89 (1990) [0018] [Non-patent document 14] Malik, N. et al., J. Biol. Chem. 271 (37), 22754-22758 (1996) [0019] [Non-patent document 15] Kopito, R. R. et al., Proc. Natl. Acad. Sci. U.S.A. 77 (10), 5738-5740 (1980) [0020] [Non-patent document 16] Schafer, B. L. et al., J. Biol. Chem. 267 (19), 13229-13238 (1992) [0021] [Non-patent document 17] Wu, X. et al., Genomics 80 (6), 553-557 (2002) [0022] [Non-patent document 18] Bach, I. et al., Nat. Genet. 22 (4), 394-399 (1999) [0023] [Non-patent document 19] Katoh, M. et al., Int. J. Mol. Med. 13 (4), 607-613 (2004)

DISCLOSURE OF THE INVENTION

Problems to be Solved by the Invention

[0024] Analyzing a biomarker specific for the brain/nerve cells or specific for nerve cell differentiation leads to the development of, for example, a reagent for nerve cell identification or nerve cell differentiation state determination, a diagnostic reagent for a disease based on a nerve cell disorder, a pharmaceutical for a disease based on a nerve cell disorder, having a new mechanism of action, and the like. Based on the findings obtained by expression profile analysis of specified genes, the present invention is directed to providing such reagents, pharmaceuticals and the like, and providing a means useful in developing such reagents, pharmaceuticals and the like.

Means of Solving the Problems

[0025] The present inventors conducted extensive investigations and discovered brain/nerve-specific genes 1 to 10 as biomarkers specific for the brain/nerves or specific for nerve cell differentiation. The present inventors also discovered novel variants of the brain/nerve-specific genes 1 to 10 that can be used as biomarkers specific for the brain/nerves or specific for nerve cell differentiation. Therefore, it is thought that by utilizing the brain/nerve-specific genes 1 to 10 and/or novel variants thereof, it will become possible to identify nerve cells, to determine nerve cell differentiation states, to diagnose a disease based on a nerve cell disorder, and the like. In particular, because the brain/nerve-specific genes 1 to 10 and/or novel variants thereof are expressed specifically in particular differentiation stages of nerve cells, the accuracy of the determination of nerve cells in the particular differentiation stages can be increased. It is also thought that by utilizing the brain/nerve-specific genes 1 to 10 and/or novel variants thereof, it will become possible to develop a novel pharmaceutical for a specified disease such as a disease based on a nerve cell disorder, and the like.

[0026] Based on the findings shown above, the present inventors developed the present invention.

[0027] Accordingly, the present invention relates to the following aspects and the like.

[1] A polypeptide of any one of 1) to 10) below or a specific partial peptide thereof: 1) a polypeptide having an amino acid sequence shown by SEQ ID NO:18 or SEQ ID NO:10 or substantially the same amino acid sequence thereas; 2) a polypeptide having the amino acid sequence shown by SEQ ID NO:43 or substantially the same amino acid sequence thereas; 3) a polypeptide having the amino acid sequence shown by SEQ ID NO:58 or substantially the same amino acid sequence thereas; 4) a polypeptide having the amino acid sequence shown by SEQ ID NO:74 or substantially the same amino acid sequence thereas; 5) a polypeptide having an amino acid sequence shown by SEQ ID NO:89 or SEQ ID NO:99 or substantially the same amino acid sequence thereas; 6) a polypeptide having the amino acid sequence shown by SEQ ID NO:118 or substantially the same amino acid sequence thereas; 7) a polypeptide having the amino acid sequence shown by SEQ ID NO:133 or substantially the same amino acid sequence thereas; 8) a polypeptide having an amino acid sequence shown by SEQ ID NO:152 or SEQ ID NO:159 or substantially the same amino acid sequence thereas; 9) a polypeptide having an amino acid sequence shown by SEQ ID NO:184 or SEQ ID NO:190 or substantially the same amino acid sequence thereas; and 10) a polypeptide having an amino acid sequence shown by SEQ ID NO:207, SEQ ID NO:213, SEQ ID NO:219, SEQ ID NO:225, SEQ ID NO:231 or SEQ ID NO:236 or substantially the same amino acid sequence thereas. [2] The polypeptide or specific partial peptide thereof according to [1] above, wherein the polypeptide is any of the polypeptides 1) to 10) below: 1) a polypeptide consisting of an amino acid sequence shown by SEQ ID NO:18 or SEQ ID NO:10; 2) a polypeptide consisting of the amino acid sequence shown by SEQ ID NO:43; 3) a polypeptide consisting of the amino acid sequence shown by SEQ ID NO:58; 4) a polypeptide consisting of the amino acid sequence shown by SEQ ID NO:74; 5) a polypeptide consisting of an amino acid sequence shown by SEQ ID NO:89 or SEQ ID NO:99; 6) a polypeptide consisting of the amino acid sequence shown by SEQ ID NO:118; 7) a polypeptide consisting of the amino acid sequence shown by SEQ ID NO:133; 8) a polypeptide consisting of an amino acid sequence shown by SEQ ID NO:152 or SEQ ID NO:159; 9) a polypeptide consisting of an amino acid sequence shown by SEQ ID NO:184 or SEQ ID NO:190; and 10) a polypeptide consisting of an amino acid sequence shown by SEQ ID NO:207, SEQ ID NO:213, SEQ ID NO:219, SEQ ID NO:225, SEQ ID NO:231 or SEQ ID NO:236. [3] The polypeptide or specific partial peptide thereof according to [1] or [2] above, which is fused with a polypeptide consisting of a heterologous amino acid sequence. [4] A partial peptide specific for a polypeptide encoded by one of the brain/nerve-specific genes 1 to 10, being any one of the partial peptides 1) to 10) below: 1) a partial peptide consisting of an amino acid sequence shown by SEQ ID NO:12, SEQ ID NO:15, SEQ ID NO:20 or SEQ ID NO:22 or a partial amino acid sequence thereof; 2) a partial peptide consisting of the amino acid sequence shown by SEQ ID NO:264 or a partial amino acid sequence thereof; 3) a partial peptide having the amino acid sequence shown by SEQ ID NO:60; 4) a partial peptide consisting of the amino acid sequence shown by SEQ ID NO:265 or a partial amino acid sequence thereof; 5) a partial peptide consisting of an amino acid sequence shown by SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:96, or SEQ ID NO:266 or a partial amino acid sequence thereof; 6) a partial peptide consisting of the amino acid sequence shown by SEQ ID NO:120 or a partial amino acid sequence thereof; 7) a partial peptide consisting of an amino acid sequence shown by SEQ ID NO:135, SEQ ID NO:138 or SEQ ID NO:139 or a partial amino acid sequence thereof; 8) a partial peptide consisting of an amino acid sequence shown by SEQ ID NO:156, SEQ ID NO:161 or SEQ ID NO:163 or a partial amino acid sequence thereof; 9) a partial peptide consisting of an amino acid sequence shown by SEQ ID NO:186 or SEQ ID NO:192 or a partial amino acid sequence thereof; and 10) a partial peptide consisting of an amino acid sequence shown by SEQ ID NO:209, SEQ ID NO:215, SEQ ID NO:221 or SEQ ID NO:227 or a partial amino acid sequence thereof, or a partial peptide having the amino acid sequence shown by SEQ ID NO:238. [5] A polynucleotide that encodes any one of the polypeptides [1] to [3] above, or any one of the specific partial peptides [1] to [4] above. [6] A polynucleotide of any one of 1) to 10) below or a specific partial nucleotide thereof: 1) a polynucleotide having a nucleic acid sequence shown by SEQ ID NO:16 or SEQ ID NO:8, or a nucleic acid sequence corresponding to the ORF thereof, or substantially the same nucleic acid sequence thereas; 2) a polynucleotide having the nucleic acid sequence shown by SEQ ID NO:41, or a nucleic acid sequence corresponding to the ORF thereof, or substantially the same nucleic acid sequence thereas; 3) a polynucleotide having the nucleic acid sequence shown by SEQ ID NO:56, or a nucleic acid sequence corresponding to the ORF thereof, or substantially the same nucleic acid sequence thereas; 4) a polynucleotide having the nucleic acid sequence shown by SEQ ID NO:72, or a nucleic acid sequence corresponding to the ORF thereof, or substantially the same nucleic acid sequence thereas; 5) a polynucleotide having a nucleic acid sequence shown by SEQ ID NO:87 or SEQ ID NO:97, or a nucleic acid sequence corresponding to the ORF thereof, or substantially the same nucleic acid sequence thereas; 6) a polynucleotide having the nucleic acid sequence shown by SEQ ID NO:116, or a nucleic acid sequence corresponding to the ORF thereof, or substantially the same nucleic acid sequence thereas; 7) a polynucleotide having the nucleic acid sequence shown by SEQ ID NO:131, or a nucleic acid sequence corresponding to the ORF thereof, or substantially the same nucleic acid sequence thereas; 8) a polynucleotide having a nucleic acid sequence shown by SEQ ID NO:150 or SEQ ID NO:157, or a nucleic acid sequence corresponding to the ORF thereof, or substantially the same nucleic acid sequence thereas; 9) a polynucleotide having a nucleic acid sequence shown by SEQ ID NO:182 or SEQ ID NO:188, or a nucleic acid sequence corresponding to the ORF thereof, or substantially the same nucleic acid sequence thereas; and 10) a polynucleotide having a nucleic acid sequence shown by SEQ ID NO:205, SEQ ID NO:211, SEQ ID NO:217, SEQ ID NO:223, SEQ ID NO:229 or SEQ ID NO:234, or a nucleic acid sequence corresponding to the ORF thereof, or substantially the same nucleic acid sequence thereas. [7] The polynucleotide or specific partial nucleotide thereof according to [6] above, wherein the any one of the polynucleotides 1) to 10) is any one of the polynucleotides 1) to 10) below: 1) a polynucleotide consisting of a nucleic acid sequence shown by SEQ ID NO:16 or SEQ ID NO:8 or a nucleic acid sequence corresponding to the ORF thereof; 2) a polynucleotide consisting of the nucleic acid sequence shown by SEQ ID NO:41 or a nucleic acid sequence corresponding to the ORF thereof; 3) a polynucleotide consisting of the nucleic acid sequence shown by SEQ ID NO:56 or a nucleic acid sequence corresponding to the ORF thereof; 4) a polynucleotide consisting of the nucleic acid sequence shown by SEQ ID NO:72 or a nucleic acid sequence corresponding to the ORF thereof; 5) a polynucleotide consisting of a nucleic acid sequence shown by SEQ ID NO:87 or SEQ ID NO:97 or a nucleic acid sequence corresponding to the ORF thereof; 6) a polynucleotide consisting of the nucleic acid sequence shown by SEQ ID NO:116 or a nucleic acid sequence corresponding to the ORF thereof; 7) a polynucleotide consisting of the nucleic acid sequence shown by SEQ ID NO:131 or a nucleic acid sequence corresponding to the ORF thereof; 8) a polynucleotide consisting of a nucleic acid sequence shown by SEQ ID NO:150 or SEQ ID NO:157 or a nucleic acid sequence corresponding to the ORF thereof; 9) a polynucleotide consisting of a nucleic acid sequence shown by SEQ ID NO:182 or SEQ ID NO:188 or a nucleic acid sequence corresponding to the ORF thereof; and 10) a polynucleotide consisting of a nucleic acid sequence shown by SEQ ID NO:205, SEQ ID NO:211, SEQ ID NO:217, SEQ ID NO:223, SEQ ID NO:229 or SEQ ID NO:234 or a nucleic acid sequence corresponding to the ORF thereof. [8] A partial nucleotide specific for any one of the polynucleotides encoded by the brain/nerve-specific genes 1 to 10, being any one of the partial nucleotides 1) to 10) below: 1) a partial nucleotide consisting of a nucleic acid sequence shown by SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:29, SEQ ID NO:33, SEQ ID NO:39 or SEQ ID NO:40 or a partial nucleic acid sequence thereof; 2) a partial nucleotide consisting of a nucleic acid sequence shown by SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:48, SEQ ID NO:51 or SEQ ID NO:55 or a partial nucleic acid sequence thereof; 3) a partial nucleotide consisting of a nucleic acid sequence shown by SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:64, SEQ ID NO:67 or SEQ ID NO:71 or a partial nucleic acid sequence thereof; 4) a partial nucleotide consisting of a nucleic acid sequence shown by SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:79, SEQ ID NO:82 or SEQ ID NO:86 or a partial nucleic acid sequence thereof; 5) a partial nucleotide consisting of a nucleic acid sequence shown by SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:95, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:104, SEQ ID NO:107, SEQ ID NO:110, SEQ ID NO:114 or SEQ ID NO:115 or a partial nucleic acid sequence thereof; 6) a partial nucleotide consisting of a nucleic acid sequence shown by SEQ ID NO:119, SEQ ID NO:123, SEQ ID NO:126 or SEQ ID NO:130 or a partial nucleic acid sequence thereof; 7) a partial nucleotide consisting of a nucleic acid sequence shown by SEQ ID NO:134, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:142, SEQ ID NO:145 or SEQ ID NO:149 or a partial nucleic acid sequence thereof; 8) a partial nucleotide consisting of a nucleic acid sequence shown by SEQ ID NO:153, SEQ ID NO:154, SEQ ID NO:155, SEQ ID NO:160, SEQ ID NO:162, SEQ ID NO:166, SEQ ID NO:170, SEQ ID NO:174, SEQ ID NO:180 or SEQ ID NO:181 or a partial nucleic acid sequence thereof; 9) a partial nucleotide consisting of a nucleic acid sequence shown by SEQ ID NO:185, SEQ ID NO:187, SEQ ID NO:191, SEQ ID NO:193, SEQ ID NO:199, SEQ ID NO:203 or SEQ ID NO:204 or a partial nucleic acid sequence thereof; and 10) a partial nucleotide consisting of a nucleic acid sequence shown by SEQ ID NO:208, SEQ ID NO:210, SEQ ID NO:214, SEQ ID NO:216, SEQ ID NO:220, SEQ ID NO:222, SEQ ID NO:226, SEQ ID NO:228, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:237, SEQ ID NO:239, SEQ ID NO:242, SEQ ID NO:245, SEQ ID NO:248, SEQ ID NO:251, SEQ ID NO:254, SEQ ID NO:258, SEQ ID NO:259, SEQ ID NO:260, SEQ ID NO:261, SEQ ID NO:262 or SEQ ID NO:263 or a partial nucleic acid sequence thereof. [9] An expression vector for the polypeptide according to any one of [1] to [3] above or the specific partial peptide according to any one of [1] to [4] above, comprising the polynucleotide according to any one of [5] to [7] above or the specific partial nucleotide according to any one of [6] to [8] above, and a promoter operably linked thereto. [10] A transformant incorporating the expression vector according to [9] above. [11] An antisense molecule comprising a nucleic acid sequence complementary to the nucleic acid sequence of the specific partial nucleotide according to [7] or [8] above, and capable of suppressing the expression of any one of the polypeptides encoded by the brain/nerve-specific genes 1 to 10. [12] An RNAi-inducing nucleic acid capable of suppressing the expression of any one of the polypeptides encoded by the brain/nerve-specific genes 1 to 10, that is configured by a sense strand consisting of the nucleic acid sequence of the specific partial nucleotide according to [7] or [8] above, and an antisense strand consisting of a nucleic acid sequence complementary thereto, and that may have an overhang at the 5' terminus and/or 3' terminus of one or both of the sense strand and the antisense strand. [13] The RNAi-inducing nucleic acid according to [12] above, wherein the RNAi-inducing nucleic acid is an siRNA. [14] An aptamer capable of binding to any one of the polypeptides encoded by the brain/nerve-specific genes 1 to 10 via a region corresponding to the specific partial peptide according to any one of [2] to [4] above. [15] An antibody capable of binding to any one of the polypeptides encoded by the brain/nerve-specific genes 1 to 10 via a region corresponding to the specific partial peptide according to any one of [2] to [4] above. [16] The antibody according to [15] above, wherein the antibody is any one of the i) to iii) below: i) a polyclonal antibody; ii) a monoclonal antibody or a portion thereof; iii) a chimeric antibody, a humanized antibody or a human antibody. [17] A cell that produces the antibody according to [15] or [16] above. [18] The cell according to [17] above, wherein the cell is a hybridoma. [19] A composition comprising the polypeptide according to any one of [1] to [3] above, the antisense molecule according to [11] above, the RNAi-inducing nucleic acid according to [12] or [13] above, the aptamer according to [14] above, the antibody according to [15] or [16] above, or an expression vector therefor, and a pharmaceutically acceptable carrier. [20] A mammalian cell or non-human mammal wherein the expression or a function of the polypeptide according to any one of [1] to [3] above is regulated. [21] A primer set specific for any one of the polynucleotides encoded by the brain/nerve-specific genes 1 to 10 or a specific partial nucleotide thereof, comprising the following (a) or (b): (a) a sense primer corresponding to a first nucleic acid sequence of the polynucleotide according to [7] above or the specific partial nucleotide according to [7] or [8] above; and (b) an antisense primer corresponding to a nucleic acid sequence complementary to a second nucleic acid sequence of the polynucleotide according to [7] above or the specific partial nucleotide according to [7] or [8] above. [22] A nucleic acid probe specific for any one of the polynucleotides encoded by the brain/nerve-specific genes 1 to 10 or a specific partial nucleotide thereof, being any one of the following (a) or (b): (a) a single-stranded polynucleotide comprising a nucleic acid sequence complementary to the nucleic acid sequence of the specific partial nucleotide according to [7] or [8] above; or (b) a double-stranded polynucleotide configured by a sense strand comprising the nucleic acid sequence of the specific partial nucleotide according to [7] or [8] above, and an antisense strand comprising a nucleic acid sequence complementary thereto. [23] A reagent or kit for detection or quantification of any one of the polypeptides or polynucleotides encoded by the brain/nerve-specific genes 1 to 10, comprising one or more substances or sets selected from among the aptamer according to [14] above, the antibody according to [15] or [16] above, the primer set according to [21] above and the nucleic acid probe according to [22] above. [24] The reagent or kit according to [23] above, being a reagent or kit for determination of nerve cell differentiation. [25] A method of detecting or quantifying any one of the polypeptides or polynucleotides encoded by the brain/nerve-specific genes 1 to 10, comprising measuring the expression of the polypeptide or polynucleotide in a biological sample or cell or tissue culture obtained from a mammal, wherein the biological sample or the culture contains a nerve cell or a tissue in the brain. [26] A method of detecting or quantifying the polypeptide according to [2] or [3] above or the polynucleotide according to [7] above, comprising measuring the expression of the polypeptide or the polynucleotide in a biological sample or cell or tissue culture obtained from a mammal. [27] The method of detection or quantification according to [26] above, wherein the biological sample or the culture contains a nerve cell or a tissue in the brain.

Effect of the Invention

[0028] A polypeptide of the present invention and a partial peptide of the present invention can be useful, for example, as a biomarker specific for the brain/nerves or specific for nerve cell differentiation, and in developing a substance capable of specifically recognizing a polypeptide of the present invention or a known polypeptide, or a substance capable of comprehensively recognizing both a polypeptide of the present invention and a known polypeptide, and a substance capable of specifically regulating a function of a polypeptide of the present invention or a known polypeptide, or a substance capable of comprehensively regulating functions of both a polypeptide of the present invention and a known polypeptide.

[0029] A polynucleotide of the present invention and a partial nucleotide of the present invention can be useful, for example, as a biomarker specific for the brain/nerves or specific for nerve cell differentiation, and in developing a substance capable of specifically recognizing a polynucleotide of the present invention or a known polynucleotide, or a substance capable of comprehensively recognizing both a polynucleotide of the present invention and a known polynucleotide, and a substance capable of specifically regulating the expression of a polypeptide of the present invention or a known polypeptide, or a substance capable of comprehensively regulating the expression of both a polypeptide of the present invention and a known polypeptide.

[0030] Related substances of the present invention (e.g., antisense molecules, RNAi-inducing nucleic acids such as siRNAs, aptamers and antibodies, and expression vectors therefor) can be useful as, for example, pharmaceuticals or reagents.

[0031] A cell of the present invention can be useful in, for example, producing a polypeptide of the present invention and a partial peptide of the present invention, and an antibody of the present invention. A cell of the present invention can also be useful in developing a pharmaceutical (e.g., a prophylactic or therapeutic drug for a disease based on a nerve cell disorder), identifying a further marker gene specific for the brain/nerves or specific for nerve cell differentiation, and analyzing a mechanism associated with nerve cell differentiation.

[0032] An animal of the present invention can be useful in, for example, developing a pharmaceutical, identifying a further marker gene specific for the brain/nerves or specific for nerve cell differentiation, and analyzing a mechanism associated with nerve cell differentiation.

[0033] Measuring means (e.g., primer set, nucleic acid probe, antibody, aptamer) and measuring methods of the present invention can be useful in, for example, specific detection and quantitation of a polynucleotide of the present invention or a known polynucleotide, or a polypeptide of the present invention or a known polypeptide, or comprehensive detection and quantitation of both a polynucleotide of the present invention and a known polynucleotide, or both a polypeptide of the present invention and a known polypeptide. These means and methods can also be utilized for determining nerve cell differentiation states and screening for pharmaceuticals, reagents or foods.

BEST MODE FOR CARRYING OUT THE INVENTION

1. Brain/Nerve-Specific Genes

[0034] A gene of the present invention can be a gene derived from an optionally chosen mammal. As examples of the mammal, primates and rodents, as well as laboratory animals, domestic animals, working animals, companion animals and the like can be mentioned. In detail, as examples of the mammal, humans, monkeys, rats, mice, rabbits, horses, cattle, goat, sheep, dogs, cats and the like can be mentioned. Preferably, the mammal is a human.

[0035] A gene of the present invention is capable or incapable of being expressed specifically in a tissue in the brain. A gene of the present invention is also capable of being expressed at a higher or lower level in a tissue in the brain, compared with a known polynucleotide and/or a known polypeptide. As examples of such tissues in the brain, the cerebrum, cerebral cortex, cerebellum, caudate nucleus, corpus callosum, hippocampus, substantia nigra, thalamus, hypothalamus, subthalamic nucleus, hypophysis, amygdala and the like can be mentioned.

[0036] A gene of the present invention is capable or incapable of being expressed specifically in nerve cells. A gene of the present invention is also capable of being expressed at a higher or lower level in nerve cells, compared with a known polynucleotide and/or a known polypeptide. As examples of such nerve cells, nerve cells in the aforementioned tissues can be mentioned.

[0037] Hereinafter, the polypeptides and partial peptides thereof, and polynucleotides and partial nucleotides thereof, provided by the present invention, are described.

1.1. Polypeptides and Partial Peptides Thereof

[0038] The present invention provides a polypeptide having an amino acid sequence shown by SEQ ID NO:X or substantially the same amino acid sequence thereas (abbreviated as "amino acid sequence shown by SEQ ID NO:X and the like" as required).

[0039] "SEQ ID NO:X" denotes the SEQ ID NO of an optionally chosen amino acid sequence disclosed herein. A polypeptide "having" an amino acid sequence shown by SEQ ID NO:X and the like means a polypeptide "consisting of" an amino acid sequence shown by SEQ ID NO:X and the like, and a polypeptide "comprising" the amino acid sequence and the like.

[0040] In one embodiment, substantially the same amino acid sequence as an amino acid sequence shown by SEQ ID NO:X can be an amino acid sequence having a specified amino acid sequence identity to the amino acid sequence shown by SEQ ID NO:X. The degree of amino acid sequence identity can be about 90% or more, preferably about 92% or more, more preferably about 95% or more, still more preferably about 96% or more, and most preferably about 97% or more, about 98% or more or about 99% or more. Amino acid sequence identity can be determined by a method known per se. Unless otherwise specified, amino acid sequence identity (%) is calculated by, for example, executing the commands for the maximum matching method, using the DNASIS sequence analytical software (Hitachi Software Engineering). The parameters for the calculation should be used in default settings. Amino acid sequence identity (%) can also be determined, without following the above procedures, using a program in common use in the art (for example, BLAST, FASTA and the like) in the default settings thereof. In another aspect, the identity (%) can be determined using an optionally chosen algorithm publicly known in the art, for example, the algorithms of Needleman et al. (1970) (J. Mol. Biol. 48: 444-453) and Myers and Miller (CABIOS, 1988, 4: 11-17) and the like. The algorithm of Needleman et al. is incorporated in the GAP program in the GCG software package, and the identity (%) can be determined by, for example, using BLOSUM 62 matrix or PAM250 matrix, with a gap weight of 16, 14, 12, 10, 8, 6 or 4, and a length weight of 1, 2, 3, 4, 5 or 6. The algorithm of Myers and Miller is incorporated in the ALIGN program, which is a portion of the GCG sequence alignment software package. When the ALIGN program is utilized to compare amino acid sequences, for example, PAM120 weight residue table, gap length penalty 12, gap penalty 4, can be used. For calculating amino acid sequence identity, the method that produces the least value among the above-mentioned methods may be employed.

[0041] In another embodiment, substantially the same amino acid sequence as an amino acid sequence shown by SEQ ID NO:X can be an amino acid sequence shown by SEQ ID NO:X wherein one or more amino acids have one or more modifications selected from among substitutions, additions, deletions and insertions. The number of amino acids modified is not particularly limited, as far as it is one or more; the number can be, for example, 1 to about 50, preferably 1 to about 30, more preferably 1 to about 20, still more preferably 1 to about 10, and most preferably 1 to about 5 (e.g., 1 or 2).

[0042] Substantially the same amino acid sequence as an amino acid sequence shown by SEQ ID NO:X may completely retain a characteristic portion thereof (e.g., a portion corresponding to a specific partial polypeptide described below), and may have another portion (e.g., a portion present in a known polypeptide) being substantially the same as the corresponding portion of the amino acid sequence shown by SEQ ID NO:X. Alternatively, substantially the same amino acid sequence as an amino acid sequence shown by SEQ ID NO:X may have a non-characteristic portion thereof being identical to the corresponding portion of the amino acid sequence shown by SEQ ID NO:X, and a characteristic portion thereof being substantially identical to the corresponding portion of the amino acid sequence shown by SEQ ID NO:X.

[0043] A polypeptide of the present invention can have a function that is homogenous or heterogeneous to that of a known polypeptide (e.g., known variant). A polypeptide of the present invention can also have an enhanced or reduced function compared with a known polypeptide (e.g., known variant).

[0044] In detail, the novel polypeptides of the brain/nerve-specific genes 1 to 10 are as follows.

1) Brain/Nerve-Specific Gene 1

[0045] D-BRACE3000012.1 (SEQ ID NO:18)

[0046] D-UTERU2026184.1 (SEQ ID NO:10)

[0047] As a known variant of the brain/nerve-specific gene 1, for example, a variant disclosed in an Example (human zinc finger protein 418 (ZNF418); total number of nucleotides in the ORF nucleic acid sequence: 2031; total number of amino acids in the protein: 676; see GenBank accession number: NM.sub.--133460.1) has been reported. A known variant of the brain/nerve-specific gene 1 can have a specified function (e.g., transcription regulatory capacity) (see, e.g., Ota, T. et al., Nat. Genet. 36 (1), 40-45 (2004)). Generally, it is known that a plurality of variants resulting from a single locus (splicing variants) have similar functions, although the degree can vary. Therefore, novel variants of the brain/nerve-specific gene 1 can also have these functions.

2) Brain/Nerve-Specific Gene 0.2

[0048] D-NT2RP8004156.1 (SEQ ID NO:43)

[0049] As a known variant of the brain/nerve-specific gene 2, for example, a variant disclosed in an Example (human v-akt mouse thymoma virus oncogene homologue 1 (AKT1); total number of nucleotides in the ORF nucleic acid sequence: 1443; total number of amino acids in the protein: 480; see GenBank accession number: NM.sub.--005163.1) has been reported. It has been reported that known variants of the brain/nerve-specific gene 2 have a specified function (e.g., kinase activity, anti-apoptotic activity, or cell cycle regulatory capacity) (see, e.g., Mirza, A. M. et al., Mol. Cell. Biol. 24 (24), 10868-10881 (2004); Koga, M. et al., Biochem. Biophys. Res. Commun. 324 (1), 321-325 (2004)). Generally, it is known that a plurality of variants resulting from a single locus (splicing variants) have similar functions, although the degree can vary. Therefore, novel variants of the brain/nerve-specific gene 2 can also have these functions.

3) Brain/Nerve-Specific Gene 3

[0050] D-NT2RI3005525.1 (SEQ ID NO:58)

[0051] As a known variant of the brain/nerve-specific gene 3, for example, a variant disclosed in an Example (human budding-related, EVH1 domain-containing 2 (SPRED2); total number of nucleotides in the ORF nucleic acid sequence: 1257; total number of amino acids in the protein: 418; see GenBank accession number: NM.sub.--181784.1) has been reported. It has been reported that known variants of the brain/nerve-specific gene 3 have a specified function (e.g., MAP kinase activation inhibitory capacity, tyrosine kinase-mediated Erk activation inhibitory capacity) (see, e.g., Nobuhisa, I. et al., J. Exp. Med. 199 (5), 737-742 (2004); Kato, R. et al., Biochem. Biophys. Res. Commun. 302 (4), 767-772 (2003)). Generally, it is known that a plurality of variants resulting from a single locus (splicing variants) have similar functions, although the degree can vary. Therefore, novel variants of the brain/nerve-specific gene 3 can also have these functions.

4) Brain/Nerve-Specific Gene 4

[0052] D-NT2RP8004592.1 (SEQ ID NO:74)

[0053] As a known variant of the brain/nerve-specific gene 4, for example, a variant disclosed in an Example (human src kinase related phosphoprotein 2 (SKAP2); total number of nucleotides in the ORF nucleic acid sequence: 1080; total number of amino acids in the protein: 359; see GenBank accession number: NM.sub.--003930.3) has been reported. It has been reported that known variants of the brain/nerve-specific gene 4 have a specified function (e.g., .alpha.-synuclein phosphorylation inhibitory capacity) (see, e.g., Takahashi, T. et al., J. Biol. Chem. 278 (43), 42225-42233 (2003)). Generally, it is known that a plurality of variants resulting from a single locus (splicing variants) have similar functions, although the degree can vary. Therefore, novel variants of the brain/nerve-specific gene 4 can also have these functions.

5) Brain/Nerve-Specific Gene 5

[0054] D-NT2RI2014164.1 (SEQ ID NO:89)

[0055] D-BRAMY2029564.1 (SEQ ID NO:99)

[0056] As a known variant of the brain/nerve-specific gene 5, for example, a variant disclosed in an Example (human monoamine oxidase B (MAOB); total number of nucleotides in the ORF nucleic acid sequence: 1563; total number of amino acids in the protein: 520; see GenBank accession number: NM.sub.--000898.3) has been reported. It has been reported that known variants of the brain/nerve-specific gene 5 have a specified function (e.g., monoamine oxidase activity) (see, e.g., Bach, A. W. et al., Proc. Natl. Acad. Sci. U.S.A. 85 (13), 4934-4938 (1988)). Generally, it is known that a plurality of variants resulting from a single locus (splicing variants) have similar functions, although the degree can vary. Therefore, novel variants of the brain/nerve-specific gene 5 can also have these functions.

6) Brain/Nerve-Specific Gene 6

[0057] D-BRHIP2003515.1 (SEQ ID NO:118)

[0058] As a known variant of the brain/nerve-specific gene 6, for example, a variant disclosed in an Example (human tumor protein D52 (TPD52); total number of nucleotides in the ORF nucleic acid sequence: 555; total number of amino acids in the protein: 184; see GenBank accession number: NM.sub.--005079.1) has been reported. It has been reported that known variants of the brain/nerve-specific gene 6 have a specified function (e.g., capability of Ca.sup.2+ dependent interaction with annexin VI) (see, e.g., Tiacci, E. et al., Blood 105 (7), 2812-2820 (2005)). Generally, it is known that a plurality of variants resulting from a single locus (splicing variants) have similar functions, although the degree can vary. Therefore, novel variants of the brain/nerve-specific gene 6 can also have these functions.

7) Brain/Nerve-Specific Gene 7

[0059] D-BRACE2044661.1 (SEQ ID NO:133)

[0060] As a known variant of the brain/nerve-specific gene 7, for example, a variant disclosed in an Example (human ATPase, Na.sup.+/K.sup.+ transport property, .beta.3 polypeptide (ATP1B3); total number of nucleotides in the ORF nucleic acid sequence: 840; total number of amino acids in the protein: 279; see GenBank accession number: NM.sub.--001679.2) has been reported. It has been reported that known variants of the brain/nerve-specific gene 7 have a specified function (e.g., ATP hydrolysis activity in the presence of an ion such as Na.sup.+ or K.sup.+) (see, e.g., Malik, N. et al., J. Biol. Chem. 271 (37), 22754-22758 (1996)). Generally, it is known that a plurality of variants resulting from a single locus (splicing variants) have similar functions, although the degree can vary. Therefore, novel variants of the brain/nerve-specific gene 7 can also have these functions.

8) Brain/Nerve-Specific Gene 8

[0061] D-3NB692002462.1 (SEQ ID NO:152)

[0062] D-BRCAN2027778.1 (SEQ ID NO:159)

[0063] As a known variant of the brain/nerve-specific gene 8, for example, a variant disclosed in an Example (human mevalonic acid kinase (MVK); total number of nucleotides in the ORF nucleic acid sequence: 1191; total number of amino acids in the protein: 396; see GenBank accession number: NM.sub.--000431.1) has been reported. It has been reported that known variants brain/nerve-specific gene 8 have a specified function (e.g., mevalonic acid kinase activity) (see, e.g., Hogenboom, S. et al., J. Cell. Sci. 117 (PT 4), 631-639 (2004)). Generally, it is known that a plurality of variants resulting from a single locus (splicing variants) have similar functions, although the degree can vary. Therefore, novel variants of the brain/nerve-specific gene 8 can also have these functions.

9) Brain/Nerve-Specific Gene 9

[0064] D-NT2RI3001005.1 (SEQ ID NO:184)

[0065] D-NT2RI3005261.1 (SEQ ID NO:190)

[0066] As a known variant of the brain/nerve-specific gene 9, for example, a variant disclosed in an Example (human solute carrier family 2 (promoting glucose transporter), member 14 (SLC2A14); total number of nucleotides in the ORF nucleic acid sequence: 1563; total number of amino acids in the protein: 520; see GenBank accession number: NM.sub.--153449.2) has been reported. Known variants of the brain/nerve-specific gene 9 can have a specified function (e.g., glucose transportation capacity) (see, e.g., Wu, X. et al., Genomics 80 (6), 553-557 (2002)). Generally, it is known that a plurality of variants resulting from a single locus (splicing variants) have similar functions, although the degree can vary. Therefore, novel variants of the brain/nerve-specific gene 9 can also have these functions.

10) Brain/Nerve-Specific Gene 10

[0067] D-OCBBF2010718.1 (SEQ ID NO:207)

[0068] D-OCBBF3004194.1 (SEQ ID NO:213)

[0069] D-NT2RP8000826.1 (SEQ ID NO:219)

[0070] D-NT2RP7007268.1 (SEQ ID NO:225)

[0071] D-BRAWH3008172.1 (SEQ ID NO:331)

[0072] D-BRAWH3011965.1 (SEQ ID NO:236)

[0073] As a known variant of the brain/nerve-specific gene 10, for example, a variant disclosed in an Example (human PDZ domain-containing RING finger 3 (PDZRN3); total number of nucleotides in the ORF nucleic acid sequence: 3201; total number of amino acids in the protein: 1066; see GenBank accession number: NM.sub.--015009.1) has been reported. Known variants of the brain/nerve-specific gene 10 can have a specified function (e.g., capability of binding to a cell surface protein such as neuroligin via the PDZ domain thereof) (see, e.g., Meyer, G. et al., Neuropharmacology 47 (5), 724-733 (2004)). Generally, it is known that a plurality of variants resulting from a single locus (splicing variants) have similar functions, although the degree can vary. Therefore, novel variants of the brain/nerve-specific gene 10 can also have these functions.

[0074] A polypeptide of the present invention can be useful in, for example, developing a substance capable of specifically recognizing a polypeptide of the present invention, a substance incapable of specifically recognizing a polypeptide of the present invention, or a substance capable of comprehensively recognizing both a polypeptide of the present invention and a known polypeptide, and in developing a substance capable of specifically regulating a function of a polypeptide of the present invention, a substance incapable of specifically regulating a function of a polypeptide of the present invention, or a substance capable of comprehensively recognizing functions of both a polypeptide of the present invention and a known polypeptide.

[0075] The present invention also provides a partial peptide.

[0076] "A partial peptide" consists of at least 6, preferably at least 8, more preferably at least 10, still more preferably at least 12, and most preferably at least 15, consecutive amino acid residues selected from among subject polypeptides, that can have a specified utility (e.g., use as an immunogenic or antigenic peptide, a functional peptide having a particular domain and the like).

[0077] "An insert amino acid sequence of a polypeptide of the present invention" refers to an amino acid sequence that is incorporated in a polypeptide of the present invention (e.g., novel variant), but lacked in a known polypeptide (e.g., known variant). Meanwhile, "an insert amino acid sequence of a known polypeptide" refers to an amino acid sequence that is incorporated in a known polypeptide (e.g., known variant), but lacked in a polypeptide of the present invention (e.g., novel variant). These insert amino acid sequences are obvious from the disclosure herein.

[0078] "A deleted amino acid sequence of a polypeptide of the present invention" refers to an amino acid sequence that is lacked in a polypeptide of the present invention (e.g., novel variant), but incorporated in a known polypeptide (e.g., known variant). Meanwhile, "a deleted amino acid sequence of a known polypeptide" refers to an amino acid sequence that is lacked in a known polypeptide (e.g., known variant), but incorporated in a polypeptide of the present invention (e.g., novel variant). These deleted amino acid sequences are obvious from the disclosure herein. "A deleted amino acid sequence of a polypeptide of the present invention" can have the same definition as that for "an insert amino acid sequence of a known polypeptide"; "a deleted amino acid sequence of a known polypeptide" can have the same definition as that for "an insert amino acid sequence of a polypeptide of the present invention".

[0079] A partial peptide of the present invention can be a) a specific partial peptide of a polypeptide of the present invention, capable of distinguishing a polypeptide of the present invention from a known polypeptide (abbreviated as "specific partial peptide A" as required), b) a specific partial peptide of a known polypeptide, capable of distinguishing a known polypeptide from a polypeptide of the present invention (abbreviated as "specific partial peptide B" as required), or c) a partial peptide common to both a polypeptide of the present invention and a known polypeptide (abbreviated as "shared partial peptide" as required). For these particular partial peptides, there appears a motivation for preparing them or utilizing them as markers on the basis of the present inventors' findings; however, without these findings, there is no motivation for preparing them or utilizing them as markers. Being partial peptides specific for the polypeptides encoded by the brain/nerve-specific genes 1 to 10, the specific partial peptides A and B are abbreviated as "specific partial peptides of the present invention" or "specific partial peptides" as required.

[0080] The specific partial peptide A of the present invention is a partial peptide that is present only in a polypeptide having an amino acid sequence shown by SEQ ID NO:X and the like, and that is not present in any known polypeptide. As examples of the specific partial peptide A, i) a partial peptide consisting of an insert amino acid sequence of a polypeptide of the present invention or a partial amino acid sequence thereof, ii) a partial peptide consisting of an insert amino acid sequence of a polypeptide of the present invention or a terminal partial amino acid sequence thereof and an adjacent amino acid sequence thereof, and iii) a partial peptide consisting of an amino acid sequence wherein both amino acid sequences present on the N-terminal side and C-terminal side relative to an insert amino acid sequence of a known polypeptide are linked together, formed as a result of exon deletion, can be mentioned.

[0081] The specific partial peptide A of i) above consists of an insert amino acid sequence of a polypeptide of the present invention or a partial amino acid sequence thereof. Such partial amino acid sequences are obvious from the disclosure herein.

[0082] The specific partial peptide A of ii) above consists of an insert amino acid sequence of a polypeptide of the present invention or a terminal partial amino acid sequence thereof and an adjacent amino acid sequence thereof. As such terminal partial amino acid sequences, an amino acid sequence corresponding to an N-terminal portion of an insert amino acid sequence of a polypeptide of the present invention (abbreviated as "N-terminal partial amino acid sequence A" as required), and an amino acid sequence corresponding to a C-terminal portion of an insert amino acid sequence of a polypeptide of the present invention (abbreviated as "C-terminal partial amino acid sequence A" as required) can be mentioned. As such adjacent amino acid sequences, an amino acid sequence present on the N-terminal side relative to an insert amino acid sequence of a polypeptide of the present invention (abbreviated as "N-terminal adjacent amino acid sequence A" as required), and an amino acid sequence present on the C-terminal side relative to an insert amino acid sequence of a polypeptide of the present invention (abbreviated as "C-terminal adjacent amino acid sequence A" as required) can be mentioned. Therefore, the specific partial peptide A of ii) above can be a partial peptide consisting of an amino acid sequence spanning from a specified position of the N-terminal adjacent amino acid sequence A to a specified position of an insert amino acid sequence of a polypeptide of the present invention, a partial peptide consisting of an amino acid sequence spanning from a specified position of an insert amino acid sequence of a polypeptide of the present invention to a specified position of the C-terminal adjacent amino acid sequence A, or a partial peptide consisting of an amino acid sequence comprising the whole insert amino acid sequence of a polypeptide of the present invention, spanning from a specified position of the N-terminal adjacent amino acid sequence A to a specified position of the C-terminal adjacent amino acid sequence A. The number of amino acid residues in the insert amino acid sequence (or N-terminal or C-terminal partial amino acid sequence A) or adjacent amino acid sequence (or N-terminal or C-terminal adjacent amino acid sequence A), contained in the specific partial peptide A of ii) above, is not particularly limited, as far as it is a number that ensures the specificity of the specific partial peptide A of ii) above; the number can be, for example, at least 3, preferably at least 4, more preferably at least 5, still more preferably at least 6, and most preferably at least 7, 8, 9 or 10. Such terminal partial amino acid sequences and such adjacent amino acid sequences are obvious from the disclosure herein.

[0083] The specific partial peptide A of iii) above is a partial peptide not present in a known polypeptide, consisting of an amino acid sequence wherein both amino acid sequences present on the N-terminal side and C-terminal side relative to an insert amino acid sequence of a known polypeptide are linked together (in a polypeptide of the present invention, these amino acid sequences are linked together as a result of exon deletion). The number of amino acid residues in each amino acid sequence present on the N-terminal side and C-terminal side relative to an insert amino acid sequence of a known polypeptide, contained in the specific partial peptide A of iii) above, is not particularly limited, as far as it is a number that ensures the specificity of the specific partial peptide A of iii) above; the number can be, for example, at least 3, preferably at least 4, more preferably at least 5, still more preferably at least 6, and most preferably at least 7, 8, 9 or 10.

[0084] The specific partial peptide A of the present invention can be useful as, for example, a target for specifically detecting a polypeptide of the present invention, and as a marker specific for the brain/nerves or specific for nerve differentiation. The specific partial peptide A of the present invention can also be useful in developing a substance capable of specifically recognizing a polypeptide of the present invention, or a substance incapable of specifically recognizing a polypeptide of the present invention, or developing a substance capable of specifically regulating a function of a polypeptide of the present invention, or a substance incapable of specifically regulating a function of a polypeptide of the present invention.

[0085] The specific partial peptide B of the present invention is a partial peptide that is present only in a known polypeptide, and that is not present in a polypeptide having an amino acid sequence shown by SEQ ID NO:X and the like. As examples of the specific partial peptide B, i) a partial peptide consisting of an insert amino acid sequence of a known polypeptide or a partial amino acid sequence thereof, ii) a partial peptide consisting of an insert amino acid sequence of a known polypeptide or a terminal partial amino acid sequence thereof and an adjacent amino acid sequence thereof, and iii) a partial peptide consisting of an amino acid sequence wherein both amino acid sequences present on the N-terminal side and C-terminal side relative to an insert amino acid sequence of a polypeptide of the present invention are linked together, formed as a result of exon deletion, can be mentioned.

[0086] The specific partial peptide B of i) above consists of an insert amino acid sequence of a known polypeptide or a partial amino acid sequence thereof. Such partial amino acid sequences are obvious from the disclosure herein.

[0087] The specific partial peptide B of ii) above consists of an insert amino acid sequence of a known polypeptide or a terminal partial amino acid sequence thereof and an adjacent amino acid sequence thereof. As such terminal partial amino acid sequences, an amino acid sequence corresponding to an N-terminal portion of an insert amino acid sequence of a known polypeptide (abbreviated as "N-terminal partial amino acid sequence B" as required), and an amino acid sequence corresponding to a C-terminal portion of an insert amino acid sequence of a known polypeptide (abbreviated as "C-terminal partial amino acid sequence B" as required) can be mentioned. As such adjacent amino acid sequences, an amino acid sequence present on the N-terminal side relative to an insert amino acid sequence of a known polypeptide (abbreviated as "N-terminal adjacent amino acid sequence B" as required), and an amino acid sequence present on the C-terminal side relative to an insert amino acid sequence of a known polypeptide (abbreviated as "C-terminal adjacent amino acid sequence B" as required) can be mentioned. Therefore, the specific partial peptide B of ii) above can be a partial peptide consisting of an amino acid sequence spanning from a specified position of the N-terminal adjacent amino acid sequence B to a specified position of an insert amino acid sequence of a known polypeptide, a partial peptide consisting of an amino acid sequence spanning from a specified position of an insert amino acid sequence of a known polypeptide to a specified position of the C-terminal adjacent amino acid sequence B, or a partial peptide consisting of an amino acid sequence comprising the whole insert amino acid sequence of a known polypeptide, spanning from a specified position of the N-terminal adjacent amino acid sequence B to a specified position of the C-terminal adjacent amino acid sequence B. The number of amino acid residues in the insert amino acid sequence (or N-terminal or C-terminal partial amino acid sequence B) or adjacent amino acid sequence (or N-terminal or C-terminal adjacent amino acid sequence B), contained in the specific partial peptide B of ii) above, is not particularly limited, as far as it is a number that ensures the specificity of the specific partial peptide B of ii) above; the number can be, for example, at least 3, preferably at least 4, more preferably at least 5, still more preferably at least 6, and most preferably at least 7, 8, 9 or 10. Such terminal partial amino acid sequences and such adjacent amino acid sequences are obvious from the disclosure herein.

[0088] The specific partial peptide B of iii) above is a partial peptide that is not present in a polypeptide of the present invention, consisting of an amino acid sequence wherein both amino acid sequences present on the N-terminal side and C-terminal side relative to an insert amino acid sequence of a polypeptide of the present invention are linked together (in a known polypeptide, these amino acid sequences are linked together as a result of exon deletion). The number of amino acid residues in each amino acid sequence present on the N-terminal side and C-terminal side relative to the insert amino acid sequence of a polypeptide of the present invention, contained in the specific partial peptide B of iii) above, is not particularly limited, as far as it is a number that ensures the specificity of the specific partial peptide B of iii) above; the number can be, for example, at least 3, preferably at least 4, more preferably at least 5, still more preferably at least 6, and most preferably at least 7, 8, 9 or 10, respectively.

[0089] The specific partial peptide B of the present invention can be useful as, for example, a target for specifically detecting a known polypeptide, and as a marker specific for the brain/nerves or specific for nerve differentiation, or as a marker not specific therefor. The specific partial peptide B of the present invention can also be useful in developing a substance capable of specifically recognizing a known polypeptide, or a substance incapable of specifically recognizing a known polypeptide, or developing a substance capable of specifically regulating a function of a known polypeptide, or a substance incapable of specifically regulating a function of a known polypeptide.

[0090] A shared partial peptide of the present invention can be a non-specific partial peptide that is present in both a polypeptide of the present invention and a known polypeptide. Such partial peptides are obvious from the disclosure herein. A shared partial peptide of the present invention can be useful as, for example, a target for comprehensively detecting both a polypeptide of the present invention and a known polypeptide, and as a marker specific for the brain/nerves or specific for nerve differentiation, or as a marker not specific therefor. A shared partial peptide of the present invention can also be useful in developing a substance capable of comprehensively recognizing both a polypeptide of the present invention and a known polypeptide, or a substance capable of comprehensively regulating functions of both a polypeptide of the present invention and a known polypeptide.

[0091] A polypeptide of the present invention or a specific partial peptide thereof may be fused with a polypeptide consisting of a heterologous amino acid sequence. As such a polypeptide, a polypeptide that facilitates purification or solubilization can be mentioned. In detail, as such polypeptides, histidine tag, maltose-binding protein (MBP), glutathione-S-transferase (GST), calmodulin-binding peptide (CBP), FLAG, and the Fc region of IgG molecule can be mentioned.

[0092] A polypeptide of the present invention and a partial peptide thereof may be provided in the form of a salt. As examples of the salt, salts with inorganic bases (e.g., alkali metals such as sodium and potassium; alkaline earth metals such as calcium and magnesium; aluminum, ammonium), salts with organic bases (e.g., trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N-dibenzylethylenediamine), salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid), salts with organic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid), salts with basic amino acids (e.g., arginine, lysine, ornithine) or salts with acidic amino acids (e.g., aspartic acid, glutamic acid) and the like can be mentioned.

[0093] A polypeptide of the present invention and a partial peptide thereof can be prepared by a method known per se. For example, a polypeptide of the present invention and a partial peptide thereof 1) may be recovered from an expression site, 2) may be recovered from a transformant described below, which expresses a polypeptide of the present invention and a partial peptide thereof, or a culture supernatant thereof, 3) may be synthesized using a cell-free system based on a rabbit reticulocyte lysate, wheat germ lysate, Escherichia coli lysate and the like, or 4) may be synthesized organochemically (e.g., solid phase synthesis). A polypeptide of the present invention and a partial peptide thereof are purified as appropriate by methods based on differences in solubility, such as salting-out and solvent precipitation; methods based mainly on differences in molecular weight, such as dialysis, ultrafiltration, gel filtration, and SDS-polyacrylamide gel electrophoresis; methods based on differences in electric charge, such as ion exchange chromatography; methods based on specific affinity, such as affinity chromatography and use of antibody; methods based on differences in hydrophobicity, such as reverse phase high performance liquid chromatography; methods based on differences in isoelectric point, such as isoelectric focusing; and combinations thereof the like.

1.2. Polynucleotides and Partial Nucleotides Thereof

[0094] The present invention provides a polynucleotide having a nucleic acid sequence shown by SEQ ID NO:Y, or the nucleic acid sequence Y1 or the nucleic acid sequence Y2, or substantially the same nucleic acid sequence thereas (abbreviated as "nucleic acid sequence shown by SEQ ID NO:Y and the like" as required).

[0095] "SEQ ID NO:Y" denotes the SEQ ID NO of an optionally chosen nucleic acid sequence disclosed herein. A polynucleotide "having" SEQ ID NO:Y and the like means a polynucleotide "consisting of" SEQ ID NO:Y and the like, or a polynucleotide "comprising" the nucleic acid sequence and the like.

[0096] "The nucleic acid sequence Y1" denotes a nucleic acid sequence corresponding to the coding portion (that is, the entire open reading frame (ORF) or a portion thereof) in a nucleic acid sequence shown by SEQ ID NO:Y. In other words, "the nucleic acid sequence Y1" denotes a nucleic acid sequence shown by SEQ ID NO:Y when the nucleic acid sequence shown by SEQ ID NO:Y consists of a nucleic acid sequence corresponding to the coding portion only, and it denotes a nucleic acid sequence corresponding to the coding portion only when the nucleic acid sequence shown by SEQ ID NO:Y comprises nucleic acid sequences corresponding to both the coding portion and the non-coding portion.

[0097] "The nucleic acid sequence Y2" denotes a nucleic acid sequence corresponding to a non-coding portion (e.g., 5' or 3' noncoding region) in a nucleic acid sequence shown by SEQ ID NO:Y. In other words, "the nucleic acid sequence Y2" denotes a nucleic acid sequence shown by SEQ ID NO:Y when the nucleic acid sequence shown by SEQ ID NO:Y consists of a nucleic acid sequence corresponding to the non-coding portion only, and it denotes a nucleic acid sequence corresponding to the non-coding portion only when the nucleic acid sequence shown by SEQ ID NO:Y comprises nucleic acid sequences corresponding to both the non-coding portion and the coding portion.

[0098] Therefore, a nucleic acid sequence denoted by "SEQ ID NO:Y" can be denoted by any one of i) the nucleic acid sequence Y1 (when the nucleic acid sequence shown by SEQ ID NO:Y as a whole is a nucleic acid sequence corresponding to the coding portion), ii) the nucleic acid sequence Y2 (when the nucleic acid sequence shown by SEQ ID NO:Y as a whole is a nucleic acid sequence corresponding to the non-coding portion), or iii) a nucleic acid sequence comprising the nucleic acid sequence Y1 and the nucleic acid sequence Y2 (when the nucleic acid sequence shown by SEQ ID NO:Y comprises nucleic acid sequences corresponding to the coding portion and the non-coding portion).

[0099] In one embodiment, substantially the same nucleic acid sequence as a nucleic acid sequence shown by SEQ ID NO:Y, or the nucleic acid sequence Y1 or the nucleic acid sequence Y2 can be a nucleic acid sequence having a specified sequence identity to the nucleic acid sequence shown by SEQ ID NO:Y, or the nucleic acid sequence Y1 or the nucleic acid sequence Y2. The degree of nucleic acid sequence identity can be about 90% or more, preferably about 92% or more, more preferably about 95% or more, still more preferably about 96% or more, and most preferably about 97% or more, about 98% or more or about 99% or more. Nucleic acid sequence identity can be determined by a method known per se. For example, nucleic acid sequence identity (%) can be determined by the same method as that described above for amino acid sequence identity (%).

[0100] In another embodiment, substantially the same nucleic acid sequence as a nucleic acid sequence shown by SEQ ID NO:Y or the nucleic acid sequence Y1 or the nucleic acid sequence Y2 can be the nucleic acid sequence shown by SEQ ID NO:Y or the nucleic acid sequence Y1 or the nucleic acid sequence Y2, wherein one or more nucleotides have one or more modifications selected from among substitutions, additions, deletions and insertions. The number of nucleotides modified is not particularly limited, as far as it is one or more, and the number can be, for example, 1 to about 100, preferably 1 to about 70, more preferably 1 to about 50, still more preferably 1 to about 30, and most preferably 1 to about 20, 1 to about 10 or 1 to about 5 (e.g., 1 or 2).

[0101] In still another embodiment, substantially the same nucleic acid sequence as a nucleic acid sequence shown by SEQ ID NO:Y, or the nucleic acid sequence Y1 or the nucleic acid sequence Y2 can be a polynucleotide that can be hybridized to a nucleic acid sequence complementary to the nucleic acid sequence shown by SEQ ID NO:Y, or the nucleic acid sequence Y1 or the nucleic acid sequence Y2 under high stringent conditions. Hybridization conditions under high stringent conditions can be set with reference to reported conditions (see, e.g., Current Protocols in Molecular Biology, John Wiley & Sons, 6.3.1-6.3.6 (1999)). For example, as hybridization conditions under high stringent conditions, hybridization with 6.times.SSC (sodium chloride/sodium citrate)/45.degree. C., followed by washing with 0.2.times.SSC/0.1% SDS/50 to 65.degree. C. once or twice or more, can be mentioned.

[0102] Substantially the same nucleic acid sequence as a nucleic acid sequence shown by SEQ ID NO:Y, or the nucleic acid sequence Y1 or the nucleic acid sequence Y2 may completely retain a characteristic portion thereof (e.g., a portion corresponding to a specific partial nucleotide described below), and may have another portion (e.g., a portion present in a known polynucleotide) being substantially the same as the corresponding portion of the nucleic acid sequence shown by SEQ ID NO:Y, or the nucleic acid sequence Y1 or the nucleic acid sequence Y2. Alternatively, substantially the same nucleic acid sequence as a nucleic acid sequence shown by SEQ ID NO:Y, or the nucleic acid sequence Y1 or the nucleic acid sequence Y2 may have a non-characteristic portion thereof being the same as the corresponding portion of the nucleic acid sequence shown by SEQ ID NO:Y, or the nucleic acid sequence Y1 or the nucleic acid sequence Y2, and a characteristic portion thereof being substantially the same as the corresponding portion of the nucleic acid sequence shown by SEQ ID NO:Y, or the nucleic acid sequence Y1 or the nucleic acid sequence Y2.

[0103] A polynucleotide of the present invention is capable of encoding a polypeptide of the present invention. Therefore, a polynucleotide of the present invention can be a polynucleotide such that the polypeptide encoded thereby is capable of being functionally equivalent to a polypeptide of the present invention.

[0104] In detail, for the brain/nerve-specific genes 1 to 10, the nucleic acid sequence Y of the polynucleotide, and the SEQ ID NO:Y and Ya-th to Yb-th of the ORF-corresponding portion thereof (Ya-th to Yb-th nucleotide residues in the nucleic acid sequence Y) are as follows.

1) Brain/Nerve-Specific Gene 1

[0105] D-BRACE3000012.1 (SEQ ID NO:16 or SEQ ID NO:17, and 465th to 2558th)

[0106] D-UTERU2026184.1 (SEQ ID NO:8 or SEQ ID NO:9, and 191st to 2119th)

2) Brain/Nerve-Specific Gene 2

[0107] D-NT2RP8004156.1 (SEQ ID NO:41 or SEQ ID NO:42, and 131st to 1387th)

3) Brain/Nerve-Specific Gene 3

[0108] D-NT2RI3005525.1 (SEQ. ID NO:56 or SEQ ID NO:57, and 45th to 1292nd)

4) Brain/Nerve-Specific Gene 4

[0109] D-NT2RP8004592.1 (SEQ ID NO:72 or SEQ ID NO:73, and 620th to 1183rd)

5) Brain/Nerve-Specific Gene 5

[0110] D-NT2RI2014164.1 (SEQ ID NO:87 or SEQ ID NO:88, and 162nd to 1397th)

[0111] D-BRAMY2029564.1 (SEQ ID NO:97 or SEQ ID NO:98, and 143rd to 1657th)

6) Brain/Nerve-Specific Gene 6

[0112] D-BRHIP2003515.1 (SEQ ID NO:116 or SEQ ID NO:117, and 84th to 707th)

7) Brain/Nerve-Specific Gene 7

[0113] D-BRACE2044661.1 (SEQ ID NO:131 or SEQ ID NO:132, and 297th to 878th)

8) Brain/Nerve-Specific Gene 8

[0114] D-3NB692002462.1 (SEQ ID NO:150 or SEQ ID NO:151, and 343rd to 951st)

[0115] D-BRCAN2027778.1 (SEQ ID NO:157 or SEQ ID NO:158, and 52nd to 1086th)

9) Brain/Nerve-Specific Gene 9

[0116] D-NT2RI3001005.1 (SEQ ID NO:182 or SEQ ID NO:183, and 22nd to 1629th)

[0117] D-NT2RI3005261.1 (SEQ ID NO:188 or SEQ ID NO:189, and 22nd to 1629th)

10) Brain/Nerve-Specific Gene 10

[0118] D-OCBBF2010718.1 (SEQ ID NO:205 or SEQ ID NO:206, and 144th to 2495th)

[0119] D-OCBBF3004194.1 (SEQ ID NO:211 or SEQ ID NO:212, and 129th to 2480th)

[0120] D-NT2RP8000826.1 (SEQ ID NO:217 or SEQ ID NO:218, and 95th to 2461st)

[0121] D-NT2RP7007268.1 (SEQ ID NO:223 or SEQ ID NO:224, and 95th to 2461st)

[0122] D-BRAWH3008172.1 (SEQ ID NO:229 or SEQ ID NO:330, and 281st to 2452nd)

[0123] D-BRAWH3011965.1 (SEQ ID NO:234 or SEQ ID NO:235, and 300th to 1574th)

[0124] A polynucleotide of the present invention can be useful in, for example, developing a substance capable of specifically recognizing a polynucleotide of the present invention, a substance incapable of specifically recognizing a polynucleotide of the present invention, or a substance capable of comprehensively recognizing both a polynucleotide of the present invention and a known polynucleotide, and developing a substance capable of specifically regulating the expression of a polypeptide of the present invention, a substance incapable of specifically regulating the expression of a polypeptide of the present invention, or a substance capable of comprehensively regulating the expression of both a polypeptide of the present invention and a known polypeptide.

[0125] The present invention also provides a partial nucleotide.

[0126] "A partial nucleotide" consists of at least 15, preferably at least 16, more preferably at least 18, still more preferably at least 20, and most preferably at least 22, 23, 24 or 25, consecutive nucleotide residues selected from among subject polynucleotides, that can have a specified utility (e.g., use as a probe, a primer, a polynucleotide that encodes an immunogenic or antigenic peptide, a polynucleotide that encodes a functional peptide having a particular domain and the like).

[0127] "An insert nucleic acid sequence of a polynucleotide of the present invention" refers to a nucleic acid sequence that is incorporated in a polynucleotide of the present invention (e.g., novel variant), but lacked in a known polynucleotide (e.g., known variant). Meanwhile, "an insert nucleic acid sequence of a known polynucleotide" refers to a nucleic acid sequence that is incorporated in a known polynucleotide (e.g., known variant), but lacked in a polynucleotide of the present invention (e.g., novel variant). These insert nucleic acid sequences are obvious from the disclosure herein.

[0128] "A deletion nucleic acid sequence of a polynucleotide of the present invention" refers to a nucleic acid sequence that is lacked in a polynucleotide of the present invention (e.g., novel variant), but inserted in a known polynucleotide (e.g., known variant). Meanwhile, "a deletion nucleic acid sequence of a known polynucleotide" refers to a nucleic acid sequence that is lacked in a known polynucleotide (e.g., known variant), but inserted in a polynucleotide of the present invention (e.g., novel variant). These deletion nucleic acid sequences are obvious from the disclosure herein. "A deletion nucleic acid sequence of a polynucleotide of the present invention" can have the same definition as that for "an insert nucleic acid sequence of a known polynucleotide"; "a deletion nucleic acid sequence of a known polynucleotide" can have the same definition as that for "an insert nucleic acid sequence of a polynucleotide of the present invention".

[0129] A partial nucleotide of the present invention can be a) a specific partial nucleotide of a polynucleotide of the present invention, capable of distinguishing a polynucleotide of the present invention from a known polynucleotide (abbreviated as "specific partial nucleotide A" as required), b) a specific partial nucleotide of a known polynucleotide, capable of distinguishing a known polynucleotide from a polynucleotide of the present invention (abbreviated as "specific partial nucleotide B" as required, or c) a partial nucleotide common to both a polynucleotide of the present invention and a known polynucleotide (abbreviated as "shared partial nucleotide" as required). For these particular partial nucleotides, there appears a motivation for preparing them or utilizing them as markers on the basis of the present inventors' findings, but without these findings, there is no motivation for preparing them or utilizing them as markers. Being partial nucleotides specific for polynucleotides encoded by brain/nerve-specific genes 1 to 10, the specific partial nucleotides A and B are abbreviated as "specific partial nucleotides of the present invention" or "specific partial nucleotides" as required.

[0130] The specific partial nucleotide A of the present invention is a partial nucleotide that is present only in a polynucleotide having a nucleic acid sequence shown by SEQ ID NO:Y and the like, and that is not present in any known polynucleotide. As examples of the specific partial nucleotide A, i) a partial nucleotide consisting of an insert nucleic acid sequence of a polynucleotide of the present invention or a partial nucleic acid sequence thereof, ii) a partial nucleotide consisting of an insert nucleic acid sequence of a polynucleotide of the present invention or a terminal partial nucleic acid sequence thereof and an adjacent nucleic acid sequence thereof, and iii) a partial nucleotide consisting of a nucleic acid sequence wherein both nucleic acid sequences present on the 5' and 3' sides relative to an insert nucleic acid sequence of a known polynucleotide are linked together, formed as a result of exon deletion, can be mentioned.

[0131] The specific partial nucleotide A of i) above consists of an insert nucleic acid sequence of a polynucleotide of the present invention or a partial nucleic acid sequence thereof. Such partial nucleic acid sequences are obvious from the disclosure herein.

[0132] The specific partial nucleotide A of ii) above consists of an insert nucleic acid sequence of a polynucleotide of the present invention or a terminal partial nucleic acid sequence thereof and an adjacent nucleic acid sequence thereof. As such terminal partial nucleic acid sequences, a nucleic acid sequence corresponding to a 5'-terminal portion in an insert nucleic acid sequence of a polynucleotide of the present invention (abbreviated as "5'-terminal partial nucleic acid sequence A" as required), and a nucleic acid sequence corresponding to a 3'-terminal portion in an insert nucleic acid sequence of a polypeptide of the present invention (abbreviated as "3'-terminal partial nucleic acid sequence A" as required) can be mentioned. As such adjacent nucleic acid sequences, a nucleic acid sequence present on the 5' side relative to an insert nucleic acid sequence of a polynucleotide of the present invention (abbreviated as "5' adjacent nucleic acid sequence A" as required), and a nucleic acid sequence present on the 3' side relative to an insert nucleic acid sequence of a polynucleotide of the present invention (abbreviated as "3' adjacent nucleic acid sequence A" as required) can be mentioned. Therefore, the specific partial nucleotide A of ii) above can be a partial nucleotide consisting of a nucleic acid sequence spanning from a specified position of the 5' adjacent nucleic acid sequence A to a specified position of an insert nucleic acid sequence of a polynucleotide of the present invention, a partial nucleotide consisting of a nucleic acid sequence spanning from a specified position of an insert nucleic acid sequence of a polynucleotide of the present invention to a specified position of the 3' adjacent nucleic acid sequence A, or a partial nucleotide consisting of a nucleic acid sequence comprising the whole insert nucleic acid sequence of a polynucleotide of the present invention, spanning from a specified position of the 5' adjacent nucleic acid sequence A to a specified position of the 3' adjacent nucleic acid sequence A. The number of nucleotide residues in the insert nucleic acid sequence (or 5'-terminal or 3'-terminal partial nucleic acid sequence A) or adjacent nucleic acid sequence (or 5'-terminal or 3'-terminal adjacent nucleic acid sequence A), contained in the specific partial nucleotide A of ii) above, is not particularly limited, as far as it is a number that ensures the specificity of the specific partial nucleotide A of ii) above; the number can be, for example, at least 3, preferably at least 4, more preferably at least 5, still more preferably at least 6, and most preferably at least 7, 8, 9 or 10. Such terminal partial nucleic acid sequences and such adjacent nucleic acid sequences are obvious from the disclosure herein.

[0133] The specific partial nucleotide A of iii) above is a partial nucleotide not present in a known polynucleotide, which nucleotide consisting of a nucleic acid sequence wherein both nucleic acid sequences present on the 5' and 3' sides relative to an insert nucleic acid sequence of a known polynucleotide are linked together (in a polynucleotide of the present invention, these nucleic acid sequences are linked together as a result of exon deletion). The number of nucleotide residues in each nucleic acid sequence present on the 5' and 3' sides relative to an insert nucleic acid sequence of a known polynucleotide, contained in the specific partial nucleotide A of iii) above, is not particularly limited, as far as it is a number that ensures the specificity of the specific partial nucleotide A of iii) above; the number can be, for example, at least 3, preferably at least 4, more preferably at least 5, still more preferably at least 6, and most preferably at least 7, 8, 9 or 10, respectively.

[0134] The specific partial nucleotide A of the present invention can be useful as, for example, a target for specifically detecting a polynucleotide of the present invention, and as a biomarker specific for the brain/nerves or specific for nerve differentiation. The specific partial nucleotide A of the present invention can also be useful in developing a substance capable of specifically recognizing a polynucleotide of the present invention, or a substance incapable of specifically recognizing a polynucleotide of the present invention, or developing a substance capable of specifically regulating the expression of a polypeptide of the present invention, or a substance incapable of specifically regulating the expression of a polypeptide of the present invention.

[0135] The specific partial nucleotide B of the present invention is a partial nucleotide that is present only in a known polynucleotide, and not present in a polynucleotide having a nucleic acid sequence shown by SEQ ID NO:X and the like. As examples of the specific partial nucleotide B, i) a partial nucleotide consisting of an insert nucleic acid sequence of a known polynucleotide or a partial nucleic acid sequence thereof, ii) a partial nucleotide consisting of an insert nucleic acid sequence of a known polynucleotide or a terminal partial nucleic acid sequence thereof and an adjacent nucleic acid sequence thereof, and iii) a partial nucleotide consisting of a nucleic acid sequence wherein both nucleic acid sequences present on the 5' and 3' sides relative to an insert nucleic acid sequence of a polynucleotide of the present invention are linked together, formed as a result of exon deletion, can be mentioned.

[0136] The specific partial nucleotide B of i) above consists of an insert nucleic acid sequence of a known polynucleotide or a partial nucleic acid sequence thereof. Such partial nucleic acid sequences are obvious from the disclosure herein.

[0137] The specific partial nucleotide B of ii) above consists of an insert nucleic acid sequence of a known polynucleotide or a terminal partial nucleic acid sequence thereof and an adjacent nucleic acid sequence thereof. As such terminal partial nucleic acid sequences, a nucleic acid sequence corresponding to a 5'-terminal portion in an insert nucleic acid sequence of a known polynucleotide (abbreviated as "5'-terminal partial nucleic acid sequence B" as required), and a nucleic acid sequence corresponding to a 3'-terminal portion in an insert nucleic acid sequence of a known polynucleotide (abbreviated as "3'-terminal partial nucleic acid sequence B" as required) can be mentioned. As such adjacent nucleic acid sequences, a nucleic acid sequence present on the 5' side relative to an insert nucleic acid sequence of a known polynucleotide (abbreviated as "5' adjacent nucleic acid sequence B" as required), and a nucleic acid sequence present on the 3' side relative to an insert nucleic acid sequence of a known polynucleotide (abbreviated as "3' adjacent nucleic acid sequence B" as required) can be mentioned. Therefore, the specific partial nucleotide B of ii) above can be a partial nucleotide consisting of a nucleic acid sequence spanning from a specified position of the 5' adjacent nucleic acid sequence B to a specified position of an insert nucleic acid sequence of a known polynucleotide, a partial nucleotide consisting of a nucleic acid sequence spanning from a specified position of an insert nucleic acid sequence of a known polynucleotide to a specified position of the 3' adjacent nucleic acid sequence B, or a partial nucleotide consisting of a nucleic acid sequence comprising the whole insert nucleic acid sequence of a known polynucleotide, spanning from a specified position of the 5' adjacent nucleic acid sequence B to a specified position of the 3' adjacent nucleic acid sequence B. The number of nucleotide residues in the insert nucleic acid sequence (or 5'-terminal or 3'-terminal partial nucleic acid sequence B) or adjacent nucleic acid sequence (or 5'-terminal or 3'-terminal adjacent nucleic acid sequence B), contained in the specific partial nucleotide B of ii) above, is not particularly limited, as far as it is a number that ensures the specificity of the specific partial nucleotide B of ii) above; the number can be, for example, at least 3, preferably at least 4, more preferably at least 5, still more preferably at least 6, and most preferably at least 7, 8, 9 or 10. Such terminal partial nucleic acid sequences and such adjacent nucleic acid sequences are obvious from the disclosure herein.

[0138] The specific partial nucleotide B of iii) above is a partial nucleotide not present in a polynucleotide of the present invention, consisting of a nucleic acid sequence wherein both nucleic acid sequences present on the 5' and 3' sides relative to an insert nucleic acid sequence of a polynucleotide of the present invention are linked together (in a known polynucleotide, these nucleic acid sequences are linked together as a result of exon deletion). The number of nucleotide residues in each nucleic acid sequence present on the 5' and 3' sides relative to an insert nucleic acid sequence of a polynucleotide of the present invention, contained in the specific partial nucleotide B of iii) above, is not particularly limited, as far as it is a number that ensures the specificity of the specific partial nucleotide B of iii) above, and the number can be, for example, at least 3, preferably at least 4, more preferably at least 5, still more preferably at least 6, and most preferably at least 7, 8, 9 or 10, respectively.

[0139] The specific partial nucleotide B of the present invention can be useful as, for example, as a target for specifically detecting a known polynucleotide, and as a biomarker specific for the brain/nerves or specific for nerve differentiation, or as a marker not specific therefor. The specific partial nucleotide B of the present invention can also be useful in developing a substance capable of specifically recognizing a known polynucleotide, or a substance incapable of specifically recognizing a known polynucleotide, or developing a substance capable of specifically regulating the expression of a known polypeptide, or a substance incapable of specifically regulating the expression of a known polypeptide.

[0140] A shared partial nucleotide of the present invention can be a nonspecific partial nucleotide that is present in both a polynucleotide of the present invention and a known polynucleotide. Such partial nucleotides are obvious from the disclosure herein. A shared partial nucleotide of the present invention can be useful as, for example, a target for comprehensively detecting both a polynucleotide of the present invention and a known polynucleotide, and as a biomarker specific for the brain/nerves or specific for nerve differentiation, or as a marker not specific therefor. A shared partial nucleotide of the present invention can also be useful in developing a substance capable of comprehensively recognizing both a polynucleotide of the present invention and a known polynucleotide, or a substance capable of comprehensively regulating the expression of both a polypeptide of the present invention and a known polypeptide.

[0141] A polynucleotide of the present invention and a partial nucleotide thereof are capable of encoding a polypeptide of the present invention or a partial peptide of the present invention. A polynucleotide of the present invention or a partial nucleotide of the present invention may be fused with a polynucleotide consisting of a heterologous nucleic acid sequence. As such heterologous nucleic acid sequences, those that encode the above-described heterologous amino acid sequences can be mentioned.

[0142] A polynucleotide of the present invention and a partial nucleotide thereof may be provided in the form of a salt. As the salt, those described above can be mentioned.

[0143] A polynucleotide of the present invention and a partial nucleotide thereof can be prepared by a method known per se. For example, the same nucleic acid sequence as a nucleic acid sequence shown by SEQ ID NO:Y, or the nucleic acid sequence Y1 or the nucleic acid sequence Y2 can be cloned using a specified tissue or cell. Moreover, substantially the same nucleic acid sequence as a nucleic acid sequence shown by SEQ ID NO:Y or the nucleic acid sequence Y1 or the nucleic acid sequence Y2 can be prepared by introducing a mutation into a polynucleotide cloned as described above. As examples of the method of mutagenesis, methods such as the synthetic oligonucleotide site-directed mutagenesis method, the gapped duplex method, a method of randomly introducing point mutations (for example, treatment with nitrous acid or sulfurous acid), the cassette mutation method, the linker scanning method, and the mismatch primer method can be mentioned.

2. Related Substances

[0144] The present invention provides a series of related substances that can be developed on the basis of a polypeptide of the present invention and a partial peptide of the present invention, and a polynucleotide of the present invention and a partial nucleotide of the present invention. The related substances of the present invention described below can be useful as, for example, pharmaceuticals. When a related substance of the present invention is a pharmaceutical, the target disease can be, for example, a disease based on a nerve cell disorder. In detail, as such diseases, Parkinson's disease, Huntington's chorea, Alzheimer's disease, ischemic cerebral diseases (e.g., cerebral stroke), epilepsy, brain trauma, motor nerve disease, multiple sclerosis, amyotrophic lateral sclerosis, diseases caused by nerve toxic disorders and the like can be mentioned.

2.1. Antisense Molecules

[0145] The present invention provides antisense molecules.

[0146] The type of the antisense molecule may be a DNA or an RNA, or may be a DNA/RNA chimera. The antisense molecule may be one having a phosphodiester bond of the natural type, or a modified nucleotide of the thiophosphate type (P.dbd.O in phosphate bond replaced with P.dbd.S), 2'-O-methyl type or the like, which are stable to degrading enzymes. Other important factors for the designing of the antisense molecule include increases in water-solubility and cell membrane permeability and the like; these can also be cleared by choosing appropriate dosage forms such as those using liposome or microspheres. The length of the antisense molecule is not particularly limited, as far as the molecule is capable of specifically hybridizing to the transcription product; the antisense molecule may be of a sequence of about 15 nucleotides for the shortest, or of a sequence complementary to the entire sequence of the transcription product for the longest. Considering the ease of synthesis, antigenicity issue and the like, for example, oligonucleotides consisting of about 15 nucleotides or more, preferably about 15 to about 100 nucleotides, and more preferably about 18 to about 50 nucleotides, can be mentioned. Furthermore, the antisense molecule may be one capable of not only inhibiting the translation of the transcription product by hybridizing thereto, but also binding to a double-stranded DNA to form a triple strand (triplex) to inhibit the transcription into mRNA.

[0147] An antisense molecule of the present invention can comprise a nucleic acid sequence complementary to a nucleic acid sequence corresponding to a partial nucleotide of the present invention (e.g., specific partial nucleotides A and B of the present invention, a shared partial nucleotide of the present invention). Therefore, an antisense molecule of the present invention can be an antisense molecule specific for a polynucleotide of the present invention, an antisense molecule specific for a known polynucleotide, or an antisense molecule common to both a polynucleotide of the present invention and a known polynucleotide. An antisense molecule of the present invention can be useful in specifically suppressing the expression of a polypeptide of the present invention or a known polypeptide, or comprehensively suppressing the expression of both a polypeptide of the present invention and a known polypeptide.

2.2. RNAi-Inducing Nucleic Acids

[0148] The present invention provides RNAi-inducing nucleic acids.

[0149] An RNAi-inducible nucleic acid refers to a polynucleotide, preferably an RNA, capable of inducing the RNA interference (RNAi) effect when transferred into cells. The RNAi effect refers to the phenomenon in which a double-stranded RNA comprising the same nucleic acid sequence as that of mRNA, or a partial sequence thereof, suppresses the expression of the mRNA. To obtain the RNAi effect, it is preferable to use, for example, a double-stranded RNA having the same nucleic acid sequence as that of a target mRNA comprising at least 20 or more continuous bases (or a partial sequence thereof). The double-stranded structure may be configured by different strands, or may be a double strand conferred by stem loop structure of a single RNA. As examples of the RNAi-inducing nucleic acid, siRNA, miRNA and the like can be mentioned, and siRNA is preferable. The siRNA is not particularly limited, as far as it can induce RNAi, and the siRNA can be, for example, 21 to 27 bases long, preferably 21 to 25 bases long.

[0150] An RNAi-inducing nucleic acid of the present invention can be a double-stranded polynucleotide configured by a sense strand consisting of a nucleic acid sequence corresponding to a partial nucleotide of the present invention (e.g., specific partial nucleotides A and B of the present invention, a shared partial nucleotide of the present invention), and an antisense strand consisting of a nucleic acid sequence complementary thereto. An RNAi-inducing nucleic acid of the present invention may also have an overhang at the 5' terminus and/or 3' terminus of one or both of the sense strand and the antisense strand. The overhang can be one formed as a result of the addition of one to several (e.g., 1, 2 or 3) bases at the 5' terminus and/or 3' terminus of the sense strand and/or antisense strand. An RNAi-inducing nucleic acid of the present invention can be an RNAi-inducing nucleic acid specific for a polynucleotide of the present invention, an RNAi-inducing nucleic acid specific for a known polynucleotide, or an RNAi-inducing nucleic acid common to both a polynucleotide of the present invention and a known polynucleotide. An RNAi-inducing nucleic acid of the present invention can be useful in specifically suppressing the expression of a polypeptide of the present invention or a known polypeptide, or comprehensively suppressing the expression of both a polypeptide of the present invention and a known polypeptide.

2.3. Aptamers

[0151] The present invention provides aptamers.

[0152] An aptamer refers to a polynucleotide having a binding activity (or inhibitory activity) on a specified target molecule. An aptamer of the present invention can be an RNA, a DNA, a modified nucleotide or a mixture thereof. An aptamer of the present invention can also be in a linear or circular form. The length of the aptamer is not particularly limited, and can normally be about 16 to about 200 nucleotides, and can be, for example, about 100 nucleotides or less, preferably about 50 nucleotides or less, and more preferably about 40 nucleotides or less. The length of an aptamer of the present invention may be, for example, about 18, about 20, about 25 or about 30 nucleotides or more. The aptamer, for increasing the bindability, stability, drug delivering quality and the like, may be one wherein a sugar residue (e.g., ribose) of each nucleotide is modified. As examples of a portion of the sugar residue modified, ones wherein the oxygen atom at the 2'-position, 3'-position and/or 4'-position of the sugar residue is replaced with another atom and the like can be mentioned. As examples of types of modifications, fluorination, O-alkylation, O-allylation, S-alkylation, S-allylation and amination can be mentioned (see, e.g., Sproat et al., (1991) Nucle. Acid. Res. 19, 733-738; Cotton et al., (1991) Nucl. Acid. Res. 19, 2629-2635). The aptamer may be one wherein a purine or pyrimidine is altered. As examples of such alterations, alteration of the 5-position pyrimidine, alteration of the 8-position purine, alteration by an exocyclic amine, substitution by 4-thiouridine, and substitution by 5-bromo or 5-iodo-uracil can be mentioned. The phosphate group contained in an aptamer of the present invention may be altered to make it resistant to nuclease and hydrolysis. For example, the phosphate group may be substituted by a thioate, a dithioate or an amidate. An aptamer can be prepared according to available reports (for example, Ellington et al., (1990) Nature, 346, 818-822; Tuerk et al., (1990) Science, 249, 505-510).

[0153] An aptamer of the present invention is capable of binding specifically to a polypeptide of the present invention or a known polypeptide, or both a polypeptide of the present invention and a known polypeptide, via a region corresponding to a partial peptide of the present invention. Therefore, an aptamer of the present invention can be an aptamer specific for a polypeptide of the present invention, an aptamer specific for a known polypeptide, or an aptamer common to both a polypeptide of the present invention and a known polypeptide. Such a specific aptamer can be prepared by, for example, selecting (a) a polynucleotide that binds to a polypeptide of the present invention or a specific partial peptide thereof, and that does not bind to a known polypeptide, (b) a polynucleotide that binds to a known polypeptide or a specific partial peptide thereof, and that does not bind to a polypeptide of the present invention, or (c) a polynucleotide that binds to both a polypeptide of the present invention and a known polypeptide or to a shared partial peptide of the present invention, by the SELEX method.

2.4. Antibodies

[0154] The present invention provides antibodies.

[0155] An antibody of the present invention may be a polyclonal antibody (antiserum) or a monoclonal antibody, and can be prepared by a commonly known immunological technique. Although the monoclonal antibody may be of any isotype, IgG, IgM, IgA, IgD, IgE, or the like, IgG or IgM is preferable.

[0156] For example, the polyclonal antibody can be acquired by administering the above-described antigen (as required, may be prepared as a complex crosslinked to a carrier protein such as bovine serum albumin or KLH ((Keyhole Limpet Hemocyanin)), along with a commercially available adjuvant (for example, Freund's complete or incomplete adjuvant), to an animal subcutaneously or intraperitoneally about 2 to 4 times at intervals of 2 to 3 weeks (the antibody titer of partially drawn serum has been determined by a known antigen-antibody reaction and its elevation has been confirmed in advance), collecting whole blood about 3 to about 10 days after final immunization, and purifying the antiserum. As the animal to receive the antigen, mammals such as rats, mice, rabbits, goat, guinea pigs, and hamsters can be mentioned.

[0157] The monoclonal antibody can also be prepared by a cell fusion method. For example, the above-described antigen, along with a commercially available adjuvant, is subcutaneously or intraperitoneally administered to a mouse 2 to 4 times, and 3 days after final administration, the spleen or lymph nodes are collected, and leukocytes are collected. These leukocytes and myeloma cells (for example, NS-1, P3X63Ag8 and the like) are cell-fused to obtain a hybridoma that produces a monoclonal antibody against the factor. This cell fusion may be performed by the PEG method or the voltage pulse method. A hybridoma that produces the desired monoclonal antibody can be selected by detecting an antibody that binds specifically to the antigen, in the culture supernatant, using a widely known EIA or RIA method and the like. Cultivation of the hybridoma that produces the monoclonal antibody can be performed in vitro, or in vivo such as in ascitic fluid of a mouse or rat, preferably a mouse, and the antibody can be acquired from the culture supernatant of the hybridoma and the ascitic fluid of the animal.

[0158] An antibody of the present invention may also be a chimeric antibody, a humanized antibody or a human antibody.

[0159] A chimeric antibody means a monoclonal antibody derived from immunoglobulins of animal species having mutually different variable regions and constant regions. For example, a chimeric antibody can be a mouse/human chimeric monoclonal antibody whose variable region is a variable region derived from a mouse immunoglobulin, and whose constant region is a constant region derived from a human immunoglobulin. The constant region derived from a human immunoglobulin has an amino acid sequence unique depending on the isotype, such as IgG, IgM, IgA, IgD, and IgE, and the constant region of a recombinant chimeric monoclonal antibody in the present invention may be the constant region of a human immunoglobulin belonging to any isotype. The constant region of human IgG is preferable.

[0160] A chimeric antibody can be prepared by a method known per se. For example, a mouse/human chimeric monoclonal antibody can be prepared according to available reports (e.g., Jikken Igaku (extra issue), Vol. 6, No. 10, 1988 and JP-B-HEI-3-73280). In detail, a chimeric antibody can be prepared by inserting the C.sub.H gene acquired from the DNA that encodes a human immunoglobulin (C gene that encodes H chain constant region) downstream of the active V.sub.H gene acquired from the DNA that encodes a mouse monoclonal antibody isolated from a hybridoma that produces the mouse monoclonal antibody (rearranged VDJ gene that encodes H chain variable region), and inserting the C.sub.L gene acquired from the DNA that encodes a human immunoglobulin (C gene that encodes L chain constant region) downstream of the active V.sub.L gene acquired from the DNA that encodes a mouse monoclonal antibody isolated from the hybridoma (rearranged VJ gene that encodes L chain variable region), in a way that allows the expression of each gene, into one or separate expression vectors, transforming a host cell with the expression vector, and culturing the transformant cell.

[0161] A humanized antibody means a monoclonal antibody prepared by a gene engineering technique, for example, a human type monoclonal antibody wherein a portion or all of the complementarity-determining region of the ultra-variable region thereof is derived from a mouse monoclonal antibody, and the framework region of the variable region thereof and the constant region thereof are derived from a human immunoglobulin. The complementarity-determining regions of the ultra-variable region are three regions that are present in the ultra-variable region in the variable region of the antibody, and that complementarily directly bind to the antigen (Complementarity-determining regions; CDR1, CDR2, CDR3), and the framework regions of the variable region are four relatively highly conserved regions locating in the front and back of the three complementarity-determining regions (Framework; FR1, FR2, FR3, FR4). In other words, a humanized antibody means, for example, a monoclonal antibody wherein all regions other than a portion or all of the complementarity-determining region of the ultra-variable region of a mouse monoclonal antibody is replaced with a corresponding region of a human immunoglobulin.

[0162] A humanized antibody can be prepared by a method known per se. For example, a recombinant humanized antibody derived from a mouse monoclonal antibody can be prepared according to available reports (e.g., Japanese Patent Application Kohyo Publication No. HEI-4-506458 and JP-A-SHO-62-296890). In detail, from a hybridoma that produces a mouse monoclonal antibody, at least one mouse H chain CDR gene and at least one mouse L chain CDR gene corresponding to the mouse H chain CDR gene are isolated, and from a human immunoglobulin gene, the human H chain gene that encodes all regions other than the human H chain CDR corresponding to the mouse H chain gene and the human L chain gene that encodes all regions other than the human L chain CDR corresponding to the mouse L chain CDR are isolated. The mouse H chain CDR gene and human H chain gene isolated are introduced into an appropriate expression vector expressibly; likewise, the mouse L chain CDR gene and the human L chain gene are introduced into another appropriate expression vector expressively. Alternatively, the mouse H chain CDR gene/human H chain gene and the mouse L chain CDR gene/human L chain gene can be introduced into the same expression vector expressively. By transforming a host cell with the expression vector thus prepared to obtain a cell that produces a humanized antibody, and culturing the cell, a desired humanized antibody can be obtained from the culture supernatant.

[0163] A human antibody means an antibody wherein all regions comprising the variable regions and constant regions of the H chain and L chain constituting an immunoglobulin are derived from the gene that encodes a human immunoglobulin.

[0164] A human antibody can be prepared by a method known per se. For example, a human antibody can be produced by immunologically sensitizing with an antigen a transgenic animal prepared by incorporating at least a human immunoglobulin gene into a gene locus of a non-human mammal such as a mouse, in the same way as the above-described method of preparing a polyclonal antibody or a monoclonal antibody. For example, a transgenic mouse that produces a human antibody can be prepared according to available reports (Nature Genetics, Vol. 15, p. 146-156, 1997; Nature Genetics, Vol. 7, p. 13-21, 1994; Japanese Patent Application Kohyo Publication No. HEI-4-504365; International Patent Application Publication WO94/25585; Nature, Vol. 368, p. 856-859, 1994; and Japanese Patent Application Kohyo Publication No. HEI-6-500233).

[0165] An antibody of the present invention can also be a portion of an antibody of the present invention described above (e.g., monoclonal antibody). As examples of such antibodies, F(ab').sub.2, Fab', Fab, and Fv fragments, and single-chain antibodies can be mentioned.

[0166] An antibody of the present invention is capable of binding specifically to a polypeptide of the present invention or a known polypeptide, or both a polypeptide of the present invention and a known polypeptide, via a region corresponding to a partial peptide of the present invention. Therefore, an antibody of the present invention can be an antibody specific for a polypeptide of the present invention, an antibody specific for a known polypeptide, or an antibody common to both a polypeptide of the present invention and a known polypeptide. Such a specific antibody can be prepared by, for example, using a specific partial peptide of a polypeptide of the present invention, a specific partial peptide of a known polypeptide, or a shared partial peptide of the present invention as an antigen.

2.5. Expression Vectors

[0167] The present invention provides expression vectors for the above-described substances.

[0168] An expression vector of the present invention can comprise a polynucleotide that encodes a desired polypeptide to be expressed or a desired polynucleotide to be expressed, and a promoter operably linked to the polynucleotide. "A promoter is operably linked to a polynucleotide" means that the promoter is bound to a polynucleotide that encodes the gene in a way such that allows the expression of the polynucleotide under the control thereof, or the expression of the polypeptide encoded by the polynucleotide.

[0169] The backbone for an expression vector of the present invention is not particularly limited, as far as it allows production of a desired substance in a specified cell; for example, plasmid vectors and viral vectors can be mentioned. When an expression vector is used as a pharmaceutical, as vectors suitable for administration to mammals, viral vectors such as adenovirus, retrovirus, adeno-associated virus, herpesvirus, vaccinia virus, poxvirus, poliovirus, Sindbis virus, and Sendai virus can be mentioned.

[0170] When a prokaryotic cell is used as the host cell, an expression vector allowing the prokaryotic cell to be utilized as the host cell can be used. Such an expression vector can comprise, for example, elements such as a promoter-operator region, an initiation codon, a polynucleotide that encods a polypeptide of the present invention or a partial peptide thereof, a stop codon, a terminator region and a replication origin. A promoter-operator region for expressing a polypeptide of the present invention in a bacterium comprises a promoter, an operator and a Shine-Dalgarno (SD) sequence. These elements may be ones known per se.

[0171] When a eukaryotic cell is used as the host cell, an expression vector allowing the eukaryotic cell to be utilized as the host cell can be used. In this case, the promoter used is not particularly limited, as far as it is capable of functioning in eukaryotic organisms such as mammals. When the expression of a polypeptide is desired, as examples of such promoters, viral promoters such as SV40-derived initial promoter, cytomegalovirus LTR, Rous sarcoma virus LTR, MoMuLV-derived LTR, and adenovirus-derived initial promoter, and mammalian constituent protein gene promoters such as .beta.-actin gene promoter, PGK gene promoter, and transferrin gene promoter, and the like can be mentioned. When the expression of a polynucleotide is desired, the promoter can be a polIII promoter (e.g., tRNA promoter, U6 promoter, H1 promoter).

[0172] An expression vector of the present invention can further comprise sites for transcription initiation and transcription termination, and a ribosome-binding site required for translation in the transcription region, a replication origin and a selection marker gene (e.g., ampicillin, tetracycline, kanamycin, spectinomycin, erythromycin, chloramphenicol) and the like. An expression vector of the present invention can be prepared by a method known per se (see, e.g., Molecular Cloning, 2.sup.nd edition, Sambrook et al., Cold Spring Harbor Lab. Press (1989)).

3. Compositions

[0173] The present invention provides compositions comprising the above-described substances.

[0174] A composition of the present invention can comprise, in addition to the above-described substances, an optionally chosen carrier, for example, a pharmaceutically acceptable carrier. As examples of the pharmaceutically acceptable carrier, excipients such as sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, and calcium carbonate, binders such as cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, and starch, disintegrants such as starch, carboxymethylcellulose, hydroxypropylstarch, sodium-glycol-starch, sodium hydrogen carbonate, calcium phosphate, and calcium citrate, lubricants such as magnesium stearate, Aerosil, talc, and sodium lauryl sulfate, flavoring agents such as citric acid, menthol, glycyrrhizin ammonium salt, glycine, and orange flour, preservatives such as sodium benzoate, sodium hydrogen sulfite, methylparaben, and propylparaben, stabilizing agents such as citric acid, sodium citrate, and acetic acid, suspending agents such as methyl cellulose, polyvinylpyrrolidone, and aluminum stearate, dispersing agents such as surfactants, diluents such as water, physiological saline, and orange juice, and base waxes such as cacao butter, polyethylene glycol, and kerosene, and the like can be mentioned, which, however, are not to be construed as limiting.

[0175] Preparations suitable for oral administration are liquids prepared by dissolving an effective amount of a substance in a diluent such as water, physiological saline or orange juice, capsules, saches or tablets containing an effective amount of a substance in the form of solids or granules, suspensions prepared by suspending an effective amount of a substance in an appropriate dispersant, emulsions prepared by dispersing and emulsifying a solution, an effective amount of a substance is dissolved therein, in an appropriate dispersant, and the like.

[0176] Preparations suitable for parenteral administration (for example, intravenous injection, subcutaneous injection, intramuscular injection, topical injection, intraperitoneal administration and the like) are aqueous and non-aqueous isotonic sterile injectable liquids, which may contain an antioxidant, a buffer solution, a bacteriostatic agent, an isotonizing agent and the like. Aqueous and non-aqueous sterile suspensions can also be mentioned, which may contain a suspending agent, a solubilizer, a thickening agent, a stabilizer, an antiseptic and the like. These preparations can be enclosed in containers such as ampoules and vials for unit dosage or a plurality of dosages. It is also possible to freeze-dry the active ingredient and a pharmaceutically acceptable carrier, and store the preparation in a state that may be dissolved or suspended in an appropriate sterile vehicle just before use.

[0177] Although the dosage of a composition of the present invention varies depending on the activity and kind of active ingredient, seriousness of illness, recipient animal species, the recipient's drug tolerance, body weight, age, and the like, it is normally about 0.001 to about 500 mg/kg as the amount of active ingredient per day for an adult.

[0178] A composition of the present invention enables a regulation (e.g., promotion or suppression) of the expression or a function of a polypeptide of the present invention. A composition of the present invention can be useful as, for example, a pharmaceutical (e.g., a prophylactic or therapeutic drug for a disease as described above), reagent or food.

4. Cells

[0179] The present invention provides transformants that produce a polypeptide of the present invention or a partial peptide of the present invention, cells that produce an antibody of the present invention, and cells wherein the expression or a function of a polynucleotide or polypeptide of the present invention is regulated.

4.1. Transformants

[0180] A transformant of the present invention can be a cell transformed with an expression vector of the present invention, that expresses a polypeptide of the present invention or a partial peptide of the present invention. The host cell used to prepare the transformant is not particularly limited, as far as it is compatible with the expression vector, and capable of expressing the desired polynucleotide or polypeptide and the like; for example, primary culture cells or cell lines can be mentioned. In detail, as examples of such host cells, cells of prokaryotic organisms such as Escherichia coli, bacteria of the genus Bacillus (e.g., Bacillus subtilis), and actinomyces, and cells of eukaryotic organisms, such as yeast, insect cells, bird cells, and mammalian cells (e.g., cells derived from the above-described mammals: e.g., CHO cells) can be mentioned. A transformant of the present invention can be prepared by a method known per se (see, e.g., Molecular Cloning, 2.sup.nd edition, Sambrook et al., Cold Spring Harbor Lab. Press (1989)).

[0181] Cultivation of the transformant can be performed in a nutrient medium such as a liquid medium by a method known per se. The medium preferably contains a carbon source, a nitrogen source, an inorganic substance and the like necessary for the growth of the transformant. Here, as examples of the carbon source, glucose, dextrin, soluble starch, sucrose and the like can be mentioned; as examples of the nitrogen source, inorganic or organic substances such as an ammonium salt, a nitrate salt, corn steep liquor, peptone, casein, meat extract, soybean cake, potato extract and the like can be mentioned; as examples of the inorganic substance, calcium chloride, sodium dihydrogen phosphate, magnesium chloride and the like can be mentioned. In addition, the medium may be supplemented with yeast extract, vitamins and the like. Culturing conditions, for example, temperature, medium pH and culturing time, are chosen as appropriate to allow a polypeptide of the present invention to be produced in a large amount. Culturing temperature is, for example, 30 to 37.degree. C.

4.2. Antibody Producing Cells

[0182] An antibody-producing cell of the present invention can be an optionally chosen cell that produces an antibody of the present invention. As antibody-producing cells of the present invention, the above-described hybridomas, and a transformant cell incorporating an expression vector for one of the above-described antibodies can be mentioned. When an antibody-producing cell of the present invention is a transformant cell, details of the expression vector, host cell, cell culture and the like used to prepare the transformant cell can be the same as those described above.

4.3. Cells Wherein the Expression or a Function of a Polypeptide of the Present Invention is Regulated

[0183] The present invention provides cells wherein the expression or a function of a polypeptide of the present invention is regulated.

[0184] A cell of the present invention can be an isolated and/or purified one. A cell of the present invention can be a cell derived from one of the above-described tissues, or a cell of one of the above-described kinds. A cell of the present invention can be derived from one of the above-described mammals. A cell of the present invention can be a primary culture cell or cell line, or a normal cell, or a cell derived from a mammal with one of the above-described diseases. A cell of the present invention can be a cell wherein the expression or a function of a polypeptide of the present invention is regulated specifically. A cell of the present invention can have a nerve cell-related action or nerve cell-related phenotype thereof being variable as a result of a regulation (e.g., promotion, suppression) of the expression or a function of a polypeptide of the present invention. A cell of the present invention can be a cell wherein the expression of a polypeptide of the present invention is regulated transiently, or a cell wherein the expression is regulated permanently (e.g., homozygousity- or heterozygousity-deficient cells). A cell of the present invention can also be a transformant or a non-transformant.

[0185] A cell of the present invention can be prepared by, for example, treating a cell with one of the above-described substances capable of regulating the expression or a function of a polynucleotide of the present invention or a polypeptide of the present invention (e.g., polypeptides of the present invention, antisense molecules, RNAi-inducing nucleic acids, antibodies, or expression vectors therefor). A cell of the present invention can also be prepared by isolating and/or purifying a cell from a transgenic animal or gene-deficient (so-called knockout) animal described below.

[0186] A cell wherein the expression or a function of a polypeptide of the present invention is regulated can be useful in, for example, developing a pharmaceutical (e.g., a prophylactic or therapeutic drug as described above), reagent or food, identifying a further marker gene specific for the brain/nerves or specific for nerve cell differentiation, and analyzing mechanisms associated with nerve cell differentiation. These can be performed by, for example, an expression profile analysis comprising measuring the expression profile in a cell of the present invention using a microarray, protein chip (e.g., antibody chip, or non-antibody chip such as chip manufactured by Ciphergen) and the like, and comparing the profile with the expression profile of a control cell. A cell of the present invention can also be useful as a cell model of a disease as described above.

5. Animals

[0187] The present invention provides animals wherein the expression or a function of a polypeptide of the present invention is regulated.

[0188] An animal of the present invention can be an animal with or without a genome alteration. The species of an animal of the present invention can be, for example, the same as one of the above-described non-human mammals.

[0189] In one embodiment, an animal of the present invention can be a transgenic animal with a genome alteration. A transgenic animal of the present invention is capable of expressing a polypeptide of the present invention. A transgenic animal of the present invention is also capable of expressing a polypeptide of the present invention specifically in one of the above-described cells or tissues.

[0190] A transgenic animal of the present invention can be prepared by a method known per se. In more detail, a transgenic animal of the present invention can be prepared by, for example, introducing a polynucleotide of the present invention linked operably to a specified promoter (e.g., a promoter that is non-specific or specific for one of the above-described cells or tissues) (e.g., may be in the form of an expression vector of the present invention) into a fertilized egg of an animal or another cell (e.g., unfertilized egg, spermatozoon or a progenitor cell thereof) in the initial stage of development. As examples of the method of gene introduction, the electroporation method, lipofection method, aggregation method, calcium phosphate coprecipitation method, and microinjection method can be mentioned. A transgenic animal of the present invention may be an animal prepared by mating a thus-prepared animal and another animal of the same species (e.g., animal model of a disease as described above).

[0191] In another embodiment, an animal of the present invention can be a gene-deficient animal with a genome alteration. A gene-deficient animal of the present invention is incapable of expressing a polypeptide of the present invention. A gene-deficient animal of the present invention is also incapable of expressing a polypeptide of the present invention specifically in one of the above-described cells or tissues.

[0192] A gene-deficient animal of the present invention can be prepared by a method known per se. In more detail, a gene-deficient animal of the present invention can be prepared using an embryonic stem cell (ES cell) specifically lacking a brain/nerve-specific gene. Such an ES cell can be prepared by, for example, introducing a specified targeting vector into ES cells, and selecting an ES cell showing homologous recombination from among the ES cells incorporating the targeting vector.

[0193] As a targeting vector, a targeting vector capable of inducing homologous recombination that causes specific expressional failure of a polynucleotide or polypeptide of the present invention can be used. Such a targeting vector comprises a first polynucleotide and second polynucleotide that are homologous or specifically homologous to a brain/nerve-specific gene (of the polynucleotides, at least one comprises a splicing donor signal for the brain/nerve-specific gene, and comprises a mutation that nullifies the splicing that produces at least one isoform in the signal), and, as required, a selection marker. A splicing donor signal for the brain/nerve-specific gene, and a mutation that nullifies the splicing that produces at least one isoform in the signal can be easily determined by a person skilled in the art. The first and second polynucleotides are polynucleotides having a sequence identity and length that are sufficient to produce homologous recombination in the genomic DNA associated with the brain/nerve-specific gene. The first and second polynucleotides are chosen in a way such that specific deficiency of a particular isoform is produced. As selection markers, positive selection markers (e.g., neomycin resistance gene, hygromycin B phosphotransferase (BPH) gene, blasticidin S deaminase gene, puromycin resistance gene), negative selection markers (e.g., herpes simplex virus (HSV) thymidine kinase (tk) gene, diphtheria toxin A fragment (DTA) gene) and the like can be mentioned. The targeting vector can comprise either a positive selection marker or a negative selection marker or both. The targeting vector may comprise two or more recombinase target sequences (e.g., loxP sequence, which is used in the Cre/loxP system derived from bacteriophage P1, FRT sequence, which is used in yeast-derived FLP/FRT system). The present invention also provides such a targeting vector.

[0194] As the method for introducing a targeting vector into an ES cell, a method known per se can be used. As examples of such methods, the calcium phosphate method, lipofection method/liposome method, electroporation method and the like can be mentioned. When a targeting vector is introduced into a cell, homologous recombination of the genomic DNA associated with the brain/nerve-specific gene occurs in the cell. Although an ES cell may be established by culturing an inner cell mass separated from a blastocyst of an optionally chosen animal on feeder cells, an existing ES cell may be utilized.

[0195] To select an ES cell showing homologous recombination, cells after introduction of a targeting vector are screened for. For example, after selection is performed by positive selection, negative selection and the like, screening based on genotype (for example, PCR method, Southern blot hybridization method) is performed. It is also preferable to further perform karyotype analysis on the ES cell obtained. In the karyotype analysis, the absence of chromosome aberrations in the selected ES cell is checked. Karyotype analysis can be performed by a method known per se. It is preferable that the karyotype of the ES cell be confirmed in advance before introducing the targeting vector.

[0196] A gene-deficient animal of the present invention can be prepared by transplanting to an animal a chimeric embryo obtained by introducing an ES cell obtained as described above into an embryo, and then mating the chimeric animal obtained. As examples of the embryo, blastocysts, 8-cell stage embryos and the like can be mentioned. The embryo can be obtained by mating a female animal undergoing an overovulation treatment with a hormone preparation (for example, PMSG, which has FSH-like action, and hCG, which has LH action, are used) and the like with a male animal, and the like. As methods of introducing an ES cell into an embryo, the micromanipulation method, aggregation method and the like can be mentioned.

[0197] The animal receiving a chimeric embryo transplanted is preferably a pseudo-pregnant animal. A pseudo-pregnant animal can be obtained by mating a female animal in the normal sexual cycle with a male animal emasculated by vasoligation and the like. The animal incorporating the chimeric embryo becomes pregnant and delivers a chimeric animal. Next, it is determined whether or not the animal born is a chimeric animal. Whether or not the animal born is a chimeric animal can be determined by a method known per se, for example, by the body color or coat color. For the determination, a DNA may be extracted from a portion of the body and subjected to Southern blot analysis or PCR assay. The mating can be performed preferably between a wild-type animal and a chimeric animal, or between chimeric animals. Whether or not the deficiency of the brain/nerve-specific gene has been introduced into the germ cell line of the chimeric animal and heterozygous offspring lacking the brain/nerve-specific gene has been obtained can be determined by a method known per se with various characters as indexes; for example, this can be determined by the body color or coat color of the offspring animal. For the determination, a DNA may be extracted from a portion of the body and subjected to Southern blot analysis or PCR assay. Furthermore, by mating thus-obtained heterozygotes, a homozygote can be prepared. A gene-deficient animal of the present invention may also be an animal prepared by mating an animal thus prepared and another animal of the same species (e.g., animal model of disease based on nerve cell disorder, transgenic animal).

[0198] In a still another embodiment, an animal of the present invention can be an animal without a genome alteration. Such an animal can be prepared by treating an animal with one of the above-described substances capable of regulating the expression or a function of a polynucleotide of the present invention or a polypeptide of the present invention (e.g., polypeptides of the present invention, antisense molecules, RNAi-inducing nucleic acids, antibodies, or expression vectors therefor). Such an animal can also be an animal capable or incapable of expressing a polypeptide of the present invention specifically in one of the above-described tissues by topical treatment. The animal treatment can be performed using a method mentioned with respect to a composition of the present invention.

[0199] An animal of the present invention can be useful in, for example, developing a pharmaceutical (e.g., a prophylactic or therapeutic drug as described above), reagent or food, identifying a further marker gene specific for the brain/nerves or specific for nerve cell differentiation, and analyzing mechanisms associated with nerve cell differentiation. These can be performed by, for example, an expression profile analysis comprising measuring an expression profile (particularly expression profile of a nerve cell or a tissue in the brain) using a microarray, protein chip (e.g., antibody chip, or non-antibody chip such as a chip manufactured by Ciphergen) and the like in an animal of the present invention, and comparing the profile with the expression profile of a control animal. An animal of the present invention can also be useful as an animal model of a disease as described above.

6. Measuring Means and Measuring Method

[0200] The present invention provides measuring means (e.g., primer set, nucleic acid probe, antibody, aptamer) and measuring methods for target polynucleotides and polypeptides.

6.1. Primer Set and Method of Use Thereof

[0201] A primer set of the present invention can be used for specific detection and quantitation of a polynucleotide of the present invention or a known polynucleotide, or comprehensive detection and quantitation of both a polynucleotide of the present invention and a known polynucleotide. For example, such detection and quantitation can be achieved, after preparing total RNA from a biological sample, by utilizing a method of gene amplification such as a PCR (e.g., RT-PCR, real-time PCR, quantitative PCR), LAMP (Loop-mediated isothermal amplification) (see, e.g., WO00/28082), or ICAN (Isothermal and Chimeric primer-initiated Amplification of Nucleic acids) (see, e.g., WO00/56877). Because the number of primers required differs depending on the kind of the method of gene amplification, the number of primers is not particularly limited; for example, a primer set of the present invention can comprise two or more primers constituted by a sense and antisense primer. The two or more primers may be mixed in advance or not. Each of the sense and antisense primers is not particularly limited, as far as it is of a size enabling specific amplification of the target region; each primer consists of 12 (for example, at least about 15, preferably at least about 18, more preferably at least about 20 and the like) consecutive nucleotide residues. The sense and antisense primer, when the size of the polynucleotide amplified thereby is to be visually detected, can be designed to allow it to be visually detectable. The visually detectable size is not particularly limited, and can be, for example, at least about 50, preferably at least 70, more preferably at least about 100, still more preferably at least about 150, and most preferably at least about 200, about 300, about 400, about 500 or more nucleotide residues long. The sense and antisense primer do not require that the polynucleotide amplified thereby be visually detected, and may be detected by a fluorescence signal and the like, as is commonly used in real-time PCR.

[0202] A primer set of the present invention can be a) a primer set specific for a polynucleotide of the present invention, capable of distinguishing a polynucleotide of the present invention from a known polynucleotide (abbreviated as "specific primer set A" as required), b) a primer set specific for a known polynucleotide, capable of distinguishing a known polynucleotide from a polynucleotide of the present invention (abbreviated as "specific primer set B" as required), or c) a primer set common to both a polynucleotide of the present invention and a known polynucleotide (abbreviated as "shared primer set" as required) wherein a polynucleotide of the present invention and a known polynucleotide do not distinguish each other.

[0203] The specific primer set A of the present invention can comprise i) a sense and antisense primer designed to make it possible to distinguish the size of the polynucleotide of the present invention or partial nucleotide thereof to be amplified from the size of the known polynucleotide or partial nucleotide thereof to be amplified, or ii) a sense and antisense primer designed to allow a polynucleotide of the present invention or a partial nucleotide thereof alone to be amplified, and not to allow a known polynucleotide to be amplified.

[0204] The sense and antisense primers of i) above are preferably, for example, a) a sense primer corresponding to a nucleic acid sequence present on the 5' side relative to the nucleic acid sequence of the above-described specific partial nucleotide A (particularly an insert nucleic acid sequence of a polynucleotide of the present invention), and an antisense primer corresponding to a nucleic acid sequence complementary to a nucleic acid sequence present on the 3' side relative to the nucleic acid sequence, or b) a sense primer corresponding to a nucleic acid sequence present on the 5' side relative to the nucleic acid sequence of the above-described specific partial nucleotide B (particularly an insert nucleic acid sequence of a known polynucleotide), and an antisense primer corresponding to a nucleic acid sequence complementary to a nucleic acid sequence present on the 3' side relative to the nucleic acid sequence.

[0205] The sense and antisense primers of ii) above are preferably, for example, a) a sense primer corresponding to the nucleic acid sequence of the above-described specific partial nucleotide A (particularly an insert nucleic acid sequence of a polynucleotide of the present invention), and a specified antisense primer, b) a specified sense primer, and a sense primer corresponding to the nucleic acid sequence of the above-described specific partial nucleotide A (particularly an insert nucleic acid sequence of a polynucleotide of the present invention), or c) a sense and antisense primer corresponding to the nucleic acid sequence of the above-described specific partial nucleotide A (particularly an insert nucleic acid sequence of a polynucleotide of the present invention).

[0206] The specific primer set B of the present invention can comprise i) a sense and antisense primer designed to make it possible to distinguish the size of the known polynucleotide or partial nucleotide thereof to be amplified from the size of the polynucleotide of the present invention or partial nucleotide thereof to be amplified, or ii) a sense and antisense primer designed to allow a known polynucleotide or a partial nucleotide thereof alone to be amplified, and not to allow a polynucleotide of the present invention to be amplified.

[0207] The sense and antisense primers of i) above are preferably, for example, a) a sense primer corresponding to a nucleic acid sequence present on the 5' side relative to the nucleic acid sequence of the above-described specific partial nucleotide B (particularly an insert nucleic acid sequence of a known polynucleotide), and an antisense primer corresponding to a nucleic acid sequence complementary to a nucleic acid sequence present on the 3' side relative to the nucleic acid sequence, or b) a sense primer corresponding to a nucleic acid sequence present on the 5' side relative to the nucleic acid sequence of the above-described specific partial nucleotide A (particularly an insert nucleic acid sequence of a polynucleotide of the present invention), and an antisense primer corresponding to a nucleic acid sequence complementary to a nucleic acid sequence present on the 3' side relative to the nucleic acid sequence.

[0208] The sense and antisense primers of ii) above are preferably, for example, a) a sense primer corresponding to the nucleic acid sequence of the above-described specific partial nucleotide B (particularly an insert nucleic acid sequence of a known polynucleotide), and a specified antisense primer, b) a specified sense primer, and a sense primer corresponding to the nucleic acid sequence of the above-described specific partial nucleotide B (particularly an insert nucleic acid sequence of a known polynucleotide), or c) a sense and antisense primer corresponding to the nucleic acid sequence of the above-described specific partial nucleotide B (particularly an insert nucleic acid sequence of a known polynucleotide).

[0209] A shared primer set of the present invention can comprise a sense and antisense primer designed to equalize the size of the known polynucleotide or partial nucleotide thereof to be amplified to the size of the polynucleotide of the present invention or partial nucleotide thereof to be amplified. Such a sense and antisense primer are preferably, for example, a sense and antisense primer designed not to allow the polynucleotide of the present invention or partial nucleotide thereof to be amplified, and the known polynucleotide or partial nucleotide thereof to be amplified, to comprise the nucleic acid sequences of the above-described specific partial nucleotides A and B.

6.2. Nucleic Acid Probe and Method of Use Thereof

[0210] A nucleic acid probe of the present invention can be used for specific detection and quantitation of a polynucleotide of the present invention or a known polynucleotide, or comprehensive detection and quantitation of both a polynucleotide of the present invention and a known polynucleotide. For example, such a detection and quantitation can be achieved, after preparing total RNA from a biological sample, by utilizing Northern blotting, a nucleic acid array wherein a nucleic acid probe of the present invention is immobilized, and the like. Although the nucleic acid probe can be a DNA, an RNA, a modified nucleic acid or a chimeric molecule thereof and the like, a DNA is preferable in consideration of safety, convenience and the like. The nucleic acid probe may also be any one of a single-stranded or a double-stranded polynucleotide. The size of the nucleic acid probe is not particularly limited, as far as it is capable of specifically hybridizing to the transcription product of the target gene; the size is, for example, at least about 15 or 16, preferably about 15 to about 1000, more preferably about 20 to about 500, and still more preferably about 25 to about 300. When a nucleic acid probe of the present invention is a single-stranded polynucleotide, the nucleic acid probe of the present invention can be the same as an antisense molecule of the present invention. When a nucleic acid probe of the present invention is a double-stranded polynucleotide, the nucleic acid probe of the present invention can be configured by an antisense molecule of the present invention and a polynucleotide molecule complementary thereto.

[0211] A nucleic acid probe of the present invention can be a) a nucleic acid probe specific for a polynucleotide of the present invention, capable of distinguishing a polynucleotide of the present invention from a known polynucleotide (abbreviated as "specific nucleic acid probe A" as required), b) a nucleic acid probe specific for a known polynucleotide, capable of distinguishing a known polynucleotide from a polynucleotide of the present invention (abbreviated as "specific nucleic acid probe B" as required), or c) a nucleic acid probe common to both a polynucleotide of the present invention and a known polynucleotide, wherein a polynucleotide of the present invention and a known polynucleotide do not distinguish each other (abbreviated as "shared nucleic acid probe" as required).

[0212] The specific nucleic acid probe A of the present invention can be a polynucleotide having a nucleic acid sequence complementary to the nucleic acid sequence of the above-described specific partial nucleotide A (particularly an insert nucleic acid sequence of a polynucleotide of the present invention) (a single-stranded polynucleotide), or a polynucleotide having the nucleic acid sequence of the above-described specific partial nucleotide A (particularly an insert nucleic acid sequence of a polynucleotide of the present invention) and a nucleic acid sequence complementary to the nucleic acid sequence (a double-stranded polynucleotide).

[0213] The specific nucleic acid probe B of the present invention can be a polynucleotide having a nucleic acid sequence complementary to the nucleic acid sequence of the above-described specific partial nucleotide B (particularly an insert nucleic acid sequence of a known polynucleotide) (a single-stranded polynucleotide), or a polynucleotide having the nucleic acid sequence of the above-described specific partial nucleotide B (particularly an insert nucleic acid sequence of a known polynucleotide) and a nucleic acid sequence complementary to the nucleic acid sequence (a double-stranded polynucleotide).

[0214] A shared nucleic acid probe of the present invention can be a polynucleotide having a nucleic acid sequence complementary to the nucleic acid sequence of the above-described shared partial nucleotide (a single-stranded polynucleotide), or a polynucleotide having a nucleic acid sequence complementary to the nucleic acid sequence of the above-described shared partial nucleotide and the nucleic acid sequence (a double-stranded polynucleotide).

[0215] A nucleic acid probe of the present invention may be provided in a state immobilized on a support (i.e., as an array). The support for such a nucleic acid array is not particularly limited, as far as it is a support in common use in the art; for example, membranes (e.g., nylon membranes), glass, plastics, metals, plates and the like can be mentioned. A nucleic acid array in the present invention can assume a form known per se; for example, an array wherein a nucleic acid is directly synthesized on a support (so-called affimetrix type), an array wherein a nucleic acid is immobilized on a support (so-called Stanford type), fiber-type array, and electrochemical array (ECA) can be mentioned.

6.3. Antibodies and Aptamers and Method of Use Thereof

[0216] An antibody and aptamer of the present invention can be used for specific detection and quantitation of a polypeptide of the present invention, a known polypeptide, or both a polypeptide of the present invention and a known polypeptide. For example, such a detection and quantitation can be achieved, after preparing an extract from a biological sample, or using a biological sample, by an immunological technique or an affinity-based method. As examples of such immunological techniques, enzyme immunoassay (EIA) (e.g., direct competitive ELISA, indirect competitive ELISA, sandwich ELISA), radioimmunoassay (RIA), fluorescent immunoassay (FIA), immunochromatography, luminescence immunoassay, spin immunoassay, Western blotting, and immunohistochemical staining can be mentioned. An affinity-based method can be performed in accordance with one of the above-described immunological techniques. The antibody and aptamer used for a measurement of a polypeptide of the present invention, a known polypeptide, or both a polypeptide of the present invention and a known polypeptide can be the same as the above-described antibody and aptamer of the present invention.

[0217] An antibody and aptamer of the present invention can be a) an antibody and aptamer specific for a polypeptide of the present invention, that make it possible to distinguish a polypeptide of the present invention from a known polypeptide (abbreviated as "specific antibody and aptamer A" as required), b) an antibody and aptamer specific for a known polypeptide, that make it possible to distinguish a known polypeptide from a polypeptide of the present invention (abbreviated as "specific antibody and aptamer B" as required), or c) an antibody and an aptamer common to both a polypeptide of the present invention and a known polypeptide, that do not distinguish between a polypeptide of the present invention and a known polypeptide (abbreviated as "shared antibody and aptamer" as required). The specific antibody and aptamer A of the present invention are capable of binding to the above-described specific partial peptide A (particularly a partial peptide consisting of an insert amino acid sequence of a polypeptide of the present invention). The specific antibody and aptamer B of the present invention are capable of binding to the above-described specific partial peptide B (particularly a partial peptide consisting of an insert amino acid sequence of a known polypeptide). A shared antibody and aptamer of the present invention are capable of binding to the above-described shared partial peptide.

[0218] An antibody and aptamer of the present invention may be provided in a form immobilized on a support (i.e., as an array). The support for such a nucleic acid array is not particularly limited, as far as it is a support in common use in the art; for example, membranes (e.g., nitrocellulose membranes), glass, plastics, metals, and plates (e.g., multiwell plates) can be mentioned.

6.4. Supplementary Matters Concerning Measuring Means of the Present Invention

[0219] A measuring means of the present invention can be provided in a form labeled with a labeling substance as required. As examples of the labeling substance, fluorescent substances such as FITC and FAM, luminescent substances such as luminol, luciferin and lucigenin, radioisotopes such as .sup.3H, .sup.14C, .sup.32P, .sup.35S, and .sup.123I, affinity substances such as biotin and streptavidin, and the like can be mentioned.

[0220] A measuring means of the present invention may be provided in the form of a kit comprising an additional constituent, in addition to the measuring means. In this case, the various constituents contained in the kit can be provided in mutually isolated forms, for example, in forms housed in different containers. For example, when the measuring means is not labeled with a labeling substance, the kit can further comprise a labeling substance. A kit of the present invention can comprise two or more measuring means for two or more target genes (e.g., a combination of a brain/nerve-specific gene and a known gene, a combination of two or more brain/nerve-specific genes). When the measuring means of the present invention is provided in the form of an array, the array of the present invention can be one wherein two or more measuring means for two or more target genes are immobilized. A kit and array of to the present invention can also comprise a measuring means as described above with respect to a housekeeping gene (e.g., GAPDH, .beta.-actin).

6.5. Measuring Methods of the Present Invention

[0221] The present invention also provides a method of detecting or quantifying a target polypeptide or polynucleotide using a measuring means of the present invention.

[0222] A measurement of a target polynucleotide and polypeptide can be properly performed according to the kind of the measuring means by the above-described method.

[0223] In a method of the present invention, the expression level of a target polynucleotide or polypeptide in a biological sample obtained from one of the above-described mammals (e.g., human) or a culture (e.g., cell or tissue culture) can be measured. The biological sample is not particularly limited, as far as it is, for example, a sample containing a cell or tissue expressing the target polynucleotide or polynucleotide, or, if the target polynucleotide or polypeptide is secreted or oozed or the like, an animal-derived sample (e.g., blood, plasma, serum, saliva, cerebrospinal fluid, tear, urine) containing the polynucleotide or polypeptide secreted or oozed or the like. The biological sample can be one containing one of the above-described cells or tissues (e.g., nerve cell or a tissue in the brain). The biological sample used in the present invention, unless otherwise specified, can be a biological sample collected from a mammal in advance; in a particular aspect, a method of the present invention can comprise collecting a biological sample from a mammal.

[0224] In one embodiment, a method of the present invention can be utilized to identify a nerve cell, to determine a nerve cell differentiation state, or to diagnose a disease based on a nerve cell disorder (e.g., determination of onset or likelihood of onset). This method can comprise measuring the expression level of a target polynucleotide or polypeptide in a biological sample collected from an animal, and evaluating the onset or likelihood of onset of a target disease on the basis of the measured expression level or relative expression rate. For example, the measured expression level or relative expression rate is compared with the expression level in a mammal not suffering the target disease (e.g., normal animal). The expression level or expression rate in a mammal not suffering the target disease can be determined by a method known per se. By such a comparison, it is determined whether or not the animal possibly has the target disease, or whether or not the animal is likely to suffer the disease. It is known that in a mammal having a particular disease manifested, an expressional change in the gene associated with the disease is often observed. It is also known that before the onset of a particular disease, an expressional change in a particular gene is often observed. Therefore, by such an analysis, it is possible to determine the onset or likelihood of onset of a target disease. Such a method can be useful in, for example, conveniently determining and early detecting a target disease. Of course, a measuring means of the present invention and a reagent or kit of the present invention can also be utilized for such a determination.

[0225] In detail, the changes in the expression profiles of the brain/nerve-specific genes 1 to 10 in nerve cells or tissues in the brain are as described in Examples. Therefore, using a measuring means of the present invention that enables a specific measurement of a polynucleotide of the present invention and a partial nucleotide of the present invention (e.g., specific partial nucleotide A of the present invention, specific partial nucleotide B of the present invention, shared partial nucleotide of the present invention), and a polypeptide of the present invention and a partial peptide of the present invention (e.g., specific partial peptide A of the present invention, specific partial peptide B of the present invention, shared partial peptide of the present invention), by evaluating the degree of the expression of the brain/nerve-specific genes 1 to 10 and/or relative expression ratios thereof, it is possible to identify a nerve cell, to determine a differentiation state of a nerve cell, or to diagnose a disease based on a nerve cell disorder.

[0226] In another embodiment, a method of the present invention can be utilized for screening for a pharmaceutical, reagent or food and the like. For example, in one methodology, the screening method can comprise determining whether or not a test material is capable of regulating (e.g., increasing or decreasing) the number of nerve cells. Because the number of nerve cells and the expression level of a brain/nerve-specific gene can correlate with each other, such a screening can be performed by measuring the expression level of the brain/nerve-specific gene. In another methodology, the screening method can comprise determining whether or not a test material is capable of regulating the expression or a function of a target polynucleotide or polypeptide. Such a screening method can be utilized as, for example, a screening method for a pharmaceutical effective for a specified disease (e.g., disease based on a nerve cell disorder) and the like, comprising selecting a test substance capable of regulating the expression or a function of a target, and a screening method for a pharmaceutical with a decreased specified action (e.g., adverse reactions such as nerve cell differentiation regulatory action) and the like, comprising selecting a test substance incapable of regulating the expression or a function of a target. The test material subjected to the screening method can be a commonly known compound or a novel compound or a composition; as examples, nucleic acids, glucides, lipids, proteins, peptides, organic low molecular compounds, compound libraries prepared using combinatorial chemistry technology, random peptide libraries prepared by solid phase synthesis or the phage display method, or naturally occurring ingredients derived from microorganisms, animals, plants, marine organisms and the like, existing pharmaceuticals, reagents or foods and the like can be mentioned. In the screening method, mammals, cells and tissues (e.g., nerve cell and a tissue in the brain), or reconstitution systems (non-cell systems) as described above can be used. Pharmaceuticals and the like obtained by the screening method are also provided by the present invention.

[0227] The disclosures in all publications mentioned herein, including patents and patent application specifications, are incorporated herein by reference to the extent that all of them have been given expressly.

EXAMPLES

[0228] The present invention is hereinafter described in further detail with reference to Examples; however, the present invention is not limited to the Examples and the like by any means.

Example 1

Preparation and Sequence Analysis of Human cDNA Libraries

[0229] (1) Preparation and Sequence Analysis of cDNA Libraries by the Improved Oligocap method 1) Extraction and Purchase of mRNAs

[0230] From human tissues (shown below), by a method described in a literature document (J. Sambrook, E. F. Fritsch & T. Maniatis, Molecular Cloning Second edition, Cold Spring harbor Laboratory Press, 1989), mRNAs were extracted as total RNAs. After cultivation of cultured human cells or primary culture human cells (shown below) by the methods described in the catalogues thereof, mRNAs were extracted as total RNAs by a method described in a literature document (J. Sambrook, E. F. Fritsch & T. Maniatis, Molecular Cloning Second edition, Cold Spring harbor Laboratory Press, 1989).

[0231] Hereinafter, the relationships between the names of libraries and the derivations thereof are shown in the order of "name of library: derivation". If a library was generated by subtraction, how to generate the subtraction library is also shown.

<Extraction of mRNAs from Human Tissues> NTONG: Tongue; CTONG: Tongue, Tumor; FCBBF: Brain, Fetal; OCBBF: Brain, Fetal; PLACE: Placenta; SYNOV: Synovial membrane tissue from rheumatioid arthritis; CORDB: Cord blood. <Extraction of mRNAs from Cultured Cells> BNGH4: H4 cell (ATCC #HTB-148); IMR32: IMR32 cell (ATCC #CCL-127); SKNMC: SK-N-MC cell (ATCC #HTB-10); 3NB69: NB69 cell (RCB #RCB0480); BGGI1: GI1 cell (RCB #RCB0763); NB9N4: NB9 cell (RCB #RCB0477); SKNSH: SK-N-SH cell (RCB #RCB0426); AHMSC: HMSC cell (Human mesenchymal cell); CHONS: Chondrocyte; ERLTF: TF-1 cell (erythroleukemia); HELAC: HeLa cell; JCMLC: leukemia cell (Leukemia, myelogenous); MESTC: Mesenchyme stem cell; N1ESE: Mesenchymal stem cell; NCRRM: Embryonal carcinoma; NCRRP: Embryonal carcinoma treated with retinoic acid (RA) to induce differentiation; T1ESE: Mesenchymal stem cell treated with trichostatin and 5-azacytidine to induce differentiation; NT2RM: NT2 cell (STARATAGENE #204101); NT2RP: NT2 cell treated with retinoic acid (RA) to induce differentiation for 5 weeks; NT2RI: NT2 cell treated with RA to induce differentiation for 5 weeks, and thereafter treated with a growth inhibitor for 2 weeks; NT2NE: NT2 cell treated with RA and treated with a growth inhibitor to induce nerve differentiation, followed by nerve concentration and recovery (NT2 Neuron); NTISM: a library generated by subtracting cDNAs that overlap with the mRNA of undifferentiated NT2 cells from a cDNA library prepared from an mRNA of NT2 cell (STARATAGENE #204101) treated with RA to induce differentiation for 5 weeks, and thereafter treated with a growth inhibitor for 2 weeks, using Subtract Kit (Invitrogen #K4320-01) (NT2RI-NT2RM). RCB indicates that the cell line was supplied by the RIKEN Gene Bank--Cell Development Bank, and ATCC indicates that the cell line was supplied by the American Type Culture Collection. <Extraction of mRNAs from Primary Culture Cells> ASTRO: Normal Human Astrocyte NHA5732, Takara Shuzo #CC2565; DFNES: Normal Human Dermal Fibroblasts (Neonatal Skin); NHDF-Neo) NHDF2564, Takara Shuzo #CC2509; MESAN: Normal human mesangial cells NHMC56046-2, Takara Shuzo #CC2559; NHNPC: Normal human neural progenitor cells NHNP5958, Takara Shuzo #CC2599; PEBLM: Human peripheral blood mononuclear cells HPBMC5939, Takara Shuzo #CC2702; HSYRA: HS-RA (Human synoviocytes from rheumatioid arthritis), Toyobo #T404K-05; PUAEN: Human pulmonary artery endothelial cells, Toyobo #T302K-05; UMVEN: Human umbilical vein endothelial cells HUVEC, Toyobo #T200K-05; HCASM: HCASMC (Human coronary artery smooth muscle cells), Toyobo #T305K-05; HCHON: HC (Human Chondrocytes), Toyobo #T402K-05; HHDPC: HDPC (Human dermal papilla cells), Toyobo #THPCK-001; CD34C: CD34+ cell (AllCells, LLC #CB14435M); D3OST: CD34+ cells treated with osteoclast differentiation factor (ODF) to induce differentiation for 3 days; D6OST: CD34+ cells treated with an ODF to induce differentiation for 6 days; D9OST: CD34+ cells treated with ODF to induce differentiation for 9 days; ACTVT: activated T-cell; LYMPB: Lymphoblast, EB virus transferred B cell; NETRP: Neutrophil.

[0232] Next, mRNAs extracted as total RNAs from the human tissues shown below were purchased. Hereinafter, the relationships between the names of libraries and the derivations thereof are shown in the order of "name of library: derivation". If a library was generated by subtraction, how to generate the subtraction library is also shown.

<mRNAs from Human Tissues Purchased as Total RNAs> ADRGL: Adrenal gland, CLONTECH #64016-1; BRACE: Brain, cerebellum, CLONTECH #64035-1; BRAWH: Brain, whole, CLONTECH #64020-1; FEBRA: Brain, Fetal, CLONTECH #64019-1; FELIV: Liver, Fetal, CLONTECH #64018-1; HEART: Heart, CLONTECH #64025-1; HLUNG: Lung, CLONTECH #64023-1; KIDNE: Kidney, CLONTECH #64030-1; LIVER: Liver, CLONTECH #64022-1; MAMGL: Mammary Gland, CLONTECH #64037-1; PANCR: Pancreas, CLONTECH #64031-1; PROST: Prostate, CLONTECH #64038-1; SALGL: Salivary Gland, CLONTECH #64026-1; SKMUS: Skeletal Muscle, CLONTECH #64033-1; SMINT: Small Intestine, CLONTECH #64039-1; SPLEN: Spleen, CLONTECH #64034-1; STOMA: Stomach, CLONTECH #64090-1; TBAES: Breast, Tumor, CLONTECH #64015-1; TCERX: Cervix, Tumor, CLONTECH #64010-1; TCOLN: Colon, Tumor, CLONTECH #64014-1; TESTI: Testis, CLONTECH #64027-1; THYMU: Thymus, CLONTECH #64028-1; TLUNG: Lung, Tumor, CLONTECH #64013-1; TOVAR: Ovary, Tumor, CLONTECH #64011-1; TRACH: Trachea, CLONTECH #64091-1; TUTER: Uterus, Tumor, CLONTECH #64008-1; UTERU: Uterus, CLONTECH #64029-1; ADIPS: Adipose, Invitrogen #D6005-01; BLADE: Bladder, Invitrogen #D6020-01; BRALZ: Brain, cortex, Alzheimer, Invitrogen #D6830-01; CERVX: Cervix, Invitrogen #D6047-01; COLON: Colon, Invitrogen #D6050-0; NESOP: Esophagus, Invitrogen #D6060-01; PERIC: Pericardium, Invitrogen #D6105-01; RECTM: Rectum, Invitrogen #D6110-01; TESOP: Esophageal, Tumor, Invitrogen #D6860-01; TKIDN: Kidney, Tumor, Invitrogen #D6870-01; TLIVE: Liver, Tumor, Invitrogen #D6880-01; TSTOM: Stomach, Tumor, Invitrogen #D6920-01; BEAST: Adult Breast, STARATAGENE #735044; FEHRT: Heart, Fetal, STARATAGENE #738012; FEKID: Kidney, Fetal, STARATAGENE #738014; FELNG: Lung, Fetal, STARATAGENE #738020; NOVAR: Adult Ovary, STARATAGENE #735260; BRASW: a library generated by subtracting cDNAs that overlap with the mRNA of BRAWH (Brain, whole, CLONTECH #64020-1) from a cDNA library prepared from the mRNA of BRALZ (Brain, cortex, Alzheimer, Invitrogen #D6830-01), using Subtract Kit (Invitrogen #K4320-01) (BRALZ-BRAWH).

[0233] Furthermore, mRNAs extracted and purified as polyA(+) RNAs from the human tissues shown below were purchased. From an RNA prepared by mixing polyA(+) RNA derived from each tissue with polyA(-) RNA, a cDNA library was prepared. The polyA(-) RNA was prepared by removing the polyA(+) RNA from the total RNA of Brain, whole, CLONTECH #64020-1 by means of oligo dT cellulose. Hereinafter, the relationships between the names of libraries and the derivations thereof are shown in the order of "name of library: derivation".

<mRNAs from Human Tissues Purchased as PolyA(+) RNAs> BRAMY: Brain, amygdala, CLONTECH #6574-1; BRCAN: Brain, caudate nucleus, CLONTECH #6575-1; BRCOC: Brain, corpus callosum, CLONTECH #6577-1; BRHIP: Brain, hippocampus, CLONTECH #6578-1; BRSSN: Brain, substantia nigra, CLONTECH #6580-1; BRSTN: Brain, subthalamic nucleus, CLONTECH #6581-1; BRTHA: Brain, thalamus, CLONTECH #6582-1. 2) Preparation of cDNA Libraries by the Improved Oligocap Method

[0234] From each RNA, by a method (WO 01/04286) developed by improving the oligocap method [M. Maruyama and S. Sugano, Gene, 138: 171-174 (1994)], a cDNA library was prepared. Using an Oligo-cap linker (SEQ ID NO:1) and an Oligo dT primer (SEQ ID NO:2), as described in WO 01/04286, BAP (Bacterial Alkaline Phosphatase) treatment, TAP (Tobacco Acid Pyrophosphatase) treatment, RNA ligation, synthesis of first strand cDNA and removal of RNA were performed. Next, using 5' (SEQ ID NO:3) and 3' (SEQ ID NO:4) PCR primers, by PCR (polymerase chain reaction), the first strand cDNA was converted to a double-stranded cDNA, and cleaved with SfiI. Next, the cDNA fragment, usually fractionated into 2 kb or more (3 kb or more as the case may be), was cloned into the vector pME18SFL3 (GenBank AB009864, Expression vector), previously cleaved with DraIII, in a determined orientation of the cDNA, whereby a cDNA library was prepared.

[0235] The relationships between the names of the cDNA libraries used for 5'-terminal sequence analysis of the cDNAs and the derivations thereof are shown in Tables 1-1 to 1-6. The number of the 5'-terminal sequences of the cDNAs in each cDNA library after mapping onto the human genome are also shown in Table 1.

3) 5'-terminal sequence analysis of cDNAs from cDNA Libraries Prepared by the Improved Oligocap Method

[0236] The 5'-terminal nucleic acid sequences of cDNAs acquired from each cDNA library, after a sequencing reaction using a DNA sequencing reagent (BigDye Terminator Cycle Sequencing FS Ready Reaction Kit, manufactured by PE Biosystems) according to the manual, were analyzed using a DNA sequencer (ABI PRISM 3700, manufactured by PE Biosystems). For the data obtained, a database was constructed. The 5'-terminus full-length rate of each cDNA library prepared by the improved oligocap method was 90% on average, being a high full-length rate (calculated with the protein coding region of a known mRNA as an index).

4) Full-Length cDNA Nucleic Acid Analysis

[0237] For cDNAs selected for full-length cDNA nucleic acid analysis, the nucleic acid sequence of each full-length cDNA was determined. The nucleic acid sequences were determined mainly by a primer walking method based on the dideoxy terminator method using a custom-synthesized DNA primer. Specifically, a sequencing reaction was performed using a custom-synthesized DNA primer with a DNA sequencing reagent manufactured by PE Biosystem as directed in the manual, after which the DNA nucleic acid sequence was analyzed using a sequencer manufactured by the same company. The full-length nucleic acid sequence was finally established by completely overlapping the partial nucleic acid sequences determined by the above-described method. Next, the region of translation into protein was predicted from the determined full-length cDNA nucleic acid sequence, and the amino acid sequence was determined.

(2) Preparation of cDNA Libraries by the Oligocap Method and Sequence Analysis 1) Preparation of cDNA libraries by the oligocap method

[0238] Being human fetal testis derived teratocarcinoma cells, NT-2 neuronal precursor cells (purchased from Stratagene), which can be differentiated into nerve cells by retinoic acid treatment, were used after being treated per the attached manual as follows. [0239] NT-2 cells cultured without differentiation induction with retinoic acid (NT2RM) [0240] NT-2 cells cultured, followed by differentiation induction by the addition of retinoic acid, then cultured for 2 days and 2 weeks (NT2RP)

[0241] Cultured human cell SK-N-MC (ATCC HTB-10) (SKNMC), cultured human cell Y79 (ATCC HTB-18) (Y79AA), cultured human cell GI1 (RCB RCB0763) (BGGI1), cultured human cell H4 (ATCC HTB-148) (BNGH4), cultured human cell IMR32 (ATCC CCL-127) (IMR32), and cultured human cell NB9 (RCB #RCB0477) (NB9N4) were cultured by the methods described in the catalogues thereof. RCB indicates that the cell line was supplied by the RIKEN Gene Bank--Cell Development Bank, and ATCC indicates that the cell line was supplied by the American Type Culture Collection.

[0242] The cultured cells of each line were collected, and by a method described in a literature document (J. Sambrook, E. F. Fritsch & T. Maniatis, Molecular Cloning Second edition, Cold Spring harbor Laboratory Press 1989), mRNAs were extracted. Furthermore, poly(A)+ RNAs were purified by means of oligo dT cellulose. Likewise, from human placenta tissue (PLACE), human ovarian cancer tissue (OVARC), tissue rich in head portion from 10-week-gestional fetal human (HEMBA), tissue rich in trunk portion from 10-week-gestional fetal human (HEMBB), human mammary gland tissue (MAMMA), human thyroid tissue (THYRO), and human vascular endothelial tissue primary culture cell (VESEN), by a method described in a literature document (J. Sambrook, E. F. Fritsch & T. Maniatis, Molecular Cloning Second edition, Cold Spring harbor Laboratory Press, 1989), mRNAs were extracted. Furthermore, poly(A)+ RNAs were purified by means of oligo dT cellulose.

[0243] From all these poly(A)+ RNAs, by the oligocap method [M. Maruyama and S. Sugano, Gene, 138: 171-174 (1994)], respective cDNA libraries were prepared. Using an Oligo-cap linker (SEQ ID NO:1) and an Oligo dT primer (SEQ ID NO:2), as directed in a literature document [Suzuki and Sugano, Protein, Nucleic Acid and Enzyme, 41: 197-201 (1996), Y. Suzuki et al., Gene, 200: 149-156 (1997)], BAP (Bacterial Alkaline Phosphatase) treatment, TAP (Tobacco Acid Phosphatase) treatment, RNA ligation, synthesis of first strand cDNA and removal of RNA were performed. Next, using 5' (SEQ ID NO:3) and 3' (SEQ ID NO:4) PCR primers, the first strand cDNA was converted to a double-stranded cDNA by PCR (polymerase chain reaction), and cleaved with SfiI. Next, the cDNA was cloned into the vector pUC19FL3 (for some cases of NT2RM and NT2RP) or pME18SFL3 (GenBank AB009864, Expression vector), previously cleaved with DraIII, in a determined orientation of the cDNA, whereby a cDNA library was prepared.

[0244] The relationships between the names of the cDNA libraries used for 5'-terminal sequence analysis of the cDNAs and the derivations thereof are shown in Tables 1-1 to 1-6. The number of 5'-terminal sequences of the cDNAs in each cDNA library after mapping onto the human genome are also shown in Tables 1-1 to 1-6.

TABLE-US-00001 TABLES 1-1 to 1-6 number of 5'-terminal sequences (only those which permitted mapping onto human genome) Improved oligocap method CORDB Cord blood Extraction of mRNAs from 708 human tissues CTONG Tongue, Cancer Extraction of mRNAs from 31,371 human tissues FCBBF Brain, Fetal Extraction of mRNAs from 31,986 human tissues NTONG Tongue Extraction of mRNAs from 7,125 human tissues OCBBF Brain, Fetal Extraction of mRNAs from 47,574 human tissues PLACE Placenta Extraction of mRNAs from 33,231 human tissues SYNOV Synovial membrane tissue from Extraction of mRNAs from 27,489 rheumatoid arthritis human tissues BRAMY Brain, amygdala, CLONTECH #6574-1 mRNAs from human tissues 58,640 purchased as polyA(+) RNAs BRCAN Brain, caudate nucleus, CLONTECH mRNAs from human tissues 25,786 #6575-1 purchased as polyA(+) RNAs BRCOC Brain, corpus callosum, CLONTECH mRNAs from human tissues 16,718 #6577-1 purchased as polyA(+) RNAs BRHIP Brain, hippocampus, CLONTECH #6578-1 mRNAs from human tissues 57,918 purchased as polyA(+) RNAs BRSSN Brain, substantia nigra, CLONTECH mRNAs from human tissues 15,897 #6580-1 purchased as polyA(+) RNAs BRSTN Brain, subthalamic nucleus, CLONTECH mRNAs from human tissues 16,308 #6581-1 purchased as polyA(+) RNAs BRTHA Brain, thalamus, CLONTECH #6582-1 mRNAs from human tissues 53,267 purchased as polyA(+) RNAs ADIPS Adipose, Invitrogen #D6005-01 mRNAs from human tissues 608 purchased as total RNAs ADRGL Adrenal gland, CLONTECH #64016-1 mRNAs from human tissues 10,223 purchased as total RNAs BEAST Adult Breast, STARATAGENE #735044 mRNAs from human tissues 2,731 purchased as total RNAs BLADE Bladder, Invitrogen #D6020-01 mRNAs from human tissues 8,431 purchased as total RNAs BRACE Brain, cerebellum, CLONTECH #64035-1 mRNAs from human tissues 82,880 purchased as total RNAs BRALZ Brain, cortex, Alzheimer, Invitrogen mRNAs from human tissues 16,360 #D6830-01 purchased as total RNAs BRASW A library generated by subtracting cDNAs mRNAs from human tissues 157 that overlap with the mRNA of BRAWH purchased as total RNAs (Brain, whole, CLONTECH #64020-1) from a cDNA library prepared from the mRNA of BRALZ (Brain, cortex, Alzheimer, Invitrogen #D6830-01), using Subtract Kit (Invitrogen #K4320-01) (BRALZ-BRAWH) BRAWH Brain, whole, CLONTECH #64020-1 mRNAs from human tissues 59,069 purchased as total RNAs CERVX Cervix, Invitrogen #D6047-01 mRNAs from human tissues 2,836 purchased as total RNAs COLON Colon, Invitrogen #D6050-0 mRNAs from human tissues 8,398 purchased as total RNAs FEBRA Brain, Fetal, CLONTECH #64019-1 mRNAs from human tissues 23,578 purchased as total RNAs FEHRT Heart, Fetal, STARATAGENE #738012 mRNAs from human tissues 2,859 purchased as total RNAs FEKID Kidney, Fetal, STARATAGENE #738014 mRNAs from human tissues 2,747 purchased as total RNAs FELIV Liver, Fetal, CLONTECH #64018-1 mRNAs from human tissues 186 purchased as total RNAs FELNG Lung, Fetal, STARATAGENE #738020 mRNAs from human tissues 2,764 purchased as total RNAs HEART Heart, CLONTECH #64025-1 mRNAs from human tissues 8,889 purchased as total RNAs HLUNG Lung, CLONTECH #64023-1 mRNAs from human tissues 16,146 purchased as total RNAs KIDNE Kidney, CLONTECH #64030-1 mRNAs from human tissues 17,008 purchased as total RNAs LIVER Liver, CLONTECH #64022-1 mRNAs from human tissues 6,843 purchased as total RNAs MAMGL Mammary Gland, CLONTECH #64037-1 mRNAs from human tissues 182 purchased as total RNAs NESOP Esophagus, Invitrogen #D6060-01 mRNAs from human tissues 2,690 purchased as total RNAs NOVAR Adult Ovary, STARATAGENE #735260 mRNAs from human tissues 2,486 purchased as total RNAs PANCR Pancreas, CLONTECH #64031-1 mRNAs from human tissues 179 purchased as total RNAs PERIC Pericardium, Invitrogen #D6105-01 mRNAs from human tissues 8,781 purchased as total RNAs PROST Prostate, CLONTECH #64038-1 mRNAs from human tissues 16,671 purchased as total RNAs RECTM Rectum, Invitrogen #D6110-01 mRNAs from human tissues 2,723 purchased as total RNAs SALGL Salivary Gland, CLONTECH #64026-1 mRNAs from human tissues 183 purchased as total RNAs SKMUS Skeletal Muscle, CLONTECH #64033-1 mRNAs from human tissues 8,424 purchased as total RNAs SMINT Small Intestine, CLONTECH #64039-1 mRNAs from human tissues 16,767 purchased as total RNAs SPLEN Spleen, CLONTECH #64034-1 mRNAs from human tissues 33,950 purchased as total RNAs STOMA Stomach, CLONTECH #64090-1 mRNAs from human tissues 8,685 purchased as total RNAs TBAES Breast, Tumor, CLONTECH #64015-1 mRNAs from human tissues 8,416 purchased as total RNAs TCERX Cervix, Tumor, CLONTECH #64010-1 mRNAs from human tissues 2,797 purchased as total RNAs TCOLN Colon, Tumor, CLONTECH #64014-1 mRNAs from human tissues 2,798 purchased as total RNAs TESOP Esophageal, Tumor, Invitrogen #D6860-01 mRNAs from human tissues 8,500 purchased as total RNAs TESTI Testis, CLONTECH #64027-1 mRNAs from human tissues 90,188 purchased as total RNAs THYMU Thymus, CLONTECH #64028-1 mRNAs from human tissues 70,578 purchased as total RNAs TKIDN Kidney, Tumor, Invitrogen #D6870-01 mRNAs from human tissues 15,970 purchased as total RNAs TLIVE Liver, Tumor, Invitrogen #D6880-01 mRNAs from human tissues 8,627 purchased as total RNAs TLUNG Lung, Tumor, CLONTECH #64013-1 mRNAs from human tissues 2,844 purchased as total RNAs TOVAR Ovary, Tumor, CLONTECH #64011-1 mRNAs from human tissues 2,722 purchased as total RNAs TRACH Trachea, CLONTECH #64091-1 mRNAs from human tissues 52,352 purchased as total RNAs TSTOM Stomach, Tumor, Invitrogen #D6920-01 mRNAs from human tissues 2,757 purchased as total RNAs TUTER Uterus, Tumor, CLONTECH #64008-1 mRNAs from human tissues 2,668 purchased as total RNAs UTERU Uterus, CLONTECH #64029-1 mRNAs from human tissues 49,561 purchased as total RNAs ACTVT Activated T-cell Extraction of mRNAs from 679 primary culture human cells ASTRO Normal Human Astrocyte NHA5732, Extraction of mRNAs from 17,162 Takara Shuzo #CC2565 primary culture human cells CD34C CD34+ cell (AllCells, LLC #CB14435M) Extraction of mRNAs from 1,420 primary culture human cells D3OST CD34+ cells treated with osteoclast Extraction of mRNAs from 5,092 differentiation factor (ODF) to induce primary culture human cells differentiation for 3 days D6OST CD34+ cells treated with osteoclast Extraction of mRNAs from 888 differentiation factor (ODF) to induce primary culture human cells differentiation for 6 days D9OST CD34+ cells treated with osteoclast Extraction of mRNAs from 4,407 differentiation factor (ODF) to induce primary culture human cells differentiation for 9 days DFNES Normal Human Dermal Fibroblasts Extraction of mRNAs from 10,103 (Neonatal Skin; NHDF-Neo) NHDF2564, primary culture human cells Takara Shuzo #CC2509 HCASM HCASMC (Human coronary artery smooth Extraction of mRNAs from 8,949 muscle cells), Toyobo #T305K-05 primary culture human cells HCHON HC (Human Chondrocytes), Toyobo Extraction of mRNAs from 9,397 #T402K-05 primary culture human cells HHDPC HDPC (Human dermal papilla cells), Extraction of mRNAs from 8,453 Toyobo #THPCK-001 primary culture human cells HSYRA HS-RA (Human synoviocytes from Extraction of mRNAs from 7,955 rheumatioid arthritis), Toyobo #T404K-05 primary culture human cells LYMPB Lymphoblast, EB virus transferred B cell Extraction of mRNAs from 2,617 primary culture human cells MESAN Normal human mesangial cells Extraction of mRNAs from 16,053 NHMC56046-2, Takara Shuzo primary culture human cells NETRP Neutrophil Extraction of mRNAs from 9,170 primary culture human cells NHNPC Normal human neural progenitor cells Extraction of mRNAs from 2,377 NHNP5958, Takara Shuzo primary culture human cells PEBLM Human peripheral blood mononuclear cells Extraction of mRNAs from 7,900 HPBMC5939, Takara Shuzo #CC2702 primary culture human cells PUAEN Human pulmonary artery endothelial cells, Extraction of mRNAs from 10,544 Toyobo #T302K-05 primary culture human cells UMVEN Human umbilical vein endothelial cells Extraction of mRNAs from 631 HUVEC, Toyobo primary culture human cells 3NB69 NB69 cell (RCB #RCB0480) Extraction of mRNAs from 8,153 cultured human cells AHMSC HMSC cell (Human mesenchymal cell) Extraction of mRNAs from 668 cultured human cells BGGI1 GI1 cell (Gioma separated from Extraction of mRNAs from 1,899 gliosarcoma; RCB #RCB0763) cultured human cells BNGH4 H4 cell (Neuroglioma; ATCC #HTB-148) Extraction of mRNAs from 7,699 cultured human cells CHONS Chondrocyte; Cell Applications, Inc. Extraction of mRNAs from 2,687 #1205F cultured human cells ERLTF TF-1 cell (erythroleukemia) Extraction of mRNAs from 2,169 cultured human cells HELAC HeLa cell (from cervical cancer) Extraction of mRNAs from 676 cultured human cells IMR32 IMR32 cell (Neuroblastoma; ATCC #CCL- Extraction of mRNAs from 16,867 127) cultured human cells JCMLC Leukemia, myelogenous Extraction of mRNAs from 2,156 cultured human cells MESTC Mesenchyme stem cell Extraction of mRNAs from 687 cultured human cells N1ESE Mesenchymal stem cell Extraction of mRNAs from 2,624 cultured human cells NB9N4 NB9 cell (Neuroblastoma; RCB #RCB0477) Extraction of mRNAs from 1,759 cultured human cells NCRRM Embryonal carcinoma Extraction of mRNAs from 698 cultured human cells NCRRP Embryonal carcinoma treated with retinoic Extraction of mRNAs from 691 acid (RA) to induce differentiation cultured human cells NT2NE NT2 cell treated with RA and treated with a Extraction of mRNAs from 16,337 growth inhibitor to induce nerve cultured human cells differentiation, followed by nerve concentration and recovery (NT2 Neuron) NT2RI NT2 cell treated with RA to induce Extraction of mRNAs from 32,662 differentiation for 5 weeks, and thereafter cultured human cells treated with a growth inhibitor for 2 weeks NT2RM NT2 cell (STARATAGENE #204101) Extraction of mRNAs from 2,026 cultured human cells NT2RP NT2 cell treated with retinoic acid (RA) to Extraction of mRNAs from 24,634 induce differentiation for 5 weeks cultured human cells NTISM a library generated by subtracting cDNAs Extraction of mRNAs from 180 that overlap with the mRNA of cultured human cells undifferentiated NT2 cells from a cDNA library prepared from an mRNA of NT2 cell (STARATAGENE #204101) treated with RA to induce differentiation for 5 weeks, and thereafter treated with a growth inhibitor for 2 weeks, using Subtract Kit (Invitrogen #K4320-01) (NT2RI-NT2RM) SKNMC SK-N-MC cell (Neuroepithelioma; ATCC Extraction of mRNAs from 7,607 #HTB-10) cultured human cells SKNSH SK-N-SH cell (Neuroblastoma; RCB Extraction of mRNAs from 8,662 #RCB0426) cultured human cells T1ESE Mesenchymal stem cell treated with Extraction of mRNAs from 2,685 trichostatin and 5-azacytidine to induce cultured human cells differentiation Oligocap method

HEMBA tissue rich in head portion from 10-week- mRNAs from human tissues 7,033 gestional fetal human (whole embryo, mainly head) HEMBB tissue rich in trunk portion from 10-week- mRNAs from human tissues 2,581 gestional fetal human (whole embryo, mainly body) MAMMA Mammary Gland mRNAs from human tissues 2,987 OVARC Ovary, Tumor mRNAs from human tissues 2,058 PLACE Placenta mRNAs from human tissues 12,859 THYRO Thyroid gland mRNAs from human tissues 1,863 VESEN Human umbilical vein endothelial cells Extraction of mRNAs from 1,309 primary culture human cells NB9N3 NB9 cell (Neuroblastoma; RCB #RCB0477) Extraction of mRNAs from 96 cultured human cells NT2RM NT2 cell (STARATAGENE #204101) Extraction of mRNAs from 5,375 cultured human cells NT2RP NT2 cell treated with retinoic acid (RA) to Extraction of mRNAs from 14,608 induce differentiation for 2 days and 2 cultured human cells weeks Y79AA Y79 cell (Retinoblastoma; ATCC HTB-18) Extraction of mRNAs from 2,377 cultured human cells BGGI1 GI1 cell (Gioma separated from Extraction of mRNAs from 62 gliosarcoma; RCB #RCB0763) cultured human cells BNGH4 H4 cell (Neuroglioma; ATCC #HTB-148) Extraction of mRNAs from 89 cultured human cells IMR32 IMR32 cell (Neuroblastoma; ATCC #CCL- Extraction of mRNAs from 94 127) cultured human cells SKNMC SK-N-MC cell (Neuroepithelioma; ATCC Extraction of mRNAs from 92 #HTB-10) cultured human cells either oligocap method or improved oligocap method, not distinguished BGGI1 GI1 cell (Gioma separated from Extraction of mRNAs from 1 gliosarcoma; RCB #RCB0763) cultured human cells BNGH4 H4 cell (Neuroglioma; ATCC #HTB-148) Extraction of mRNAs from 3 cultured human cells IMR32 IMR32 cell (Neuroblastoma; ATCC #CCL- Extraction of mRNAs from 1 127) cultured human cells SKNMC SK-N-MC cell (Neuroepithelioma; ATCC Extraction of mRNAs from 1 #HTB-10) cultured human cells NT2RM NT2 cell (STARATAGENE #204101) Extraction of mRNAs from 48 cultured human cells Total 1,440,790

2) 5'-terminal sequence analysis of cDNAs from cDNA Libraries Prepared by the Oligocap Method

[0245] The 5'-terminal or 3'-terminal nucleic acid sequences of cDNAs acquired from each cDNA library, after a sequencing reaction using a DNA sequencing reagent (Dye Terminator Cycle Sequencing FS Ready Reaction Kit, dRhodamine Terminator Cycle Sequencing FS Ready Reaction Kit or BigDye Terminator Cycle Sequencing FS Ready Reaction Kit, manufactured by PE Biosystems) according to the manual, were analyzed for DNA nucleic acid sequences using a DNA sequencer (ABI PRISM 377, manufactured by PE Biosystems). For the data obtained, a database was constructed. The 5'-terminus full-length rate of each cDNA library prepared by the oligocap method was 60% on average (calculated with the protein coding region of a known mRNA as an index).

3) Full-Length cDNA Nucleic Acid Analysis

[0246] For cDNAs selected for full-length cDNA nucleic acid analysis, the nucleic acid sequence of each full-length cDNA was determined. The nucleic acid sequences were determined mainly by a primer walking method based on the dideoxy terminator method using a custom-synthesized DNA primer. Specifically, a sequencing reaction was performed using a custom-synthesized DNA primer with a DNA sequencing reagent manufactured by PE Biosystem as directed in the manual, after which the DNA nucleic acid sequence was analyzed using a sequencer manufactured by the same company. For some clones, a DNA sequencer manufactured by Licor was also utilized. For some cDNAs, no custom primer was used, but the shotgun method, in which cDNA-containing plasmids are randomly cleaved, was used with a DNA sequencer to determine the DNA nucleic acid sequence. The full-length nucleic acid sequence was finally established by completely overlapping the partial nucleic acid sequences determined by the above-described method. Next, the region of translation into protein was predicted from the determined full-length nucleic acid sequence, and the amino acid sequence was determined.

Example 2

Genome Mapping and Clustering

(1) Sequence Data Set

[0247] The following sequences were used as a data set.

[0248] Human genome sequence: UCSC hg 17 (NCBI Build 35) (http://www.genome.ucsc.edu/)

[0249] Human full-length cDNAs, 19,265 sequences, newly acquired and subjected to full-length cDNA sequence analysis by us

[0250] Out of human full-length cDNA sequences acquired and subjected to full-length cDNA sequence analysis by us, and registered with an existing public database (DDBJ/GenBank/EMBL) (accession numbers: AB038269, AB045981, AB056476, AB056477, AK000001 to AK002212, AK021413 to AK027260, AK027263 to AK027902, AK054561 to AK058202, AK074029 to AK074481, AK074483 to AK075325, AK075326 to AK075566, AK090395 to AK098842, AK122580 to AK129030, AK129488 to AK131107, AK131190 to AK131575, AK160364 to AK160386, AK172724 to AK172740, AK172741 to AK172866), 30,754 sequences that can be used for genome mapping

[0251] 2039 sequences that had been registered with the database HUGE of Kazusa DNA Research Institute by Feb. 3, 2005 (http://www.kazusa.or.jp/huge/)

[0252] Human full-length cDNAs, 20,878 sequences, that had been listed on the Full Length Clone List on the website of Mammalian Gene Collection (http://mgc.nci.nih.gov/) and included in GenBank gbpri (ftp://ftp.ncbi.nih.gov/genbank/) by Jan. 30, 2005

[0253] Human full-length cDNAs, 9,280 sequences, that had been registered as Deutsches Krebsforschungszentrum (DKFZ) in GenBank gbpri before Jan. 30, 2005

[0254] Human full-length cDNAs, 13,984 sequences, being constituent sequences of the human RefSeq sequences of the Jan. 31, 2005 version (http://www.ncbi.nlm.nih.gov/RefSeq/), registered as mRNAs, and included in GenBank gbpri

[0255] Human RefSeq sequences of the Jan. 31, 2005 version (http://www.ncbi.nlm.nih.gov/RefSeq/), 28,931 sequences

[0256] Out of the human genome assemble sequences in Feb. 10, 2005 Ensembl (http://www.ensembl.org/) (NCBI35.nov.sub.--26.35), 33,666 sequences of NCBI35.nov.sub.--26.35 that had been mapped to the hg 17 human genome in UCSC (University of California, Santa Cruz, http://www.genome.ucsc.edu/)

[0257] Human cDNA 5'-terminal sequence, 1,456,213 sequences, and 3'-terminal sequence, 109,283 sequences, subjected to sequence analysis in our project (including published sequences with accession numbers: AU116788 to AU160826, AU279383 to AU280837, DA000001 to DA999999, DB000001 to DB384947)

(2) Genome Mapping

[0258] The above-described data set was subjected to genome mapping using BLASTN (ftp://ftp.ncbi.nih.gov/blast/), under the conditions of Identity of 95% or more and consensus length of 50 base pairs (bp) or more. About 99% of the sequences in the data set used for the mapping permitted genome mapping.

(3) Clustering

[0259] After the genome mapping, a sequence group contained in a genome region, as a single assembly, was allowed to form a cluster. Hence, each cluster was chosen in a way such that the outer sides of both ends of each genome region in the sequence group would not overlap the sequences mapped on each genome region. As a result, a total of 87,173 clusters existed. Therefrom, 17,535 clusters configured solely with human cDNA 3'-terminal sequences that were acquired and subjected to sequence analysis in our project were excluded, leaving 69,638 clusters. Of these clusters, 36,782 clusters were excluded since they were configured solely with human cDNA 5'-terminal sequences that were acquired and subjected to sequence analysis in our project (those having none of full-length cDNA, RefSeq, and Ensembl sequences were excluded). As a result, 32,856 clusters were found to comprise at least one of full-length cDNAs, RefSeq, and Ensembl sequences. By selecting clusters comprising one or more of full-length cDNAs, RefSeq, and Ensembl sequences, which are expected to have an ORF (open reading frame, coding region) with a reliability above a given level, 21,703 clusters were acquired. For these 21,703 clusters, expression specificity was determined.

Example 3

Experimental Procedures for Real-Time PCR

[0260] (1) Synthesis of Template cDNAs 1) Human mRNA (Human Total RNA) Used as Template

[0261] A reaction was carried out with 50 .mu.g of Human Total RNA per 150 .mu.l of the system.

[0262] To 50 .mu.g of Total RNA dissolved in 87 .mu.l of H.sub.2O, 10 .mu.l of a random primer (concentration 65 ng/.mu.l) and 7.5 .mu.l of dNTP Mix (concentration 10 mM each dNTP Mix) were added. This was followed by incubation at 65.degree. C. for 5 minutes and on ice for 1 minute. 30 .mu.l of 5.times. reaction buffer solution (attached to the Invitrogen SuperScript III RT kit) and 7.5 .mu.l of 0.1M DTT and 3 .mu.l of RNase Inhibitor (STRATAGENE) and 5 .mu.l of SuperScript III RT (Invitrogen) were added. This was followed by incubation at 25.degree. C. for 5 minutes, incubation at 50.degree. C. for 60 minutes, and incubation at 70.degree. C. for 15 minutes. After the reaction, phenol-chloroform extraction was performed to deactivate the enzyme. By adding 3 .mu.l of EDTA (0.5M) and 22.5 .mu.l of 0.1N NaOH, alkali treatment was performed to degrade the RNA. After 30 .mu.l of Tris (1M pH 7.8) was added to neutralize the reaction liquid, ethanol precipitation was performed, and the precipitate was dissolved in 100 .mu.l of TE buffer solution.

[0263] Human mRNAs from the mRNA sources (Human Total RNAs) were acquired by the method described in Example 1.

[0264] A list of the human mRNAs used in the experiments is shown in Table 2.

2) Human mRNA (Human PolyA(+) RNA) Used as Template

[0265] A reaction was carried out with 5 .mu.g of human PolyA RNA per 100 .mu.l of the system.

[0266] To 5 .mu.g of PolyA(+) RNA dissolved in 58 .mu.l of H.sub.2O, 5 .mu.l of a random primer (concentration 65 ng/.mu.l) and 5 .mu.l of dNTP Mix (concentration 10 mM each dNTP Mix) were added. This was followed by incubation at 65.degree. C. for 5 minutes and incubation on ice for 1 minute. 20 .mu.l of 5.times. reaction buffer solution (attached to the Invitrogen SuperScript III RTkit), 5 .mu.l of 0.1M DTT, 2 .mu.l of RNase Inhibitor (STRATAGENE) and 5 .mu.l of SuperScript III RT (Invitrogens) were added. This was followed by incubation at 25.degree. C. for 5 minutes, incubation at 50.degree. C. for 60 minutes, and incubation at 70.degree. C. for 15 minutes. After the reaction, phenol-chloroform extraction was performed to deactivate the enzyme. By adding 2 .mu.l of EDTA (0.5M) and 15 .mu.l of 0.1N NaOH, alkali treatment was performed to degrade the RNA. After 20 .mu.l of Tris (1M pH 7.8) was added to neutralize the reaction liquid, ethanol precipitation was performed, and the precipitate was dissolved in 50 .mu.l of TE buffer solution.

[0267] A list of the human mRNAs used in the experiments is shown in Table 2.

TABLE-US-00002 TABLE 2 Product name Manufacturer Catalog number Human total RNA purchased 1 Bone Marrow Human Bone Marrow Total Clontech 636548 RNA 2 Brain, whole Human Brain Total RNA Clontech 636530 3 Fetal Brain Human Fetal Brain Total Clontech 636526 RNA 4 Heart Human Heart Total RNA Clontech 636532 5 Kidney Human Kidney Total RNA Clontech 636529/636514 6 Liver Human Liver Total RNA Clontech 636531 7 Lung Human Lung Total RNA Clontech 636524 8 Thymus Human Thymus Total RNA Clontech 636549 9 Uterus Human Uterus Total RNA Clontech 636551/636513 10 Spinal Cord Human Spinal Cord Total Clontech 636554 RNA 11 Colon Human Colon Total RNA Clontech 636521 12 Colon Tumor Human Colon Tumor Total Clontech 636634 RNA 13 Kidney Tumor Human Kidney Tumor Total Clontech 636632 RNA 14 Liver Tumor Human Liver Total RNA CHEMICOM RNA569 15 Lung Tumor Human Lung Tumor Total Clontech 636633 RNA 16 Ovary Human Ovary Total RNA Clontech 636555 17 Ovary Tumor Human Ovary Tumor Total Clontech 636631 RNA 18 Spleen Human Spleen Total RNA Clontech 636525 19 Stomach Human Stomach Total RNA Clontech 636522 20 Stomach Tumor Human Stomach Tumor Clontech 636629 Total RNA 21 Uterus Tumor Human Uterus Tumor Total Clontech 636628 RNA 22 ALZ Visual Cortex Occipital Human Visual Cortex Ambion B6336 Occipital ALZ Total RNA Human polyA(+) RNA purchased 1 Brain, whole Human Brain, whole Clontech 636102 PolyARNA 2 Brain cerebellum Brain, cerebellum Clontech 636122 3 Brain, amygdala Brain, amygdala Clontech 6574-1 4 Brain, caudate nucleus Brain, caudate nucleus Clontech 6575-1 5 Brain, corpus callosum Brain, corpus callosum Clontech 636133 6 Brain, hippocampus Brain, hippocampus Clontech 636134 7 Brain, substantia nigra Brain, substantia nigra Clontech 6580-1 8 Brain, thalamus Brain, thalamus Clontech 636135 9 Brain, subthalamic nucleus Brain, subthalamic nucleus Clontech 636167 Extraction of human total RNA Explanation of the derivation from an RNA source of mRNA 1 Tongue (normal) Normal tongue tissue 2 Tongue Tumor Tongue tumor tissue 3 NT2 cell (STARATAGENE Before treatment with NT2 #204101) retinoic acid (RA(-)) 4 NT2 cell treated with NT2 cell treated with retinoic retinoic acid (RA) to induce acid (RA) to induce differentiation differentiation for 5 weeks 5 NT2 cell treated with RA to NT2 cell treated with RA to induce differentiation induce differentiation for 5 followed by treatment with weeks, and thereafter a growth inhibitor (Inh) treated with a growth inhibitor for 2 weeks 6 NT2 cell treated with RA to NT2 cell treated with retinoic induce differentiation acid (RA) to induce differentiation for 1 day 7 NT2 cell treated with RA to NT2 cell treated with retinoic induce differentiation acid (RA) to induce differentiation for 2 days 8 NT2 cell treated with RA to NT2 cell treated with retinoic induce differentiation acid (RA) to induce differentiation for 1 week 9 NT2 cell treated with RA NT2 cell treated with RA and and treated with a-Inh to treated with a growth induce nerve differentiation inhibitor to induce nerve differentiation, followed by nerve cell concentration and recovery

(2) Design of Primers and Probes

[0268] Using Primer Express software 3.0, the primer design software attached to the Applied Biosystems real-time PCR 7500 Fast, with the sequences of portions that serve as the borders of the changing region, primers and probes were designed to allow the individual detection of cDNAs having other splice patterns transcribed from the same chromosome region as the cDNA to be comparatively examined under the conditions recommended by the software. Using the designed primers, real-time PCR was performed, and they were confirmed to produce a single band and to be capable of specifically detecting only one kind of cDNA.

(3) Expressional Analysis Using Real-Time PCR

[0269] 1) mRNAs Used

[0270] All mRNAs used were of human derivation.

[0271] The experiments on the four clusters chr14-45, chr7-2007, chr12-1875, and chr3-1507, out of the 10 experimental systems, were performed using SYBR GREEN as a real-time PCR reaction system, with 16 kinds of samples as template cDNAs: NT2 cells [NT2 RA(-)], NT2 cells treated with retinoic acid (RA) to induce differentiation for 24 hours [NT2 RA(+) 24 hr], NT2 cells treated with retinoic acid (RA) to induce differentiation for 48 hours [NT2 RA(+) 48 hr], NT2 cells treated with retinoic acid (RA) to induce differentiation for 1 week [NT2 RA(+) 1 week], NT2 cells treated with retinoic acid (RA) to induce differentiation for 5 weeks [NT2 RA(+)], NT2 cells treated with RA to induce differentiation for 5 weeks, and thereafter treated with a growth inhibitor for 2 weeks [NT2 RA(+) Inh(+)], NT2 cells treated with RA and treated with a growth inhibitor to induce nerve differentiation, followed by nerve concentration and recovery (NT2 Neuron), Brain, Fetal, Brain, whole, Alzheimer patient cerebral cortex (ALZ Visual Cortex Occipital), Mix, viscus tissues [Heart, Kidney, Liver, Lung, Colon, Stomach], Mix, blood cells and related tissues [Bone Marrow, Thymus, Spinal Cord, Spleen], Mix, tumor tissues [Colon Tumor, Kidney Tumor, Liver Tumor, Lung Tumor, Ovary Tumor, Stomach Tumor, Uterus Tumor, Tongue Tumor], Mix, normal tissues [Colon, Kidney, Liver, Lung, Ovary, Stomach, Uterus, Tongue], whole brain polyA(+)RNA [Brain, whole PolyA(+) RNA], and Brain, hippocampus.

[0272] For the cluster chr12-1875, experiments were also performed with, in addition to the foregoing 16 kinds, additional samples: Colon, Kidney, Liver, Lung, Ovary, Stomach, Uterus, Tongue, Colon Tumor, Kidney Tumor, Liver Tumor, Lung Tumor, Ovary Tumor, Stomach Tumor, Uterus Tumor, and Tongue Tumor.

[0273] For the cluster chr3-1507, experiments were also performed with, in addition to the foregoing 16 kinds, additional samples: Brain cerebellum, Brain, amygdala, Brain, caudate nucleus, Brain, corpus callosum, Brain, substantia nigra, Brain, thalamus, and Brain, subthalamic nucleus.

[0274] The experiments on the 2 clusters chr19-32 and chr12+1658, out of the 10 experimental systems, were performed using TaqMan manufactured by Applied Biosystems as a real-time PCR reaction system, with a total of 16 kinds of samples as template cDNAs: NT2 cells [NT2 RA(-)], NT2 cells treated with retinoic acid (RA) to induce differentiation for 24 hours [NT2 RA(+) 24 hr], NT2 cells treated with retinoic acid (RA) to induce differentiation for 48 hours [NT2 RA(+) 48 hr], NT2 cells treated with retinoic acid (RA) to induce differentiation for 1 week [NT2 RA(+) 1 week], NT2 cells treated with retinoic acid (RA) to induce differentiation for 5 weeks [NT2 RA(+)], NT2 cells treated with RA to induce differentiation for 5 weeks, and thereafter treated with a growth inhibitor for 2 weeks [NT2 RA(+) Inh(+)], NT2 cells treated with RA and treated with a growth inhibitor to induce nerve differentiation, followed by nerve concentration and recovery (NT2 Neuron), Brain, Fetal, Brain, whole, Alzheimer patient cerebral cortex (ALZ Visual Cortex Occipital), Mix, viscus tissues [Heart, Kidney, Liver, Lung, Colon, Stomach], Mix, blood cells and related tissues [Bone Marrow, Thymus, Spinal Cord, Spleen], Mix, tumor tissues [Colon Tumor, Kidney Tumor, Liver Tumor, Lung Tumor, Ovary Tumor, Stomach Tumor, Uterus Tumor, Tongue Tumor], Mix, normal tissues [Colon, Kidney, Liver, Lung, Ovary, Stomach, Uterus, Tongue], Brain, whole PolyA(+) RNA, and Brain, hippocampus.

[0275] The experiments on the 4 clusters chr2-2324, chrX-900, chr8-916, and chr3+2014, out of the 10 experimental systems, were performed using SYBR GREEN as a real-time PCR reaction system, with a total of 23 kinds of samples as template cDNAs: NT2 cells [NT2 RA(-)], NT2 cells treated with retinoic acid (RA) to induce differentiation for 24 hours [NT2 RA(+) 24 hr], NT2 cells treated with retinoic acid (RA) to induce differentiation for 48 hours [NT2 RA(+) 48 hr], NT2 cells treated with retinoic acid (RA) to induce differentiation for 1 week [NT2 RA(+) 1 week], NT2 cells treated with retinoic acid (RA) to induce differentiation for 5 weeks [NT2 RA(+)], NT2 cells treated with RA to induce differentiation for 5 weeks, and thereafter treated with a growth inhibitor for 2 weeks [NT2 RA(+) Inh(+)], NT2 cells treated with RA and treated with a growth inhibitor to induce nerve differentiation, followed by nerve concentration and recovery (NT2 Neuron), Brain, Fetal, Brain, whole, Alzheimer patient cerebral cortex (ALZ Visual Cortex Occipital), Mix, viscus tissues [Heart, Kidney, Liver, Lung, Colon, Stomach], Mix, blood cells and related tissues [Bone Marrow, Thymus, Spinal Cord, Spleen], Mix, tumor tissues [Colon Tumor, Kidney Tumor, Liver Tumor, Lung Tumor, Ovary Tumor, Stomach Tumor, Uterus Tumor, Tongue Tumor], Mix, normal tissues [Colon, Kidney, Liver, Lung, Ovary, Stomach, Uterus, Tongue], Brain, whole PolyA(+) RNA, Brain, hippocampus, Brain cerebellum, Brain, amygdala, Brain, caudate nucleus, Brain, corpus callosum, Brain, substantia nigra, Brain, thalamus, and Brain, subthalamic nucleus.

2) Reaction System Using SYBR GREEN

[0276] The SYBR GREEN I Dye assay chemistry is an experimental system based on the characteristic of SYBR GREEN to emit strong fluorescence by binding to a double-stranded DNA. When the DNA denatures to single-stranded during the PCR reaction, SYBR GREEN leaves from the DNA and the fluorescence decreases rapidly; however, with the subsequent annealing/extension reaction, it binds to the double-stranded DNA to emit fluorescence again. In the SYBR GREEN I Dye assay chemistry, fluorescence intensity, which increases with every PCR cycle, is detected.

[0277] To a cDNA derived from each tissue, 0.2 .mu.l (equivalent to 100 ng of Total RNA), as the template, Forward Primer (final concentration 250 nM), Reverse Primer (final concentration 250 nM), and SYBR Green PCR Master Mix (ABI 4309155) were added, to make a total volume of 20 .mu.l. For endogenous control, GAPDH (Accession No; NM.sub.--002046.2) always served as a reaction control for all templates.

[0278] A PCR was performed under the conditions shown below, which represent the standard protocol for Applied Biosystems real-time PCR 7500 Fast. After an initial step at 50.degree. C. for 2 minutes and at 95.degree. C. for 10 minutes, denaturation at 95.degree. C. for 15 seconds and annealing elongation at 60.degree. C. for 1 minute were repeated in 40 cycles.

GAPDH-F (SEQ ID NO:5): Forward Primer for endogenous control GAPDH GAPDH-R (SEQ ID NO:6): Reverse Primer for endogenous control GAPDH

3) Reaction System Using TaqMan

[0279] The TaqMan assay chemistry is an experimental system employing the TaqMan probe, a probe phosphorylated at the 3' terminus and labeled with a Fluorescenin-series fluorescent dye (reporter) at the 5' terminus, and a Rhodamine-series fluorescent dye (quencher) at the 3' terminus. When the TaqMan probe occurs alone, the fluorescence energy of the reporter is consumed as excitation energy for the quencher, and the fluorescence of the reporter is suppressed, because the fluorescence wavelength is close to that of the quencher even if reporter excitation light is irradiated. However, when the TaqMan probe is degraded by the 5'-3' exonuclease activity of DNA polymerase during the elongation from the primer in the PCR reaction, the fluorescent dye of the reporter leaves from the 5' terminus of the TaqMan probe, and the distance from the fluorescent dye of the quencher increases, resulting in the emission of fluorescence. In the TaqMan assay chemistry, the fluorescence intensity from the reporter, which increases with every PCR cycle, is detected.

[0280] To 0.2 .mu.l (equivalent to 100 ng as converted to Total RNA) of a cDNA derived from each tissue as a template, Forward Primer (final concentration 900 nM), Reverse Primer (final concentration 900 nM), TaqMan Probe (final concentration 250 nM), and TaqMan Fast Universal PCR Master Mix (ABI 466073) were added, to make a total volume of 20 .mu.l. For endogenous control, GAPDH always served as a reaction control for all templates.

[0281] A PCR was performed under the conditions shown below, which represent the Fast protocol for Applied Biosystems real-time PCR 7500 Fast. After enzyme activation 95.degree. C. for 20 seconds, denaturation at 95.degree. C. for 3 seconds and annealing elongation at 60.degree. C. for 30 seconds were repeated in 40 cycles. GAPDH-Probe (SEQ ID NO:7): TaqMan Probe for endogenous control GAPDH

(4) Method of Statistical Analysis of Data

[0282] The results were analyzed using a relative quantitation method.

[0283] Using the RQ study software for Applied Biosystems real-time PCR 7500 Fast, a threshold was set in an exponential functional amplification region of the amplification curve. The number of cycles at that time was used as the Ct (threshold cycle). To make a correction for initial RNA content, the Ct of the endogenous control GAPDH was subtracted from the Ct obtained, and this value was used as the dCt [dCt=Target Ct-ENDOGENUS Ct (GAPDH)]. The dCt of the sample serving as the reference standard (control) was further subtracted from the dCt obtained, and this value was used as the ddCt [ddCt=Target dCt-Control dCt]. On the basis of this value, relative value was calculated, and this was used as the RQ [RQ=2.sup.-ddCt]. On the basis of this result, a logarithmic graph was generated, and the amounts amplified and hence expression levels with each primer and probe were compared.

[0284] In each Example, analytical results for RQ and Log.sub.10 RQ are shown. RQ scores are shown to the first decimal point. For samples not allowing detection by real-time PCR, "Undet." was written in the fields for RQ score and the score of Log.sub.10 RQ. Log.sub.10 RQ scores are shown to the second decimal point. However, for a mixed sample of control normal visceral tissues (Mix, viscus tissues) (RQ value "1.0"), "0.0" was written in the field for Log.sub.10 RQ scores.

Example 4

Cluster chr19-32 (Data Set: 103)

(1) Cluster Analysis

1) Cluster Characteristics

[0285] An analysis was performed on 8 sequences of full-length cDNAs subjected to genome mapping onto the cluster chr19-32 (Human genome UCSC hg18 (NCBI Build34) chromosome 19, 63,124,000 bp to 63,140,000 bp) [D-UTERU2026184.1, D-BRACE3000012.1, AB075836.1, AY695825.1, C-NT2RI2001083, ENST00000358502, ENST00000361044, NM.sub.--133460.1]. They were classifiable according to expression pattern difference into the following 3 kinds.

[1] D-UTERU2026184.1

[2] D-BRACE3000012.1

[3] AB075836.1, AY695825.1, C-NT2RI2001083 (AK056113.1), ENST00000358502, ENST00000361044, NM.sub.--133460.1

[0286] [1] and [2] are cDNAs that were newly acquired and subjected to full-length cDNA sequence analysis by us, having an ORF different from that of [3], which had been registered in an existing public DB (DDBJ/Genbank/EMBL).

[0287] [1], compared with the known [3], had a different ORF region because of the deletion of portions corresponding to the second and third exons of [3] in the ORF region.

[0288] [2], compared with the known [3], had an altered translation initiation point and a different ORF region because of the insertion of an exon different from the other patterns into the ORF region.

[0289] It was found that the ORF regions present in the 3 kinds of cDNA patterns [1] to [3] undergo splicing in different patterns, such as exon deletions and insertions, from the same chromosome region, resulting in alterations of the amino acid sequences to produce diverse proteins and mRNAs.

2) Characteristics of D-UTERU2026184.1 ([1]), which was Newly Acquired and Subjected to Full-Length cDNA Sequence Analysis by Us 103.sub.--[1].sub.--1-N0 (SEQ ID NO:8): The entire nucleic acid sequence region of D-UTERU2026184.1 103.sub.--[1].sub.--1-NA0 (SEQ ID NO:9): Both the entire nucleic acid sequence region and amino acid sequence of D-UTERU2026184.1 103.sub.--[1].sub.--1-A0 (SEQ ID NO:10): The entire amino acid sequence region of D-UTERU2026184.1

[0290] The 213-base exon present at the 213th to 425th bases of NM.sub.--133460.1 (SEQ ID NO:13), which is registered with an existing public DB, and serves for control, is deleted and not present in the region at the 223rd to 224th bases of D-UTERU2026184.1. The 2 bases present at the 520th to 521st bases of NM.sub.--133460.1 (SEQ ID NO:14) are also deleted and not present in the region at the 317th to 318th bases of D-UTERU2026184.1 (SEQ ID NO:11). Although the translation initiation point of NM.sub.--133460.1 is present on the 128-base insertion exon, D-UTERU2026184.1 is present on the first exon, which is shared by NM.sub.--133460.1; therefore, compared with NM.sub.--133460.1, the N-terminal amino acids differed by 43 residues.

103.sub.--[1].sub.--1-N1 (SEQ ID NO:11): Deletion nucleic acid sequence region of D-UTERU2026184.1 103.sub.--[1].sub.--1-A1 (SEQ ID NO:12): Amino acid region altered as a result of deletion of D-UTERU2026184.1 103.sub.--[1].sub.--1-N2 (identical to SEQ ID NO:11): ORF nucleic acid region in the deletion nucleic acid region of D-UTERU2026184.1 103.sub.--[1].sub.--1-A2 (identical to SEQ ID NO:12): ORF amino acid region related to the deletion nucleic acid region of D-UTERU2026184.1 103.sub.--[1]_C-N1 (SEQ ID NO:13): 213-base insert nucleic acid sequence present at the 213th to 425th bases of NM.sub.--133460.1 inserted into the region at the 223rd to 224th bases of D-UTERU2026184.1 103.sub.--[1]_C--N2 (SEQ ID NO:14): 2-base insert nucleic acid sequence present at the 520th to 521 bases of NM.sub.--133460.1 inserted into the region at the 317th to 318th bases of D-UTERU2026184.1 103.sub.--[1]_C-A1 (SEQ ID NO:15): Amino acid region related to the insert nucleic acid sequences at the 213th to 425th bases and the 520th to 521st bases of NM.sub.--133460.1, inserted into the region at the 223rd to 224th bases and the region at the 317th to 318th bases of D-UTERU2026184.1.

[0291] With this change, the Pfam motif "KRAB box", which is present at the 5th to 45th amino acids of NM.sub.--133460.1, which serves for control, disappeared in D-UTERU2026184.1 (http://pfam.janelia.org/).

3) Characteristics of D-BRACE3000012.1 ([2]), which was Newly Acquired and Subjected to Full-Length cDNA Sequence Analysis by Us 103.sub.--[2].sub.--1-N0 (SEQ ID NO:16): The entire nucleic acid sequence region of D-BRACE3000012.1 103.sub.--[2].sub.--1-NA0 (SEQ ID NO:17): Both the entire nucleic acid sequence region and amino acid sequence of D-BRACE3000012.1 103.sub.--[2].sub.--1-A0 (SEQ ID NO:18): The entire amino acid sequence region of D-BRACE3000012.1

[0292] The sequence at the 314th to 533rd bases of D-BRACE3000012.1 (SEQ ID NO:19) is a variant with insertion of an exon not present in NM.sub.--133460.1, which is registered with an existing public DB and serves for control; because of its presence on the exon inserted, along with the translation initiation point, compared with the NM.sub.--133460.1, the N-terminal amino acids differed by 23 residues (SEQ ID NO:20).

103.sub.--[2].sub.--1-N1 (SEQ ID NO:19): 220-base insert nucleic acid sequence region of D-BRACE3000012.1 103.sub.--[2].sub.--1-A1 (SEQ ID NO:20): 23-residue insert amino acid sequence region of D-BRACE3000012.1 103.sub.--[2].sub.--1-N2 (SEQ ID NO:21): ORF nucleic acid sequence region in 220-base insert region of D-BRACE3000012.1 103.sub.--[2].sub.--1-A2 (SEQ ID NO:22): ORF amino acid region related to 220-base insert region of D-BRACE3000012.1

4) Expression Specificity Analysis and Design of Primers and TaqMan Probes for Real-Time PCR

[0293] To clearly distinguish between the characteristic regions shown above, and examine the respective expression levels thereof, the following regions were used as detection regions. It seemed possible to compare the expression levels of the individual characteristic regions by comparing the expression levels of the detection regions.

103.sub.--01--A region specifically extracted by means of the sequence information at the border of a region lacking an exon in the cDNA pattern [1]: an ORF-altering region with exon deletion in the cDNA pattern [1], which was newly subjected to full-length cDNA sequence analysis by us .fwdarw.Fragment 103.sub.--01 (SEQ ID NO:25) amplified by Primer103.sub.--01F (SEQ ID NO:23) and Primer103.sub.--01R (SEQ ID NO:24) TaqMan probe used 103.sub.--01TP: (SEQ ID NO:26) 103.sub.--02--A region specifically extracted by means of the sequence information on a region with exon insertion in the cDNA pattern [2]: an ORF-altering region with exon insertion in the cDNA pattern [2], which was newly subjected to full-length cDNA sequence analysis by us .fwdarw.Fragment 103.sub.--02 (SEQ ID NO:29) amplified by Primer103.sub.--02F (SEQ ID NO:27) and Primer103.sub.--02R (SEQ ID NO:28) TaqMan probe used 103.sub.--02TP: (SEQ ID NO:30) 103.sub.--03--A specific region that is distinguishable from both the deletion region [1] and insert region of [2] in the cDNA pattern [3] registered with an existing public DB, serving as a control for comparing [1] and [2] .fwdarw.Fragment 103.sub.--03 (SEQ ID NO:33) amplified by Primer103.sub.--03F (SEQ ID NO:31) and Primer103.sub.--03R (SEQ ID NO:32) TaqMan probe used 103.sub.--03TP: (SEQ ID NO:34) 103.sub.--04--A common region shared by all of [1] to [3]: a region common to all patterns, serving for control to compare the overall expression levels of the cDNA patterns [1] and [2], which were newly subjected to full-length cDNA sequence analysis by us, and the cDNA pattern [3], registered with an existing public DB .fwdarw.Fragment 103.sub.--04 (SEQ ID NO:37) amplified by Primer103.sub.--04F (SEQ ID NO:35) and Primer103.sub.--04R (SEQ ID NO:36) TaqMan probe 103.sub.--04TP used: (SEQ ID NO:38)

[0294] By mapping the 5'-terminal sequences of about 1.44 million sequences acquired using the oligocap method onto the human genome sequence, and comparatively analyzing them, the exon regions specific for the cDNA patterns [1], [2], and [3] shown above, respectively, were found to be expressed at the following frequencies.

[0295] In the cDNA pattern [1], which was newly acquired and analyzed by us, one 5'-terminal sequence was present, the derivation thereof being Uterus for 1 sequence (analytical parameter 49,561).

[0296] In the cDNA pattern [2], which was newly acquired and analyzed by us, two 5'-terminal sequences were present, the derivations thereof being Brain, cerebellum for 1 sequence (analytical parameter 82,880), and NT2 cells treated with retinoic acid (RA) to induce differentiation (NT2RP) for 1 sequence (analytical parameter 39,242).

[0297] In the cDNA pattern [3], which is registered with an existing public DB, fourteen 5'-terminal sequences were present, the derivations thereof being NT2 cells treated with retinoic acid (RA) to induce differentiation for 5 weeks (NT2RP) for 4 sequences (analytical parameter 39,242), NT2 cells treated with RA to induce differentiation for 5 weeks, and thereafter treated with a growth inhibitor for 2 weeks (NT2RI) for 2 sequences (analytical parameter 32,662), Brain, cerebellum for 1 sequence (analytical parameter 82,880), Brain, amygdala for 1 sequence (analytical parameter 58,640), Brain, hippocampus for 1 sequence (analytical parameter 57,918), Brain, substantia nigra for 1 sequence (analytical parameter 15,897), Normal Human Dermal Fibroblasts for 1 sequence (analytical parameter 10,103), Brain, Fetal for 2 sequences (analytical parameter 79,560), and Uterus for 1 sequence (analytical parameter 49,561).

[0298] From this result, it was found that the exon-deletion pattern [1] was expressed in Uterus, and that the exon-insertion pattern [2] was expressed in Brain, cerebellum and NT2 cells treated with retinoic acid to induce differentiation (NT2RP). It was found that the known sequence [3] was abundantly expressed in NT2 cells treated with retinoic acid to induce differentiation (NT2RP) and in brain tissues.

(2) Analysis of Expression Specificity by Real-Time PCR

[0299] To detect protein expression diversity changes due to exon selectivity, details of expression levels were analyzed by real-time PCR. The results are shown in Table 3.

TABLE-US-00003 TABLE 3 RQ Score Log.sub.10RQ Score 103_01 103_02 103_03 103_04 103_01 103_02 103_03 103_04 01 NT2RA(-) 0.1 6.3 0.9 0.4 -0.86 0.80 -0.04 -0.45 02 NT2RA(+) 24 hr 0.3 2.7 0.6 0.3 -0.54 0.42 -0.19 -0.59 03 NT2RA(+) 48 hr 0.2 2.0 0.7 0.3 -0.68 0.29 -0.14 -0.52 04 NT2RA(+) 1 week 1.9 1.5 0.9 0.8 0.27 0.17 -0.03 -0.11 05 NT2RA(+) 5 weeks 6.7 8.6 2.9 1.1 0.83 0.93 0.46 0.05 06 NT2RA(+) 5 weeks, Inh(+) 2.1 1.5 1.1 0.5 0.32 0.19 0.05 -0.30 07 NT2 Neuron 0.2 0.2 0.5 1.3 -0.77 -0.74 -0.30 0.10 08 Brain, Fetal 4.0 5.0 17.3 8.4 0.60 0.70 1.24 0.92 09 Brain, whole 8.6 3.2 6.1 5.3 0.93 0.51 0.78 0.73 10 ALZ Visual Cortex 1.2 0.7 2.2 3.0 0.08 -0.18 0.34 0.47 Occipital 11 Mix, viscus tissues 1.0 1.0 1.0 1.0 0.0 0.0 0.0 0.0 12 Mix, blood cells and 12.7 6.0 2.7 2.6 1.11 0.78 0.43 0.42 related tissues 13 Mix, tumor tissues 2.3 0.9 0.5 0.7 0.36 -0.02 -0.28 -0.17 14 Mix, normal tissues 2.4 1.9 1.2 1.8 0.37 0.29 0.09 0.24 15 Brain, whole PolyA(+) RNA 4.8 2.2 5.9 3.1 0.68 0.34 0.77 0.49 16 Brain, hippocampus 2.4 1.9 4.1 2.6 0.39 0.28 0.61 0.42

[0300] Expression levels were compared using the 16 samples shown in Example 3, including Brain, hippocampus, Brain, whole, Brain, Fetal, Alzheimer patient cerebral cortex (ALZ Visual Cortex Occipital), and NT2 cells in 7 differentiation stages. For experimental control, comparisons were made using the sample prepared by mixing normal visceral tissues in Example 3 (Mix, viscus tissues).

[0301] The ratio of ORF alteration due to exon insertion/deletion selectivity as compared between 103.sub.--01 (SEQ ID NO:25) and 103.sub.--02 (SEQ ID NO:29) changed greatly among the following differentiation stages of the brain and NT2 cells.

[0302] The expression of the exon-deletion pattern shown by 103.sub.--01 (SEQ ID NO:25) was low in undifferentiated NT2 cells NT2RA (-) and NT2RA (+) 48 hr, which represents the initial stage in which retinoic acid was added to induce differentiation; the expression was high in NT2RA(+) 1 week to NT2RA (+) 5 weeks, Inh (+), which represent the late stage of differentiation induction, and was low in NT2 Neuron. The expression in Brain, Fetal was also low (Table 3).

[0303] The expression of the exon insertion pattern shown by 103.sub.--02 (SEQ ID NO:29) was abundant in undifferentiated NT2 cells NT2RA(-) and the initial stage in which retinoic acid was added to induce differentiation, to NT2RA (+) 5 weeks, Inh (+); the expression was low in NT2 Neuron (Table 3). Not only in Fetal Brain, but also in the whole brain, the expression was low (Table 3).

[0304] These results demonstrated that by comparing the expression of selective exon regions 103.sub.--[1].sub.--1-N1 (SEQ ID NO:11) and 103.sub.--[2].sub.--1-N1 (SEQ ID NO:19) of newly acquired cDNAs shown by the detection regions 103.sub.--01 (SEQ ID NO:25) and 103.sub.--02 (SEQ ID NO:29), it is possible to use these regions as differentiation markers for detecting stages of nerve cell differentiation or regeneration. It also seems possible to develop a new drug by means of a compound, antibody, siRNA or the like that targets a region that exhibits specificity.

[0305] The following regions also seem to be useful as differentiation markers for detecting nerve cell differentiation or regeneration stages.

Upstream sequence 062.sub.--[1].sub.--1-N3 (SEQ ID NO:39), which comprises the 285th to 306th bases undergoing priming by Primer10301R (SEQ ID NO:24) in D-UTERU2026184.1 of the cDNA pattern [1]. Upstream sequence 062.sub.--[1].sub.--1-N3 (SEQ ID NO:40), which comprises the 521st to 541st bases undergoing priming by Primer103.sub.--02R (SEQ ID NO:28) in D-BRACE3000012.1 of the cDNA pattern [2]. Region 10301 (SEQ ID NO:25) amplified by Primer10301F (SEQ ID NO:23) and Primer103.sub.--01R (SEQ ID NO:24) in the cDNA pattern [1] Region 103.sub.--02 (SEQ ID NO:29) amplified by Primer103.sub.--02F (SEQ ID NO:27) and Primer103.sub.--02R (SEQ ID NO:28) in the cDNA pattern [2]

Example 5

Cluster chr14-45 (Data Set: 019)

(1) Cluster Analysis

1) Cluster Characteristics

[0306] An analysis was performed on 13 sequences of full-length cDNAs subjected to genome mapping onto the cluster chr14-45 (Human genome UCSC hg18 (NCBI Build34) chromosome 14, 104,305,000 bp to 104,335,000 bp) [D-NT2RP8004156.1, BC000479.2, BC084538.1, BX647722.1, BX648205.1, C-BRACE2006105, C-BRHIP2019884, C-PLACE7003657, C-TEST14021482, ENST00000310523, ENST00000349310, M63167.1, NM.sub.--005163.1]. They were classified according to expression pattern difference into 7 kinds, which mainly included the following 2 kinds.

[1] D-NT2RP8004156.1

[2] BC000479.2, BC084538.1, BX648205.1, C-PLACE7003657 (AK122894.1), ENST00000310523, M63167.1, NM.sub.--005163.1

[0307] [1] is a cDNA which was newly acquired and subjected to full-length cDNA sequence analysis by us, having an ORF different from that of [2] registered in an existing public DB.

[0308] [1] had a different ORF region because of its expression from a chromosome region located downstream of the known [2].

[0309] It was found that the ORF regions present in the 2 kinds of cDNA patterns [1] to [2] cause expression starting at different transcription initiation points, from the same chromosome region, resulting in alterations of the amino acid sequences to produce diverse proteins and mRNAs.

2) Characteristics of D-NT2RP8004156.1 ([1]), Which was Newly Acquired and Subjected to Full-Length cDNA Sequence Analysis by Us 019.sub.--[1].sub.--1-N0 (SEQ ID NO:41): The entire nucleic acid sequence region of D-NT2RP8004156.1 019.sub.--[1].sub.--1-NA0 (SEQ ID NO:42): Both the entire nucleic acid sequence region and amino acid sequence of D-NT2RP8004156.1 019.sub.--[1].sub.--1-A0 (SEQ ID NO:43): The entire amino acid sequence region of D-NT2RP8004156.1

[0310] The 1st to 119th bases of D-NT2RP8004156.1 (SEQ ID NO:44) is an exon that is not present in NM.sub.--005163.1, which is registered in an existing public DB and serves as a control, lacking homology to NM.sub.--005163.1.

[0311] With this change, the translation initiation point of D-NT2RP8004156.1 shifts toward the 3' side relative to NM.sub.--005163.1, and the 131st base of D-NT2RP8004156.1 becomes the translation initiation point. For this reason, the N-terminal amino acid sequence shortened by 62 residues compared with NM.sub.--005163.1 (SEQ ID NO:264).

019.sub.--[1].sub.--1-N1 (SEQ ID NO:44): A 119-base insert nucleic acid sequence region of D-NT2RP8004156.1 019.sub.--[1].sub.--1-N2 (SEQ ID NO:45): A 130-base 5'UTR region of an ORF whose translation initiation point is the 131st base of D-NT2RP8004156.1 019.sub.--[1]_C-A1 (SEQ ID NO:264): Amino acid sequence region lacking 62 residues of D-NT2RP8004156.1 present in NM.sub.--005163.1

[0312] With this change, the Pfam motif "PH domain" present at the 6th to 108th amino acids of NM.sub.--005163.1 disappeared in D-NT2RP8004156.1.

3) Expression Specificity Analysis and Design of Primers for Real-Time PCR

[0313] To clearly distinguish between the characteristic regions shown above, and examine the respective expression levels thereof, the following regions were used as detection regions. It seemed possible to compare the expression levels of the individual characteristic regions by comparing the expression levels of the detection regions.

019.sub.--01--A specific region present on the N-terminal side of the cDNA pattern [1]: a translation initiation region of the cDNA pattern [1], which was newly subjected to full-length cDNA sequence analysis by us, being a novel region not registered with an existing public DB .fwdarw.Fragment 019.sub.--01 (SEQ ID NO:48) amplified by Primer019.sub.--01F (SEQ ID NO:46) and Primer019.sub.--01R (SEQ ID NO:47) 019.sub.--02--A transcription initiation point region of [2], which is registered with an existing public DB, serving as a control for comparing [1] .fwdarw.Fragment 019.sub.--02 (SEQ ID NO:51) amplified by Primer019.sub.--02F (SEQ ID NO:49) and Primer01902R (SEQ ID NO:50) 019.sub.--03--A common region shared by all of [1] to [2]: a region common to all patterns, serving for control to compare the overall expression levels of the cDNA pattern [1], which was newly subjected to full-length cDNA sequence analysis by us, and the cDNA pattern [2], which is registered with an existing public DB .fwdarw.Fragment 019.sub.--03 (SEQ ID NO:54) amplified by Primer019.sub.--03F (SEQ ID NO:52) and Primer019.sub.--03R (SEQ ID NO:53)

[0314] By mapping the 5'-terminal sequences of about 1.44 million sequences acquired using the oligocap method onto the human genome sequence, and comparatively analyzing them, the exon regions specific for the respective cDNA patterns [1] to [2] shown above, respectively, were found to be expressed at the following frequencies.

[0315] In the cDNA pattern [1], which was newly acquired and analyzed by us, four 5'-terminal sequences were present, the derivation thereof being NT2 cells treated with retinoic acid (RA) to induce differentiation (NT2RP) for all sequences.

[0316] It was found that in the cDNA pattern [2], which is registered with an existing public DB, eleven 5'-terminal sequences were present: 4 sequences derived from brain tissues and 7 sequences from a plurality of other organs and the like were expressed.

[0317] From this result, it was found that the transcription initiation point of [1] was expressed specifically in NT2 cells after differentiation. From the transcription initiation point of [2], expression in a variety of organs was observed. Hence, it was thought that the mechanism of transcription in this chromosome region might be unique to the nerve cell differentiation stage of NT2 cells after differentiation, with a different transcription initiation point being used.

(2) Analysis of Expression Specificity by Real-Time PCR

[0318] To determine what are the states in which the transcription initiation point used for the expression changes, details of expression levels were analyzed by real-time PCR. The results are shown in Table 4 and Table 5.

TABLE-US-00004 TABLE 4 RQ Score Log.sub.10RQ Score 019_01 019_02 019_03 019_01 019_02 019_03 01 NT2RA(-) 0.2 0.1 0.1 -0.73 -1.02 -1.03 02 NT2RA(+) 24 hr 0.5 0.1 0.1 -0.29 -1.16 -1.15 03 NT2RA(+) 48 hr 0.2 0.1 0.1 -0.71 -1.05 -1.10 04 NT2RA(+) 1 week 1.4 0.1 0.2 0.16 -0.84 -0.75 05 NT2RA(+) 5 weeks 94.2 0.4 0.5 1.97 -0.35 -0.34 06 NT2RA(+) 5 weeks, Inh(+) 4.7 0.4 0.5 0.67 -0.37 -0.32 07 NT2 Neuron 0.0 0.1 0.0 -1.40 -1.03 -1.80 08 Brain, Fetal 1.1 1.5 1.4 0.03 0.17 0.16 09 Brain, whole 0.1 0.6 0.6 -1.06 -0.24 -0.25 10 ALZ Visual Cortex 0.1 0.2 0.2 -1.00 -0.74 -0.72 Occipital 11 Mix, viscus tissues 1.0 1.0 1.0 0.0 0.0 0.0 12 Mix, blood cells and 1.7 0.7 0.4 0.23 -0.15 -0.38 related tissues 13 Mix, tumor tissues 2.2 0.7 0.8 0.35 -0.18 -0.09 14 Mix, normal tissues 1.3 0.9 0.9 0.10 -0.02 -0.04 15 Brain, whole PolyA(+) RNA 0.2 0.4 0.3 -0.75 -0.35 -0.46 16 Brain, hippocampus 0.2 0.4 0.3 -0.81 -0.43 -0.51

TABLE-US-00005 TABLE 5 RQ Score Log.sub.10RQ Score 019_01 019_02 019_03 019_01 019_02 019_03 01 NT2RA(-) 0.1 0.1 0.1 -1.01 -1.01 -1.01 02 NT2RA(+) 24 hr 0.2 0.1 0.1 -0.66 -1.23 -1.11 03 NT2RA(+) 48 hr 0.0 0.1 0.1 -1.66 -1.02 -1.08 04 NT2RA(+) 1 week 0.6 0.2 0.2 -0.22 -0.80 -0.72 05 NT2RA(+) 5 weeks 40.2 0.5 0.5 1.60 -0.32 -0.29 06 NT2RA(+) 5 weeks, Inh(+) 2.0 0.5 0.6 0.30 -0.29 -0.25 07 NT2 Neuron 0.0 0.1 0.0 -1.52 -1.04 -1.80 08 Brain, Fetal 0.4 1.5 1.5 -0.36 0.19 0.17 09 Brain, whole 0.2 0.6 0.6 -0.73 -0.21 -0.22 10 ALZ Visual Cortex 0.0 0.2 0.2 -1.40 -0.72 -0.72 Occipital 11 Mix, viscus tissues 1.0 1.0 1.0 0.0 0.0 0.0 12 Mix, blood cells and 1.1 0.9 0.7 0.03 -0.07 -0.13 related tissues 13 Mix, tumor tissues 0.7 0.6 0.6 -0.17 -0.25 -0.19 14 Mix, normal tissues 0.3 0.9 0.9 -0.59 -0.03 -0.04 15 Brain, whole PolyA(+) RNA 0.1 0.6 0.4 -1.11 -0.25 -0.36 16 Brain, hippocampus 0.1 0.5 0.4 -1.08 -0.29 -0.40

[0319] Expression levels were compared using the 16 samples shown in Example 3, including Brain, hippocampus, Brain, whole, Brain, Fetal, ALZ Visual Cortex Occipital, and NT2 cells at 7 different differentiation stages. The comparison was made using the mixed sample of normal visceral tissues shown in Example 3 (Mix, viscus tissues) as an experimental control.

[0320] The ratio of ORF alteration due to transcription initiation point selectivity as compared between 019.sub.--01 (SEQ ID NO:48) and 019.sub.--02 (SEQ ID NO:51) changed greatly depending on NT2 cell differentiation stage. When compared in detail with respect to NT2 cell differentiation, no major difference was observed between the 2 kinds of transcription initiation points shown by 019.sub.--01 (SEQ ID NO:48) and 019.sub.--02 (SEQ ID NO:51) in undifferentiated NT2 cells NT2RA (-) and NT2RA (+) 48 hr, which represents the initial stage in which retinoic acid was added to induce differentiation (Table 4 and Table 5). However, in NT2RA (+) 1 week, which represents an advanced stage of differentiation, the difference widened; in NT2RA (+) 5 weeks, the ratio of transcription from the downstream transcription initiation point shown by 019.sub.--01 (SEQ ID NO:48) increased considerably (Table 4 and Table 5). However, thereafter in NT2RA (+) 5 weeks, Inh (+), the difference decreased; in NT2% Neuron, on the contrary, the ratio of transcription from the known transcription initiation point shown by 019.sub.--02 (SEQ ID NO:51) increased (Table 4 and Table 5). In other tissues, no major difference was observed.

[0321] These results demonstrated that by comparing the expression of the 5'-terminal region of a newly acquired cDNA region shown by the detection region 019.sub.--01 (sequence No. 019-8) (a region close to the transcription initiation point) 019.sub.--[1].sub.--1-N1 (SEQ ID NO:44), it is possible to use the 5'-terminal region as a differentiation marker for detecting cells in nerve cell differentiation or regeneration stages, particularly in the late stage of nerve differentiation or regeneration. It also seems possible to develop a new drug by means of a compound, antibody, siRNA or the like that targets a region that exhibits specificity.

[0322] The following regions also seem to be useful as differentiation markers for detecting cells in the late stage of nerve differentiation or regeneration.

Upstream sequence 019.sub.--[1].sub.--1-N3 (SEQ ID NO:55), which comprises the 195th to 213th bases undergoing priming by Primer019.sub.--01R (SEQ ID NO:47) in D-NT2RP8004156.1 of the cDNA pattern [1]. Region 019.sub.--01 (SEQ ID NO:48) amplified by Primer019.sub.--01F (SEQ ID NO:46) and Primer019.sub.--01R (SEQ ID NO:47) in the cDNA pattern [1]

Example 6

Cluster chr2-2324 (Data Set: 031)

(1) Cluster Analysis

1) Cluster Characteristics

[0323] An analysis was performed on 7 sequences of full-length cDNAs subjected to genome mapping onto the cluster chr2-2324 (Human genome UCSC hg18 (NCBI Build34) chromosome 2, 65,440,000 bp to 65,580,000 bp) [D-NT2RI3005525.1, D-TRACH3029063.1, AY299090.1, C-HEP03447, C-NT2RP7004925, ENST00000356388, NM.sub.--181784.1]. They were classified according to expression pattern difference into 5 kinds, which mainly included the following 2 kinds.

[1] D-NT2RI3005525.1

[2] AY299090.1, C-NT2RP7004925 (AK056479.1), NM.sub.--181784.1

[0324] [1] is a cDNA which was newly acquired and subjected to full-length cDNA by us, and had a different ORF from [2] registered with an existing public DB.

[0325] [1] had a different ORF region because of its expression from a chromosome region located downstream of the known [2], and also because of the presence of the translation initiation point on a new exon lacking identity to [2].

[0326] It was found that the ORF regions present in the 2 kinds of cDNA patterns [1] to [2] cause expression starting at different transcription initiation points, from the same chromosome region, resulting in alterations of the amino acid sequences to produce diverse proteins and mRNAs.

2) Characteristics of D-NT2RI3005525.1 ([1]), which was Newly Acquired and Subjected to Full-Length cDNA by Us 031.sub.--[1].sub.--1-N0 (SEQ ID NO:56): The entire nucleic acid sequence region of D-NT2RI3005525.1 031.sub.--[1].sub.--1-NA0 (SEQ ID NO:57): Both the entire nucleic acid sequence region and amino acid sequence of D-NT2RI3005525.1 031.sub.--[1].sub.--1-A0 (SEQ ID NO:58): The entire amino acid sequence region of D-NT2RI3005525.1

[0327] The sequence at the 1st to 61st bases of D-NT2RI3005525.1 (SEQ ID NO:59) is a variant incorporating an exon that is not present in NM.sub.--181784.1, which is registered with an existing public DB, and serves for control; because of the presence thereof along with the translation initiation point on the exon inserted, the N-terminal amino acids differed by 6 residues, compared with NM.sub.--181784.1 (SEQ ID NO:60).

031.sub.--[1].sub.--1-N1 (SEQ ID NO:59): 61-base insert nucleic acid sequence region of D-NT2RI3005525.1 031.sub.--[1].sub.--1-A1 (SEQ ID NO:60): 6-residue insert amino acid sequence region of D-NT2RI3005525.1 031.sub.--[1].sub.--1-N2 (SEQ ID NO:61): ORF nucleic acid sequence region in 61-base insert region of D-NT2RI3005525.1 031.sub.--[1].sub.--1-A2 (identical to SEQ ID NO:60): ORF amino acid region related to 61-base insert region of D-NT2RI3005525.1

3) Expression Specificity Analysis and Design of Primer for Real-Time PCR

[0328] To clearly distinguish between the characteristic regions shown above, and examine the respective expression levels thereof, the following regions were used as detection regions. It seemed possible to compare the expression levels of the individual characteristic regions by comparing the expression levels of the detection regions.

031.sub.--01--A specific region present on the N-terminal side of the cDNA pattern [1]: a translation initiation region of the cDNA pattern [1], which was newly subjected to full-length cDNA sequence analysis by us, being a novel region not registered with an existing public DB .fwdarw.Fragment 031.sub.--01 (SEQ ID NO:64) amplified by Primer031.sub.--01F (SEQ ID NO:62) and Primer031.sub.--01R (SEQ ID NO:63) 031.sub.--02--A transcription initiation point region of [2], registered with an existing public DB, serving as a control for comparing [1] .fwdarw.Fragment 031.sub.--02 (SEQ ID NO:67) amplified by Primer031.sub.--02F (SEQ ID NO:65) and Primer031.sub.--02R (SEQ ID NO:66) 031.sub.--03--A common region shared by all of [1] to [2]: a region common to all patterns, serving for control to compare the overall expression levels of the cDNA pattern [1], which was newly subjected to full-length cDNA sequence analysis by us, and the cDNA pattern [2], which is registered with an existing public DB .fwdarw.Fragment 031.sub.--03 (SEQ ID NO:70) amplified by Primer031.sub.--03F (SEQ ID NO:68) and Primer03103R (SEQ ID NO:69)

[0329] By mapping the 5'-terminal sequences of about 1.44 million sequences acquired using the oligocap method onto the human genome sequence, and comparatively analyzing them, the exon regions specific for the cDNA patterns [1] and [2] shown above, respectively, were found to be expressed at the following frequencies.

[0330] In the cDNA pattern [1], which was newly acquired and analyzed by us, twenty-eight 5'-terminal sequences were present, the derivations thereof being Brain, whole for 13 sequences (analytical parameter 59,069), Brain, hippocampus for 8 sequences (analytical parameter 57,918), Brain, amygdala for 5 sequences (analytical parameter 58,640), HDPC (Human dermal papilla cells) for 1 sequence (analytical parameter 8,453), and NT2 cells treated with retinoic acid (RA) to induce differentiation for 5 weeks, and thereafter treated with a growth inhibitor for 2 weeks (NT2RI) for 1 sequence (analytical parameter 32,662).

[0331] In the cDNA pattern [2], which is registered with an existing public DB, thirty-five 5'-terminal sequences were present, the derivations thereof being Brain, whole for 10 sequences (analytical parameter 59,069), Brain, cerebellum for 5 sequences (analytical parameter 82,880), Brain, Fetal for 5 sequences (analytical parameter 47,574), Brain, hippocampus for 3 sequences (analytical parameter 57,918), Trachea for 3 sequences (analytical parameter 52,352), Brain, thalamus for 2 sequences (analytical parameter 53,267), NT2 cells treated with retinoic acid (RA) to induce differentiation (NT2RP) for 2 sequences (analytical parameter 39,242), Thymus for 2 sequences (analytical parameter 70,578), NT2 cells treated with retinoic acid (RA) to induce differentiation for 5 weeks, and thereafter treated with a growth inhibitor for 2 weeks (NT2RI) for 1 sequence (analytical parameter 32,662), Testis for 1 sequence (analytical parameter 90,188), and Uterus for 1 sequence (analytical parameter 49,561).

[0332] From this result, it was found that the transcription initiation point of [1] was expressed abundantly in the brain, particularly in Brain, hippocampus and Brain, amygdala. It was found that the transcription initiation point of [2] was also abundantly expressed in the brain, but expressed in a wider variety of tissues compared with the transcription initiation point of [1]. From this result, it was thought that the mechanism of transcription in this chromosome region might be unique to particular portions of the brain, with a different is transcription initiation point being used.

(2) Analysis of Expression Specificity by Real-Time PCR

[0333] To determine what are the portions and states in which the transcription initiation point used for the expression changes, details of expression levels were analyzed by real-time PCR. The results are shown in Table 6 and Table 7.

TABLE-US-00006 TABLE 6 RQ Score Log.sub.10RQ Score 031_01 031_02 031_03 031_01 031_02 031_03 01 NT2RA(-) 0.0 0.1 0.2 -3.12 -0.85 -0.82 02 NT2RA(+) 24 hr 0.0 0.5 0.8 -2.48 -0.34 -0.09 03 NT2RA(+) 48 hr 0.0 0.4 0.9 -2.48 -0.41 -0.03 04 NT2RA(+) 1 week 0.0 0.2 0.4 -2.32 -0.81 -0.43 05 NT2RA(+) 5 weeks 0.9 0.4 0.4 -0.03 -0.45 -0.39 06 NT2RA(+) 5 weeks, Inh(+) 2.3 0.4 0.5 0.36 -0.37 -0.29 07 NT2 Neuron 0.1 0.0 0.1 -1.00 -1.51 -0.83 08 Brain, Fetal 0.5 1.7 2.1 -0.33 0.22 0.32 09 Brain, whole 15.4 1.4 2.1 1.19 0.16 0.31 10 ALZ Visual Cortex 8.1 0.4 0.6 0.91 -0.44 -0.20 Occipital 11 Mix, viscus tissues 1.0 1.0 1.0 0.0 0.0 0.0 12 Mix, blood cells and 0.6 0.7 0.9 -0.21 -0.17 -0.06 related tissues 13 Mix, tumor tissues 0.5 0.4 0.5 -0.31 -0.35 -0.29 14 Mix, normal tissues 0.9 0.9 1.2 -0.04 -0.04 0.08 15 Brain, whole PolyA(+) RNA 4.2 0.2 0.3 0.63 -0.71 -0.59 16 Brain, hippocampus 2.8 0.1 0.2 0.44 -0.87 -0.74 17 Brain, cerebellum 0.0 0.2 0.3 -1.61 -0.65 -0.55 18 Brain, amygdala 3.1 0.1 0.2 0.49 -0.95 -0.75 19 Brain, caudate nucleus 0.2 0.1 0.1 -0.78 -1.00 -0.88 20 Brain, corpus callosum 0.2 0.1 0.1 -0.61 -1.10 -1.02 21 Brain, substantia nigra 0.2 0.1 0.2 -0.72 -0.85 -0.78 22 Brain, thalamus 0.2 0.1 0.1 -0.75 -1.16 -1.05 23 Brain, subthalamic nucleus 0.1 0.1 0.1 -1.16 -1.24 -0.96

TABLE-US-00007 TABLE 7 RQ Score Log.sub.10RQ Score 031_01 031_02 031_03 031_01 031_02 031_03 01 Brain, Fetal 0.3 1.9 1.8 -0.46 0.28 0.27 02 Brain, whole 10.2 1.3 1.8 1.01 0.10 0.26 03 ALZ Visual Cortex 5.6 0.4 0.6 0.75 -0.44 -0.21 Occipital 04 Mix, viscus tissues 1.0 1.0 1.0 0.0 0.0 0.0 05 Mix, blood cells and 0.5 0.8 0.9 -0.31 -0.11 -0.03 related tissues 06 Mix, tumor tissues 0.8 0.7 0.8 -0.11 -0.17 -0.08 07 Mix, normal tissues 0.8 1.1 1.3 -0.11 0.05 0.13 08 Brain, whole PolyA(+) RNA 3.0 0.1 0.3 0.48 -0.82 -0.57 09 Brain, hippocampus 2.1 0.1 0.2 0.32 -0.88 -0.72 10 Brain, cerebellum 0.0 0.1 0.2 -1.96 -0.87 -0.80 11 Brain, amygdala 2.3 0.1 0.2 0.37 -0.97 -0.75 12 Brain, caudate nucleus 0.1 0.1 0.1 -0.96 -1.06 -0.96 13 Brain, corpus callosum 0.2 0.1 0.1 -0.82 -1.16 -1.09 14 Brain, substantia nigra 0.1 0.1 0.1 -0.99 -1.01 -0.95 15 Brain, thalamus 0.1 0.0 0.1 -1.05 -1.34 -1.23 16 Brain, subthalamic nucleus 0.0 0.1 0.1 -1.37 -1.28 -1.03

[0334] Expression levels were compared using the 23 kinds of samples shown in Example 3, including 11 kinds of brain tissues and NT2 cells at 7 different differentiation stages. The comparison was made using the mixed sample of normal visceral tissues shown in Example 3 (Mix, viscus tissues) as an experimental control.

[0335] The ratio of ORF alteration due to transcription initiation point selectivity as compared between 031.sub.--01 (SEQ ID NO:64) and 031.sub.--02 (SEQ ID NO:67) changed greatly among the following brain portions and NT2 cell differentiation stages.

[0336] In the brain, particularly in Brain, hippocampus and Brain, amygdala, the transcription from the downstream transcription initiation point shown by 031.sub.--01 (SEQ ID NO:64) was abundant (Table 6 and Table 7). No major difference was observed among the other portions of the brain.

[0337] Furthermore, when compared in detail with respect to NT2 cell differentiation, the expression of the mRNA transcribed from the transcription initiation point shown by 031.sub.--02 (SEQ ID NO:67), registered with an existing public DB, was abundant in undifferentiated NT2 cells NT2RA (-) and NT2RA (+) 1 week, which represents the initial stage in which retinoic acid was added to induce differentiation; however, in NT2RA (+) 5 weeks, predicted to be rich in nerve cells after differentiation, the expression level reversed; in the subsequent stages of NT2RA (+) 5 weeks, Inh (+), and NT2 Neuron, the expression of the mRNA transcribed from the downstream transcription initiation point shown by 031.sub.--01 (SEQ ID NO:64) was abundant (Table 6 and Table 7).

[0338] These results demonstrated that by comparing the expression of the 5'-terminal region 031.sub.--[1]-N1 (SEQ ID NO:59) of a newly acquired cDNA shown by the detection region 031.sub.--01 (SEQ ID NO:64) (a region close to the transcription initiation point), it is possible to use the 5'-terminal region as a marker specific for the brain, particularly for nerve-rich portions such as Brain, hippocampus (nerve differentiation, nerve regeneration marker and the like), and as a differentiation marker for detecting cells in nerve cell differentiation or regeneration stages, particularly those that have differentiated into a nerve. It also seems possible to develop a new drug by means of a compound, antibody, siRNA or the like that targets a region that exhibits specificity.

[0339] The following regions also seem to be useful as markers specific to the brain, particularly to the nerve-rich portions such as Brain, hippocampus (nerve differentiation, nerve regeneration marker and the like), and as differentiation markers for detecting nerve cells in differentiation or regeneration stages, particularly those that have differentiated into nerves.

Upstream sequence 031.sub.--[1].sub.--1-N3 (SEQ ID NO:71), which comprises the 80th to 101st bases undergoing priming by Primer031.sub.--01R (SEQ ID NO:63) in D-NT2RI3005525.1 of the cDNA pattern [1]. Region 031.sub.--01 (SEQ ID NO:64) amplified by Primer031.sub.--01F (SEQ ID NO:62) and Primer031.sub.--01R (SEQ ID NO:63) in the cDNA pattern [1]

Example 7

Cluster chr7-2007 (Data Set: 067)

(1) Cluster Analysis

1) Cluster Characteristics

[0340] An analysis was performed on 10 sequences of full-length cDNAs subjected to genome mapping onto the cluster chr7-2007 (Human genome UCSC hg18 (NCBI Build34) chromosome 7, 26,400,000 bp to 26,850,000 bp) [D-NT2RP8004592.1, D-NT2RP7010844.1, Z-NT2RP7020087-01, BC002893.2, BC036044.1, ENST00000338865, ENST00000345317, NM.sub.--003930.3, XM.sub.--498174.1, XM.sub.--499404.1]. They were classified according to expression pattern difference into 5 kinds, which mainly included the following 2 kinds.

[1] D-NT2RP8004592.1

[2] BC002893.2, BC036044.1, NM.sub.--003930.3

[0341] [1] is a cDNA which was newly acquired and subjected to full-length cDNA sequence analysis by us, having a different ORF from [2], which is registered with an existing public DB.

[0342] [1] had a different ORF region from [2] because of its expression from a chromosome region located downstream of the known [2], and hence a shift of the translation initiation point toward the C-terminal side.

[0343] It was found that the ORF regions present in the 2 kinds of cDNA patterns [1] and [2] cause expression starting at different transcription initiation points, from the same chromosome region, resulting in alterations of the amino acid sequences to produce diverse proteins and mRNAs.

2) Characteristics of D-NT2RP8004592.1 ([1]), which was Newly Acquired and Subjected to Full-Length cDNA Sequence Analysis by Us 067.sub.--[1].sub.--1-N0 (SEQ ID NO:72): The entire nucleic acid sequence region of D-NT2RP8004592.1 067.sub.--[1].sub.--1-NA0 (SEQ ID NO:73): Both the entire nucleic acid sequence region and amino acid sequence of D-NT2RP8004592.1 067.sub.--[1].sub.--1-A0 (SEQ ID NO:74): The entire amino acid sequence region of D-NT2RP8004592.1

[0344] The exon at the 1st to 169th bases of D-NT2RP8004592.1 (SEQ ID NO:75) (1st exon) is an exon that is not present in NM.sub.--003930.3, which is registered with an existing public DB, and serves for control, lacking homology thereto. The exon at the 1st to 359th bases of NM.sub.--003930.3 (first exon) is an exon that is not present in D-NT2RP8004592.1, lacking homology thereto. The second exon and beyond are present commonly in both cDNAs. The translation termination point of the ORF of NM.sub.--003930.3 is the same as that of D-NT2RP8004592.1; however, because the translation initiation point is present on the 1st exon, which is not present in D-NT2RP8004592.1, the N-terminus of the ORF differed. Because the translation initiation point of D-NT2RP8004592.1 is present on the 6th exon, which is shared by NM.sub.--003930.3, the amino acid sequence on the N-terminal side shortened by 172 residues, compared with NM.sub.--003930.3 (SEQ ID NO:265).

067.sub.--[1].sub.--1-N 1 (SEQ ID NO:75): A 169-base insert nucleic acid sequence region of D-NT2RP8004592.1 067.sub.--[1].sub.--1-N 2 (SEQ ID NO:76): A 619-base 5'UTR region of an ORF whose translation initiation point is the 620th base of D-NT2RP8004592.1 067.sub.--[1]_C-A1 (SEQ ID NO:265): A 172-residue deletion amino acid sequence region of D-NT2RP8004592.1 present in NM.sub.--003930.3

3) Expression Specificity Analysis and Design of Primers for Real-Time PCR

[0345] To clearly distinguish between the characteristic regions shown above, and examine the respective expression levels thereof, the following regions were used as detection regions. It seemed possible to compare the expression levels of the individual characteristic regions by comparing the expression levels of the detection regions.

067.sub.--01--A specific region present on the N-terminal side of the cDNA pattern [1]: a translation initiation region of the cDNA pattern [1], which was newly subjected to full-length cDNA sequence analysis by us, being a novel region not registered with an existing public DB .fwdarw.Fragment 067.sub.--01 (SEQ ID NO:79) amplified by Primer067.sub.--01F (SEQ ID NO:77) and Primer067.sub.--01R (SEQ ID NO:78) 067.sub.--03--Transcription initiation point region of [2], which is registered with an existing public DB, serving as a control for comparing [1] .fwdarw.Fragment 067.sub.--03 (SEQ ID NO:82) amplified by Primer067.sub.--03F (SEQ ID NO:80) and Primer067.sub.--03R (SEQ ID NO:81) 067.sub.--04--A common region shared by all of [1] to [2]: a region common to all patterns, serving for control to compare the overall expression levels of the cDNA pattern [1], which was newly subjected to full-length cDNA sequence analysis by us, and the cDNA pattern [2], which is registered with an existing public DB .fwdarw.Fragment 067.sub.--04 (SEQ ID NO:85) amplified by Primer067.sub.--04F (SEQ ID NO:83) and Primer067.sub.--04R (SEQ ID NO:84)

[0346] By mapping the 5'-terminal sequences of about 1.44 million sequences acquired using the oligocap method onto the human genome sequence, and comparatively analyzing them, the exon regions specific for the cDNA patterns [1] to [2] shown above, respectively, were found to be expressed at the following frequencies.

[0347] In the cDNA pattern [1], which was newly acquired and analyzed by us, eighteen 5'-terminal sequences were present, the derivations thereof being NT2 cells treated with retinoic acid (RA) to induce differentiation (NR2RP) for 16 sequences (analytical parameter 39,242), and NT2 cells treated with retinoic acid (RA) to induce differentiation for 5 weeks, and thereafter treated with a growth inhibitor for 2 weeks (NT2RI) for 2 sequences (analytical parameter 32,662); all were derived from NT2 cells after differentiation.

[0348] In the cDNA pattern [2], which is registered with an existing public DB, one hundred twenty-two (122) 5'-terminal sequences were present, the derivations thereof being NT2 cells for 45 sequences, brain tissues for 25 sequences, and others for 47 sequences.

[0349] From this result, it was found that the transcription initiation point of [1] was expressed specifically in NT2 cells after differentiation. From the transcription initiation point of [2], expression was observed in NT2 cells, brain tissues and various other tissues. Hence, it was suggested that in this chromosome region, the mechanism of transcription may differ, and may result in different transcription initiation points being used only at the nerve cell differentiation states of NT2 cells after differentiation.

(2) Analysis of Expression Specificity by Real-Time PCR

[0350] To determine what are the states in which the transcription initiation point used for the expression changes, details of expression levels were analyzed by real-time PCR. The results are shown in Table 8 and Table 9.

TABLE-US-00008 TABLE 8 RQ Score Log.sub.10RQ Score 067_01 067_03 067_04 067_01 067_03 067_04 01 NT2RA(-) 0.0 0.0 0.0 -1.58 -2.04 -1.79 02 NT2RA(+) 24 hr 3.1 0.5 0.6 0.49 -0.29 -0.19 03 NT2RA(+) 48 hr 8.6 1.6 1.5 0.93 0.21 0.19 04 NT2RA(+) 1 week 21.6 1.5 1.9 1.33 0.16 0.27 05 NT2RA(+) 5 weeks 103.8 3.3 11.3 2.02 0.52 1.05 06 NT2RA(+) 5 weeks, Inh(+) 3.2 1.2 2.6 0.51 0.07 0.41 07 NT2 Neuron 30.3 0.7 0.4 1.48 -0.16 -0.37 08 Brain, Fetal 0.1 0.2 0.3 -0.95 -0.66 -0.51 09 Brain, whole 0.9 0.6 1.0 -0.05 -0.19 0.01 10 ALZ Visual Cortex 0.4 0.3 0.7 -0.36 -0.51 -0.17 Occipital 11 Mix, viscus tissues 1.0 1.0 1.0 0.0 0.0 0.0 12 Mix, blood cells and 2.3 1.9 2.5 0.36 0.27 0.40 related tissues 13 Mix, tumor tissues 0.7 0.3 0.3 -0.14 -0.46 -0.49 14 Mix, normal tissues 2.3 1.0 1.2 0.37 -0.01 0.07 15 Brain, whole PolyA(+) RNA 0.2 0.2 0.5 -0.71 -0.66 -0.29 16 Brain, hippocampus 0.1 0.2 0.4 -0.94 -0.75 -0.35

TABLE-US-00009 TABLE 9 RQ Score Log.sub.10RQ Score 067_01 067_03 067_04 067_01 067_03 067_04 01 NT2RA(-) 0.0 0.0 0.0 -1.53 -2.04 -1.78 02 NT2RA(+) 24 hr 3.2 0.6 0.8 0.50 -0.23 -0.11 03 NT2RA(+) 48 hr 10.6 1.6 1.7 1.03 0.21 0.22 04 NT2RA(+) 1 week 25.0 1.5 1.9 1.40 0.18 0.28 05 NT2RA(+) 5 weeks 125.3 3.7 13.6 2.10 0.57 1.13 06 NT2RA(+) 5 weeks, Inh(+) 4.4 1.3 3.4 0.64 0.11 0.53 07 NT2 Neuron 25.5 0.6 0.4 1.41 -0.19 -0.37 08 Brain, Fetal 0.2 0.2 0.3 -0.63 -0.64 -0.48 09 Brain, whole 1.0 0.7 1.2 -0.01 -0.16 0.10 10 ALZ Visual Cortex 0.4 0.3 0.7 -0.35 -0.47 -0.15 Occipital 11 Mix, viscus tissues 1.0 1.0 1.0 0.0 0.0 0.0 12 Mix, blood cells and 2.1 2.1 3.2 0.32 0.32 0.50 related tissues 13 Mix, tumor tissues 0.4 0.3 0.4 -0.45 -0.48 -0.42 14 Mix, normal tissues 2.7 0.9 1.2 0.44 -0.02 0.08 15 Brain, whole PolyA(+) RNA 0.2 0.3 0.7 -0.60 -0.54 -0.16 16 Brain, hippocampus 0.1 0.2 0.6 -0.88 -0.62 -0.22

[0351] Expression levels were compared using the 16 samples shown in Example 3, including Brain, hippocampus, Brain, whole, Brain, Fetal, Alzheimer patient cerebral cortex (ALZ Visual Cortex Occipital), and NT2 cells at 7 different differentiation stages and the like. The comparison was made using the mixed sample of normal visceral tissues shown in Example 3 (Mix, viscus tissues) as an experimental control.

[0352] The ratio of ORF alteration due to transcription initiation point selectivity as compared between 067.sub.--01 (SEQ ID NO:79) and 067.sub.--03 (SEQ ID NO:82) changed greatly depending on NT2 cell differentiation stage. When compared in detail with respect to NT2 cell differentiation, the ratio of the transcription from the transcription initiation point shown by 067.sub.--01 (SEQ ID NO:79) was higher than that from the transcription initiation point shown by 067.sub.--03 (SEQ ID NO:82) in NT2RA (+) 1 week to NT2RA (+) 5 weeks, advanced stages of differentiation, compared with undifferentiated NT2 cells NT2RA (-) and NT2RA (+) 48 hr, which represents the initial stage in which retinoic acid was added to induce differentiation (Table 8 and Table 9). Subsequently, in NT2RA (+) 5 weeks, Inh (+), the difference narrowed, but in NT2 Neuron, the ratio of transcription represented by 067.sub.--01 (SEQ ID NO:79) increased again (Table 8 and Table 9).

[0353] These results demonstrated that by comparing the expression of the 5'-terminal region (a region close to the transcription initiation point) 067.sub.--[1]-N1 (SEQ ID NO:75) of a newly acquired cDNA shown by the detection region 067.sub.--01 (SEQ ID NO:79), it is possible to use the 5'-terminal region as a differentiation marker for detecting cells in nerve cell differentiation or regeneration stages, particularly those that have differentiated into a nerve. It also seems possible to develop a new drug by means of a compound, antibody, siRNA or the like that targets a region that exhibits specificity.

[0354] The following regions also seem to be useful as differentiation markers for detecting nerve cells in differentiation or regeneration stages, particularly those that have differentiated into nerves.

Upstream sequence 067.sub.--[1].sub.--1-N3 (SEQ ID NO:86), which comprises the 65th to 84th bases undergoing priming by Primer067.sub.--01R (SEQ ID NO:78) in D-NT2RP8004592.1 of the cDNA pattern [1]. Region 067.sub.--01 (SEQ ID NO:79) amplified by Primer067.sub.--01F (SEQ ID NO:77) and Primer067.sub.--01R (SEQ ID NO:78) in the cDNA pattern [1].

Example 8

Cluster chrX-900 (Data Set: 122)

(1) Cluster Analysis

1) Cluster Characteristics

[0355] An analysis was performed on 7 full-length cDNAs subjected to genome mapping onto the cluster chrX-900 (Human genome UCSC hg18 (NCBI Build34) chromosome X, 43,380,000 bp to 43,500,000 bp) [D-NT2RI2014164.1, D-BRAMY2029564.1, D-BRAMY2029564.1, BC022494.1, ENST00000265833, M69177.1, NM.sub.--000898.3]. They were classified according to expression pattern difference into 4 kinds, which mainly included the following 3 kinds.

[1] D-NT2RI2014164.1

[2] D-BRAMY2029564.1

[3] BC022494.1, ENST00000265833, M69177.1, NM.sub.--000898.3

[0356] [1] is a cDNA which was newly acquired and subjected to full-length cDNA sequence analysis by us, and had a different ORF from that of [3], which is registered with an existing public DB, because of the expression thereof from a chromosome region located downstream of the known [3].

[0357] [2] is a cDNA which was newly acquired and subjected to full-length cDNA sequence analysis by us, having a different ORF from that of the known [3] because of the insertion of an exon different from the other patterns in the ORF region [3].

[0358] It was found that the ORF regions present in the 3 kinds of cDNA patterns [1] to [3] cause expression starting at different transcription initiation points, from the same chromosome region, and have different splice patterns, such as exon insertions, resulting in alterations of the amino acid sequences to produce diverse proteins and mRNAs.

2) Characteristics of D-NT2RI2014164.1 ([1]), which was Newly Acquired and Subjected to Full-Length cDNA Sequence Analysis by Us 122.sub.--[1].sub.--1-N0 (SEQ ID NO:87): The entire nucleic acid sequence region of D-NT2RI2014164.1 122.sub.--[1].sub.--1-NA0 (SEQ ID NO:88): Both the entire nucleic acid sequence region and amino acid sequence of D-NT2RI2014164.1 122.sub.--[1].sub.--1-A0 (SEQ ID NO:89): The entire amino acid sequence region of D-NT2RI2014164.1

[0359] The sequence at the 1st to 156th bases of D-NT2RI2014164.1 (SEQ ID NO:90) is an exon that is not present in NM.sub.--000898.3, which is registered with an existing public DB, and serves for control, lacking homology to NM.sub.--000898.3. With this change, the translation initiation point of D-NT2RI2014164.1 shifts toward the 3' side relative to NM.sub.--000898.3, and the 162nd base of D-NT2RI2014164.1 becomes the translation initiation point. For this reason, the amino acid sequence shortened by 16 residues, compared with NM.sub.--000898.3 (SEQ ID NO:266).

[0360] The 98-base exon present at the 1,274th to 1,371st bases of NM.sub.--000898.3 (SEQ ID NO:95) is lacked and not present in the region at the 1,250th to 1,251st bases of D-NT2RI2014164.1 (SEQ ID NO:92).

[0361] With this change, because of a translation frame change to cause the termination of the ORF at a stop codon different from that of NM.sub.--000898.3, the C-terminal amino acids differed by 48 residues, compared with NM.sub.--000898.3 (SEQ ID NO:93). 122.sub.--[1].sub.--1-N1 (SEQ ID NO:90): A 156-base insert nucleic acid sequence region of D-NT2RI2014164.1

122.sub.--[1].sub.--1-N2 (SEQ ID NO:91): A 161-base 5'UTR region of an ORF whose translation initiation point is the 162nd base of D-NT2RI2014164.1 122.sub.--[1].sub.--1-N3 (SEQ ID NO:92): A deletion nucleic acid sequence region of D-NT2RI2014164.1 122.sub.--[1].sub.--1-A1 (SEQ ID NO:93): Amino acid sequence region 122.sub.--[1].sub.--1-N4 altered as a result of deletion of D-NT2RI2014164.1 (identical to SEQ ID NO:92): an ORF nucleic acid region in the deletion region of D-NT2RI2014164.1 122.sub.--[1].sub.--1-A2 (SEQ ID NO:94): An ORF amino acid sequence region related to the deletion region of D-NT2RI2014164.1 122.sub.--[1]_C-N1 (SEQ ID NO:95): A 98-base exon nucleic acid sequence present at the 1,274th to 1,371th bases of NM.sub.--000898.3 inserted into the region at the 1,250th to 1,251st bases of D-NT2RI2014164.1 122.sub.--[1]_C-A1 (SEQ ID NO:96): A 33-residue amino acid sequence related to the 98-base exon nucleic acid sequence present at the 1,274th to 1,371st bases of NM.sub.--000898.3 inserted into the region at the 1,250th to 1,251st bases of D-NT2RI2014164.1 122.sub.--[1]_C-A2 (SEQ ID NO:266): A 16-residue deletion amino acid sequence region of D-NT2RI2014164.1 present in NM.sub.--000898.3 3) Characteristics of D-BRAMY2029564.1 ([2]), which was Newly Acquired and Subjected to Full-Length cDNA Sequence Analysis by Us 122.sub.--[2].sub.--1-N0 (SEQ ID NO:97): The entire nucleic acid sequence region of D-BRAMY2029564.1 122.sub.--[2].sub.--1-NA0 (SEQ ID NO:98): Both the entire nucleic acid sequence region and amino acid sequence of D-BRAMY2029564.1 122.sub.--[2].sub.--1-A0 (SEQ ID NO:99): The entire amino acid sequence region of D-BRAMY2029564.1

[0362] The 90th to 140th bases of D-BRAMY2029564.1 (SEQ ID NO:100) is an exon that is not present in NM.sub.--000898.3, which is registered with an existing public DB, and serves for control, lacking homology to NM.sub.--000898.3. With this change, the translation initiation point of D-BRAMY2029564.1 shifts toward the 3' side, compared with NM.sub.--000898.3, and the 143rd base of D-BRAMY2029564.1 becomes a translation initiation point. For this reason, the amino acid sequence shortened by 16 residues, compared with NM.sub.--000898.3 (identical to SEQ ID NO:266).

122.sub.--[2].sub.--1-N1 (SEQ ID NO:100): A 43-base insert nucleic acid sequence region of D-BRAMY2029564.1 122.sub.--[2].sub.--1-N2 (SEQ ID NO:101): A 142-base 5'UTR region of an ORF whose translation initiation point is the 143rd base of D-BRAMY2029564.1 122.sub.--[2]_C-A1 (identical to SEQ ID NO:266): A 16-residue deletion amino acid sequence region of D-BRAMY2029564.1 present in NM.sub.--000898.3

4) Expression Specificity Analysis and Design of Primers for Real-Time PCR

[0363] To clearly distinguish between the characteristic regions shown above, and examine the respective expression levels thereof, the following regions were used as detection regions. It seemed possible to compare the expression levels of the individual characteristic regions by comparing the expression levels of the detection regions.

122.sub.--01--A specific region present on the N-terminal side of the cDNA pattern [1]: a translation initiation region of the cDNA pattern [1], which was newly subjected to full-length cDNA sequence analysis by us, being a novel region not registered with an existing public DB .fwdarw.Fragment 122.sub.--01 (SEQ ID NO:104) amplified by Primer122.sub.--01F (SEQ ID NO:102) and Primer122.sub.--01R (SEQ ID NO:103) 122.sub.--02--A region specifically extracted by means of the sequence information on regions of the exon insertion of cDNA pattern [2]: an ORF-altering exon insert region in the cDNA pattern [2], which was newly subjected to full-length cDNA sequence analysis by us .fwdarw.Fragment 122.sub.--02 (SEQ ID NO:107) amplified by Primer122.sub.--02F (SEQ ID NO:105) and Primer122.sub.--02R (SEQ ID NO:106) 122.sub.--03--A transcription initiation point region of [3], which is registered with an existing public DB, serving as a control for comparing [1] and [2] .fwdarw.Fragment 122.sub.--03 (SEQ ID NO:110) amplified by Primer122.sub.--03F (SEQ ID NO:108) and Primer122.sub.--03R (SEQ ID NO:109) 122.sub.--04--A common region shared by all of [1] to [3]: a region common to all patterns, serving for control to compare the overall expression levels of the cDNA patterns [1] and [2], which were newly subjected to full-length cDNA sequence analysis by us, and the cDNA pattern [3], which is registered with an existing public DB .fwdarw.Fragment 122.sub.--04 (SEQ ID NO:113) amplified by Primer122.sub.--04F (SEQ ID NO:111) and Primer122.sub.--04R (SEQ ID NO:112)

[0364] By mapping the 5'-terminal sequences of about 1.44 million sequences acquired using the oligocap method onto the human genome sequence, and comparatively analyzing them, the exon regions specific to the cDNA patterns [1] to [3] shown above, respectively, were found to be expressed at the following frequencies.

[0365] In the cDNA pattern [1], which was newly acquired and analyzed by us, four 5'-terminal sequences were present, the derivations thereof being NT2 cells treated with retinoic acid (RA) and treated with a growth inhibitor to induce nerve differentiation, followed by nerve concentration and recovery (NT2NE) for 2 sequences (analytical parameter 16,337), and NT2 cells treated with retinoic acid (RA) to induce differentiation for 5 weeks, and thereafter treated with a growth inhibitor for 2 weeks (NT2RI) for 2 sequences (analytical parameter 32,662).

[0366] In the cDNA pattern [2], which was newly acquired and analyzed by us, two 5'-terminal sequences were present, the derivation thereof being Brain, amygdala for the 2 sequences (analytical parameter 58,640).

[0367] In the cDNA pattern [3], which is registered with an existing public DB, fifty-nine 5'-terminal sequences were present, the derivations thereof being Uterus for 11 sequence (analytical parameter 49,561), brain tissues for 19 sequences, and a variety of other tissues for the other sequences.

[0368] From this result, it was found that the transcription initiation point of [1] was abundantly expressed in differentiated NT2 cells. It was also found that the exon insertion pattern [2] was abundantly expressed in the brain. The transcription initiation point of [3] was expressed in various tissues. Hence, it was thought that the mechanism of transcription or splice pattern in this chromosome region might be unique to particular tissues such as the brain and nerve cells after differentiation, to alter amino acids, with a selection mechanism arising for mRNA pattern changes resulting in the expression of different proteins.

(2) Analysis of Expression Specificity by Real-Time PCR

[0369] To detect protein expression diversity changes due to transcription initiation point or exon selectivity among different tissues, details of expression levels were analyzed by real-time PCR. The results are shown in Table 10 and Table 11.

TABLE-US-00010 TABLE 10 RQ Score Log.sub.10RQ Score 122_01 122_02 122_03 122_04 122_01 122_02 122_03 122_04 01 NT2RA(-) 0.0 0.0 0.0 0.0 -1.89 -1.37 -1.82 -1.89 02 NT2RA(+) 24 hr 0.3 0.1 0.0 0.0 -0.59 -0.99 -2.55 -2.85 03 NT2RA(+) 48 hr 1.3 0.6 0.0 0.0 0.11 -0.25 -2.28 -2.58 04 NT2RA(+) 1 week 3.4 1.3 0.1 0.0 0.54 0.10 -1.16 -1.65 05 NT2RA(+) 5 weeks 0.3 0.2 0.1 0.1 -0.51 -0.72 -1.00 -1.09 06 NT2RA(+) 5 weeks, Inh(+) 0.5 0.3 0.2 0.2 -0.28 -0.59 -0.61 -0.69 07 NT2 Neuron 5.1 0.6 0.0 0.0 0.71 -0.19 -1.34 -2.21 08 Brain, Fetal 0.6 1.7 0.4 0.2 -0.19 0.22 -0.43 -0.73 09 Brain, whole 2.3 13.4 1.1 0.5 0.36 1.13 0.02 -0.26 10 ALZ Visual Cortex 1.0 6.5 0.9 0.4 -0.01 0.82 -0.07 -0.42 Occipital 11 Mix, viscus tissues 1.0 1.0 1.0 1.0 0.0 0.0 0.0 0.0 12 Mix, blood cells and 1.1 2.1 1.1 0.7 0.06 0.33 0.03 -0.13 related tissues 13 Mix, tumor tissues 0.5 0.2 0.2 0.3 -0.33 -0.61 -0.67 -0.53 14 Mix, normal tissues 3.7 4.6 1.7 1.3 0.57 0.67 0.23 0.12 15 Brain, whole PolyA(+) RNA 0.3 7.2 0.7 0.3 -0.48 0.86 -0.17 -0.48 16 Brain, hippocampus 0.4 4.6 0.9 0.5 -0.44 0.66 -0.05 -0.35 17 Brain, cerebellum 0.2 2.9 0.5 0.2 -0.81 0.47 -0.31 -0.68 18 Brain, amygdala 0.5 4.2 1.0 0.5 -0.32 0.62 0.00 -0.29 19 Brain, caudate nucleus 0.4 4.5 0.9 0.7 -0.35 0.66 -0.06 -0.17 20 Brain, corpus callosum 0.2 0.6 1.1 0.6 -0.64 -0.20 0.05 -0.19 21 Brain, substantia nigra 0.4 2.2 1.1 0.6 -0.44 0.35 0.02 -0.23 22 Brain, thalamus 0.2 4.0 0.6 0.3 -0.76 0.60 -0.23 -0.48 23 Brain, subthalamic nucleus 0.1 0.8 0.8 0.4 -1.12 -0.09 -0.07 -0.43

TABLE-US-00011 TABLE 11 RQ Score Log.sub.10RQ Score 122_01 122_02 122_03 122_04 122_01 122_02 122_03 122_04 01 NT2RA(-) 0.0 0.0 0.0 0.0 -1.68 -1.42 -1.85 -1.83 02 NT2RA(+) 24 hr 0.8 0.2 0.0 0.0 -0.08 -0.82 -2.32 -2.79 03 NT2RA(+) 48 hr 3.4 0.7 0.0 0.0 0.54 -0.15 -2.32 -2.70 04 NT2RA(+) 1 week 8.5 2.3 0.1 0.0 0.93 0.36 -1.23 -1.65 05 NT2RA(+) 5 weeks 0.8 0.3 0.1 0.1 -0.11 -0.52 -0.98 -1.15 06 NT2RA(+) 5 weeks, Inh(+) 1.4 0.5 0.3 0.2 0.16 -0.32 -0.55 -0.62 07 NT2 Neuron 14.1 0.7 0.0 0.0 1.15 -0.18 -1.36 -2.21 08 Brain, Fetal 1.6 2.7 0.4 0.2 0.21 0.43 -0.45 -0.75 09 Brain, whole 7.5 19.4 1.4 0.6 0.87 1.29 0.13 -0.21 10 ALZ Visual Cortex 3.0 10.9 1.0 0.4 0.48 1.04 -0.02 -0.40 Occipital 11 Mix, viscus tissues 1.0 1.0 1.0 1.0 0.0 0.0 0.0 0.0 12 Mix, blood cells and 1.3 4.0 1.0 0.4 0.11 0.60 0.01 -0.42 related tissues 13 Mix, tumor tissues 1.2 0.5 0.2 0.2 0.08 -0.34 -0.64 -0.74 14 Mix, normal tissues 5.0 11.8 2.0 1.8 0.70 1.07 0.30 0.25 15 Brain, whole PolyA(+) RNA 1.1 12.0 0.7 0.4 0.04 1.08 -0.13 -0.45 16 Brain, hippocampus 1.2 8.0 1.0 0.5 0.06 0.90 -0.01 -0.30 17 Brain, cerebellum 0.4 4.0 0.5 0.2 -0.43 0.60 -0.30 -0.69 18 Brain, amygdala 0.9 5.6 0.9 0.5 -0.03 0.75 -0.03 -0.31 19 Brain, caudate nucleus 1.1 6.6 1.1 0.5 0.03 0.82 0.05 -0.27 20 Brain, corpus callosum 0.5 1.1 1.1 0.6 -0.26 0.04 0.04 -0.21 21 Brain, substantia nigra 0.8 2.6 0.7 0.4 -0.10 0.41 -0.19 -0.39 22 Brain, thalamus 0.4 5.2 0.5 0.3 -0.35 0.72 -0.32 -0.58 23 Brain, subthalamic nucleus 0.2 0.9 0.6 0.3 -0.77 -0.06 -0.25 -0.57

[0370] Expression levels were compared using the 23 kinds of samples shown in Example 3, including 11 kinds of brain tissues and NT2 cells at 7 different differentiation stages. The comparison was made using the mixed sample of normal visceral tissues shown in Example 3 (Mix, viscus tissues) as an experimental control.

[0371] The ratio of ORF alteration due to transcription initiation point selectivity and exon selectivity as compared among 122.sub.--01 (SEQ ID NO:104), 122.sub.--02 (SEQ ID NO:107) and 122.sub.--03 (SEQ ID NO:110) changed greatly among the following differentiation stages of the brain and NT2 cells.

[0372] In all portions of the brain, the expression in the pattern of insertion of the exon shown by 122.sub.--02 (SEQ ID NO:107) was more abundant than 122.sub.--03 (SEQ ID NO:110) (Table 10 and Table 11).

[0373] For the downstream transcription initiation point shown by 122.sub.--01 (SEQ ID NO:104), it was found that the expression level varied greatly among the differentiation stages of NT2 cells. When compared in detail with respect to NT2 cell differentiation, it was found that the expression level of the pattern with an insertion was the same as that of the pattern without an insertion at the stage of undifferentiated NT2 cells NT2RA (-); however, in initial stages of differentiation such as NT2RA (+) 24 hr, NT2RA (+) 48 hr, and NT2RA (+) 1 week, which represent the initial stage in which retinoic acid was added to induce differentiation, the ratio of selection of the downstream transcription initiation point increased greatly, the difference being smaller in the late stage of differentiation (Table 10 and Table 11).

[0374] These results demonstrated that by comparing the expression of the 5'-terminal region of a newly acquired cDNA shown by the detection region 122.sub.--01 (SEQ ID NO:104) (a region close to the transcription initiation point), 122.sub.--[1]-N1 (SEQ ID NO:90), or the expression of a newly acquired cDNA region 122.sub.--[2]-N1 (SEQ ID NO:100), shown by the detection region 122.sub.--02 (SEQ ID NO:107), it is possible to use these regions as differentiation markers for detecting cells in nerve cell differentiation or regeneration stages, particularly those in an early stage of differentiation into nerve cells. It also seems possible to develop a new drug by means of a compound, antibody, siRNA or the like that targets a region that exhibits specificity.

[0375] The following regions also seem to be useful as differentiation markers for detecting nerve cell differentiation or regeneration stages, particularly initial stages of differentiation into nerve cells.

Upstream sequence 031.sub.--[1].sub.--1-N3 (SEQ ID NO:114), which comprises the 138th to 162nd bases undergoing priming by Primer122.sub.--01R (SEQ ID NO:103) in D-NT2RI2014164.1 of the cDNA pattern [1]. Upstream sequence 031.sub.--[1].sub.--1-N3 (SEQ ID NO:115), which comprises the 177th to 198th bases undergoing priming by Primer122.sub.--02R (SEQ ID NO:106) in D-BRAMY2029564.1 of the cDNA pattern [2]. Region 122.sub.--01 (SEQ ID NO:104) amplified by Primer122.sub.--01F (SEQ ID NO:102) and Primer122.sub.--01R (SEQ ID NO:103) in the cDNA pattern [1]. Region 122.sub.--02 (SEQ ID NO:107) amplified by Primer122.sub.--02F (SEQ ID NO:105) and Primer122.sub.--02R (SEQ ID NO:106) in the cDNA pattern [2].

Example 9

Cluster chr8-916 (Data Set: 124)

(1) Cluster Analysis

1) Cluster Characteristics

[0376] An analysis was performed on 10 sequences of full-length cDNAs subjected to genome mapping onto the cluster chr8-916 (Human genome UCSC hg18 (NCBI Build34) chromosome 8, 81,100,000 bp to 81,325,000 bp) [D-BRHIP2003515.1, D-COLON2003937.1, Z-BRCOC2013886-01, BC018117.1, BX640835.1, C-SMINT1000078, ENST00000263850, NM.sub.--005079.1, U18914.1, XM.sub.--374275.1]. They were classified according to expression pattern difference into 4 kinds, which mainly included the following 2 kinds.

[1] D-BRHIP2003515.1

[2] BC018117.1, NM.sub.--005079.1, U18914.1

[0377] [1] is a cDNA newly acquired and subjected to full-length cDNA sequence analysis by us, and having a different ORF from [2], which had been registered with an existing public DB.

[0378] [1], compared with the known [2], had a different ORF region because of amino acid sequence alteration due to the insertion of an exon different from other patterns in the ORF region.

[0379] It was found that the ORF regions present in the 2 kinds of cDNA patterns [1] to [2] have different splice patterns, from the same chromosome region, resulting in alterations of the amino acid sequences to produce diverse proteins and mRNAs.

2) Characteristics of D-BRHIP2003515.1 ([1]), which was Newly Acquired and Subjected to Full-Length cDNA Sequence Analysis by Us 124.sub.--[1].sub.--1-N0 (SEQ ID NO:116): The entire nucleic acid sequence region of D-BRHIP2003515.1 124.sub.--[1].sub.--1-NA0 (SEQ ID NO:117): Both the entire nucleic acid sequence region and amino acid sequence of D-BRHIP2003515.1 124.sub.--[1].sub.--1-A0 (SEQ ID NO:118): The entire amino acid sequence region of D-BRHIP2003515.1

[0380] The sequence at the 471st to 539th bases of D-BRHIP2003515.1 (SEQ ID NO:119) is a variant incorporating an exon that is not present in NM.sub.--005079.1, which is registered with an existing public DB, and serves for control. The translation initiation point and translation termination point of D-BRHIP2003515.1 are the same as those of NM.sub.--005079.1; however, because of the insertion of a 69-base exon into D-BRHIP2003515.1, the amino acid length increased by 23 residues, compared with NM.sub.--005079.1 (SEQ ID NO:120).

124.sub.--[1].sub.--1-N1 (SEQ ID NO:119): A 69-base insert nucleic acid sequence region of D-BRHIP2003515.1 124.sub.--[1].sub.--1-A 1 (SEQ ID NO:120): A 23-residue insert amino acid sequence region of D-BRHIP2003515.1 124.sub.--[1].sub.--1-N 2 (identical to SEQ ID NO:119): An ORF nucleic acid sequence region in the 69-base insert region of D-BRHIP2003515.1 124.sub.--[1].sub.--1-A 2 (identical to SEQ ID NO:120): An ORF amino acid region related to the 69-base insert region of D-BRHIP2003515.1

3) Expression Specificity Analysis and Design of Primers for Real-Time PCR

[0381] To clearly distinguish between the characteristic regions shown above, and examine the respective expression levels thereof, the following regions were used as detection regions. It seemed possible to compare the expression levels of the individual characteristic regions by comparing the expression levels of the detection regions.

124.sub.--04--A region specifically extracted by means of the sequence information at the border of a region having an exon inserted therein in the cDNA pattern [1]: an insert region of an ORF altering exon in the cDNA pattern [1], which was newly subjected to full-length cDNA sequence analysis by us .fwdarw.Fragment 124.sub.--04 (SEQ ID NO:123) amplified by Primer124.sub.--04F (SEQ ID NO:121) and Primer12404R (SEQ ID NO:122) 124.sub.--05--A specific region corresponding to a deletion region of the cDNA pattern [2], which is registered with an existing public DB, compared with the insertion region of [1], serving as a control for comparing [1] .fwdarw.Fragment 124.sub.--05 (SEQ ID NO:126) amplified by Primer124.sub.--05F (SEQ ID NO:124) and Primer12405R (SEQ ID NO:125) 124.sub.--06--A common region shared by all of [1] to [2]: a region common to all patterns, serving for control to compare the overall expression levels of the cDNA pattern [1], which was newly subjected to full-length cDNA sequence analysis by us, and the cDNA pattern [2], which is registered with an existing public DB .fwdarw.Fragment 124.sub.--06 (SEQ ID NO:129) amplified by Primer124.sub.--06F (SEQ ID NO:127) and Primer124.sub.--06R (SEQ ID NO:128)

[0382] By mapping the 5'-terminal sequences of about 1.44 million sequences acquired using the oligocap method onto the human genome sequence, and comparatively analyzing them, the exon regions specific to the cDNA patterns [1] to [2] shown above, respectively, were found to be expressed at the following frequencies.

[0383] In the cDNA pattern [1], which was newly acquired and analyzed by us, twenty-one 5'-terminal sequences were present, the derivations thereof being brain tissues such as Brain, amygdala, Brain, cerebellum, and Brain, hippocampus for 18 sequences and Kidney, Tumor for 3 sequences.

[0384] In the cDNA pattern [2], which is registered with an existing public DB, fifty-one 5'-terminal sequences were present, the derivations thereof being brain tissues such as Brain, substantia nigra, Brain, hippocampus, Brain, amygdala, and Brain, corpus callosum for 17 sequences, tumor tissues such as Tongue, Tumor, and Kidney, Tumor for 9 sequences, and other normal tissues such as Lung, Small Intestine, and Trachea for sequences.

[0385] From this result, it was found that the exon insertion pattern [1] was abundantly expressed in the brain. It was also found that the exon deletion pattern [2] was expressed not only in the brain, but also in other various tissues. Hence, it was thought that the mechanism for amino acid alteration due to exon insertion in this chromosome region to cause the expression of different proteins, as with the pattern [1], might be unique to particular tissues.

(2) Analysis of Expression Specificity by Real-Time PCR

[0386] To detect protein expression diversity changes due to exon selectivity among different tissues, details of expression levels were analyzed by real-time PCR. The results are shown in Table 12 and Table 13.

TABLE-US-00012 TABLE 12 RQ Score Log.sub.10RQ Score 124_04 124_05 124_06 124_04 124_05 124_06 01 NT2RA(-) 0.1 0.1 0.1 -1.28 -1.07 -1.06 02 NT2RA(+) 24 hr 0.2 0.1 0.1 -0.74 -1.21 -1.22 03 NT2RA(+) 48 hr 0.0 0.1 0.1 -1.47 -1.25 -1.27 04 NT2RA(+) 1 week 0.1 0.0 0.0 -0.83 -1.58 -1.60 05 NT2RA(+) 5 weeks 8.6 0.0 0.1 0.93 -1.32 -1.07 06 NT2RA(+) 5 weeks, Inh(+) 4.7 0.1 0.1 0.67 -1.15 -1.03 07 NT2 Neuron 1.1 0.0 0.0 0.04 -2.08 -1.79 08 Brain, Fetal 148.6 0.0 0.4 2.17 -1.59 -0.38 09 Brain, whole 465.6 0.3 2.1 2.67 -0.47 0.32 10 ALZ Visual Cortex 286.6 0.3 1.1 2.46 -0.49 0.05 Occipital 11 Mix, viscus tissues 1.0 1.0 1.0 0.0 0.0 0.0 12 Mix, blood cells and 14.6 0.5 0.6 1.16 -0.34 -0.26 related tissues 13 Mix, tumor tissues 0.4 0.9 0.8 -0.40 -0.04 -0.09 14 Mix, normal tissues 1.0 0.9 0.8 -0.01 -0.06 -0.10 15 Brain, whole PolyA(+) RNA 190.4 0.3 1.3 2.28 -0.54 0.12 16 Brain, hippocampus 189.2 0.3 1.1 2.28 -0.50 0.06 17 Brain, cerebellum 247.5 0.1 1.6 2.39 -0.84 0.21 18 Brain, amygdala 191.9 0.2 0.9 2.28 -0.74 -0.03 19 Brain, caudate nucleus 134.8 0.4 0.9 2.13 -0.45 -0.05 20 Brain, corpus callosum 25.0 1.1 1.2 1.40 0.03 0.09 21 Brain, substantia nigra 70.3 0.5 0.9 1.85 -0.29 -0.06 22 Brain, thalamus 194.7 0.3 1.0 2.29 -0.57 0.01 23 Brain, subthalamic nucleus 22.2 0.6 0.6 1.35 -0.25 -0.25

TABLE-US-00013 TABLE 13 RQ Score Log.sub.10RQ Score 124_04 124_05 124_06 124_04 124_05 124_06 01 NT2RA(-) 0.2 0.1 0.1 -0.72 -1.19 -0.99 02 NT2RA(+) 24 hr 1.0 0.1 0.1 -0.02 -1.19 -1.14 03 NT2RA(+) 48 hr 0.3 0.1 0.1 -0.48 -1.24 -1.14 04 NT2RA(+) 1 week 0.7 0.0 0.0 -0.17 -1.56 -1.47 05 NT2RA(+) 5 weeks 41.4 0.0 0.1 1.62 -1.33 -0.97 06 NT2RA(+) 5 weeks, Inh(+) 30.7 0.1 0.1 1.49 -1.09 -0.89 07 NT2 Neuron 6.2 0.0 0.0 0.79 -1.95 -1.59 08 Brain, Fetal 839.9 0.0 0.5 2.92 -1.62 -0.27 09 Brain, whole 3655.9 0.3 2.6 3.56 -0.50 0.41 10 ALZ Visual Cortex 1899.0 0.3 1.6 3.28 -0.46 0.19 Occipital 11 Mix, viscus tissues 1.0 1.0 1.0 0.0 0.0 0.0 12 Mix, blood cells and 100.9 0.5 0.7 2.00 -0.28 -0.17 related tissues 13 Mix, tumor tissues 1.9 0.8 0.9 0.28 -0.11 -0.05 14 Mix, normal tissues 8.9 0.7 1.2 0.95 -0.16 0.08 15 Brain, whole PolyA(+) RNA 1539.2 0.3 1.7 3.19 -0.55 0.22 16 Brain, hippocampus 1524.4 0.3 1.5 3.18 -0.48 0.16 17 Brain, cerebellum 2130.5 0.2 2.3 3.33 -0.80 0.36 18 Brain, amygdala 1379.6 0.2 1.2 3.14 -0.75 0.09 19 Brain, caudate nucleus 804.0 0.4 1.1 2.91 -0.45 0.04 20 Brain, corpus callosum 163.7 1.1 1.4 2.21 0.04 0.16 21 Brain, substantia nigra 386.9 0.5 1.1 2.59 -0.32 0.04 22 Brain, thalamus 1285.4 0.3 1.3 3.11 -0.59 0.10 23 Brain, subthalamic nucleus 181.6 0.6 0.8 2.26 -0.26 -0.11

[0387] Expression levels were compared using the 23 kinds of samples shown in Example 3, including 11 kinds of brain tissues and NT2 cells at 7 different differentiation stages. The comparison was made using the mixed sample of normal visceral tissues shown in Example 3 (Mix, viscus tissues) as an experimental control.

[0388] The ratio of ORF alteration due to exon insertion/deletion selectivity as compared between 124.sub.--04 (SEQ ID NO:123) and 124.sub.--05 (SEQ ID NO:126) changed greatly among the following tissues and NT2 cell differentiation stages.

[0389] In all portions of the brain, the expression of the pattern for insertion of the exon shown by 124.sub.--04 (SEQ ID NO:123) was abundant (Table 12 and Table 13).

[0390] It was found that in NT2 cells, exon selectivity changed greatly depending on the stage of differentiation. When compared in detail with respect to NT2 cell differentiation, almost no difference was observed between the two patterns 124.sub.--04 (SEQ ID NO:123) and 124.sub.--05 (SEQ ID NO:126) in undifferentiated NT2 cells NT2RA (-) and NT2RA (+) 1 week, which represent the initial stage in which retinoic acid was added to NT2 cells to induce differentiation; however, in NT2RA (+) 5 weeks to NT2 Neuron, the expression of the pattern of insertion of the exon shown by 124.sub.--04 (SEQ ID NO:123) was considerably abundant (Table 12 and Table 13).

[0391] These results demonstrated that by comparing the expression of the selective exon region 124.sub.--[1].sub.--1-N1 (SEQ ID NO:119) of a newly acquired cDNA shown by the detection region 124.sub.--04 (SEQ ID NO:123), it is possible to use the exon region as a brain-specific marker, and as a differentiation marker for detecting cells in nerve cell differentiation or regeneration stages, particularly those after nerve differentiation or nerve regeneration. It also seems possible to develop a new drug by means of a compound, antibody, siRNA or the like that targets a region that exhibits specificity.

[0392] The following regions also seem to be useful as markers specific for the brain, and as differentiation markers for detecting nerve cells in differentiation or regeneration stages, particularly those after nerve differentiation or after nerve regeneration.

Upstream sequence 124.sub.--[1].sub.--1-N3 (SEQ ID NO:130), which comprises the 472nd to 491st bases undergoing priming by Primer124.sub.--04R (SEQ ID NO:122) in D-BRHIP2003515.1 of the cDNA pattern [1]. Region 12404 (SEQ ID NO:123) amplified by Primer124.sub.--04F (SEQ ID NO:121) and Primer12404R (SEQ ID NO:122) in the cDNA pattern [1]

Example 10

Cluster chr3+2014 (Data Set: 112)

(1) Cluster Analysis

1) Cluster Characteristics

[0393] An analysis was performed on 7 full-length cDNAs subjected to genome mapping onto the cluster chr3+2014 (Human genome UCSC hg18 (NCBI Build34) chromosome 3, 143,070,000 bp to 143,130,000 bp) [D-BRACE2044661.1, BC011835.2, C-BRAMY2022929, C-PRS09188, ENST00000286371, NM.sub.--001679.2, U51478.1]. They were classified according to expression pattern difference into 4 kinds, which mainly included the following 2 kinds.

[1] D-BRACE2044661.1

[2] BC011835.2, ENST00000286371, NM.sub.--001679.2, U51478.1

[0394] [1] is a cDNA newly acquired and subjected to full-length cDNA sequence analysis by us, and having a different ORF from [2], which had been registered with an existing public DB.

[0395] [1], compared with the known [2], had a different ORF because of translation initiation point alteration due to the insertion of an exon different from other patterns in the ORF region.

[0396] It was found that the ORF regions present in the 2 kinds of cDNA patterns [1] to [2] have different splice patterns, from the same chromosome region, resulting in alterations of the amino acid sequences to produce diverse proteins and mRNAs.

2) Characteristics of D-BRACE2044661.1 ([1]), which was Newly Acquired and Subjected to Full-Length cDNA Sequence Analysis by Us 112.sub.--[1].sub.--1-N0 (SEQ ID NO:131): The entire nucleic acid sequence region of D-BRACE2044661.1 112.sub.--[1].sub.--1-NA0 (SEQ ID NO:132): Both the entire nucleic acid sequence region and amino acid sequence of D-BRACE2044661.1 112.sub.--[1].sub.--1-A0 (SEQ ID NO:133): The entire amino acid sequence region of D-BRACE2044661.1

[0397] The 272nd to 363rd bases of D-BRACE2044661.1 (SEQ ID NO:134) is an exon that is not present in NM.sub.--001679.2, which is registered with an existing public DB, and serves for control, lacking homology to NM.sub.--001679.2. Because a translation initiation point is present on this exon, the amino acids on the N-terminal side changed by 23 residues (SEQ ID NO:135).

112.sub.--[1].sub.--1-N1 (SEQ ID NO:134): A 92-base insert nucleic acid sequence region of D-BRACE2044661.1 112.sub.--[1].sub.--1-A1 (SEQ ID NO:135): A 23-residue insert amino acid sequence region D-BRACE2044661.1 112.sub.--[1].sub.--1-N2 (SEQ ID NO:136): An ORF nucleic acid sequence region in the 92-base insert region of D-BRACE2044661.1 112.sub.--[1].sub.--1-A2 (identical to SEQ ID NO:135): An ORF amino acid sequence region in the 92-base insert region of D-BRACE2044661.1

[0398] The sequence at the 837th to 856th bases of D-BRACE2044661.1 (SEQ ID NO:137) is an exon that is not present in NM.sub.--001679.2, which is registered with an existing public DB, and serves for control, lacking homology to NM.sub.--001679.2. Because of a change in the translation frame by this insert sequence, the amino acids on the C-terminal side changed by 13 residues (SEQ ID NO:138).

112.sub.--[1].sub.--1-N3 (SEQ ID NO:137): A 20-base insert nucleic acid sequence region of D-BRACE2044661.1 112.sub.--[1].sub.--1-A3 (SEQ ID NO:138): A 13-residue insert amino acid sequence region of D-BRACE2044661.1 112.sub.--[1].sub.--1-N4 (identical to SEQ ID NO:137): An ORF nucleic acid sequence region in the 20-base insert region of D-BRACE2044661.1 112.sub.--[1].sub.--1-A4 (SEQ ID NO:139): An ORF amino acid sequence region in the 20-base insert region of D-BRACE2044661.1

3) Expression Specificity Analysis and Design of Primers for Real-Time PCR

[0399] To clearly distinguish between the characteristic regions shown above, and examine the respective expression levels thereof, the following regions were used as detection regions. It seemed possible to compare the expression levels of the individual characteristic regions by comparing the expression levels of the detection regions.

112.sub.--01--A region incorporating an exon of the cDNA pattern [1], specifically extracted by means of the sequence information at the border: an ORF-altering exon insert region in the cDNA pattern [1], which was newly subjected to full-length cDNA sequence analysis by us .fwdarw.Fragment 112.sub.--01 (SEQ ID NO:142) amplified by Primer112.sub.--01F (SEQ ID NO:140) and Primer112.sub.--01R (SEQ ID NO:141) 112.sub.--02--A specific region corresponding to a deletion region of the cDNA pattern [2], which is registered with an existing public DB, compared with the insert region of [1], serving as a control for comparatively examining [1] .fwdarw.Fragment 112.sub.--02 (SEQ ID NO:145) amplified by Primer112.sub.--02F (SEQ ID NO:143) and Primer112.sub.--02R (SEQ ID NO:144) 112.sub.--03--A common region shared by all of [1] to [2]: a region common to all patterns, serving for control to compare the overall expression levels of the cDNA pattern [1], which was newly subjected to full-length cDNA sequence analysis by us, and the cDNA pattern [2], which is registered with an existing public DB .fwdarw.Fragment 112.sub.--03 (SEQ ID NO:148) amplified by Primer112.sub.--03F (SEQ ID NO:146) and Primer112.sub.--03R (SEQ ID NO:147)

[0400] By mapping the 5'-terminal sequences of about 1.44 million sequences acquired using the oligocap method onto the human genome sequence, and comparatively analyzing them, the regions specific for the 2 kinds of cDNA patterns [1] to [2] shown above, respectively, were found to be expressed at the following frequencies.

[0401] In the cDNA pattern [1], which was newly acquired and analyzed by us, six 5'-terminal sequences were present, the derivations thereof being Brain, cerebellum for 3 sequences (analytical parameter 82,880), Brain, cortex, Alzheimer for 1 sequence (analytical parameter 16,360), Brain, amygdala for 1 sequence (analytical parameter 58,640), and tissues rich in head portion from 10-week-gestional fetal human (whole embryo, mainly head) for 1 sequence (analytical parameter 7,033).

[0402] In the cDNA pattern [2], which is registered with an existing public DB, twenty-four 5'-terminal sequences were present, the derivations thereof being Placenta for 4 sequences (analytical parameter 46,090), NT2 cells treated with retinoic acid (RA) to induce differentiation (NT2RP) for 3 sequences (analytical parameter 39,242), Tongue, Tumor for 2 sequences (analytical parameter 31,371), IMR32 cells (Neuroblastoma) for 2 sequences (analytical parameter 16964), NT2 cells treated with retinoic acid and a growth inhibitor to induce nerve differentiation, followed by nerve concentration and recovery (NT2NE) for 2 sequences (analytical parameter 16,337) and the like; this pattern was expressed in various tissues.

[0403] From this result, it was found that the exon insertion pattern [1] was abundantly expressed in the brain. It was also found that the exon deletion pattern [2] was expressed not only in the brain, but also in other various tissues. Hence, it was thought that the selection mechanism for mRNA pattern change in this chromosome region, which alters N-terminal amino acids and results in the expression of different proteins because of exon insertion as with the pattern [1], might be unique to particular tissues.

(2) Analysis of Expression Specificity by Real-Time PCR

[0404] To detect protein expression diversity changes due to exon selectivity among different tissues, details of expression levels were analyzed by real-time PCR. The results are shown in Table 14.

TABLE-US-00014 TABLE 14 RQ Score Log.sub.10RQ Score 112_01 112_02 112_03 112_01 112_02 112_03 01 NT2RA(-) 0.4 0.5 1.2 -0.35 -0.26 0.09 02 NT2RA(+) 24 hr 0.5 0.3 0.5 -0.33 -0.48 -0.33 03 NT2RA(+) 48 hr 0.4 0.5 0.6 -0.41 -0.32 -0.22 04 NT2RA(+) 1 week 0.2 0.5 0.6 -0.74 -0.32 -0.21 05 NT2RA(+) 5 weeks 2.0 0.9 2.0 0.29 -0.03 0.31 06 NT2RA(+) 5 weeks, Inh(+) 4.1 0.8 1.5 0.62 -0.12 0.18 07 NT2 Neuron 7.6 0.9 1.3 0.88 -0.03 0.11 08 Brain, Fetal 23.3 1.2 2.3 1.37 0.08 0.36 09 Brain, whole 158.2 0.6 1.8 2.20 -0.21 0.26 10 ALZ Visual Cortex 109.3 0.3 1.2 2.04 -0.55 0.08 Occipital 11 Mix, viscus tissues 1.0 1.0 1.0 0.0 0.0 0.0 12 Mix, blood cells and 10.1 0.8 1.2 1.00 -0.12 0.07 related tissues 13 Mix, tumor tissues 0.9 1.6 1.2 -0.03 0.22 0.06 14 Mix, normal tissues 2.4 1.3 1.6 0.37 0.10 0.20 15 Brain, whole PolyA(+) RNA 114.0 0.3 0.9 2.06 -0.56 -0.03 16 Brain, hippocampus 56.4 0.3 0.7 1.75 -0.55 -0.15 17 Brain, cerebellum 149.9 0.6 1.6 2.18 -0.20 0.21 18 Brain, amygdala 47.5 0.3 0.9 1.68 -0.47 -0.06 19 Brain, caudate nucleus 47.9 0.3 0.8 1.68 -0.59 -0.11 20 Brain, corpus callosum 8.7 0.3 0.6 0.94 -0.53 -0.19 21 Brain, substantia nigra 56.7 0.4 1.0 1.75 -0.37 0.01 22 Brain, thalamus 124.0 0.3 1.2 2.09 -0.60 0.07 23 Brain, subthalamic nucleus 26.1 0.4 0.7 1.42 -0.37 -0.16

[0405] Expression levels were compared using the 23 kinds of samples shown in Example 3, including 11 kinds of brain tissues and NT2 cells at 7 different differentiation stages. The comparison was made using the mixed sample of normal visceral tissues shown in Example 3 (Mix, viscus tissues) as an experimental control.

[0406] The ratio of ORF alteration due to exon insertion/deletion selectivity as compared between 112.sub.--01 (SEQ ID NO:142) and 112.sub.--02 (SEQ ID NO:145) changed greatly among the following brain portions and NT2 cell differentiation stages.

[0407] In the brain, particularly in Brain, cerebellum, Brain, hippocampus, Brain, amygdala, Brain, caudate nucleus, Brain, substantia nigra, and Brain, thalamus, the pattern of insertion of the exon shown by 112.sub.--01 (SEQ ID NO:142) was abundantly observed (Table 14).

[0408] It was also found that in NT2 cells, exon selectivity varied greatly depending on the stage of differentiation. When compared in detail with respect to NT2 cell differentiation, the expression of the exon deletion pattern shown by 112.sub.--02 (SEQ ID NO:145), which is registered with an existing public DB was more abundant in undifferentiated NT2 cells NT2RA (-) and NT2RA (+) 48 hr, NT2RA (+) 1 week, which represents the initial stage in which retinoic acid was added to induce differentiation; however, in NT2RA (+) 5 weeks, which is predicted to be rich in nerve cells after differentiation, the expression level reversed; even in NT2RA (+) 5 weeks, Inh (+) and NT2 Neuron, the expression of the exon insertion pattern shown by 112.sub.--01 (SEQ ID NO:142) was abundantly observed (Table 14).

[0409] These results demonstrated that by comparing the expression of the selective exon region 112.sub.--[1]-N1 (SEQ ID NO:134) of a newly acquired cDNA shown by the detection region 112.sub.--01 (SEQ ID NO:142), it is possible to use the exon region as a marker specific for the brain, particularly for portions such as Brain, cerebellum, Brain, hippocampus, Brain, amygdala, Brain, caudate nucleus, Brain, substantia nigra, and Brain, thalamus, and as a differentiation marker for detecting cells in nerve cell differentiation or regeneration stages, particularly those that have differentiated or regenerated into a nerve. It also seems possible to develop a new drug by means of a compound, antibody, siRNA or the like that targets a region that exhibits specificity.

[0410] The following regions also seem to be useful as differentiation markers.

Upstream sequence 112.sub.--[1].sub.--1-N5 (SEQ ID NO:149), which comprises the 363rd to 390th bases undergoing priming by Primer112.sub.--01R (SEQ ID NO:141) in D-BRACE2044661.1 of the cDNA pattern [1]. Region 112.sub.--01 (SEQ ID NO:142) amplified by Primer112.sub.--01F (SEQ ID NO:140) and Primer112.sub.--01R (SEQ ID NO:141) in the cDNA pattern [1].

Example 11

Cluster chr12+1658 (Data Set: 095)

(1) Cluster Analysis

1) Cluster Characteristics

[0411] An analysis was performed on 7 sequences of full-length cDNAs subjected to genome mapping onto the cluster chr12+1658 (Human genome UCSC hg18 (NCBI Build34) chromosome 12, 108,470,000 bp to 108,500,000 bp) [D-BRCAN2027778.1, D-3NB692002462.1, BC016140.1, C-NT2RP3000875, ENST00000228510, M88468.1, NM.sub.--000431.1]. They were classifiable according to expression pattern difference mainly into the following 3 kinds.

[1] D-3NB692002462.1

[2] D-BRCAN2027778.1

[3] BC016140.1, ENST00000228510, M88468.1, NM.sub.--000431.1

[0412] [1] and [2] are cDNAs which were newly acquired and subjected to full-length cDNA sequence analysis by us, and had a different ORF from [3], which had been registered with an existing public DB.

[0413] [1], compared with the known [3], had a different ORF region because of the deletion of portions corresponding to the third and fourth exons of [3] in the ORF region.

[0414] [2], compared with the known [3], had a different ORF region because of the deletion of a portion corresponding to the fourth exon of [3] in the ORF region.

[0415] It was found that the ORF regions present in the 3 kinds of cDNA patterns [1] to [3] have different splice patterns, such as exon deletions, from the same chromosome region, resulting in alterations of the amino acid sequences to produce diverse proteins and mRNAs.

2) Characteristics of D-3NB692002462.1 ([1]), which was Newly Acquired and Subjected to Full-Length cDNA Sequence Analysis by Us 095.sub.--[1].sub.--1-N0 (SEQ ID NO:150): The entire nucleic acid sequence region of D-3NB692002462.1 095.sub.--[1].sub.--1-NA0 (SEQ ID NO:151): Both the entire nucleic acid sequence region and amino acid sequence of D-3NB692002462.1 095.sub.--[1].sub.--1-A0 (SEQ ID NO:152): The entire amino acid sequence region of D-3NB692002462.1

[0416] The 301-base exon present at the 303rd to 603rd bases of NM.sub.--000431.1, which is registered with an existing public DB, and serves for control (SEQ ID NO:155), is lacked and not present in the region at the 287th to 288th bases of D-3NB692002462.1 (SEQ ID NO:153). The translation initiation point of NM.sub.--000431.1 is present on the first exon, shared by D-3NB692002462.1; however, in D-3NB692002462.1, because of the alteration of the frame due to deletion of the 301 bases, the translation initiation point shifts toward the 3' side, compared with NM.sub.--000431.1, and the 343rd base of D-3NB692002462.1 becomes the translation initiation point. For this reason, the N-terminal amino acid sequence shortened by 194 residues, compared with NM.sub.--000431.1.

095.sub.--[1].sub.--1-N1 (SEQ ID NO:153): A deletion nucleic acid sequence region of D-3NB692002462.1 095.sub.--[1].sub.--1-N2 (SEQ ID NO:154): A 342-base 5'UTR region of an ORF whose translation initiation point is the 343rd base of D-3NB692002462.1 095.sub.--[1]_C-N1 (SEQ ID NO:155): A 301-base exon nucleic acid sequence present in the region at the 303rd to 603rd bases of NM.sub.--000431.1 inserted into the region at the 287th to 288th bases of D-3NB692002462.1 095.sub.--[1]_C-A1 (SEQ ID NO:156): A 101-residue amino acid sequence related to the 301-base exon nucleic acid sequence present in the region at the 303rd to 603rd bases of NM.sub.--000431.1 inserted into the region at the 1,250th to 1,251st bases of D-3NB692002462.1

[0417] With this change, "GHMP kinase putative ATP-binding protein", the Pfam motif present at the 128th to 346th amino acids of NM.sub.--000431.1, disappeared in D-3NB692002462.1.

3) Characteristics of D-BRCAN2027778.1 ([2]), which was Newly Acquired and Subjected to Full-Length cDNA Sequence Analysis by Us 095.sub.--[2].sub.--1-N0 (SEQ ID NO:157): The entire nucleic acid sequence region of D-BRCAN2027778.1 095.sub.--[2].sub.--1-NA0 (SEQ ID NO:158): Both the entire nucleic acid sequence region and amino acid sequence of D-BRCAN2027778.1 095.sub.--[2].sub.--1-A0 (SEQ ID NO:159): The entire amino acid sequence region of D-BRCAN2027778.1

[0418] The 156-base exon present at the 448th to 603rd bases of NM.sub.--000431.1, which is registered with an existing public DB, and serves for control (SEQ ID NO:162), is lacked and not present in the region at the 422nd to 423rd bases of D-BRCAN2027778.1 (SEQ ID NO:160).

095.sub.--[2].sub.--1-N1 (SEQ ID NO:160): A deletion nucleic acid sequence region of D-BRCAN2027778.1 095.sub.--[2].sub.--1-A1 (SEQ ID NO:161): An altered amino acid sequence region of D-BRCAN2027778.1 095.sub.--[2].sub.--1-N2 (identical to SEQ ID NO:160): An ORF nucleic acid sequence region in the deletion region of D-BRCAN2027778.1 095.sub.--[2].sub.--1-A2 (identical to SEQ ID NO:161): An ORF amino acid region related to the deletion region of D-BRCAN2027778.1 095.sub.--[2]_C-N1 (SEQ ID NO:162): A 156-base exon nucleic acid sequence present in the region at the 448th to 603rd bases of NM.sub.--000431.1 inserted into the region at the 422nd to 423rd bases of D-BRCAN2027778.1 095.sub.--[2]_C-A1 (SEQ ID NO:163): A 101-residue amino acid sequence related to the 156-base exon nucleic acid sequence present in the region at the 448th to 603rd bases of NM.sub.--000431.1 inserted into the region at the 423rd to 424th bases of D-BRCAN2027778.1

4) Expression Specificity Analysis and Design of Primers for Real-Time PCR and TaqMan Probe

[0419] To clearly distinguish between the characteristic regions shown above, and examine the respective expression levels thereof, the following regions were used as detection regions. It seemed possible to compare the expression levels of the individual characteristic regions by comparing the expression levels of the detection regions.

095.sub.--01--A region specifically extracted by means of the sequence information at the border of regions of the exon deletion of cDNA pattern [1]: an ORF-altering exon deletion region in the cDNA pattern [1], which was newly subjected to full-length cDNA sequence analysis by us .fwdarw.Fragment 095.sub.--01 (SEQ ID NO:166) amplified by Primer095.sub.--01F (SEQ ID NO:164) and Primer09501R (SEQ ID NO:165) TaqMan probe used 095.sub.--01TP: (SEQ ID NO:167) 095.sub.--02--A region specifically extracted by means of the sequence information at the border of regions of the exon deletion of cDNA pattern [2]: an ORF-altering exon deletion in the cDNA pattern [2], which was newly subjected to full-length cDNA sequence analysis by us .fwdarw.Fragment 095.sub.--02 (SEQ ID NO:170) amplified by Primer095.sub.--02F (SEQ ID NO:168) and Primer09502R (SEQ ID NO:169) TaqMan probe used 095.sub.--02TP: (SEQ ID NO:171) 095.sub.--03--A specific region of the cDNA pattern [3], which is registered with an existing public DB, that can be distinguished from both the deletion regions of [1] and [2], serving as a control for comparing [1] and [2] .fwdarw.Fragment 095.sub.--03 (SEQ ID NO:174) amplified by Primer095.sub.--03F (SEQ ID NO:172) and Primer09503R (SEQ ID NO:173) TaqMan probe used 095.sub.--03TP: (SEQ ID NO:175) 095.sub.--04--A common region shared by all of [1] to [3]: a region common to all patterns, serving for control to compare the overall expression levels of the cDNA patterns [1] and [2], which were newly subjected to full-length cDNA sequence analysis by us, and the cDNA pattern [3], which is registered with an existing public DB .fwdarw.Fragment 095.sub.--04 (SEQ ID NO:178) amplified by Primer095.sub.--04F (SEQ ID NO:176) and Primer095.sub.--04R (SEQ ID NO:177) TaqMan probe used 095.sub.--04TP: (SEQ ID NO:179)

[0420] By mapping the 5'-terminal sequences of about 1.44 million sequences acquired using the oligocap method onto the human genome sequence, and comparatively analyzing them, the exon regions specific for the cDNA patterns [1] to [3] shown above, respectively, were found to be expressed at the following frequencies.

[0421] In the cDNA pattern [1], which was newly acquired and analyzed by us, three 5'-terminal sequences were present, the derivations thereof being NB69 cells for 1 sequence (analytical parameter 8,153), NT2 cells treated with retinoic acid (RA) to induce differentiation (NT2RP) for 1 sequence (analytical parameter 39,242), and SK-N-MC cells (Neuroepithelioma) for 1 sequence (analytical parameter 7,700).

[0422] In the cDNA pattern [2], which was newly acquired and analyzed by us, three 5'-terminal sequences were present, the derivations thereof being a library generated by subtracting cDNAs that overlap with the mRNA of BRAWH: Brain, whole from a cDNA library prepared from the mRNA of BRALZ [Alzheimer patient cerebral cortex (Brain, cortex, Alzheimer)] (BRALZ-BRAWH) for 1 sequence (analytical parameter 157), Brain, caudate nucleus for 1 sequence (analytical parameter 25,786), and NT2 cells treated with retinoic acid and a growth inhibitor to induce nerve differentiation, followed by nerve concentration and recovery (NT2NE) for 1 sequence (analytical parameter 16,337).

[0423] In the cDNA pattern [3], which is registered with an existing public DB, thirty-four 5'-terminal sequences were present, and expression was observed in various tissues, the derivations thereof being Brain, cerebellum for 4 sequences (analytical parameter 82,880), Testis for 4 sequences (analytical parameter 90,188), NT2 cells treated with RA and treated with a growth inhibitor to induce nerve differentiation, followed by nerve concentration and recovery (NT2NE) for 3 sequences (analytical parameter 16,337), Brain, whole for 2 sequences (analytical parameter 59,069), Brain, subthalamic nucleus for 2 sequences (analytical parameter 16,308), Kidney for 2 sequences (analytical parameter 17,008), and Thymus for 2 sequences (analytical parameter 70,578).

[0424] From this result, it was found that the exon deletion pattern [1] was expressed in differentiated NT2 cells and the like. It was also found that the exon deletion pattern [2] was abundantly expressed in the brain. The known sequence [3], compared with the patterns [1] and [2], was expressed in a wider variety of organs. Hence, it was thought that the selection mechanism for mRNA pattern change in this chromosome region, which alters amino acid sequences and results in the expression of different proteins because of exon selectivity as with the patterns [1] and [2], might be unique to particular tissues.

(2) Analysis of Expression Specificity by Real-Time PCR

[0425] To detect protein expression diversity changes due to exon selectivity among different tissues, details of expression levels were analyzed by real-time PCR. The results are shown in Table 15.

TABLE-US-00015 TABLE 15 RQ Score Log.sub.10RQ Score 095_01 095_02 095_03 095_04 095_01 095_02 095_03 095_04 01 NT2RA(-) 0.5 0.3 0.2 0.2 -0.34 -0.49 -0.78 -0.66 02 NT2RA(+) 24 hr 0.8 0.4 0.2 0.3 -0.11 -0.43 -0.78 -0.52 03 NT2RA(+) 48 hr 0.3 0.2 0.2 0.4 -0.49 -0.66 -0.70 -0.37 04 NT2RA(+) 1 week 0.9 0.4 0.7 1.2 -0.03 -0.36 -0.18 0.07 05 NT2RA(+) 5 weeks 0.2 0.2 0.3 0.3 -0.71 -0.80 -0.58 -0.48 06 NT2RA(+) 5 weeks, Inh(+) 0.1 0.2 0.3 0.2 -0.88 -0.64 -0.58 -0.63 07 NT2 Neuron 0.2 0.0 0.1 1.7 -0.72 -1.36 -1.16 0.23 08 Brain, Fetal 2.3 0.7 0.5 1.2 0.36 -0.16 -0.26 0.09 09 Brain, whole 1.0 0.3 0.4 0.7 -0.01 -0.52 -0.41 -0.16 10 ALZ Visual Cortex 0.5 0.2 0.2 0.3 -0.30 -0.73 -0.80 -0.60 Occipital 11 Mix, viscus tissues 1.0 1.0 1.0 1.0 0.0 0.0 0.0 0.0 12 Mix, blood cells and 2.1 1.0 0.9 1.0 0.33 0.01 -0.05 0.01 related tissues 13 Mix, tumor tissues 0.4 0.3 0.5 0.5 -0.45 -0.53 -0.30 -0.31 14 Mix, normal tissues 1.3 0.8 1.2 1.0 0.11 -0.11 0.07 0.00 15 Brain, whole PolyA(+) RNA 3.6 0.9 1.2 1.3 0.55 -0.05 0.09 0.10 16 Brain, hippocampus 1.9 0.4 0.7 0.7 0.27 -0.36 -0.13 -0.17

[0426] Expression levels were compared using the 16 samples shown in Example 3, including Brain, hippocampus, Brain, whole, Brain, Fetal, Alzheimer patient cerebral cortex (ALZ Visual Cortex Occipital) and NT2 cells at 7 different differentiation stages. The comparison was made using the mixed sample of normal visceral tissues shown in Example 3 (Mix, viscus tissues) as an experimental control.

[0427] The ratio of ORF alteration due to exon deletion selectivity as compared between 095.sub.--01 (SEQ ID NO:166) and 095.sub.--02 (SEQ ID NO:170) changed greatly among the following differentiation stages of the brain and NT2 cells.

The expression of the pattern of deletion of the exon shown by 095.sub.--01 (SEQ ID NO:166) was abundant in undifferentiated NT2 cells NT2RA (-) and NT2RA (+) 1 week, which represents the initial stage in which retinoic acid was added to induce differentiation. Although the expression decreased in NT2RA (+) 5 weeks to NT2RA(+) 5 weeks, Inh (+), which represent the late stage of differentiation induction, this pattern was again abundantly expressed in NT2 Neuron (Table 15).

[0428] The expression of the pattern of deletion of the exon shown by 095.sub.--02 (SEQ ID NO:170) was abundant in undifferentiated NT2 cells NT2RA (-) and NT2RA (+) 24 hr, which represents the initial stage in which retinoic acid was added to induce differentiation. In NT2RA (+) 5 weeks to NT2RA (+)5 weeks, Inh (+), which represent the late stage of differentiation, and NT2 Neuron, the expression level decreased (Table 15).

[0429] These results demonstrated that by comparing the expression of the selective exon regions 095.sub.--[1].sub.--1-N1 (SEQ ID NO:153) and 095.sub.--[2].sub.--1-N1 (SEQ ID NO:160) of newly acquired cDNAs shown by the detection regions 095.sub.--01 (SEQ ID NO:166) and 095.sub.--02 (SEQ ID NO:170), it is possible to use the exon regions as differentiation markers for detecting nerve cell differentiation or regeneration stages, particularly initial stages of differentiation into nerve cells.

[0430] Furthermore, it was demonstrated that the selective exon region 095.sub.--[1].sub.--1-N1 (SEQ ID NO:153) of a newly acquired cDNA shown by the detection region 095.sub.--01 (sequence No. 095-17), as a brain-specific marker, can be used as one of differentiation markers for detecting cells in nerve cell differentiation or regeneration stages, particularly those after nerve differentiation or nerve regeneration. It also seems possible to develop a new drug by means of a compound, antibody, siRNA or the like that targets a region that exhibits specificity.

[0431] The following regions also seem to be useful as differentiation markers for detecting nerve cell differentiation or regeneration.

Upstream sequence 095.sub.--[1].sub.--1-N3 (SEQ ID NO:180), which comprises the 304th to 326th bases undergoing priming by Primer095.sub.--01R (SEQ ID NO:165) in D-3NB692002462.1 of the cDNA pattern [1]. Upstream sequence 095.sub.--[2].sub.--1-N3 (SEQ ID NO:181), which comprises the 444th to 466th bases undergoing priming by Primer095.sub.--02R (SEQ ID NO:169) in D-BRCAN2027778.1 of the cDNA pattern [2]. Region 095.sub.--01 (SEQ ID NO:166) amplified by Primer095.sub.--01F (SEQ ID NO:164) and Primer095.sub.--01R (SEQ ID NO:165) in the cDNA pattern [1] Region 095.sub.--02 (SEQ ID NO:170) amplified by Primer095.sub.--02F (SEQ ID NO:168) and Primer095.sub.--02R (SEQ ID NO:169) in the cDNA pattern [2]

Example 12

Cluster chr12-1875 (Data Set: 017)

(1) Cluster Analysis

1) Cluster Characteristics

[0432] Analysis was performed on 10 sequences of full-length cDNAs genome-mapped to the cluster chr12-1875 (Human genome UCSC hg18 (NCBI Build34) chromosome 12, 7,840,000 bp to 7,960,000 bp) [D-NT2RI3001005.1, D-NT2RI3005261.1, AF481879.1, AL110298.1, AL832448.1, BC060766.1, C-TESTI1000257, C-TESTI4028880, ENST00000340749, NM.sub.--153449.2]. They were classified according to expression pattern difference into 4 kinds, which mainly included the following 2 kinds.

[1] D-NT2RI3001005.1, D-NT2RI3005261.1

[2] AF481879.1, C-TESTI4028880 (AK126026.1), NM.sub.--153449.2

[0433] [1] is a cDNA which was newly acquired and subjected to full-length cDNA sequence analysis by us, and had a different ORF region because of the expression thereof from a chromosome region upstream of the known [2], and also because of the presence of the translation initiation point on a new exon lacking identity to [2].

[0434] It was found that the ORF regions present in the 2 kinds of cDNA patterns [1] and [2] cause expression starting at different initiation points, from the same chromosome region, resulting in alterations of the amino acid sequences to produce diverse proteins and mRNAs.

2) Characteristics of D-NT2RI3001005.1 ([1]), which was Newly Acquired and Subjected to Full-Length cDNA Sequence Analysis by Us 017.sub.--[1].sub.--1-N0 (SEQ ID NO:182): The entire nucleic acid sequence region of D-NT2RI3001005.1 017.sub.--[1].sub.--1-NA0 (SEQ ID NO:183): Both the entire nucleic acid sequence region and amino acid sequence of D-NT2RI3001005.1 017.sub.--[1].sub.--1-A0 (SEQ ID NO:184): The entire amino acid sequence region of D-NT2RI3001005.1

[0435] The sequence at the 1st to 153rd bases of D-NT2RI3001005.1 (SEQ ID NO:185) is an exon that is not present in NM.sub.--153449.2, which is registered with an existing public DB, and serves for control, lacking homology to NM.sub.--153449.2. Because the translation initiation point is present on this exon, the amino acids on the N-terminal side changed by 44 residues (SEQ ID NO:186).

017.sub.--[1].sub.--1-N1 (SEQ ID NO:185): A 153-base insert nucleic acid sequence region of D-NT2RI3001005.1 017.sub.--[1].sub.--1-A1 (SEQ ID NO:186): A 44-residue insert amino acid sequence region of D-NT2RI3001005.1 017.sub.--[1].sub.--1-N2 (SEQ ID NO:187): An ORF nucleic acid sequence region in the 153-base insert region of D-NT2RI3001005.1 017.sub.--[1].sub.--1-A2 (identical to SEQ ID NO:186): An ORF amino acid sequence region in the 153-base insert region of D-NT2RI3001005.1 3) Characteristics of D-NT2RI3005261.1 ([1]), which was Newly Acquired and Subjected to Full-Length cDNA Sequence Analysis by Us 017.sub.--[1].sub.--2-N0 (SEQ ID NO:188): The entire nucleic acid sequence region of D-NT2RI3005261.1 017.sub.--[1].sub.--2-NA0 (SEQ ID NO:189): Both the entire nucleic acid sequence region and amino acid sequence of D-NT2RI3005261.1 017.sub.--[1].sub.--2-A0 (SEQ ID NO:190): The entire amino acid sequence region of D-NT2RI3005261.1

[0436] The sequence at the 1st to 153rd bases of D-NT2RI3005261.1 (SEQ ID NO:191) is an exon that is not present in NM.sub.--153449.2, which is registered with an existing public DB, and serves for control, lacking homology to NM.sub.--153449.2. Because the translation initiation point is present on this exon, the amino acids on the N-terminal side changed by 44 residues (SEQ ID NO:192).

017.sub.--[1].sub.--2-N1 (SEQ ID NO:191): A 153-base insert nucleic acid sequence region of D-NT2RI3005261.1 017.sub.--[1].sub.--2-A1 (SEQ ID NO:192): A 44-residue insert amino acid sequence region of D-NT2RI3005261.1 017.sub.--[1].sub.--2-N2 (SEQ ID NO:193): An ORF nucleic acid sequence region in the 153-base insert region of D-NT2RI3005261.1 017.sub.--[1].sub.--2-A2 (identical to SEQ ID NO:192): An ORF amino acid sequence region in the 153-base insert region of D-NT2RI3005261.1 4) Characteristics of C-TESTI4028880 (AK126026.1) ([2]), which was Acquired and Subjected to Full-Length cDNA Sequence Analysis by Us, and is Already Registered with a Public DB 017.sub.--[2].sub.--1-N0 (SEQ ID NO:194): The entire nucleic acid sequence region of C-TESTI4028880 017.sub.--[2].sub.--1-NA0 (SEQ ID NO:195): Both the entire nucleic acid sequence region and amino acid sequence of C-TESTI4028880 017.sub.--[2].sub.--1-A0 (SEQ ID NO:196): The entire amino acid sequence region of C-TESTI4028880

5) Expression Specificity Analysis and Design of Primers for Real-Time PCR

[0437] To clearly distinguish between the characteristic regions shown above, and examine the respective expression levels thereof, the following regions were used as detection regions. It seemed possible to compare the expression levels of the individual characteristic regions by comparing the expression levels of the detection regions.

017.sub.--01--A specific region present on the N-terminal side of the cDNA pattern [1]: a translation initiation region of the cDNA pattern [1], which was newly subjected to full-length cDNA sequence analysis by us, being a novel region not registered with an existing public DB .fwdarw.Fragment 017.sub.--01 (SEQ. ID NO:199) amplified by Primer017.sub.--01F (SEQ ID NO:197) and Primer017.sub.--01R (SEQ ID NO:198) 017.sub.--03--A common region shared by all of [1] to [2]: a region common to all patterns, serving for control to compare the overall expression levels of the cDNA pattern [1], which was newly subjected to full-length cDNA sequence analysis by us, and the cDNA pattern [2], which is registered with an existing public DB .fwdarw.Fragment 017.sub.--03 (SEQ ID NO:202) amplified by Primer017.sub.--03F (SEQ ID NO:200) and Primer017.sub.--03R (SEQ ID NO:201)

[0438] By mapping the 5'-terminal sequences of about 1.44 million sequences acquired using the oligocap method onto the human genome sequence, and comparatively analyzing them, the regions specific for the 2 kinds of cDNA patterns [1] to [2] shown above, respectively, were found to be expressed at the following frequencies.

[0439] In the cDNA pattern [1], which was newly acquired and analyzed by us, fourteen 5'-terminal sequences were present, the derivations thereof being NT2 cells treated with retinoic acid (RA) to induce differentiation for 5 weeks, and thereafter treated with a growth inhibitor for 2 weeks (NT2RI) for 13 sequences (analytical parameter 32,662), and NT2 cells treated with retinoic acid (RA) to induce differentiation (NT2RP) for 1 sequence (analytical parameter 39,242).

[0440] In the cDNA pattern [2], which is registered with an existing public DB, eighty-six 5'-terminal sequences were present, the derivations thereof being Testis for 85 sequences (analytical parameter 90,188), and NT2 cells treated with RA to induce differentiation for 5 weeks, and thereafter treated with a growth inhibitor for 2 weeks (NT2RI) for 1 sequence (analytical parameter 32,662).

[0441] From this result, it was found that the transcription initiation point of [1] was expressed specifically in NT2 cells after differentiation. From the transcription initiation point of [2], the expression in Testis was very abundant. Hence, it was thought that the mechanism of transcription in this chromosome region might be different only it the situation of nerve cell differentiation of NT2 cells after differentiation, with a different transcription initiation point being used.

(2) Analysis of Expression Specificity by Real-Time PCR

[0442] To determine what are the states in which the transcription initiation point used for the expression changes, details of expressions level were analyzed by real-time PCR. The results are shown in Table 16 and Table 17.

TABLE-US-00016 TABLE 16 RQ Score Log.sub.10RQ Score 017_01 017_03 017_01 017_03 01 NT2RA(-) 81.1 4.7 1.91 0.67 02 NT2RA(+) 24 hr 29.4 1.8 1.47 0.25 03 NT2RA(+) 48 hr 34.8 1.6 1.54 0.21 04 NT2RA(+) 1 week 177.5 2.6 2.25 0.41 05 NT2RA(+) 5 weeks 39.2 0.8 1.59 -0.07 06 NT2RA(+) 5 weeks, Inh(+) 1250.2 7.0 3.10 0.85 07 NT2 Neuron 319.1 0.6 2.50 -0.19 08 Brain, Fetal 1.2 1.5 0.07 0.18 09 Brain, whole 0.6 2.3 -0.25 0.35 10 ALZ Visual Cortex 0.6 0.6 -0.23 -0.21 Occipital 11 Mix, viscus tissues 1.0 1.0 0.0 0.0 12 Mix, blood cells and 1.4 2.1 0.15 0.32 related tissues 13 Mix, tumor tissues 0.6 0.3 -0.24 -0.60 14 Mix, normal tissues 32.4 1.1 1.51 0.06 15 Brain, whole PolyA(+) RNA 0.1 0.5 -0.88 -0.27 16 Brain, hippocampus 0.7 0.5 -0.15 -0.31

TABLE-US-00017 TABLE 17 RQ Score Log.sub.10RQ Score 017_01 017_03 017_01 017_03 01 NT2RA(-) 30.9 5.2 1.49 0.72 02 NT2RA(+) 24 hr 11.3 1.7 1.05 0.22 03 NT2RA(+) 48 hr 15.5 1.6 1.19 0.22 04 NT2RA(+) 1 week 77.1 2.9 1.89 0.46 05 NT2RA(+) 5 weeks 17.5 1.0 1.24 -0.02 06 NT2RA(+) 5 weeks, Inh(+) 497.7 7.6 2.70 0.88 07 NT2 Neuron 145.3 0.6 2.16 -0.20 08 Brain, Fetal 1.0 1.8 -0.02 0.24 09 Brain, whole 0.3 2.6 -0.57 0.41 10 ALZ Visual Cortex 0.3 0.7 -0.46 -0.14 Occipital 11 Mix, viscus tissues 1.0 1.0 0.0 0.0 12 Mix, blood cells and 0.9 2.7 -0.02 0.43 related tissues 13 Mix, tumor tissues 1.7 0.3 0.24 -0.57 14 Mix, normal tissues 19.8 1.2 1.30 0.07 15 Brain, whole PolyA(+) RNA 0.2 0.7 -0.79 -0.16 16 Brain, hippocampus 0.5 0.7 -0.29 -0.16 17 Colon 0.8 0.1 -0.12 -0.92 18 Colon Tumor Undet. 0.0 Undet. -1.65 19 Kidney 0.7 0.3 -0.15 -0.50 20 Kidney Tumor 0.0 0.2 -1.60 -0.61 21 Liver 2.2 0.1 0.34 -0.94 22 Liver Tumor 14.8 0.1 1.17 -0.94 23 Lung 0.1 2.0 -0.91 0.30 24 Lung Tumor 0.3 0.6 -0.60 -0.25 25 Ovary 93.4 2.0 1.97 0.29 26 Ovary Tumor 6.7 0.2 0.83 -0.70 27 Stomach 1.1 0.7 0.04 -0.17 28 Stomach Tumor Undet. 0.1 Undet. -1.25 29 Uterus 2.5 1.6 0.40 0.21 30 Uterus Tumor 0.6 0.3 -0.21 -0.53 31 Tongue 33.7 0.2 1.53 -0.65 32 Tumor Tongue 15.6 0.1 1.19 -0.91

[0443] Expression levels were compared using the 32 samples shown in Example 3, including Brain, hippocampus, Brain, whole, Brain, Fetal, Alzheimer patient cerebral cortex (ALZ Visual Cortex Occipital), NT2 cells at 7 different differentiation stages, 8 kinds of normal tissues, and 8 kinds of tumor tissues and the like. The comparison was made using the mixed sample of normal visceral tissues shown in Example 3 (Mix, viscus tissues) as an experimental control.

[0444] The transcription initiation point shown by 017.sub.--01 (SEQ ID NO:199) is used selectively in NT2 cells. Hence, in NT2 cells at all stages, whether undifferentiated or differentiated, the ratio of transcription from the upstream transcription initiation point was considerably high (Table 16 and Table 17).

[0445] These results demonstrated that by detecting the expression of the 5'-terminal regions (regions close to the transcription initiation point) 017.sub.--[1].sub.--1-N1 (SEQ ID NO:185) and 017.sub.--[1].sub.--2-N1 (SEQ ID NO:191) of a newly acquired cDNA region shown by the detection region 017.sub.--01 (SEQ ID NO:199), it is possible to use the 5'-terminal regions as nerve cell markers. It also seems possible to develop a new drug by means of a compound, antibody, siRNA or the like that targets a region that exhibits specificity.

[0446] The following regions also seem to be useful as nerve cell markers.

Upstream sequence 017.sub.--[1].sub.--1-N3 (SEQ ID NO:203), which comprises the 143rd to 159th bases undergoing priming by Primer017.sub.--01R (SEQ ID NO:198) in D-NT2RI3001005.1 of the cDNA pattern [1]. Upstream sequence 017.sub.--[1].sub.--2-N3 (SEQ ID NO:204), which comprises the 143rd to 159th bases undergoing priming by Primer017.sub.--01R (SEQ ID NO:198) in D-NT2RI3005261.1 of the cDNA pattern [1]. Region 017.sub.--01 (SEQ ID NO:199) amplified by Primer017.sub.--01F (SEQ ID NO:197) and Primer017.sub.--01R (SEQ ID NO:198) in the cDNA pattern [1].

Example 13

Cluster chr3-1507 (Data Set: 023)

(1) Cluster Analysis

1) Cluster Characteristics

[0447] An analysis was performed on 15 sequences of full-length cDNAs subjected to genome mapping onto the cluster chr3-1507 (Human genome UCSC hg18 (NCBI Build34) chromosome 3, 73,500,000 bp to 73,800,000 bp) [D-OCBBF2010718.1, D-OCBBF3004194.1, D-NT2RP8000826.1, D-NT2RP7007268.1, D-BRAWH3008172.1, D-BRAWH3011965.1, AB029018.1, AL049958.1, AL157498.1, BC014432.1, C-HEMBA1005489, ENST00000263666, ENST00000308537, ENST00000319719, NM.sub.--015009.1]. They were classified according to expression pattern difference into 8 kinds, which mainly included the following 5 kinds.

[1] D-OCBBF2010718.1, D-OCBBF3004194.1

[2] D-NT2RP8000826.1, D-NT2RP7007268.1

[3] D-BRAWH3008172.1

[4] D-BRAWH3011965.1

[5] AB029018.1, ENST00000263666, NM.sub.--015009.1

[0448] [1], [2], [3], and [4] are cDNAs which were newly acquired and subjected to full-length cDNA sequence analysis by us, and had a different ORF from [5], which had been registered with an existing public DB.

[0449] [1], [2], [3], and [4] had a different ORF region because of the expression thereof from a chromosome region located downstream of the known [5], and also because of the presence of a translation initiation point different from [5].

[0450] It was found that the ORF regions present in the 5 kinds of cDNA patterns [1] to [5] cause expression starting at different transcription initiation points, from the same chromosome region, resulting in alterations of the amino acid sequences to produce diverse proteins and mRNAs.

2) Characteristics of D-OCBBF2010718.1 ([1]), which was Newly Acquired and Subjected to Full-Length cDNA Sequence Analysis by Us 023.sub.--[1].sub.--1-N0 (SEQ ID NO:205): The entire nucleic acid sequence region of D-OCBBF2010718.1 023.sub.--[1].sub.--1-NA0 (SEQ ID NO:206): Both the entire nucleic acid sequence region and amino acid sequence of D-OCBBF2010718.1 023.sub.--[1].sub.--1-A0 (SEQ ID NO:207): The entire amino acid sequence region of D-OCBBF2010718.1

[0451] The 1st to 212th bases of D-OCBBF2010718.1 (SEQ ID NO:208) is an exon that is not present in NM.sub.--015009.1, which is registered with an existing public DB, and serves for control, lacking homology to NM.sub.--015009.1. Because the translation initiation point is present on this exon, the amino acids on the N-terminal side changed by 23 residues (SEQ ID NO:209).

023.sub.--[1].sub.--1-N1 (SEQ ID NO:208): A 212-base insert nucleic acid sequence region of D-OCBBF2010718.1 023.sub.--[1].sub.--1-A1 (SEQ ID NO:209): A 23-residue insert amino acid sequence region of D-OCBBF2010718.1 023.sub.--[1].sub.--1-N2 (SEQ ID NO:210): An ORF nucleic acid sequence region in the 212-base insert region of D-OCBBF2010718.1 023.sub.--[1].sub.--1-A2 (identical to SEQ ID NO:209): An ORF amino acid sequence region in the 212-base insert region of D-OCBBF2010718.1 3) Characteristics of D-OCBBF3004194.1 ([1]), which was Newly Acquired and Subjected to Full-Length cDNA Sequence Analysis by Us 023.sub.--[1].sub.--2-N0 (SEQ ID NO:211): The entire nucleic acid sequence region of D-OCBBF3004194.1 023.sub.--[1].sub.--2-NA0 (SEQ ID NO:212): Both the entire nucleic acid sequence region and amino acid sequence of D-OCBBF3004194.1 023.sub.--[1].sub.--2-A0 (SEQ ID NO:213): The entire amino acid sequence region of D-OCBBF3004194.1

[0452] The sequence at the 1st to 197th bases of D-OCBBF3004194.1 (SEQ ID NO:214) is an exon that is not present in NM.sub.--015009.1, which is registered with an existing public DB, and serves for control, lacking homology to NM.sub.--015009.1. Because the translation initiation point is present on this exon, the amino acids on the N-terminal side changed by 23 residues (SEQ ID NO:215).

023.sub.--[1].sub.--2-N1 (SEQ ID NO:214): A 197-base insert nucleic acid sequence region of D-OCBBF3004194.1 023.sub.--[1].sub.--2-A1 (SEQ ID NO:215): A 23-residue insert amino acid sequence region of D-OCBBF3004194.1 023.sub.--[1].sub.--2-N2 (SEQ ID NO:216): An ORF nucleic acid sequence region in the 197-base insert region of D-OCBBF3004194.1 023.sub.--[1].sub.--2-A2 (identical to SEQ ID NO:215): An ORF amino acid sequence region in the 197-base insert region of D-OCBBF3004194.1 4) Characteristics of D-NT2RP8000826.1 ([2]), which was Newly Acquired and Subjected to Full-Length cDNA Sequence Analysis by Us 023.sub.--[2].sub.--1-N0 (SEQ ID NO:217): The entire nucleic acid sequence region of D-NT2RP8000826.1 023.sub.--[2].sub.--1-NA0 (SEQ ID NO:218): Both the entire nucleic acid sequence region and amino acid sequence of D-NT2RP8000826.1 023.sub.--[2].sub.--1-A0 (SEQ ID NO:219): The entire amino acid sequence region of D-NT2RP8000826.1

[0453] The sequence at the 1st to 178th bases of D-NT2RP8000826.1 (SEQ ID NO:220) is an exon that is not present in NM.sub.--015009.1, which is registered with an existing public DB, and serves for control, lacking homology to NM.sub.--015009.1. Because the translation initiation point is present on this exon, the amino acids on the N-terminal side changed by 28 residues (SEQ ID NO:221).

023.sub.--[2].sub.--1-N1 (SEQ ID NO:220): A 178-base insert nucleic acid sequence region of D-NT2RP8000826.1 023.sub.--[2].sub.--1-A1 (SEQ ID NO:221): A 28-residue insert amino acid sequence region of D-NT2RP8000826.1 023.sub.--[2].sub.--1-N2 (SEQ ID NO:222): An ORF nucleic acid sequence region in the 178-base insert region of D-NT2RP8000826.1 023.sub.--[2].sub.--1-A2 (identical to SEQ ID NO:221): An ORF amino acid sequence region in the 178-base insert region of D-NT2RP8000826.1 5) Characteristics of D-NT2RP7007268.1 ([2]), which was Newly Acquired and Subjected to Full-Length cDNA Sequence Analysis by Us 023.sub.--[2].sub.--2-N0 (SEQ ID NO:223): The entire nucleic acid sequence region of D-NT2RP7007268.1 023.sub.--[2].sub.--2-NA0 (SEQ ID NO:224): Both the entire nucleic acid sequence region and amino acid sequence of D-NT2RP7007268.1 023.sub.--[2].sub.--2-A0 (SEQ ID NO:225): The entire amino acid sequence region of D-NT2RP7007268.1

[0454] The sequence at the 1st to 178th bases of D-NT2RP7007268.1 (SEQ ID NO:226) is an exon that is not present in NM.sub.--015009.1, which is registered with an existing public DB, and serve for control, lacking homology to NM.sub.--015009.1. Because the translation initiation point is present on this exon, the amino acids on the N-terminal side changed by 28 residues (SEQ ID NO:227).

023.sub.--[2].sub.--2-N1 (SEQ ID NO:226): A 178-base insert nucleic acid sequence region of D-NT2RP7007268.1 023.sub.--[2].sub.--2-A1 (SEQ ID NO:227): A 28-residue insert amino acid sequence region of D-NT2RP7007268.1 023.sub.--[2].sub.--2-N2 (SEQ ID NO:228): An ORF nucleic acid sequence region in the 178-base insert region of D-NT2RP7007268.1 023.sub.--[2].sub.--2-A2 (identical to SEQ ID NO:227): An ORF amino acid sequence region in the 178-base insert region of D-NT2RP7007268.1 6) Characteristics of D-BRAWH3008172.1 ([3]), which was Newly Acquired and Subjected to Full-Length cDNA Sequence Analysis by Us 023.sub.--[3].sub.--1-N0 (SEQ ID NO:229): The entire nucleic acid sequence region of D-BRAWH3008172.1 023.sub.--[3].sub.--1-NA0 (SEQ ID NO:230): Both the entire nucleic acid sequence region and amino acid sequence of D-BRAWH3008172.1 023.sub.--[3].sub.--1-A0 (SEQ ID NO:231): The entire amino acid sequence region of D-BRAWH3008172.1

[0455] The sequence at the 1st to 169th bases of D-BRAWH3008172.1 (SEQ ID NO:232) is an exon that is not present in NM.sub.--015009.1, which is registered with an existing public DB, and serves for control, lacking homology to NM.sub.--015009.1. With this change, the translation initiation point of D-BRAWH3008172.1 shifts toward the 3' side relative to NM.sub.--015009.1, and the 281st base of D-BRAWH3008172.1 becomes the translation initiation point. For this reason, the amino acid sequence shortened by 343 residues compared with NM.sub.--015009.1.

023.sub.--[3].sub.--1-N1 (SEQ ID NO:232): A 169-base insert nucleic acid sequence region of D-BRAWH3008172.1 023.sub.--[3].sub.--1-N2 (SEQ ID NO:233): A 280-base 5'UTR region of an ORF whose translation initiation point is the 281st base of D-BRAWH3008172.1 7) Characteristics of D-BRAWH3011965.1 ([4]), which was Newly Acquired and Subjected to Full-Length cDNA Sequence Analysis by Us 023.sub.--[4].sub.--1-N0 (SEQ ID NO:234): The entire nucleic acid sequence region of D-BRAWH3011965.1 023.sub.--[4].sub.--1-NA0 (SEQ ID NO:235): Both the entire nucleic acid sequence region and amino acid sequence of D-BRAWH3011965.1 023.sub.--[4].sub.--1-A0 (SEQ ID NO:236): The entire amino acid sequence region of D-BRAWH3011965.1

[0456] The sequence at the 1st to 311th bases of D-BRAWH3011965.1 (SEQ ID NO:237) is an exon that is not present in NM.sub.--015009.1, which is registered in an existing public DB and serves as a control, lacking homology to NM.sub.--015009.1. Because the translation initiation point is present on this exon, the amino acids on the N-terminal side changed by 4 residues (SEQ ID NO:238).

023.sub.--[4].sub.--1-N1 (SEQ ID NO:237): A 311-base insert nucleic acid sequence region of D-BRAWH3011965.1 023.sub.--[4].sub.--1-A1 (SEQ ID NO:238): A 4-residue insert amino acid sequence region of D-BRAWH3011965.1 023.sub.--[4].sub.--1-N2 (SEQ ID NO:239): An ORF nucleic acid sequence region in the 311-base insert region of D-BRAWH3011965.1 023.sub.--[4].sub.--1-A2 (identical to SEQ ID NO:238): An ORF amino acid sequence region in the 311-base insert region of D-BRAWH3011965.1

8) Expression Specificity Analysis and Design of Primers for Real-Time PCR

[0457] To clearly distinguish between the characteristic regions shown above, and examine the respective expression levels thereof, the following regions were used as detection regions. It seemed possible to compare the expression levels of the individual characteristic regions by comparing the expression levels of the detection regions.

023.sub.--01--A specific region present on the N-terminal side of the cDNA pattern [1]: a translation initiation region of the cDNA pattern [1], which was newly subjected to full-length cDNA sequence analysis by us, being a novel region not registered with an existing public DB .fwdarw.Fragment 023.sub.--01 (SEQ ID NO:242) amplified by Primer023.sub.--01F (SEQ ID NO:240) and Primer023.sub.--01R (SEQ ID NO:241) 023.sub.--02--A specific region present on the N-terminal side of the cDNA pattern [2]: a translation initiation region of the cDNA pattern [2], which was newly subjected to full-length cDNA sequence analysis by us, being a novel region not registered with an existing public DB .fwdarw.Fragment 023.sub.--02 (SEQ ID NO:245) amplified by Primer023.sub.--02F (SEQ ID NO:243) and Primer023.sub.--02R (SEQ ID NO:244) 023.sub.--03--A specific region present on the N-terminal side of the cDNA pattern [3]: a translation initiation region of the cDNA pattern [3], which was newly subjected to full-length cDNA sequence analysis by us, being a novel region not registered with an existing public DB .fwdarw.Fragment 023.sub.--03 (SEQ ID NO:248) amplified by Primer023.sub.--03F (SEQ ID NO:246) and Primer023.sub.--03R (SEQ ID NO:247) 023.sub.--04--A specific region present on the N-terminal side of the cDNA pattern [4]: a translation initiation region of the cDNA pattern [4], which was newly subjected to full-length cDNA sequence analysis by us, being a novel region not registered with an existing public DB .fwdarw.Fragment 023.sub.--04 (SEQ ID NO:251) amplified by Primer023.sub.--04F (SEQ ID NO:249) and Primer023.sub.--04R (SEQ ID NO:250) 023.sub.--05--A specific region of the cDNA pattern [5], which is registered with an existing public DB, that can be distinguished from all of [1], [2], [3], and [4], serving as a control for comparing [1], [2], [3], and [4] .fwdarw.Fragment 023.sub.--05 (SEQ ID NO:254) amplified by Primer023.sub.--05F (SEQ ID NO:252) and Primer023.sub.--05R (SEQ ID NO:253) 023.sub.--06--A common region shared by all of [1] to [5]: a region common to all patterns, serving for control to compare the overall expression levels of the cDNA patterns [1], [2], [3], and [4], which were newly subjected to full-length cDNA sequence analysis by us, and the cDNA pattern [5] registered with an existing public DB .fwdarw.Fragment 023.sub.--06 (SEQ ID NO:257) amplified by Primer023.sub.--06F (SEQ ID NO:255) and Primer023.sub.--06R (SEQ ID NO:256)

[0458] By mapping the 5'-terminal sequences of about 1.44 million sequences acquired using the oligocap method onto the human genome sequence, and comparatively analyzing them, the regions specific for the 2 kinds of cDNA patterns [1] to [2] shown above, respectively, were found to be expressed at the following frequencies.

[0459] In the cDNA pattern [1], which was newly acquired and analyzed by us, thirty-two 5'-terminal sequences were present, the derivations thereof being NT2 cells treated with retinoic acid (RA) to induce differentiation (NT2RP) for 21 sequences (analytical parameter 39,242), Brain, Fetal for 8 sequences (analytical parameter 103,138), NT2 cells treated with retinoic acid (RA) to induce differentiation for 5 weeks, and thereafter treated with a growth inhibitor for 2 weeks (NT2RI) for 1 sequence (analytical parameter 32,662), Brain, hippocampus for 1 sequence (analytical parameter 57,918), and Brain, amygdala for 1 sequence (analytical parameter 58,640).

[0460] In the cDNA pattern [2], which was newly acquired and analyzed by us, twenty 5'-terminal sequences were present, the derivation thereof being NT2 cells treated with retinoic acid (RA) to induce differentiation (NT2RP) for the 20 sequences (analytical parameter 39,242).

[0461] In the cDNA pattern [3], which was newly acquired and analyzed by us, sixteen 5'-terminal sequences were present, the derivations thereof being Brain, whole for 8 sequences (analytical parameter 59,069), Brain, amygdala for 5 sequences (analytical parameter 58,640), Kidney, Tumor for 1 sequence (analytical parameter 15,970), Brain, thalamus for 1 sequence (analytical parameter 53,267), and Testis for 1 sequence (analytical parameter 90,188).

[0462] In the cDNA pattern [4], which was newly acquired and analyzed by us, five 5'-terminal sequences were present, the derivations thereof being Brain, whole for 3 sequences (analytical parameter 59,069), Brain, hippocampus for 1 sequence (analytical parameter 57,918), and Brain, thalamus for 1 sequence (analytical parameter 53,267).

[0463] In the cDNA pattern [5], which is registered with an existing public DB, two 5'-terminal sequences were present, the derivations thereof being Stomach, Tumor for 1 sequence (analytical parameter 2,757), and Prostate for 1 sequence (analytical parameter 16,671).

[0464] From this result, it was found that the transcription initiation point of [1] was abundantly expressed in differentiated NT2 cells and the fetal brain. It was found that the transcription initiation point of [2] was abundantly expressed in differentiated NT2 cells. It was found that the transcription initiation points of [3] and [4] were abundantly expressed in the brain. The known sequence [5] was expressed in gastric cancer and the prostate. Hence, it was thought that the mechanism of transcription in this chromosome region might differ among various organs and cell conditions, with different transcription initiation points being used.

(2) Analysis of Expression Specificity by Real-Time PCR

[0465] To determine what are the states in which the transcription initiation point used for expression changes, details of expression levels were analyzed by real-time PCR. The results are shown in Tables 18-1 and 18-2 and Tables 19-1 and 19-2.

TABLE-US-00018 TABLES 18-1, 18-2 RQ Score Log.sub.10RQ Score 023_01 023_02 023_03 023_04 023_05 023_06 023_01 023_02 023_03 023_04 023_05 023_06 01 NT2RA(-) 0.0 0.0 Undet. 0.0 0.0 0.0 -2.32 -2.82 Undet. -2.07 -1.63 -1.54 02 NT2RA(+) 24 hr 0.1 0.1 0.0 0.2 0.0 0.0 -1.11 -1.22 -3.03 -0.71 -1.62 -1.40 03 NT2RA(+) 48 hr 1.3 0.4 0.0 0.8 0.1 0.2 0.12 -0.38 -2.12 -0.11 -1.13 -0.81 04 NT2RA(+) 1 week 19.1 1.8 0.1 5.6 0.3 1.8 1.28 0.25 -1.24 0.75 -0.55 0.25 05 NT2RA(+) 5 weeks 39.7 1.2 0.0 0.2 0.4 1.9 1.60 0.08 -1.58 -0.63 -0.43 0.27 06 NT2RA(+) 5 weeks, Inh(+) 2.0 0.0 0.0 0.1 0.1 0.3 0.30 -1.64 -1.65 -1.29 -0.84 -0.55 07 NT2 Neuron 2.9 0.7 0.0 1.4 0.0 0.2 0.46 -0.17 -1.95 0.16 -1.77 -0.66 08 Brain, Fetal 53.3 3.5 34.6 11.3 1.7 3.5 1.73 0.54 1.54 1.05 0.23 0.54 09 Brain, whole 0.8 1.0 58.9 2.7 0.4 1.0 -0.12 -0.01 1.77 0.42 -0.46 0.01 10 ALZ Visual Cortex 0.5 0.6 27.6 1.2 0.2 0.6 -0.26 -0.24 1.44 0.07 -0.71 -0.20 Occipital 11 Mix, viscus tissues 1.0 1.0 1.0 1.0 1.0 1.0 0.0 0.0 0.0 0.0 0.0 0.0 12 Mix, blood cells and 1.0 0.3 0.3 0.6 0.3 0.4 -0.02 -0.54 -0.51 -0.20 -0.46 -0.40 related tissues 13 Mix, tumor tissues 1.0 0.1 0.0 0.0 0.1 0.3 -0.01 -1.22 -1.36 -1.41 -0.87 -0.50 14 Mix, normal tissues 2.1 2.9 3.0 4.2 2.3 2.4 0.33 0.47 0.48 0.63 0.36 0.37 15 Brain, whole PolyA(+) RNA 0.2 0.1 19.0 0.8 0.1 0.4 -0.71 -0.99 1.28 -0.12 -1.01 -0.38 16 Brain, hippocampus 0.3 0.0 9.7 0.4 0.1 0.3 -0.55 -1.39 0.98 -0.40 -0.96 -0.48

TABLE-US-00019 TABLES 19-1, 19-2 RQ Score Log.sub.10RQ Score 023_01 023_02 023_03 023_04 023_05 023_06 023_01 023_02 023_03 023_04 023_05 023_06 01 NT2RA(-) 0.0 0.0 Undet. 0.0 0.0 0.0 -2.22 -2.59 Undet. -1.70 -1.59 -1.53 02 NT2RA(+) 24 hr 0.1 0.1 0.0 0.5 0.0 0.0 -1.02 -0.91 -2.71 -0.31 -1.54 -1.34 03 NT2RA(+) 48 hr 1.7 0.6 0.0 1.2 0.1 0.2 0.23 -0.20 -2.18 0.08 -0.96 -0.65 04 NT2RA(+) 1 week 25.8 3.2 0.1 10.6 0.4 2.6 1.41 0.51 -0.96 1.03 -0.39 0.42 05 NT2RA(+) 5 weeks 48.9 1.8 0.0 0.2 0.5 3.0 1.69 0.26 -1.37 -0.62 -0.29 0.48 06 NT2RA(+) 5 weeks, Inh(+) 2.8 0.0 0.0 0.1 0.2 0.5 0.45 -1.36 -1.66 -1.02 -0.66 -0.32 07 NT2 Neuron 3.1 0.9 0.0 2.3 0.0 0.3 0.49 -0.02 -1.45 0.35 -1.85 -0.58 08 Brain, Fetal 67.9 6.0 54.2 25.8 1.9 4.3 1.83 0.78 1.73 1.41 0.29 0.63 09 Brain, whole 0.8 1.5 90.6 5.4 0.4 1.0 -0.10 0.17 1.96 0.74 -0.44 0.02 10 ALZ Visual Cortex 0.6 0.9 40.4 2.5 0.2 0.6 -0.21 -0.07 1.61 0.40 -0.65 -0.26 Occipital 11 Mix, viscus tissues 1.0 1.0 1.0 1.0 1.0 1.0 0.0 0.0 0.0 0.0 0.0 0.0 12 Mix, blood cells and 1.2 0.4 0.7 1.2 0.3 0.4 0.06 -0.35 -0.16 0.07 -0.50 -0.42 related tissues 13 Mix, tumor tissues 1.0 0.1 0.0 0.0 0.1 0.3 -0.02 -1.29 -1.53 -1.41 -0.92 -0.58 14 Mix, normal tissues 2.2 4.0 4.3 6.6 2.2 2.3 0.34 0.60 0.63 0.82 0.35 0.37 15 Brain, whole PolyA(+) RNA 0.3 0.2 31.4 1.3 0.1 0.5 -0.54 -0.75 1.50 0.12 -0.88 -0.28 16 Brain, hippocampus 0.4 0.1 16.0 0.7 0.1 0.5 -0.40 -1.13 1.20 -0.15 -0.86 -0.30 17 Brain, cerebellum 0.1 0.0 0.1 0.0 0.1 0.2 -0.86 -1.81 -0.86 -1.80 -1.09 -0.79 18 Brain, amygdala 1.4 0.1 11.9 0.5 0.1 0.5 0.14 -1.11 1.08 -0.33 -1.02 -0.31 19 Brain, caudate nucleus 0.1 0.0 1.3 0.1 0.1 0.2 -1.15 -1.56 0.12 -0.84 -1.13 -0.70 20 Brain, corpus callosum 0.1 0.0 1.1 0.2 0.1 0.2 -1.14 -1.61 0.05 -0.64 -1.05 -0.64 21 Brain, substantia nigra 0.1 0.1 2.4 0.3 0.1 0.2 -0.83 -1.13 0.39 -0.56 -1.04 -0.73 22 Brain, thalamus 0.2 0.0 4.4 0.2 0.0 0.2 -0.78 -1.57 0.65 -0.77 -1.41 -0.82 23 Brain, subthalamic nucleus 0.0 0.0 0.3 0.0 0.1 0.2 -1.70 -2.49 -0.55 -1.82 -1.24 -0.77

[0466] Expression levels were compared using the 23 samples shown in Example 3, including Brain, hippocampus, Brain, whole, Brain, Fetal, Alzheimer patient cerebral cortex (ALZ Visual Cortex Occipital), NT2 cells at 7 different differentiation stages, and 7 kinds of brain tissues. The comparison was made using the mixed sample of normal visceral tissues shown in Example 3 (Mix, viscus tissues) as an experimental control.

[0467] The transcription initiation points shown by 023.sub.--01 (SEQ ID NO:242), 023.sub.--02 (SEQ ID NO:245), and 023.sub.--04 (SEQ ID NO:251) were abundantly expressed in NT2 cells after differentiation, particularly in NT2RA (+) 1 week, which represents an advanced stage of differentiation, whereas 023.sub.--01 (SEQ ID NO:242) was most abundantly expressed in NT2RA (+) 5 weeks (Tables 18-1 and 18-2 and Tables 19-1 and 19-2). In the brain tissues, the expression from the transcription initiation points shown by 023.sub.--01 (SEQ ID NO:242), 023.sub.--03 (SEQ ID NO:248), and 023.sub.--04 (SEQ ID NO:251) was abundant, with the expression in Brain, Fetal being particularly abundant (Tables 18-1 and 18-2 and Tables 19-1 and 19-2).

[0468] These results demonstrated that by comparing the expression of transcription initiation point regions 023.sub.--[1].sub.--1-N1 (SEQ ID NO:208), 023.sub.--[1].sub.--2-N1 (SEQ ID NO:214), 023.sub.--[2].sub.--1-N1 (SEQ ID NO:220), 023.sub.--[2].sub.--2-N1 (SEQ ID NO:226), 023.sub.--[3].sub.--1-N1 (SEQ ID NO:232), and 023.sub.--[4].sub.--1-N1 (SEQ ID NO:237) of newly acquired cDNAs shown by the detection regions 023.sub.--01 (SEQ ID NO:242), 023.sub.--02 (SEQ ID NO:245), 023.sub.--03 (SEQ ID NO:248), and 023.sub.--04 (SEQ ID NO:251), it is possible to use these regions as differentiation markers for detecting nerve cell differentiation or regeneration stages, or as brain-specific markers. It also seems possible to develop a new drug by means of a compound, antibody, siRNA or the like that targets a region that exhibits specificity.

[0469] The following regions also seem to be useful as differentiation markers for detecting stages of nerve cell differentiation or regeneration and brain-specific markers.

Upstream sequence 023.sub.--[1].sub.--1-N3 (SEQ ID NO:258), which comprises the 191st to 219th bases undergoing priming by Primer023.sub.--01R (SEQ ID NO:241) in D-OCBBF2010718.1 of the cDNA pattern [1]. Upstream sequence 023.sub.--[1].sub.--2-N3 (SEQ ID NO:259), which comprises the 181st to 204th bases undergoing priming by Primer023.sub.--01R (SEQ ID NO:241) in D-OCBBF3004194.1 of the cDNA pattern [1]. Upstream sequence 023.sub.--[2].sub.--1-N3 (SEQ ID NO:260), which comprises the 158th to 179th bases undergoing priming by Primer023.sub.--02R (SEQ ID NO:244) in D-NT2RP8000826.1 of the cDNA pattern [2]. Upstream sequence 023.sub.--[2].sub.--2-N3 (SEQ ID NO:261), which comprises the 161st to 180th bases undergoing priming by Primer023.sub.--02R (SEQ ID NO:244) in D-NT2RP7007268.1 of the cDNA pattern [2]. Upstream sequence 023.sub.--[3].sub.--1-N3 (SEQ ID NO:262), which comprises the 293rd to 316th bases undergoing priming by Primer023.sub.--03R (SEQ ID NO:247) in D-BRAWH3008172.1 of the cDNA pattern [3]. Upstream sequence 023.sub.--[4].sub.--1-N3 (SEQ ID NO:263), which comprises the 65th to 84th bases undergoing priming by Primer023.sub.--04R (SEQ ID NO:250) in D-BRAWH3011965.1 of the cDNA pattern [4]. Region 023.sub.--01 (SEQ ID NO:242) amplified by Primer023.sub.--01F (SEQ ID NO:240) and Primer023.sub.--01R (SEQ ID NO:241) in the cDNA pattern [1]. Region 023.sub.--02 (SEQ ID NO:245) amplified by Primer023.sub.--02F (SEQ ID NO:243) and Primer023.sub.--02R (SEQ ID NO:244) in the cDNA pattern [2]. Region 023.sub.--03 (SEQ ID NO:248) amplified by Primer023.sub.--03F (SEQ ID NO:246) and Primer023.sub.--03R (SEQ ID NO:247) in the cDNA pattern [3]. Region 023.sub.--04 (SEQ ID NO:251) amplified by Primer023.sub.--04F (SEQ ID NO:249) and Primer023.sub.--04R (SEQ ID NO:250) in the cDNA pattern [4].

Example 14

OFR Information on Full-Length cDNA Sequences and Results of Homology Analysis and Results of Analysis of Motif and the Like

[0470] To determine the functions of 19 sequences of full-length cDNAs that were newly acquired and subjected to full-length cDNA sequence analysis by us, ORF prediction and annotation analysis were performed. Results of the annotation analysis can be updated when the database or analytical software for comparison is upgraded. Thereby, it is sometimes possible to newly add an annotation to sequences with no annotation given under the same conditions.

1) Prediction of ORFs of cDNAs undergoing Full-Length cDNA Sequence Analysis

[0471] Using ORF prediction/evaluation systems such as ATGpr (A. Salamov et al. (1998) Bioinformatics 14: 384-390) and TRins (K. Kimura et al. (2003) Genome Informatics 14: 456-457), ORFs were predicted from full-length cDNA sequences. The ORF region information predicted from the full-length cDNA sequences is shown below.

[0472] The ORF regions were denoted in compliance with the rules of "DDBJ/EMBL/GenBank Feature Table Definition" (http://www.ncbi.nlm.nih.gov/collab/FT/index.html). The ORF start position is the first character of the methionine-encoding base "ATG", and the stop position represents the third character of the stop codon. These are indicated by a partition "..". However, for the ORFs that do not have a stop codon, the stop position is indicated with the use of ">" in compliance with the denotation rules.

TABLE-US-00020 Name of cDNA sequence ORF region D-UTERU2026184.1 191 . . . 2119 D-BRACE3000012.1 465 . . . 2558 D-NT2RP8004156.1 131 . . . 1387 D-NT2RI3005525.1 45 . . . 1292 D-NT2RP8004592.1 620 . . . 1183 D-NT2RI2014164.1 162 . . . 1397 D-BRAMY2029564.1 143 . . . 1657 D-BRHIP2003515.1 84 . . . 707 D-BRACE2044661.1 297 . . . 878 D-3NB692002462.1 343 . . . 951 D-BRCAN2027778.1 52 . . . 1086 D-NT2RI3001005.1 22 . . . 1629 D-NT2RI3005261.1 22 . . . 1629 D-OCBBF2010718.1 144 . . . 2495 D-OCBBF3004194.1 129 . . . 2480 D-NT2RP8000826.1 95 . . . 2461 D-NT2RP7007268.1 95 . . . 2461 D-BRAWH3008172.1 281 . . . 2452 D-BRAWH3011965.1 300 . . . >1574

2) Results of Homology Analysis Using BLASTP (SwissProt)

[0473] Homology analysis was performed on the 19 ORF sequences shown in Example 14-1), using BLASTP (blastall 2.2.6; ftp://ftp.ncbi.nih.gov/blast/), for SwissProt of the Aug. 22, 2006 version (ftp://us.expasy.org/databases/swiss-prot/). Based on the results of the homology analysis, the sequences showing the highest homology with an E-value of 1E-10 or less are shown below. In the following cases, however, the applicable candidate is not selected, but the next candidate is shown.

Having a definition beginning with "ALU SUBFAMILY" Having a definition beginning with "Alu subfamily" Having a definition beginning with "!!!! ALU SUBFAMILY" Having a definition beginning with "B-CELL GROWTH FACTOR PRECURSOR" Having a definition including "NRK2" Having a definition beginning with "PROLINE-RICH" Having a definition beginning with "GLYCINE-RICH" Having a definition beginning with "EXTENSIN PRECURSOR" Having a definition beginning with "COLLAGEN" Having a definition beginning with "100 KD" Having a definition beginning with "RETROVIRUS-RELATED POL POLYPROTEIN" Having a definition beginning with "CUTICLE COLLAGEN" Having a definition beginning with "HYPOTHETICAL" Having a definition beginning with "Hypothetical" Having a definition beginning with "SALIVARY PROLINE-RICH PROTEIN" Having a definition beginning with "IMMEDIATE-EARLY PROTEIN" Having the accession No "P49646"

[0474] Individual data are shown with the name of cDNA sequence, ORF region, hit data accession number, hit data definition, hit data keyword, E-value, consensus length (amino acid length), and identity, separated by "//" in this order.

D-UTERU2026184.1// 191..2119// Q8TF45// Zinc finger protein 418// DNA-binding; Metal-binding; Nuclear protein; Repeat; Repressor; Transcription; Transcription regulation; Zinc; Zinc-finger.// 0// 601// 100 D-BRACE3000012.1// 465..2558// Q8TF45// Zinc finger protein 418// DNA-binding; Metal-binding; Nuclear protein; Repeat; Repressor; Transcription; Transcription regulation; Zinc; Zinc-finger.// 0// 674// 99 D-NT2RP8004156.1// 131..1387// P31749// RAC-alpha serine/threonine-protein kinase (EC2.7.11.1) (RAC-PK-alpha) (Protein kinase B) (PKB)(C-AKT)// 3D-structure; Apoptosis; ATP-binding; Carbohydrate metabolism; Glucose metabolism; Glycogen biosynthesis; Glycogen metabolism; Kinase; Nuclear protein; Nucleotide-binding; Phosphorylation; Serine/threonine-protein kinase; Sugar transport; Transferase; Translation regulation; Transport.// 0// 418// 100 D-NT2RI3005525.1// 45..1292// Q7Z698// Sprouty-related, EVH1-domain-containingprotein 2 (Spred-2)// Membrane; Phosphorylation.// 0// 409// 99 D-NT2RI2014164.1// 162..1397// P27338// Amine oxidase [flavin-containing] B (EC1.4.3.4) (Monoamine oxidase type B) (MAO-B)// 3D-structure; Acetylation; Direct protein sequencing; FAD; Flavoprotein; Membrane; Mitochondrion; Oxidoreductase; Transmembrane.// 0// 367// 93 D-BRAMY2029564.1// 143..1657// P27338// Amine oxidase [flavin-containing] B (EC1.4.3.4) (Monoamine oxidase type B) (MAO-B)// 3D-structure; Acetylation; Direct protein sequencing; FAD; Flavoprotein; Membrane; Mitochondrion; Oxidoreductase; Transmembrane.// 0// 504// 100 D-BRHIP2003515.1// 84.707// P55327// Tumor protein D52 (N8 protein)// Coiled coil.// 7E-93// 184// 88 D-BRACE2044661.1// 297.878// P54709// Sodium/potassium-transporting ATPase subunitbeta-3 (Sodium/potassium-dependent ATPase beta-3subunit) (ATPB-3) (CD298 antigen)// Glycoprotein; Ion transport; Membrane; Potassium; Potassium transport; Signal-anchor; Sodium; Sodium transport; Sodium/potassium transport; Transmembrane; Transport.// 1E-90// 158// 97 D-3NB692002462.1// 343..951// Q03426// Mevalonate kinase (EC 2.7.1.36) (MK)// ATP-binding; Cataract; Cholesterol biosynthesis; Disease mutation; Kinase; Lipid synthesis; Nucleotide-binding; Peroxisome; Polymorphism; Steroid biosynthesis; Sterol biosynthesis; Transferase.// 1E-112//202//100 D-BRCAN2027778.1// 52.1086// Q03426// Mevalonate kinase (EC 2.7.1.36) (MK)// ATP-binding; Cataract; Cholesterol biosynthesis; Disease mutation; Kinase; Lipid synthesis; Nucleotide-binding; Peroxisome; Polymorphism; Steroid biosynthesis; Sterol biosynthesis; Transferase.// 0// 343// 86 D-NT2RI3001005.1// 22.1629// Q8TDB8// Solute carrier family 2, facilitated glucosetransporter member 14 (Glucose transporter type 14)// Alternative splicing; Developmental protein; Differentiation; Glycoprotein; Membrane; Spermatogenesis; Sugar transport; Transmembrane; Transport.// 0// 490// 99 D-NT2RI3005261.1// 22..1629// Q8TDB8// Solute carrier family 2, facilitated glucosetransporter member 14 (Glucose transporter type 14)// Alternative splicing; Developmental protein; Differentiation; Glycoprotein; Membrane; Spermatogenesis; Sugar transport; Transmembrane; Transport.// 0// 491// 100 D-OCBBF2010718.1// 144..2495// Q9UPQ7// PDZ domain-containing RING finger protein 3(Ligand of Numb-protein X 3) (Semaphorin cytoplasmicdomain-associated protein 3) (SEMACAP3 protein)// 3D-structure; Alternative splicing; Coiled coil; Metal-binding; Polymorphism; Repeat; Zinc; Zinc-finger.// 0// 758// 99 D-OCBBF3004194.1// 129.2480// Q9UPQ7// PDZ domain-containing RING finger protein 3(Ligand of Numb-protein X 3) (Semaphorin cytoplasmicdomain-associated protein 3) (SEMACAP3 protein)// 3D-structure; Alternative splicing; Coiled coil; Metal-binding; Polymorphism; Repeat; Zinc; Zinc-finger.// 0// 760// 99 D-NT2RP8000826.1// 95.2461// Q9UPQ7// PDZ domain-containing RING finger protein 3(Ligand of Numb-protein X 3) (Semaphorin cytoplasmicdomain-associated protein 3) (SEMACAP3 protein)// 3D-structure; Alternative splicing; Coiled coil; Metal-binding; Polymorphism; Repeat; Zinc; Zinc-finger.// 0// 759// 99 D-NT2RP7007268.1// 95..2461// Q9UPQ7// PDZ domain-containing RING finger protein 3(Ligand of Numb-protein X 3) (Semaphorin cytoplasmicdomain-associated protein 3) (SEMACAP3 protein)// 3D-structure; Alternative splicing; Coiled coil; Metal-binding; Polymorphism; Repeat; Zinc; Zinc-finger.// 0// 759// 99 D-BRAWH3008172.1// 281..2452// Q9UPQ7// PDZ domain-containing RING finger protein 3(Ligand of Numb-protein X 3) (Semaphorin cytoplasmicdomain-associated protein 3) (SEMACAP3 protein)// 3D-structure; Alternative splicing; Coiled coil; Metal-binding; Polymorphism; Repeat; Zinc; Zinc-finger.// 0// 722// 99 D-BRAWH3011965.1// 300..>1574// Q9UPQ7// PDZ domain-containing RING finger protein 3(Ligand of Numb-protein X 3) (Semaphorin cytoplasmicdomain-associated protein 3) (SEMACAP3 protein)// 3D-structure; Alternative splicing; Coiled coil; Metal-binding; Polymorphism; Repeat; Zinc; Zinc-finger.// 0// 421// 99

3) Results of Homology Analysis Using BLASTP (RefSeq)

[0475] Homology analysis was performed on the 19 ORF sequences shown in Example 14-1), using BLASTP (blastall 2.2.6; ftp://ftp.ncbi.nih.gov/blast/), for RefSeq of the Jul. 15, 2006 version (human, mouse, rat; ftp://ftp.ncbi.nih.gov/refseq/). Based on the results of the homology analysis, the sequences showing the highest homology with an E-value of 1E-10 or less are shown below. In the following cases, however, the applicable candidate is not selected, but the next candidate is shown.

Having a definition beginning with "hypothetical protein FLJ" Having a definition beginning with "KIAA" Having a definition beginning with "hypothetical protein DKFZ" Having a definition beginning with "DKFZ" Having a definition beginning with "RIKEN cDNA" Having a definition beginning with "hypothetical protein MGC" Having a definition of "hypothetical protein" Having a definition beginning with "hypothetical protein PP" Having the definition as "neuronal thread protein" Having a definition beginning with "clone FLB" Having a definition beginning with "hypothetical protein PRO" Having the definition as "PRO0483 protein" Having a definition including "MNC" Having a definition including "MOST-1" Having a definition beginning with "similar to" Having a definition including "TPR gene on Y" Having a definition beginning with "HSPC" Having a definition beginning with "CGI-"

[0476] Individual data are shown with the name of cDNA sequence, ORF region, hit data accession number, hit data definition, E-value, consensus length (amino acid length), and identity separated by "//" in this order.

D-UTERU2026184.1// 191..2119// NP.sub.--597717.1// zinc finger protein 418 [Homo sapiens]// 0// 601// 100 D-BRACE3000012.1// 465..2558// NP.sub.--597717.1// zinc finger protein 418 [Homo sapiens]// 0// 674// 99 D-NT2RP8004156.1// 131..1387// NP.sub.--005154.2// v-akt murine thymoma viral oncogene homolog 1 [Homo sapiens]// 0// 418// 100 D-NT2RI3005525.1// 45..1292// NP.sub.--861449.1// sprouty-related protein with EVH-1 domain 2 [Homo sapiens]// 0// 408// 99 D-NT2RP8004592.1// 620..1183// NP.sub.--003921.2// src family associated phosphoprotein 2 [Homo sapiens]// 1E-110// 187// 100 D-NT2RI2014164.1// 162..1397// NP.sub.--000889.3// amine oxidase (flavin-containing) [Homo sapiens]// 0// 367// 93 D-BRAMY2029564.1// 143..1657// NP.sub.--000889.3// amine oxidase (flavin-containing) [Homo sapiens]// 0// 504// 100 D-BRHIP2003515.1// 84..707// NP.sub.--001020424.1// tumor protein D52 isoform 2 [Homo sapiens]// 1E-110// 207// 100 D-BRACE2044661.1// 297..878// NP.sub.--001670.1// Na+/K+-ATPase beta 3 subunit [Homo sapiens]// 5E-91// 158// 97 D-3NB692002462.1// 343..951// NP.sub.--000422.1// mevalonate kinase [Homo sapiens]// 1E-112// 202// 100 D-BRCAN2027778.1// 52..1086// NP.sub.--000422.1// mevalonate kinase [Homo sapiens]// 0// 343// 86 D-NT2RI3001005.1// 22..1629// NP.sub.--703150.1// glucose transporter 14 [Homo sapiens]// 0// 490// 99 D-NT2RI3005261.1// 22..1629// NP.sub.--703150.1// glucose transporter 14 [Homo sapiens]// 0// 491// 100 D-OCBBF2010718.1// 144..2495// NP.sub.--055824.1// PDZ domain containing RING finger 3 [Homo sapiens]// 0// 758// 99 D-OCBBF3004194.1// 129..2480// NP.sub.--055824.1// PDZ domain containing RING finger 3 [Homo sapiens]// 0// 760// 99 D-NT2RP8000826.1// 95..2461// NP.sub.--055824.1// PDZ domain containing RING finger 3 [Homo sapiens]// 0// 759// 99 D-NT2RP7007268.1// 95..2461// NP.sub.--055824.1// PDZ domain containing RING finger 3 [Homo sapiens]// 0// 759// 99 D-BRAWH3008172.1// 281..2452// NP.sub.--055824.1// PDZ domain containing RING finger 3 [Homo sapiens]// 0// 722// 99 D-BRAWH3011965.1// 300..>1574// NP.sub.--055824.1// PDZ domain containing RING finger 3 [Homo sapiens]// 0// 421// 99

4) Results of Motif Homology Analysis Using Pfam

[0477] Motif homology analysis was performed on the 19 ORF sequences shown in Example 14-1), using Pfam (ftp://ftp.sanger.ac.uk/pub/databases/Pfam/). The analytical program used was hmmpfam v2.3.2, and the analysis was performed for the November 2005 version of Pfam19.0. Based on the results of the homology analysis, the sequences showing the highest homology with an E-value of 1E-10 or less are shown below.

[0478] Individual data are shown with the name of cDNA sequence and ORF region, followed by hit data accession number, hit data name, hit data description, E-value, and InterPro ID, separated by " " in this order, presented repeatedly using as many "//" partitions as the hit data.

D-BRACE3000012.1// 465..2558// PF01352.15 KRAB KRAB box 2.1e-20 IPR001909 D-NT2RP8004156.1// 131..1387// PF00069.14 Pkinase Protein kinase domain 1.6e-113 IPR000719//PF07714.5 Pkinase_Tyr Protein tyrosine kinase 1.3e-18 // PF00433.12 Pkinase_C Protein kinase C terminal domain 1.4e-11 IPR000961 D-NT2RI3005525.1// 45..1292// PF05210.2 Sprouty Sprouty protein (Spry) 2.7e-11 IPR007875 D-NT2RI2014164.1// 162..1397// PF01593.12 Amino_oxidase Flavin containing amine oxidoreductase 9.2e-57 IPR002937 D-BRAMY2029564.1// 143..1657// PF01593.12 Amino_oxidase Flavin containing amine oxidoreductase 5.8e-103 IPR002937 D-BRHIP2003515.1// 84..707// PF04201.4 TPD52 Tumour protein D52 family 1.5e-119 IPR007327 D-BRACE2044661.1// 297..878// PF00287.7 Na_K-ATPase Sodium/potassium ATPase beta chain 3.1e-32 IPR000402 D-NT2RI3001005.1// 22..1629// PF00083.13 Sugar_tr Sugar (and other) transporter 6.3e-200 IPR005828// PF07690.5 MFS.sub.--1 Major Facilitator Superfamily 1.1e-14 IPR011701 D-NT2RI3005261.1// 22..1629// PF00083.13 Sugar_tr Sugar (and other) transporter 5.5e-200 IPR005828// PF07690.5 MFS.sub.--1 Major Facilitator Superfamily 1.1e-14 PRO11701 D-OCBBF2010718.1// 144..2495// PF00595.12 PDZ PDZ domain (Also known as DHR or GLGF) 2e-14 IPR001478 D-OCBBF3004194.1// 129..2480// PF00595.12 PDZ PDZ domain (Also known as DHR or GLGF) 7.1e-16 IPR001478 D-NT2RP8000826.1// 95..2461// PF00595.12 PDZ PDZ domain (Also known as DHR or GLGF) 7.1e-16 IPR001478 D-NT2RP7007268.1// 95..2461// PF00595.12 PDZ PDZ domain (Also known as DHR or GLGF) 7.1e-16 IPR001478 D-BRAWH3008172.1// 281..2452// PF00595.12 PDZ PDZ domain (Also known as DHR or GLGF) 7.1e-16 IPR001478 D-BRAWH3011965.1// 300..>1574// PF00595.12 PDZ PDZ domain (Also known as DHR or GLGF) 7.1e-16 IPR001478

5) Transmembrane Domain Prediction Analysis Using SOSUI

[0479] Transmembrane domain prediction analysis was performed on the 19 ORF sequences shown in Example 14-1), using SOSUI (http://bp.nuap.nagoya-u.ac.jp/sosui/). For the analysis, SOSUI version 1.5 was used. The sequences that permitted prediction of the transmembrane domain in the SOSUI analysis are shown below.

[0480] Individual data are shown with the name of cDNA sequence, ORF region, and number of transmembrane domain separated by "//".

D-NT2RI3005525.1// 45..1292// 1

D-BRACE2044661.1// 297..878// 2

D-NT2RI3001005.1// 22..1629// 11

D-NT2RI3005261.1// 22..1629// 11

6) N-Terminal Secretion Signal Sequence Prediction Analysis Using PSORT

[0481] N-terminal secretion signal sequence prediction was performed on the 19 ORF sequences shown in Example 14-1), using PSORT (http://psort.nibb.ac.jp/). PSORT II was used for the analysis.

[0482] In the PSORT analysis, no sequences permitted prediction of the N-terminal secretion signal sequence.

7) N-Terminal Secretion Signal Sequence Prediction Analysis Using SignalP ver. 3.0

[0483] N-terminal secretion signal sequence prediction was performed on the 19 ORF sequences shown in Example 14-1), using SignalP (http://www.cbs.dtu.dk/services/SignalP/). SignalP version 3.0 was used for the analysis. Sequences that permitted prediction of the N-terminal secretion signal sequence in the SignalP analysis are shown below.

[0484] Individual data are shown with the name of cDNA sequence and ORF region separated by "//".

D-BRACE2044661.1// 297..878

Summary of Examples 1 to 14

[0485] Although there have been remarkable advances in the analysis of human chromosome sequences thanks to the progress in human genome research, this does not mean that all the human genetic functions have been clarified. We analyzed human genes with a focus on the diversity thereof, and showed that the diversity is largely associated with gene functional changes.

[0486] By comparing human genome sequence information and data on human cDNAs, which are products of transcription therefrom, it was found that a plurality of mRNAs are transcribed from certain regions of chromosome. They occur in two cases: a case wherein there are different ORF regions predicted to encode and produce different proteins, and another case wherein there are different 5'UTR regions or 3'UTR regions, which are noncoding regions, and the same protein is produced. With an emphasis on cDNAs predicted to encode proteins different from those of known cDNAs that have already been analyzed, in particular, we performed search and sequence analysis of such cDNAs. Hence, it was found that the cause of the diversity resides mainly in transcription initiation point selectivity and exon selectivity. Regarding transcription initiation point selectivity, a change of the transcription factor used in a certain chromosome region produced a different position for transcription initiation, resulting in the cDNA diversity. As for exon selectivity, an increase or decrease in the exon used, despite transcription from the same chromosome region, at the time of transcription and splicing, resulted in the cDNA diversity.

[0487] How the genetic diversity is associated with gene functions was analyzed on the basis of our own information on the expression frequencies of mRNAs by the 5'-terminal sequences of about 1.50 million human cDNAs (5'-onepass sequences). Hence, a large number of cases were found wherein gene functions seemed to be significantly influenced by diversity features, including variation of transcription initiation region selective in a certain organ, and deletion of exon in a certain condition. We discovered genes whose diversity varies depending on the brain tissue portion and nerve cell differentiation stage, and conducted extensive analyses.

[0488] Regarding the analytical method, the expression levels were compared using real-time PCR (polymerase chain reaction). For example, assuming an exon predicted to be inserted selectively only after differentiation into nerve cells, a primer that specifically detects the exon region (01) is designed, a primer that specifically detects the pattern in which the exon is not inserted (02) is designed, and a primer that detects a region having both patterns in common (03) is designed. With the use of these 3 kinds of primers, the amounts amplified at the various stages of nerve cell differentiation are compared. The specific region detection results for 01 and 02 are compared with the amount amplified for the shared region 03 as the control at various stages of nerve cell differentiation, whereby it is possible to know how the exon selectivity was changed by nerve cell differentiation. Hence, the correlation between exon selectivity and tissue specific expression can be assessed.

[0489] By this method, we discovered many genes whose diversity is associated with tissue-specific expression. Being specific for the tissue in which the gene is expressed suggests that the diversity may significantly influence the function of the gene. Hence, by using a specific region with diversity as a gene marker, it seems possible to elucidate the function of a particular portion of the brain, and to detect nerve cell differentiation or regeneration stages in detail. Furthermore, for example, by proceeding to develop a pharmaceutical with a protein having a specific region expressed only at a certain stage of nerve cell differentiation or regeneration as the target, it seems possible to develop a pharmaceutical that is more effective with lower prevalence of adverse reactions.

<Explanation of Nerve Cell Differentiation>

[0490] The mRNAs related to nerve cell differentiation (mRNAs that induce differentiation of nervous system cells and exhibit an expressional change) are thought to be useful as therapeutic/diagnostic markers for nerve disease. By searching for an mRNA that exhibits an expressional change during the process of inducing differentiation of cultured human cells NT2 into nerve cells (retinoic acid (RA) stimulation or RA stimulation followed by treatment with growth inhibitor), such an mRNA can be discovered. These mRNAs are also thought to be associated with nerve regeneration.

<Explanation of Various Portions of the Brain>

1) Hippocampus

[0491] Among the brain tissues, the hippocampus is a very important portion that controls memory, having the function of fixing memory by determining whether or not the information obtained is necessary, and allowing other brain portions to store the memory. Clinical findings show that if the hippocampus is disordered, or, in the worst case, if the hippocampus is lacked, one is only able to remember new things for a short time. Some patients with dementia are thought to have an abnormality in the hippocampus. When comparing the whole brain tissue and the hippocampus, the mRNAs exhibiting expressional variation are mRNAs involved in memory or associated with dementia, and are thought to be useful in elucidating the mechanism for memory and as therapeutic/diagnostic markers.

2) Caudate Nucleus

[0492] The hippocampal system is a portion that is important to memory associated with spatial cognition. Spatial cognition is also said to be memory of remembering places. By contrast, the caudate nucleus is said to be a portion that is important to memory acquired through habits (habitual memory).

3) Amygdala

[0493] The amygdala is the emotional center of the brain. The information that has passed the amygdala causes emotional reactions, for example, panic and fear reactions. If a strong fear is produced upon affect assessment of a stimulus by the amygdala, the amygdala transmits warning signals to various portions of the brain. As a result, reactions such as palm sweating, palpitation, blood pressure elevation, and rapid secretion of adrenaline occur. The amygdala can also be said to be a tissue that controls a kind of instinct of defense in which warning signals are transmitted to the body to make the body in a warning state. When comparing the whole brain tissue and the amygdala, the mRNAs exhibiting expressional variation are mRNAs involved in emotional reactions, and are thought to be useful in elucidating the molecular mechanisms for emotional reactions, fear reactions, panic and the like.

4) Cerebellum

[0494] The cerebellum is the center of equilibrium, muscle movement, and motor learning. This region is thought to be involved in motor regulation; as the cerebellum acts, one can make smooth motions involuntarily. There is also increasing evidence for the involvement of the cerebellum not only in physical movement, but also in the habituation of higher movements such as reading and writing. When comparing the brain tissue as a whole and the cerebellum, the mRNAs exhibiting expressional variation are mRNAs involved in equilibrium and motor functions, and are thought to be useful in elucidating the molecular mechanisms for the motor functions under the control of the brain.

5) Thalamus

[0495] The thalamus is a portion where nerve cells that are highly associated with the cerebrum gather, transferring sensory information from the spinal cord and the like to the relevant portions of the cerebrum, and regulating the motor commands of the cerebrum. For example, in visual sensation, images are separated into size, shape, and color, and in auditory sensation, sounds are separated into volume and comfortability and sent to the sensory area of cerebral cortex. When comparing the whole brain tissue and the thalamus, the mRNAs exhibiting expressional variation are mRNAs involved in signal transduction from sensory organs, and are thought to be useful in elucidating the molecular mechanism for the signal transduction under the control of the brain.

6) Substantia Nigra

[0496] The substantia nigra is a nerve nucleus that occupies a portion of the midbrain. The substantia nigra is roughly divided into two portions: pars compacta and pars reticulata (and lateral portion), both of which are central constituents of the basal ganglion. The basal ganglion, along with the cerebellum, is known as a higher center responsible for important roles in the onset and control of voluntary movement. The basal ganglion roughly consists of the four nerve nuclei, i.e., striate body, pallidum, substantia nigra, and subthalamic nucleus, the striate body being divided into the caudate nucleus and the putamen, the pallidum into the lateral segment and the medial segment, and the substantia nigra into the pars compacta and the pars reticulata. When these nerve nuclei are re-classified from the viewpoint of the signal transduction modes of "input", "output", and "mutual communication", the striate body corresponds to the input portion of the basal ganglion, and the pallidal medial segment and the substantia nigra pars reticulata correspond to the output portion thereof. Connecting the input portion and the output portion indirectly, the pallidal lateral segment and the subthalamic nucleus are thought to be an interface of the basal ganglion; modifying the nervous activity of the striate body by dopamine, the substantia nigra pars compacta is thought to be a modifying portion of the basal ganglion.

[0497] An illness of the cerebro-nervous system characterized by an insufficient production of a neurotransmitter produced in the substantia nigra in the brain, known as dopamine, resulting in motor disorders such as hand tremor and stiffening of muscles making physical movement dull, is said to be Parkinson's disease. Brain nerve cells usually decrease little by little with aging; in Parkinson's disease, nerve cells of the substantia nigra decrease remarkably at higher rates than usual.

[0498] When comparing the whole brain tissue and the substantia nigra, the mRNAs exhibiting expressional variation are thought to be mRNAs involved in the above events.

7) Alzheimer Patient's Cerebral Cortex

[0499] Alzheimer's disease is an illness of the cerebro-nervous system characterized by loss of memory, that hampers daily activities and necessitates nursing care in advanced cases, eventually leading to atrophy of the brain. Although the causes of the onset thereof are said to be associated with environmental factors such as stress, as well as vascular factors such as hypertension and cholesterolemia, they have not been investigated in full. Therefore, when comparing normal brain tissue and Alzheimer pathologic tissues, the mRNAs exhibiting expressional variation are mRNAs associated with Alzheimer's disease, and are thought to be useful in elucidating the mechanisms for the onset of pathologic conditions, and as therapeutic/diagnostic markers.

[0500] This application is based on a patent application No. 2007-066430 filed in Japan (filing date: Mar. 15, 2007), the contents of which are incorporated in full herein by this reference.

[Sequence Listing]

Sequence CWU 1

1

266130RNAArtificial Sequencesynthesized oligo-cap linker used for oligo-cap method 1agcaucgagu cggccuuguu ggccuacugg 30242DNAArtificial Sequencesynthesized oligo(dT) primer used for oligo-cap method 2gcggctgaag acggcctatg tggccttttt tttttttttt tt 42321DNAArtificial Sequenceforward primer used for preparing cDNA library 3agcatcgagt cggccttgtt g 21421DNAArtificial Sequencereverse primer used for preparing cDNA library 4gcggctgaag acggcctatg t 21522DNAArtificial Sequenceforward primer used for detecting a polynucleotide encoding GAPDH 5ccaggtggtc tcctctgact tc 22619DNAArtificial Sequencereverse primer used for detecting a polynucleotide encoding GAPDH 6gtggtcgttg agggcaatg 19725DNAArtificial Sequenceprobe used for detecting a polynucleotide encoding GAPDH 7acagcgacac ccactcctcc acctt 2582499DNAHomo sapiens 8ggtagcgacc attttggtta atgttgggtg tgtttctgcg gtttgtgagg tgagaggcgc 60tggagctatg ggtccgaacc gcggtgtctg aacccagaag gtgaagagtc cttcttgctg 120cacagaggca gatcttaggc cccgtaacgg cgcccgccgc tcccggcagt gctttccccg 180cgtactcggg atggcggcgg ccgcgctgag gctcccggct caggttgttg gtgtggatca 240gaagatgagg aggcaccttc taagaagagc atttctatac aaagagtgtc tcaggtcagc 300actcctgggg caggtgtctc ccaagaaggc tcactcttgt gaaatgtgtg gcgcgatctt 360gggagacatt ttgcacttgg cagatcatca ggggacacat cacaagcaga aactgcacag 420gtgtgaggca tgggggaata aattgtatga tagttcaaac cgtccgcacc agaatcagta 480ccttggagag aaaccctata gaagcagtgt tgaggaagca ttgtttgtga agaggtgtaa 540gttccatgtg tcagaggagt catctatctt cattcagagt ggaaaggact ttttgcccag 600ctcaggatta ctgctgcagg aggccactca cactggggag aagtcaaaca gcaaacctga 660gtgtgagtct ccctttcagt ggggagatac tcattacagc tgtggagaat gcatgaaaca 720ttctagcacc aaacacgtat ttgttcaaca gcagagactt ccctctagag aggaatgtta 780ttgctgggaa tgtgggaaat cctttagcaa atatgatagc gtcagtaatc atcagagagt 840tcacactggg aaaagacctt atgaatgtgg agaatgtggg aaatctttta gtcataaggg 900cagccttgtt cagcatcagc gagttcacac tgggaaaaga ccttatgaat gtggagaatg 960tgggaaatct tttagtcata agggcagcct tgttcagcat cagcgagttc atactggaga 1020aagaccttat gagtgtggag aatgtgggaa atcttttagt caaaatggta ctctcattaa 1080acatcaacga gttcacactg gagaaagacc ttatgagtgt gaagaatgtg ggaaatgttt 1140tactcagaag ggcaatctca ttcaacatca acgaggtcac actagtgaaa gaccttatga 1200gtgtgaagaa tgtggaaaat gttttagtca aaagggcacc ctaactgaac atcatcgagt 1260tcacactaga gaacgacctt atgagtgtgg agaatgtggg aaatctttta gtcgaaaggg 1320acaccttagg aaccatcagc gaggtcacac tggagaaaga ccttacgagt gtggagaatg 1380tgggaaatct tttagtcgaa agggcaacct cattcagcat cagcgaagcc acactggaga 1440aaggccttat gagtgtagag agtgtaggaa attatttagg ggcaagtccc acctcattga 1500acaccagaga gttcacactg gagaaaggcc atatgaatgt aatgaatgtg ggaaatcatt 1560tcaagacagc tctgggtttc gtgttcatca gagagttcac actggagaaa aaccgtttga 1620gtgtagtgaa tgtgggaagt catttcctca aagctgttcc ctccttcgac atcggagagt 1680tcatactgga gaaaggcctt atgaatgtgg agaatgtgga aagtcatttc atcagagctc 1740ttccctcctt cgacatcaga aaacccacac tgcagaaaga ccttatgagt gcagagaatg 1800tgggaaattc ttctccagtc tccttgaaca caggagagtt cacactggag aaaggcctta 1860tgagtgcagg gaatgtggaa aaacatttac tcgaaggtct gcgcatttta aacatcagag 1920acttcatact cgaggaaagc cttacgagtg cagcgaatgt gggaaatcct ttgctgaaac 1980cttcagtctt actgaacaca ggagagtaca cactggagaa aggccttatg agtgcagtga 2040atgtggaaaa tcatttcatc gaagctcttc tctccttcga catcagagag ttcacacaga 2100aagaagtcct tacaagtgaa aagaaatttg ggaaattctt tagctaaacc tctgtgcatc 2160ttcttgatca gagggttctt actggatcag gaccttatga gtgtgacaaa cgtgggatat 2220tctttatgca gaagtcttgt tttattacat acagaagagc tcccactgca gaagggcctc 2280ttgagtgcga tgaatgtgag aaagccttct gccttctgtc attggataac agattgttct 2340cataaggaaa acactgtaca cgtacaggaa atattatttc ttgtaaaaca taacactgga 2400ggagatgcct tatgacggag ccatctgcct aaattgacat accttcagca tctgcataaa 2460ctcaattatg ttggagctgt gtggcatttt tcaccctgc 249992499DNAHomo sapiensCDS(191)..(2119) 9ggtagcgacc attttggtta atgttgggtg tgtttctgcg gtttgtgagg tgagaggcgc 60tggagctatg ggtccgaacc gcggtgtctg aacccagaag gtgaagagtc cttcttgctg 120cacagaggca gatcttaggc cccgtaacgg cgcccgccgc tcccggcagt gctttccccg 180cgtactcggg atg gcg gcg gcc gcg ctg agg ctc ccg gct cag gtt gtt 229 Met Ala Ala Ala Ala Leu Arg Leu Pro Ala Gln Val Val 1 5 10ggt gtg gat cag aag atg agg agg cac ctt cta aga aga gca ttt cta 277Gly Val Asp Gln Lys Met Arg Arg His Leu Leu Arg Arg Ala Phe Leu 15 20 25tac aaa gag tgt ctc agg tca gca ctc ctg ggg cag gtg tct ccc aag 325Tyr Lys Glu Cys Leu Arg Ser Ala Leu Leu Gly Gln Val Ser Pro Lys30 35 40 45aag gct cac tct tgt gaa atg tgt ggc gcg atc ttg gga gac att ttg 373Lys Ala His Ser Cys Glu Met Cys Gly Ala Ile Leu Gly Asp Ile Leu 50 55 60cac ttg gca gat cat cag ggg aca cat cac aag cag aaa ctg cac agg 421His Leu Ala Asp His Gln Gly Thr His His Lys Gln Lys Leu His Arg 65 70 75tgt gag gca tgg ggg aat aaa ttg tat gat agt tca aac cgt ccg cac 469Cys Glu Ala Trp Gly Asn Lys Leu Tyr Asp Ser Ser Asn Arg Pro His 80 85 90cag aat cag tac ctt gga gag aaa ccc tat aga agc agt gtt gag gaa 517Gln Asn Gln Tyr Leu Gly Glu Lys Pro Tyr Arg Ser Ser Val Glu Glu 95 100 105gca ttg ttt gtg aag agg tgt aag ttc cat gtg tca gag gag tca tct 565Ala Leu Phe Val Lys Arg Cys Lys Phe His Val Ser Glu Glu Ser Ser110 115 120 125atc ttc att cag agt gga aag gac ttt ttg ccc agc tca gga tta ctg 613Ile Phe Ile Gln Ser Gly Lys Asp Phe Leu Pro Ser Ser Gly Leu Leu 130 135 140ctg cag gag gcc act cac act ggg gag aag tca aac agc aaa cct gag 661Leu Gln Glu Ala Thr His Thr Gly Glu Lys Ser Asn Ser Lys Pro Glu 145 150 155tgt gag tct ccc ttt cag tgg gga gat act cat tac agc tgt gga gaa 709Cys Glu Ser Pro Phe Gln Trp Gly Asp Thr His Tyr Ser Cys Gly Glu 160 165 170tgc atg aaa cat tct agc acc aaa cac gta ttt gtt caa cag cag aga 757Cys Met Lys His Ser Ser Thr Lys His Val Phe Val Gln Gln Gln Arg 175 180 185ctt ccc tct aga gag gaa tgt tat tgc tgg gaa tgt ggg aaa tcc ttt 805Leu Pro Ser Arg Glu Glu Cys Tyr Cys Trp Glu Cys Gly Lys Ser Phe190 195 200 205agc aaa tat gat agc gtc agt aat cat cag aga gtt cac act ggg aaa 853Ser Lys Tyr Asp Ser Val Ser Asn His Gln Arg Val His Thr Gly Lys 210 215 220aga cct tat gaa tgt gga gaa tgt ggg aaa tct ttt agt cat aag ggc 901Arg Pro Tyr Glu Cys Gly Glu Cys Gly Lys Ser Phe Ser His Lys Gly 225 230 235agc ctt gtt cag cat cag cga gtt cac act ggg aaa aga cct tat gaa 949Ser Leu Val Gln His Gln Arg Val His Thr Gly Lys Arg Pro Tyr Glu 240 245 250tgt gga gaa tgt ggg aaa tct ttt agt cat aag ggc agc ctt gtt cag 997Cys Gly Glu Cys Gly Lys Ser Phe Ser His Lys Gly Ser Leu Val Gln 255 260 265cat cag cga gtt cat act gga gaa aga cct tat gag tgt gga gaa tgt 1045His Gln Arg Val His Thr Gly Glu Arg Pro Tyr Glu Cys Gly Glu Cys270 275 280 285ggg aaa tct ttt agt caa aat ggt act ctc att aaa cat caa cga gtt 1093Gly Lys Ser Phe Ser Gln Asn Gly Thr Leu Ile Lys His Gln Arg Val 290 295 300cac act gga gaa aga cct tat gag tgt gaa gaa tgt ggg aaa tgt ttt 1141His Thr Gly Glu Arg Pro Tyr Glu Cys Glu Glu Cys Gly Lys Cys Phe 305 310 315act cag aag ggc aat ctc att caa cat caa cga ggt cac act agt gaa 1189Thr Gln Lys Gly Asn Leu Ile Gln His Gln Arg Gly His Thr Ser Glu 320 325 330aga cct tat gag tgt gaa gaa tgt gga aaa tgt ttt agt caa aag ggc 1237Arg Pro Tyr Glu Cys Glu Glu Cys Gly Lys Cys Phe Ser Gln Lys Gly 335 340 345acc cta act gaa cat cat cga gtt cac act aga gaa cga cct tat gag 1285Thr Leu Thr Glu His His Arg Val His Thr Arg Glu Arg Pro Tyr Glu350 355 360 365tgt gga gaa tgt ggg aaa tct ttt agt cga aag gga cac ctt agg aac 1333Cys Gly Glu Cys Gly Lys Ser Phe Ser Arg Lys Gly His Leu Arg Asn 370 375 380cat cag cga ggt cac act gga gaa aga cct tac gag tgt gga gaa tgt 1381His Gln Arg Gly His Thr Gly Glu Arg Pro Tyr Glu Cys Gly Glu Cys 385 390 395ggg aaa tct ttt agt cga aag ggc aac ctc att cag cat cag cga agc 1429Gly Lys Ser Phe Ser Arg Lys Gly Asn Leu Ile Gln His Gln Arg Ser 400 405 410cac act gga gaa agg cct tat gag tgt aga gag tgt agg aaa tta ttt 1477His Thr Gly Glu Arg Pro Tyr Glu Cys Arg Glu Cys Arg Lys Leu Phe 415 420 425agg ggc aag tcc cac ctc att gaa cac cag aga gtt cac act gga gaa 1525Arg Gly Lys Ser His Leu Ile Glu His Gln Arg Val His Thr Gly Glu430 435 440 445agg cca tat gaa tgt aat gaa tgt ggg aaa tca ttt caa gac agc tct 1573Arg Pro Tyr Glu Cys Asn Glu Cys Gly Lys Ser Phe Gln Asp Ser Ser 450 455 460ggg ttt cgt gtt cat cag aga gtt cac act gga gaa aaa ccg ttt gag 1621Gly Phe Arg Val His Gln Arg Val His Thr Gly Glu Lys Pro Phe Glu 465 470 475tgt agt gaa tgt ggg aag tca ttt cct caa agc tgt tcc ctc ctt cga 1669Cys Ser Glu Cys Gly Lys Ser Phe Pro Gln Ser Cys Ser Leu Leu Arg 480 485 490cat cgg aga gtt cat act gga gaa agg cct tat gaa tgt gga gaa tgt 1717His Arg Arg Val His Thr Gly Glu Arg Pro Tyr Glu Cys Gly Glu Cys 495 500 505gga aag tca ttt cat cag agc tct tcc ctc ctt cga cat cag aaa acc 1765Gly Lys Ser Phe His Gln Ser Ser Ser Leu Leu Arg His Gln Lys Thr510 515 520 525cac act gca gaa aga cct tat gag tgc aga gaa tgt ggg aaa ttc ttc 1813His Thr Ala Glu Arg Pro Tyr Glu Cys Arg Glu Cys Gly Lys Phe Phe 530 535 540tcc agt ctc ctt gaa cac agg aga gtt cac act gga gaa agg cct tat 1861Ser Ser Leu Leu Glu His Arg Arg Val His Thr Gly Glu Arg Pro Tyr 545 550 555gag tgc agg gaa tgt gga aaa aca ttt act cga agg tct gcg cat ttt 1909Glu Cys Arg Glu Cys Gly Lys Thr Phe Thr Arg Arg Ser Ala His Phe 560 565 570aaa cat cag aga ctt cat act cga gga aag cct tac gag tgc agc gaa 1957Lys His Gln Arg Leu His Thr Arg Gly Lys Pro Tyr Glu Cys Ser Glu 575 580 585tgt ggg aaa tcc ttt gct gaa acc ttc agt ctt act gaa cac agg aga 2005Cys Gly Lys Ser Phe Ala Glu Thr Phe Ser Leu Thr Glu His Arg Arg590 595 600 605gta cac act gga gaa agg cct tat gag tgc agt gaa tgt gga aaa tca 2053Val His Thr Gly Glu Arg Pro Tyr Glu Cys Ser Glu Cys Gly Lys Ser 610 615 620ttt cat cga agc tct tct ctc ctt cga cat cag aga gtt cac aca gaa 2101Phe His Arg Ser Ser Ser Leu Leu Arg His Gln Arg Val His Thr Glu 625 630 635aga agt cct tac aag tga aaagaaattt gggaaattct ttagctaaac 2149Arg Ser Pro Tyr Lys 640ctctgtgcat cttcttgatc agagggttct tactggatca ggaccttatg agtgtgacaa 2209acgtgggata ttctttatgc agaagtcttg ttttattaca tacagaagag ctcccactgc 2269agaagggcct cttgagtgcg atgaatgtga gaaagccttc tgccttctgt cattggataa 2329cagattgttc tcataaggaa aacactgtac acgtacagga aatattattt cttgtaaaac 2389ataacactgg aggagatgcc ttatgacgga gccatctgcc taaattgaca taccttcagc 2449atctgcataa actcaattat gttggagctg tgtggcattt ttcaccctgc 249910642PRTHomo sapiens 10Met Ala Ala Ala Ala Leu Arg Leu Pro Ala Gln Val Val Gly Val Asp1 5 10 15Gln Lys Met Arg Arg His Leu Leu Arg Arg Ala Phe Leu Tyr Lys Glu 20 25 30Cys Leu Arg Ser Ala Leu Leu Gly Gln Val Ser Pro Lys Lys Ala His 35 40 45Ser Cys Glu Met Cys Gly Ala Ile Leu Gly Asp Ile Leu His Leu Ala 50 55 60Asp His Gln Gly Thr His His Lys Gln Lys Leu His Arg Cys Glu Ala65 70 75 80Trp Gly Asn Lys Leu Tyr Asp Ser Ser Asn Arg Pro His Gln Asn Gln 85 90 95Tyr Leu Gly Glu Lys Pro Tyr Arg Ser Ser Val Glu Glu Ala Leu Phe 100 105 110Val Lys Arg Cys Lys Phe His Val Ser Glu Glu Ser Ser Ile Phe Ile 115 120 125Gln Ser Gly Lys Asp Phe Leu Pro Ser Ser Gly Leu Leu Leu Gln Glu 130 135 140Ala Thr His Thr Gly Glu Lys Ser Asn Ser Lys Pro Glu Cys Glu Ser145 150 155 160Pro Phe Gln Trp Gly Asp Thr His Tyr Ser Cys Gly Glu Cys Met Lys 165 170 175His Ser Ser Thr Lys His Val Phe Val Gln Gln Gln Arg Leu Pro Ser 180 185 190Arg Glu Glu Cys Tyr Cys Trp Glu Cys Gly Lys Ser Phe Ser Lys Tyr 195 200 205Asp Ser Val Ser Asn His Gln Arg Val His Thr Gly Lys Arg Pro Tyr 210 215 220Glu Cys Gly Glu Cys Gly Lys Ser Phe Ser His Lys Gly Ser Leu Val225 230 235 240Gln His Gln Arg Val His Thr Gly Lys Arg Pro Tyr Glu Cys Gly Glu 245 250 255Cys Gly Lys Ser Phe Ser His Lys Gly Ser Leu Val Gln His Gln Arg 260 265 270Val His Thr Gly Glu Arg Pro Tyr Glu Cys Gly Glu Cys Gly Lys Ser 275 280 285Phe Ser Gln Asn Gly Thr Leu Ile Lys His Gln Arg Val His Thr Gly 290 295 300Glu Arg Pro Tyr Glu Cys Glu Glu Cys Gly Lys Cys Phe Thr Gln Lys305 310 315 320Gly Asn Leu Ile Gln His Gln Arg Gly His Thr Ser Glu Arg Pro Tyr 325 330 335Glu Cys Glu Glu Cys Gly Lys Cys Phe Ser Gln Lys Gly Thr Leu Thr 340 345 350Glu His His Arg Val His Thr Arg Glu Arg Pro Tyr Glu Cys Gly Glu 355 360 365Cys Gly Lys Ser Phe Ser Arg Lys Gly His Leu Arg Asn His Gln Arg 370 375 380Gly His Thr Gly Glu Arg Pro Tyr Glu Cys Gly Glu Cys Gly Lys Ser385 390 395 400Phe Ser Arg Lys Gly Asn Leu Ile Gln His Gln Arg Ser His Thr Gly 405 410 415Glu Arg Pro Tyr Glu Cys Arg Glu Cys Arg Lys Leu Phe Arg Gly Lys 420 425 430Ser His Leu Ile Glu His Gln Arg Val His Thr Gly Glu Arg Pro Tyr 435 440 445Glu Cys Asn Glu Cys Gly Lys Ser Phe Gln Asp Ser Ser Gly Phe Arg 450 455 460Val His Gln Arg Val His Thr Gly Glu Lys Pro Phe Glu Cys Ser Glu465 470 475 480Cys Gly Lys Ser Phe Pro Gln Ser Cys Ser Leu Leu Arg His Arg Arg 485 490 495Val His Thr Gly Glu Arg Pro Tyr Glu Cys Gly Glu Cys Gly Lys Ser 500 505 510Phe His Gln Ser Ser Ser Leu Leu Arg His Gln Lys Thr His Thr Ala 515 520 525Glu Arg Pro Tyr Glu Cys Arg Glu Cys Gly Lys Phe Phe Ser Ser Leu 530 535 540Leu Glu His Arg Arg Val His Thr Gly Glu Arg Pro Tyr Glu Cys Arg545 550 555 560Glu Cys Gly Lys Thr Phe Thr Arg Arg Ser Ala His Phe Lys His Gln 565 570 575Arg Leu His Thr Arg Gly Lys Pro Tyr Glu Cys Ser Glu Cys Gly Lys 580 585 590Ser Phe Ala Glu Thr Phe Ser Leu Thr Glu His Arg Arg Val His Thr 595 600 605Gly Glu Arg Pro Tyr Glu Cys Ser Glu Cys Gly Lys Ser Phe His Arg 610 615 620Ser Ser Ser Leu Leu Arg His Gln Arg Val His Thr Glu Arg Ser Pro625 630 635 640Tyr Lys1142DNAHomo sapiens 11gcgctgaggc tcccggctca ggttgttggt gtggatcaga ag 421243PRTHomo sapiens 12Met Ala Ala Ala Ala Leu Arg Leu Pro Ala Gln Val Val Gly Val Asp1 5 10 15Gln Lys Met Arg Arg His Leu Leu Arg Arg Ala Phe Leu Tyr Lys Glu 20 25 30Cys Leu Arg Ser Ala Leu Leu Gly Gln Val Ser 35 4013213DNAHomo sapiens 13gcatcatctg gctgcaaaga agagaacaca ctgtgtttga gggaggagga aggaggatca 60gagtttaaac tcctgccata atgcagggca ctgtggcatt tgaagatgtg gctgtgaact 120tttcccagga ggagtggagt ctccttagtg aggttcagag atgcctttac catgacgtga 180tgctggagaa ctgggtactt atatcctccc tgg 213142DNAHomo sapiens 14gt 21577PRTHomo sapiens 15Met Gln Gly Thr Val Ala Phe Glu Asp Val Ala Val Asn Phe Ser Gln1

5 10 15Glu Glu Trp Ser Leu Leu Ser Glu Val Gln Arg Cys Leu Tyr His Asp 20 25 30Val Met Leu Glu Asn Trp Val Leu Ile Ser Ser Leu Gly Cys Trp Cys 35 40 45Gly Ser Glu Asp Glu Glu Ala Pro Ser Lys Lys Ser Ile Ser Ile Gln 50 55 60Arg Val Ser Gln Val Ser Thr Pro Gly Ala Gly Val Ser65 70 75163551DNAHomo sapiens 16ctctggtagc gaccattttg gttaatgttg ggtgtgtttc tgcggtttgt gaggtgagag 60gcgctggagc tatgggtccg aaccgcggtg tctgaaccca gaaggtgaag agtccttctt 120gctgcacaga ggcagatcct aggccccgta acggcgcccg ccgctcccgg cagtgctttc 180cccgcgtact cgggatggcg gcggccgcgc tgaggctccc ggctcaggca tcatctggct 240gcaaagaaga gaacacactg tgtttgaggg aggaggaagg aggatcagag tttaaactcc 300tgccataatg cagaccattc tccataacaa gggagtggga tttaaatgac tctaggtgga 360cagaggaaag tcgtcattgt agaggggtca ccaagtgcaa cacagaagtg gaatagggcc 420atggatatct aaagccccac ctggttctgt ggggatgtgg agccatgcaa gaaggccttc 480atagaatgac ttgggactgc attgctattg ggagccatga gaattctgtg cagggcactg 540tggcatttga agatgtggct gtgaactttt cccaggagga gtggagtctc cttagtgagg 600ttcagagatg cctttaccat gacgtgatgc tggagaactg ggtacttata tcctccctgg 660gttgttggtg tggatcagaa gatgaggagg caccttctaa gaagagcatt tctatacaaa 720gagtgtctca ggtcagcact cctggggcag gtgtgtctcc caagaaggct cactcttgtg 780aaatgtgtgg cgcgatcttg ggagacattt tgcacttggc agatcatcag gggacacatc 840acaagcagaa actgcacagg tgtgaggcat gggggaataa attgtatgat agttcaaacc 900gtccgcacca gaatcagtac cttggagaga aaccctatag aagcagtgtt gaggaagcat 960tgtttgtgaa gaggtgtaag ttccatgtgt cagaggagtc atctatcttc attcagagtg 1020gaaaggactt tttgcccagc tcaggattac tgctgcagga ggccactcac actggggaga 1080agtcaaacag caaacctgag tgtgagtctc cctttcagtg gggagatact cgttacagct 1140gtggagaatg catgaaacat tctagcacca aacacgtatt tgttcaacag cagagacttc 1200cctctagaga ggaatgttat tgctgggaat gtgggaaatc ctttagcaaa tatgatagcg 1260tcagtaatca tcagagagtt cacactggga aaagacctta tgaatgtgga gaatgtggga 1320aatcttttag tcataagggc agccttgttc agcatcagcg agttcacact gggaaaagac 1380cttatgaatg tggagaatgt gggaaatctt ttagtcataa gggcagcctt gttcagcatc 1440agcgagttca tactggagaa agaccttatg agtgtggaga atgtgggaaa tcttttagtc 1500aaaatggtac tctcattaaa catcaacgag ttcacactgg agaaagacct tatgagtgtg 1560aagaatgtgg gaaatgtttt actcagaagg gcaatctcat tcaacatcaa cgaggtcaca 1620ctagtgaaag accttatgag tgtgaagaat gtggaaaatg ttttagtcaa aagggcaccc 1680taactgaaca tcatcgagtt cacactagag aacgacctta tgagtgtgga gaatgtggga 1740aatcttttag tcgaaaggga caccttagga accatcagcg gggtcacact ggagaaagac 1800cttacgagtg tggagaatgt gggaaatctt ttagtcgaaa gggcaacctc attcagcatc 1860agcgaagcca cactggagaa aggccttatg agtgtagaga gtgtaggaaa ttatttaggg 1920gcaagtccca cctcattgaa caccagagag ttcacactgg agaaaggcca tatgaatgta 1980atgaatgtgg gaaatcattt caagacagct ctgggtttcg tgttcatcag agagttcaca 2040ctggagaaaa accgtttgag tgtagtgaat gtgggaagtc atttcctcaa agctgttccc 2100tccttcgaca tcggagagtt catactggag aaaggcctta tgaatgtgga gaatgtggaa 2160agtcatttca tcagagctct tccctccttc gacatcagaa aactcacact gcagaaagac 2220cttatgagtg cagagaatgt gggaaattct tctccagtct ccttgaacac aggagagttc 2280acactggaga aaggccttat gaatgcaggg aatgtggaaa aacatttact cgaaggtctg 2340cgcattttaa acatcagaga cttcatactc gaggaaagcc ttacgagtgc agcgaatgtg 2400ggaaatcctt tgctgaaacc ttcagtctta ctgaacacag gagagtacac actggagaaa 2460ggccttatga gtgcagtgaa tgtggaaaat catttcatcg aagctcttct ctccttcgac 2520atcagagagt tcacacagaa agaagtcctt acaagtgaaa agaaatttgg gaaattcttt 2580agctaaacct ctgtgcatct tcttgatcag agggttctta ctggatcagg accttatgag 2640tgtgacaaac gtgggatatt ctttatgcag aagtcttgtt ttattacata cagaagagct 2700cccactgcag aagggcctct tgagtgcgat gaatgtgaga aagccttctg ccttctgtca 2760ttggataaca gattgttctc ataaggaaaa cactgtacac gtacaggaaa tattatttct 2820tgtaaaacat aacactggag gagatgcctt atgacggagc catctgccta aattggcata 2880ccttcagcat ctgcataaac tcaattatgt tggagctgtg tggcattttt caccctgccg 2940ggttcccttg ccagacatga tgtcggttat ctggcaaaag ccattttatg tcggccacga 3000ggcaggtgtt cactgtgcat cattcattca ccccatgatg ttctggaagt aaaccttggt 3060tgtctttcgt tggccagagg aattgaatgt ccgtctgtct gcccaggctg gagtggcacg 3120atctcagctc actgcagcct ccacctccag ggttcaagcg attctcctgc ctcagcctcc 3180cggggatctc aagggcattt ccctttgccc acctcgcctt ttcatatttg gtaaactgta 3240tgcatttgcc tccagcccaa gattataaat atgaactgat tatgatctgc atgttctctc 3300tttgggttca agcatttcct tacagaagag ccaccgtgga agtcatgggt aaatatgtgt 3360tgaattggta actccctctt ggagaatttc ttgtgaatta cacagcaata ggggaactca 3420tttaactgga gacataatct caatttgtaa agtgtggccc attttctaac atttttattt 3480tgcataccct cccctctctt ctcgattgat gaaactaaca aagaggttaa taaaagccca 3540tctcgtcatg t 3551173551DNAHomo sapiensCDS(465)..(2558) 17ctctggtagc gaccattttg gttaatgttg ggtgtgtttc tgcggtttgt gaggtgagag 60gcgctggagc tatgggtccg aaccgcggtg tctgaaccca gaaggtgaag agtccttctt 120gctgcacaga ggcagatcct aggccccgta acggcgcccg ccgctcccgg cagtgctttc 180cccgcgtact cgggatggcg gcggccgcgc tgaggctccc ggctcaggca tcatctggct 240gcaaagaaga gaacacactg tgtttgaggg aggaggaagg aggatcagag tttaaactcc 300tgccataatg cagaccattc tccataacaa gggagtggga tttaaatgac tctaggtgga 360cagaggaaag tcgtcattgt agaggggtca ccaagtgcaa cacagaagtg gaatagggcc 420atggatatct aaagccccac ctggttctgt ggggatgtgg agcc atg caa gaa ggc 476 Met Gln Glu Gly 1ctt cat aga atg act tgg gac tgc att gct att ggg agc cat gag aat 524Leu His Arg Met Thr Trp Asp Cys Ile Ala Ile Gly Ser His Glu Asn5 10 15 20tct gtg cag ggc act gtg gca ttt gaa gat gtg gct gtg aac ttt tcc 572Ser Val Gln Gly Thr Val Ala Phe Glu Asp Val Ala Val Asn Phe Ser 25 30 35cag gag gag tgg agt ctc ctt agt gag gtt cag aga tgc ctt tac cat 620Gln Glu Glu Trp Ser Leu Leu Ser Glu Val Gln Arg Cys Leu Tyr His 40 45 50gac gtg atg ctg gag aac tgg gta ctt ata tcc tcc ctg ggt tgt tgg 668Asp Val Met Leu Glu Asn Trp Val Leu Ile Ser Ser Leu Gly Cys Trp 55 60 65tgt gga tca gaa gat gag gag gca cct tct aag aag agc att tct ata 716Cys Gly Ser Glu Asp Glu Glu Ala Pro Ser Lys Lys Ser Ile Ser Ile 70 75 80caa aga gtg tct cag gtc agc act cct ggg gca ggt gtg tct ccc aag 764Gln Arg Val Ser Gln Val Ser Thr Pro Gly Ala Gly Val Ser Pro Lys85 90 95 100aag gct cac tct tgt gaa atg tgt ggc gcg atc ttg gga gac att ttg 812Lys Ala His Ser Cys Glu Met Cys Gly Ala Ile Leu Gly Asp Ile Leu 105 110 115cac ttg gca gat cat cag ggg aca cat cac aag cag aaa ctg cac agg 860His Leu Ala Asp His Gln Gly Thr His His Lys Gln Lys Leu His Arg 120 125 130tgt gag gca tgg ggg aat aaa ttg tat gat agt tca aac cgt ccg cac 908Cys Glu Ala Trp Gly Asn Lys Leu Tyr Asp Ser Ser Asn Arg Pro His 135 140 145cag aat cag tac ctt gga gag aaa ccc tat aga agc agt gtt gag gaa 956Gln Asn Gln Tyr Leu Gly Glu Lys Pro Tyr Arg Ser Ser Val Glu Glu 150 155 160gca ttg ttt gtg aag agg tgt aag ttc cat gtg tca gag gag tca tct 1004Ala Leu Phe Val Lys Arg Cys Lys Phe His Val Ser Glu Glu Ser Ser165 170 175 180atc ttc att cag agt gga aag gac ttt ttg ccc agc tca gga tta ctg 1052Ile Phe Ile Gln Ser Gly Lys Asp Phe Leu Pro Ser Ser Gly Leu Leu 185 190 195ctg cag gag gcc act cac act ggg gag aag tca aac agc aaa cct gag 1100Leu Gln Glu Ala Thr His Thr Gly Glu Lys Ser Asn Ser Lys Pro Glu 200 205 210tgt gag tct ccc ttt cag tgg gga gat act cgt tac agc tgt gga gaa 1148Cys Glu Ser Pro Phe Gln Trp Gly Asp Thr Arg Tyr Ser Cys Gly Glu 215 220 225tgc atg aaa cat tct agc acc aaa cac gta ttt gtt caa cag cag aga 1196Cys Met Lys His Ser Ser Thr Lys His Val Phe Val Gln Gln Gln Arg 230 235 240ctt ccc tct aga gag gaa tgt tat tgc tgg gaa tgt ggg aaa tcc ttt 1244Leu Pro Ser Arg Glu Glu Cys Tyr Cys Trp Glu Cys Gly Lys Ser Phe245 250 255 260agc aaa tat gat agc gtc agt aat cat cag aga gtt cac act ggg aaa 1292Ser Lys Tyr Asp Ser Val Ser Asn His Gln Arg Val His Thr Gly Lys 265 270 275aga cct tat gaa tgt gga gaa tgt ggg aaa tct ttt agt cat aag ggc 1340Arg Pro Tyr Glu Cys Gly Glu Cys Gly Lys Ser Phe Ser His Lys Gly 280 285 290agc ctt gtt cag cat cag cga gtt cac act ggg aaa aga cct tat gaa 1388Ser Leu Val Gln His Gln Arg Val His Thr Gly Lys Arg Pro Tyr Glu 295 300 305tgt gga gaa tgt ggg aaa tct ttt agt cat aag ggc agc ctt gtt cag 1436Cys Gly Glu Cys Gly Lys Ser Phe Ser His Lys Gly Ser Leu Val Gln 310 315 320cat cag cga gtt cat act gga gaa aga cct tat gag tgt gga gaa tgt 1484His Gln Arg Val His Thr Gly Glu Arg Pro Tyr Glu Cys Gly Glu Cys325 330 335 340ggg aaa tct ttt agt caa aat ggt act ctc att aaa cat caa cga gtt 1532Gly Lys Ser Phe Ser Gln Asn Gly Thr Leu Ile Lys His Gln Arg Val 345 350 355cac act gga gaa aga cct tat gag tgt gaa gaa tgt ggg aaa tgt ttt 1580His Thr Gly Glu Arg Pro Tyr Glu Cys Glu Glu Cys Gly Lys Cys Phe 360 365 370act cag aag ggc aat ctc att caa cat caa cga ggt cac act agt gaa 1628Thr Gln Lys Gly Asn Leu Ile Gln His Gln Arg Gly His Thr Ser Glu 375 380 385aga cct tat gag tgt gaa gaa tgt gga aaa tgt ttt agt caa aag ggc 1676Arg Pro Tyr Glu Cys Glu Glu Cys Gly Lys Cys Phe Ser Gln Lys Gly 390 395 400acc cta act gaa cat cat cga gtt cac act aga gaa cga cct tat gag 1724Thr Leu Thr Glu His His Arg Val His Thr Arg Glu Arg Pro Tyr Glu405 410 415 420tgt gga gaa tgt ggg aaa tct ttt agt cga aag gga cac ctt agg aac 1772Cys Gly Glu Cys Gly Lys Ser Phe Ser Arg Lys Gly His Leu Arg Asn 425 430 435cat cag cgg ggt cac act gga gaa aga cct tac gag tgt gga gaa tgt 1820His Gln Arg Gly His Thr Gly Glu Arg Pro Tyr Glu Cys Gly Glu Cys 440 445 450ggg aaa tct ttt agt cga aag ggc aac ctc att cag cat cag cga agc 1868Gly Lys Ser Phe Ser Arg Lys Gly Asn Leu Ile Gln His Gln Arg Ser 455 460 465cac act gga gaa agg cct tat gag tgt aga gag tgt agg aaa tta ttt 1916His Thr Gly Glu Arg Pro Tyr Glu Cys Arg Glu Cys Arg Lys Leu Phe 470 475 480agg ggc aag tcc cac ctc att gaa cac cag aga gtt cac act gga gaa 1964Arg Gly Lys Ser His Leu Ile Glu His Gln Arg Val His Thr Gly Glu485 490 495 500agg cca tat gaa tgt aat gaa tgt ggg aaa tca ttt caa gac agc tct 2012Arg Pro Tyr Glu Cys Asn Glu Cys Gly Lys Ser Phe Gln Asp Ser Ser 505 510 515ggg ttt cgt gtt cat cag aga gtt cac act gga gaa aaa ccg ttt gag 2060Gly Phe Arg Val His Gln Arg Val His Thr Gly Glu Lys Pro Phe Glu 520 525 530tgt agt gaa tgt ggg aag tca ttt cct caa agc tgt tcc ctc ctt cga 2108Cys Ser Glu Cys Gly Lys Ser Phe Pro Gln Ser Cys Ser Leu Leu Arg 535 540 545cat cgg aga gtt cat act gga gaa agg cct tat gaa tgt gga gaa tgt 2156His Arg Arg Val His Thr Gly Glu Arg Pro Tyr Glu Cys Gly Glu Cys 550 555 560gga aag tca ttt cat cag agc tct tcc ctc ctt cga cat cag aaa act 2204Gly Lys Ser Phe His Gln Ser Ser Ser Leu Leu Arg His Gln Lys Thr565 570 575 580cac act gca gaa aga cct tat gag tgc aga gaa tgt ggg aaa ttc ttc 2252His Thr Ala Glu Arg Pro Tyr Glu Cys Arg Glu Cys Gly Lys Phe Phe 585 590 595tcc agt ctc ctt gaa cac agg aga gtt cac act gga gaa agg cct tat 2300Ser Ser Leu Leu Glu His Arg Arg Val His Thr Gly Glu Arg Pro Tyr 600 605 610gaa tgc agg gaa tgt gga aaa aca ttt act cga agg tct gcg cat ttt 2348Glu Cys Arg Glu Cys Gly Lys Thr Phe Thr Arg Arg Ser Ala His Phe 615 620 625aaa cat cag aga ctt cat act cga gga aag cct tac gag tgc agc gaa 2396Lys His Gln Arg Leu His Thr Arg Gly Lys Pro Tyr Glu Cys Ser Glu 630 635 640tgt ggg aaa tcc ttt gct gaa acc ttc agt ctt act gaa cac agg aga 2444Cys Gly Lys Ser Phe Ala Glu Thr Phe Ser Leu Thr Glu His Arg Arg645 650 655 660gta cac act gga gaa agg cct tat gag tgc agt gaa tgt gga aaa tca 2492Val His Thr Gly Glu Arg Pro Tyr Glu Cys Ser Glu Cys Gly Lys Ser 665 670 675ttt cat cga agc tct tct ctc ctt cga cat cag aga gtt cac aca gaa 2540Phe His Arg Ser Ser Ser Leu Leu Arg His Gln Arg Val His Thr Glu 680 685 690aga agt cct tac aag tga aaagaaattt gggaaattct ttagctaaac 2588Arg Ser Pro Tyr Lys 695ctctgtgcat cttcttgatc agagggttct tactggatca ggaccttatg agtgtgacaa 2648acgtgggata ttctttatgc agaagtcttg ttttattaca tacagaagag ctcccactgc 2708agaagggcct cttgagtgcg atgaatgtga gaaagccttc tgccttctgt cattggataa 2768cagattgttc tcataaggaa aacactgtac acgtacagga aatattattt cttgtaaaac 2828ataacactgg aggagatgcc ttatgacgga gccatctgcc taaattggca taccttcagc 2888atctgcataa actcaattat gttggagctg tgtggcattt ttcaccctgc cgggttccct 2948tgccagacat gatgtcggtt atctggcaaa agccatttta tgtcggccac gaggcaggtg 3008ttcactgtgc atcattcatt caccccatga tgttctggaa gtaaaccttg gttgtctttc 3068gttggccaga ggaattgaat gtccgtctgt ctgcccaggc tggagtggca cgatctcagc 3128tcactgcagc ctccacctcc agggttcaag cgattctcct gcctcagcct cccggggatc 3188tcaagggcat ttccctttgc ccacctcgcc ttttcatatt tggtaaactg tatgcatttg 3248cctccagccc aagattataa atatgaactg attatgatct gcatgttctc tctttgggtt 3308caagcatttc cttacagaag agccaccgtg gaagtcatgg gtaaatatgt gttgaattgg 3368taactccctc ttggagaatt tcttgtgaat tacacagcaa taggggaact catttaactg 3428gagacataat ctcaatttgt aaagtgtggc ccattttcta acatttttat tttgcatacc 3488ctcccctctc ttctcgattg atgaaactaa caaagaggtt aataaaagcc catctcgtca 3548tgt 355118697PRTHomo sapiens 18Met Gln Glu Gly Leu His Arg Met Thr Trp Asp Cys Ile Ala Ile Gly1 5 10 15Ser His Glu Asn Ser Val Gln Gly Thr Val Ala Phe Glu Asp Val Ala 20 25 30Val Asn Phe Ser Gln Glu Glu Trp Ser Leu Leu Ser Glu Val Gln Arg 35 40 45Cys Leu Tyr His Asp Val Met Leu Glu Asn Trp Val Leu Ile Ser Ser 50 55 60Leu Gly Cys Trp Cys Gly Ser Glu Asp Glu Glu Ala Pro Ser Lys Lys65 70 75 80Ser Ile Ser Ile Gln Arg Val Ser Gln Val Ser Thr Pro Gly Ala Gly 85 90 95Val Ser Pro Lys Lys Ala His Ser Cys Glu Met Cys Gly Ala Ile Leu 100 105 110Gly Asp Ile Leu His Leu Ala Asp His Gln Gly Thr His His Lys Gln 115 120 125Lys Leu His Arg Cys Glu Ala Trp Gly Asn Lys Leu Tyr Asp Ser Ser 130 135 140Asn Arg Pro His Gln Asn Gln Tyr Leu Gly Glu Lys Pro Tyr Arg Ser145 150 155 160Ser Val Glu Glu Ala Leu Phe Val Lys Arg Cys Lys Phe His Val Ser 165 170 175Glu Glu Ser Ser Ile Phe Ile Gln Ser Gly Lys Asp Phe Leu Pro Ser 180 185 190Ser Gly Leu Leu Leu Gln Glu Ala Thr His Thr Gly Glu Lys Ser Asn 195 200 205Ser Lys Pro Glu Cys Glu Ser Pro Phe Gln Trp Gly Asp Thr Arg Tyr 210 215 220Ser Cys Gly Glu Cys Met Lys His Ser Ser Thr Lys His Val Phe Val225 230 235 240Gln Gln Gln Arg Leu Pro Ser Arg Glu Glu Cys Tyr Cys Trp Glu Cys 245 250 255Gly Lys Ser Phe Ser Lys Tyr Asp Ser Val Ser Asn His Gln Arg Val 260 265 270His Thr Gly Lys Arg Pro Tyr Glu Cys Gly Glu Cys Gly Lys Ser Phe 275 280 285Ser His Lys Gly Ser Leu Val Gln His Gln Arg Val His Thr Gly Lys 290 295 300Arg Pro Tyr Glu Cys Gly Glu Cys Gly Lys Ser Phe Ser His Lys Gly305 310 315 320Ser Leu Val Gln His Gln Arg Val His Thr Gly Glu Arg Pro Tyr Glu 325 330 335Cys Gly Glu Cys Gly Lys Ser Phe Ser Gln Asn Gly Thr Leu Ile Lys 340 345 350His Gln Arg Val His Thr Gly Glu Arg Pro Tyr Glu Cys Glu Glu Cys 355 360 365Gly Lys Cys Phe Thr Gln Lys Gly Asn Leu Ile Gln His Gln Arg Gly 370 375 380His Thr Ser Glu Arg Pro Tyr Glu Cys Glu Glu Cys Gly Lys Cys Phe385 390 395 400Ser Gln Lys Gly Thr Leu Thr Glu His His Arg Val His Thr Arg Glu 405 410 415Arg Pro Tyr Glu Cys Gly Glu Cys Gly Lys Ser Phe Ser Arg Lys Gly 420

425 430His Leu Arg Asn His Gln Arg Gly His Thr Gly Glu Arg Pro Tyr Glu 435 440 445Cys Gly Glu Cys Gly Lys Ser Phe Ser Arg Lys Gly Asn Leu Ile Gln 450 455 460His Gln Arg Ser His Thr Gly Glu Arg Pro Tyr Glu Cys Arg Glu Cys465 470 475 480Arg Lys Leu Phe Arg Gly Lys Ser His Leu Ile Glu His Gln Arg Val 485 490 495His Thr Gly Glu Arg Pro Tyr Glu Cys Asn Glu Cys Gly Lys Ser Phe 500 505 510Gln Asp Ser Ser Gly Phe Arg Val His Gln Arg Val His Thr Gly Glu 515 520 525Lys Pro Phe Glu Cys Ser Glu Cys Gly Lys Ser Phe Pro Gln Ser Cys 530 535 540Ser Leu Leu Arg His Arg Arg Val His Thr Gly Glu Arg Pro Tyr Glu545 550 555 560Cys Gly Glu Cys Gly Lys Ser Phe His Gln Ser Ser Ser Leu Leu Arg 565 570 575His Gln Lys Thr His Thr Ala Glu Arg Pro Tyr Glu Cys Arg Glu Cys 580 585 590Gly Lys Phe Phe Ser Ser Leu Leu Glu His Arg Arg Val His Thr Gly 595 600 605Glu Arg Pro Tyr Glu Cys Arg Glu Cys Gly Lys Thr Phe Thr Arg Arg 610 615 620Ser Ala His Phe Lys His Gln Arg Leu His Thr Arg Gly Lys Pro Tyr625 630 635 640Glu Cys Ser Glu Cys Gly Lys Ser Phe Ala Glu Thr Phe Ser Leu Thr 645 650 655Glu His Arg Arg Val His Thr Gly Glu Arg Pro Tyr Glu Cys Ser Glu 660 665 670Cys Gly Lys Ser Phe His Arg Ser Ser Ser Leu Leu Arg His Gln Arg 675 680 685Val His Thr Glu Arg Ser Pro Tyr Lys 690 69519220DNAHomo sapiens 19accattctcc ataacaaggg agtgggattt aaatgactct aggtggacag aggaaagtcg 60tcattgtaga ggggtcacca agtgcaacac agaagtggaa tagggccatg gatatctaaa 120gccccacctg gttctgtggg gatgtggagc catgcaagaa ggccttcata gaatgacttg 180ggactgcatt gctattggga gccatgagaa ttctgtgcag 2202023PRTHomo sapiens 20Met Gln Glu Gly Leu His Arg Met Thr Trp Asp Cys Ile Ala Ile Gly1 5 10 15Ser His Glu Asn Ser Val Gln 202169DNAHomo sapiens 21atgcaagaag gccttcatag aatgacttgg gactgcattg ctattgggag ccatgagaat 60tctgtgcag 692223PRTHomo sapiens 22Met Gln Glu Gly Leu His Arg Met Thr Trp Asp Cys Ile Ala Ile Gly1 5 10 15Ser His Glu Asn Ser Val Gln 202318DNAArtificial Sequenceforward primer used for specifically detecting the variant of the present invention 23gtgctttccc cgcgtact 182422DNAArtificial Sequencereverse primer used for specifically detecting the variant of the present invention 24aggagtgctg acctgagaca ct 2225138DNAArtificial Sequencepartial polynucleotide specific to the variant of the present invention, which is obtained by PCR using forward primer (SEQ ID NO23) and reverse primer (SEQ ID NO24) 25gtgctttccc cgcgtactcg ggatggcggc ggccgcgctg aggctcccgg ctcaggttgt 60tggtgtggat cagaagatga ggaggcacct tctaagaaga gcatttctat acaaagagtg 120tctcaggtca gcactcct 1382622DNAArtificial Sequenceprobe used for detecting the variants of the present invention 26ctcccggctc aggttgttgg tg 222723DNAArtificial Sequenceforward primer used for specifically detecting the variant of the present invention 27gatatctaaa gccccacctg gtt 232821DNAArtificial Sequencereverse primer used for specifically detecting the variant of the present invention 28acagtgccct gcacagaatt c 2129118DNAArtificial Sequencepartial polynucleotide specific to the variant of the present invention, which is obtained by PCR using forward primer (SEQ ID NO27) and reverse primer (SEQ ID NO28) 29gatatctaaa gccccacctg gttctgtggg gatgtggagc catgcaagaa ggccttcata 60gaatgacttg ggactgcatt gctattggga gccatgagaa ttctgtgcag ggcactgt 1183028DNAArtificial Sequenceprobe used for detecting the variants of the present invention 30atgacttggg actgcattgc tattggga 283122DNAArtificial Sequenceforward primer used for specifically detecting the known variant of the gene of the present invention 31ggaggaagga ggatcagagt tt 223220DNAArtificial Sequencereverse primer used for specifically detecting the known variant of the gene of the present invention 32agccacatct tcaaatgcca 203369DNAArtificial Sequencepartial polynucleotide specific to the known variant of the gene of the present invention, which is obtained by PCR using forward primer (SEQ ID NO31) and reverse primer (SEQ ID NO32) 33ggaggaagga ggatcagagt ttaaactcct gccataatgc agggcactgt ggcatttgaa 60gatgtggct 693425DNAArtificial Sequenceprobe used for specifically detecting the known variant of the gene of the present invention 34aactcctgcc ataatgcagg gcact 253524DNAArtificial Sequenceforward primer used for detecting the variants of the gene of the present invention 35ttccatgtgt cagaggagtc atct 243624DNAArtificial Sequencereverse primer used for detecting the variants of the gene of the present invention 36cactcaggtt tgctgtttga cttc 2437122DNAArtificial Sequencepartial polynucleotide common to the variants of the gene of the present invention, which is obtained by PCR using forward primer (SEQ ID NO35) and reverse primer (SEQ ID NO36) 37ttccatgtgt cagaggagtc atctatcttc attcagagtg gaaaggactt tttgcccagc 60tcaggattac tgctgcagga ggccactcac actggggaga agtcaaacag caaacctgag 120tg 1223827DNAArtificial Sequenceprobe used for detecting the variants of the gene of the present invention 38ttttgcccag ctcaggatta ctgctgc 2739306DNAHomo sapiens 39ggtagcgacc attttggtta atgttgggtg tgtttctgcg gtttgtgagg tgagaggcgc 60tggagctatg ggtccgaacc gcggtgtctg aacccagaag gtgaagagtc cttcttgctg 120cacagaggca gatcttaggc cccgtaacgg cgcccgccgc tcccggcagt gctttccccg 180cgtactcggg atggcggcgg ccgcgctgag gctcccggct caggttgttg gtgtggatca 240gaagatgagg aggcaccttc taagaagagc atttctatac aaagagtgtc tcaggtcagc 300actcct 30640541DNAHomo sapiens 40ctctggtagc gaccattttg gttaatgttg ggtgtgtttc tgcggtttgt gaggtgagag 60gcgctggagc tatgggtccg aaccgcggtg tctgaaccca gaaggtgaag agtccttctt 120gctgcacaga ggcagatcct aggccccgta acggcgcccg ccgctcccgg cagtgctttc 180cccgcgtact cgggatggcg gcggccgcgc tgaggctccc ggctcaggca tcatctggct 240gcaaagaaga gaacacactg tgtttgaggg aggaggaagg aggatcagag tttaaactcc 300tgccataatg cagaccattc tccataacaa gggagtggga tttaaatgac tctaggtgga 360cagaggaaag tcgtcattgt agaggggtca ccaagtgcaa cacagaagtg gaatagggcc 420atggatatct aaagccccac ctggttctgt ggggatgtgg agccatgcaa gaaggccttc 480atagaatgac ttgggactgc attgctattg ggagccatga gaattctgtg cagggcactg 540t 541411573DNAHomo sapiens 41aaaaaaaaac tgccacggag ccccagcggc tacacactcc actcactcac acctctcagg 60gccccgcacg ttcccacagc cctcagggtg tacgtgctgt aggtgtggct gtgccccaga 120gtgccagctg atgaagacgg agcggccccg gcccaacacc ttcatcatcc gctgcctgca 180gtggaccact gtcatcgaac gcaccttcca tgtggagact cctgaggagc gggaggagtg 240gacaaccgcc atccagactg tggctgacgg cctcaagaag caggaggagg aggagatgga 300cttccggtcg ggctcaccca gtgacaactc aggggctgaa gagatggagg tgtccctggc 360caagcccaag caccgcgtga ccatgaacga gtttgagtac ctgaagctgc tgggcaaggg 420cactttcggc aaggtgatcc tggtgaagga gaaggccaca ggccgctact acgccatgaa 480gatcctcaag aaggaagtca tcgtggccaa ggacgaggtg gcccacacac tcaccgagaa 540ccgcgtcctg cagaactcca ggcacccctt cctcacagcc ctgaagtact ctttccagac 600ccacgaccgc ctctgctttg tcatggagta cgccaacggg ggcgagctgt tcttccacct 660gtcccgggaa cgtgtgttct ccgaggaccg ggcccgcttc tatggcgctg agattgtgtc 720agccctggac tacctgcact cggagaagaa cgtggtgtac cgggacctca agctggagaa 780cctcatgctg gacaaggacg ggcacattaa gatcacagac ttcgggctgt gcaaggaggg 840gatcaaggac ggtgccacca tgaagacctt ttgcggcaca cctgagtacc tggcccccga 900ggtgctggag gacaatgact acggccgtgc agtggactgg tgggggctgg gcgtggtcat 960gtacgagatg atgtgcggtc gcctgccctt ctacaaccag gaccatgaga agctttttga 1020gctcatcctc atggaggaga tccgcttccc gcgcacgctt ggtcccgagg ccaagtcctt 1080gctttcaggg ctgctcaaga aggaccccaa gcagaggctt ggcgggggct ccgaggacgc 1140caaggagatc atgcagcatc gcttctttgc cggtatcgtg tggcagcacg tgtacgagaa 1200gaagctcagc ccacccttca agccccaggt cacgtcggag actgacacca ggtattttga 1260tgaggagttc acggcccaga tgatcaccat cacaccacct gaccaagatg acagcatgga 1320gtgtgtggac agcgagcgca ggccccactt cccccagttc tcctactcgg ccagcggcac 1380ggcctgaggc ggcggtggac tgcgctggac gatagcttgg agggatggag aggcggcctc 1440gtgccatgat ctgtatttaa tggtttttat ttctcgggtg catttgagag aagccacgct 1500gtcctctcga gcccagatgg aaagacgttt ttgtgctgtg ggcagcaccc tcccccgcag 1560cggggtaggg aag 1573421573DNAHomo sapiensCDS(131)..(1387) 42aaaaaaaaac tgccacggag ccccagcggc tacacactcc actcactcac acctctcagg 60gccccgcacg ttcccacagc cctcagggtg tacgtgctgt aggtgtggct gtgccccaga 120gtgccagctg atg aag acg gag cgg ccc cgg ccc aac acc ttc atc atc 169 Met Lys Thr Glu Arg Pro Arg Pro Asn Thr Phe Ile Ile 1 5 10cgc tgc ctg cag tgg acc act gtc atc gaa cgc acc ttc cat gtg gag 217Arg Cys Leu Gln Trp Thr Thr Val Ile Glu Arg Thr Phe His Val Glu 15 20 25act cct gag gag cgg gag gag tgg aca acc gcc atc cag act gtg gct 265Thr Pro Glu Glu Arg Glu Glu Trp Thr Thr Ala Ile Gln Thr Val Ala30 35 40 45gac ggc ctc aag aag cag gag gag gag gag atg gac ttc cgg tcg ggc 313Asp Gly Leu Lys Lys Gln Glu Glu Glu Glu Met Asp Phe Arg Ser Gly 50 55 60tca ccc agt gac aac tca ggg gct gaa gag atg gag gtg tcc ctg gcc 361Ser Pro Ser Asp Asn Ser Gly Ala Glu Glu Met Glu Val Ser Leu Ala 65 70 75aag ccc aag cac cgc gtg acc atg aac gag ttt gag tac ctg aag ctg 409Lys Pro Lys His Arg Val Thr Met Asn Glu Phe Glu Tyr Leu Lys Leu 80 85 90ctg ggc aag ggc act ttc ggc aag gtg atc ctg gtg aag gag aag gcc 457Leu Gly Lys Gly Thr Phe Gly Lys Val Ile Leu Val Lys Glu Lys Ala 95 100 105aca ggc cgc tac tac gcc atg aag atc ctc aag aag gaa gtc atc gtg 505Thr Gly Arg Tyr Tyr Ala Met Lys Ile Leu Lys Lys Glu Val Ile Val110 115 120 125gcc aag gac gag gtg gcc cac aca ctc acc gag aac cgc gtc ctg cag 553Ala Lys Asp Glu Val Ala His Thr Leu Thr Glu Asn Arg Val Leu Gln 130 135 140aac tcc agg cac ccc ttc ctc aca gcc ctg aag tac tct ttc cag acc 601Asn Ser Arg His Pro Phe Leu Thr Ala Leu Lys Tyr Ser Phe Gln Thr 145 150 155cac gac cgc ctc tgc ttt gtc atg gag tac gcc aac ggg ggc gag ctg 649His Asp Arg Leu Cys Phe Val Met Glu Tyr Ala Asn Gly Gly Glu Leu 160 165 170ttc ttc cac ctg tcc cgg gaa cgt gtg ttc tcc gag gac cgg gcc cgc 697Phe Phe His Leu Ser Arg Glu Arg Val Phe Ser Glu Asp Arg Ala Arg 175 180 185ttc tat ggc gct gag att gtg tca gcc ctg gac tac ctg cac tcg gag 745Phe Tyr Gly Ala Glu Ile Val Ser Ala Leu Asp Tyr Leu His Ser Glu190 195 200 205aag aac gtg gtg tac cgg gac ctc aag ctg gag aac ctc atg ctg gac 793Lys Asn Val Val Tyr Arg Asp Leu Lys Leu Glu Asn Leu Met Leu Asp 210 215 220aag gac ggg cac att aag atc aca gac ttc ggg ctg tgc aag gag ggg 841Lys Asp Gly His Ile Lys Ile Thr Asp Phe Gly Leu Cys Lys Glu Gly 225 230 235atc aag gac ggt gcc acc atg aag acc ttt tgc ggc aca cct gag tac 889Ile Lys Asp Gly Ala Thr Met Lys Thr Phe Cys Gly Thr Pro Glu Tyr 240 245 250ctg gcc ccc gag gtg ctg gag gac aat gac tac ggc cgt gca gtg gac 937Leu Ala Pro Glu Val Leu Glu Asp Asn Asp Tyr Gly Arg Ala Val Asp 255 260 265tgg tgg ggg ctg ggc gtg gtc atg tac gag atg atg tgc ggt cgc ctg 985Trp Trp Gly Leu Gly Val Val Met Tyr Glu Met Met Cys Gly Arg Leu270 275 280 285ccc ttc tac aac cag gac cat gag aag ctt ttt gag ctc atc ctc atg 1033Pro Phe Tyr Asn Gln Asp His Glu Lys Leu Phe Glu Leu Ile Leu Met 290 295 300gag gag atc cgc ttc ccg cgc acg ctt ggt ccc gag gcc aag tcc ttg 1081Glu Glu Ile Arg Phe Pro Arg Thr Leu Gly Pro Glu Ala Lys Ser Leu 305 310 315ctt tca ggg ctg ctc aag aag gac ccc aag cag agg ctt ggc ggg ggc 1129Leu Ser Gly Leu Leu Lys Lys Asp Pro Lys Gln Arg Leu Gly Gly Gly 320 325 330tcc gag gac gcc aag gag atc atg cag cat cgc ttc ttt gcc ggt atc 1177Ser Glu Asp Ala Lys Glu Ile Met Gln His Arg Phe Phe Ala Gly Ile 335 340 345gtg tgg cag cac gtg tac gag aag aag ctc agc cca ccc ttc aag ccc 1225Val Trp Gln His Val Tyr Glu Lys Lys Leu Ser Pro Pro Phe Lys Pro350 355 360 365cag gtc acg tcg gag act gac acc agg tat ttt gat gag gag ttc acg 1273Gln Val Thr Ser Glu Thr Asp Thr Arg Tyr Phe Asp Glu Glu Phe Thr 370 375 380gcc cag atg atc acc atc aca cca cct gac caa gat gac agc atg gag 1321Ala Gln Met Ile Thr Ile Thr Pro Pro Asp Gln Asp Asp Ser Met Glu 385 390 395tgt gtg gac agc gag cgc agg ccc cac ttc ccc cag ttc tcc tac tcg 1369Cys Val Asp Ser Glu Arg Arg Pro His Phe Pro Gln Phe Ser Tyr Ser 400 405 410gcc agc ggc acg gcc tga ggcggcggtg gactgcgctg gacgatagct 1417Ala Ser Gly Thr Ala 415tggagggatg gagaggcggc ctcgtgccat gatctgtatt taatggtttt tatttctcgg 1477gtgcatttga gagaagccac gctgtcctct cgagcccaga tggaaagacg tttttgtgct 1537gtgggcagca ccctcccccg cagcggggta gggaag 157343418PRTHomo sapiens 43Met Lys Thr Glu Arg Pro Arg Pro Asn Thr Phe Ile Ile Arg Cys Leu1 5 10 15Gln Trp Thr Thr Val Ile Glu Arg Thr Phe His Val Glu Thr Pro Glu 20 25 30Glu Arg Glu Glu Trp Thr Thr Ala Ile Gln Thr Val Ala Asp Gly Leu 35 40 45Lys Lys Gln Glu Glu Glu Glu Met Asp Phe Arg Ser Gly Ser Pro Ser 50 55 60Asp Asn Ser Gly Ala Glu Glu Met Glu Val Ser Leu Ala Lys Pro Lys65 70 75 80His Arg Val Thr Met Asn Glu Phe Glu Tyr Leu Lys Leu Leu Gly Lys 85 90 95Gly Thr Phe Gly Lys Val Ile Leu Val Lys Glu Lys Ala Thr Gly Arg 100 105 110Tyr Tyr Ala Met Lys Ile Leu Lys Lys Glu Val Ile Val Ala Lys Asp 115 120 125Glu Val Ala His Thr Leu Thr Glu Asn Arg Val Leu Gln Asn Ser Arg 130 135 140His Pro Phe Leu Thr Ala Leu Lys Tyr Ser Phe Gln Thr His Asp Arg145 150 155 160Leu Cys Phe Val Met Glu Tyr Ala Asn Gly Gly Glu Leu Phe Phe His 165 170 175Leu Ser Arg Glu Arg Val Phe Ser Glu Asp Arg Ala Arg Phe Tyr Gly 180 185 190Ala Glu Ile Val Ser Ala Leu Asp Tyr Leu His Ser Glu Lys Asn Val 195 200 205Val Tyr Arg Asp Leu Lys Leu Glu Asn Leu Met Leu Asp Lys Asp Gly 210 215 220His Ile Lys Ile Thr Asp Phe Gly Leu Cys Lys Glu Gly Ile Lys Asp225 230 235 240Gly Ala Thr Met Lys Thr Phe Cys Gly Thr Pro Glu Tyr Leu Ala Pro 245 250 255Glu Val Leu Glu Asp Asn Asp Tyr Gly Arg Ala Val Asp Trp Trp Gly 260 265 270Leu Gly Val Val Met Tyr Glu Met Met Cys Gly Arg Leu Pro Phe Tyr 275 280 285Asn Gln Asp His Glu Lys Leu Phe Glu Leu Ile Leu Met Glu Glu Ile 290 295 300Arg Phe Pro Arg Thr Leu Gly Pro Glu Ala Lys Ser Leu Leu Ser Gly305 310 315 320Leu Leu Lys Lys Asp Pro Lys Gln Arg Leu Gly Gly Gly Ser Glu Asp 325 330 335Ala Lys Glu Ile Met Gln His Arg Phe Phe Ala Gly Ile Val Trp Gln 340 345 350His Val Tyr Glu Lys Lys Leu Ser Pro Pro Phe Lys Pro Gln Val Thr 355 360 365Ser

Glu Thr Asp Thr Arg Tyr Phe Asp Glu Glu Phe Thr Ala Gln Met 370 375 380Ile Thr Ile Thr Pro Pro Asp Gln Asp Asp Ser Met Glu Cys Val Asp385 390 395 400Ser Glu Arg Arg Pro His Phe Pro Gln Phe Ser Tyr Ser Ala Ser Gly 405 410 415Thr Ala44119DNAHomo sapiens 44aaaaaaaaac tgccacggag ccccagcggc tacacactcc actcactcac acctctcagg 60gccccgcacg ttcccacagc cctcagggtg tacgtgctgt aggtgtggct gtgccccag 11945130DNAHomo sapiens 45aaaaaaaaac tgccacggag ccccagcggc tacacactcc actcactcac acctctcagg 60gccccgcacg ttcccacagc cctcagggtg tacgtgctgt aggtgtggct gtgccccaga 120gtgccagctg 1304622DNAArtificial Sequenceforward primer used for specifically detecting the variant of the present invention 46tcagggtgta cgtgctgtag gt 224719DNAArtificial Sequencereverse primer used for specifically detecting the variant of the present invention 47acatggaagg tgcgttcga 1948131DNAArtificial Sequencepartial polynucleotide specific to the variant of the present invention, which is obtained by PCR using forward primer (SEQ ID NO46) and reverse primer (SEQ ID NO47) 48tcagggtgta cgtgctgtag gtgtggctgt gccccagagt gccagctgat gaagacggag 60cggccccggc ccaacacctt catcatccgc tgcctgcagt ggaccactgt catcgaacgc 120accttccatg t 1314918DNAArtificial Sequenceforward primer used for specifically detecting the known variant of the gene of the present invention 49ggttggctgc acaaacga 185021DNAArtificial Sequencereverse primer used for specifically detecting the known variant of the gene of the present invention 50gagcctcacg ttggtccaca t 2151124DNAArtificial Sequencepartial polynucleotide specific to the known variant of the gene of the present invention, which is obtained by PCR using forward primer (SEQ ID NO49) and reverse primer (SEQ ID NO50) 51ggttggctgc acaaacgagg ggagtacatc aagacctggc ggccacgcta cttcctcctc 60aagaatgatg gcaccttcat tggctacaag gagcggccgc aggatgtgga ccaacgtgag 120gctc 1245218DNAArtificial Sequenceforward primer used for detecting the variants of the gene of the present invention 52ccgcgtcctg cagaactc 185318DNAArtificial Sequencereverse primer used for detecting the variants of the gene of the present invention 53cccgttggcg tactccat 1854100DNAArtificial Sequencepartial polynucleotide common to the variants of the gene of the present invention, which is obtained by PCR using forward primer (SEQ ID NO52) and reverse primer (SEQ ID NO53) 54ccgcgtcctg cagaactcca ggcacccctt cctcacagcc ctgaagtact ctttccagac 60ccacgaccgc ctctgctttg tcatggagta cgccaacggg 10055213DNAHomo sapiens 55aaaaaaaaac tgccacggag ccccagcggc tacacactcc actcactcac acctctcagg 60gccccgcacg ttcccacagc cctcagggtg tacgtgctgt aggtgtggct gtgccccaga 120gtgccagctg atgaagacgg agcggccccg gcccaacacc ttcatcatcc gctgcctgca 180gtggaccact gtcatcgaac gcaccttcca tgt 213561800DNAHomo sapiens 56aataatgcta atacccagca ctcgggctcc acaatgtaga ggaaatggca tcgcctggca 60gtgacagcta tattgtgcgt gtcaaggctg tggttatgac cagagatgac tccagcgggg 120gatggttccc acgggaagga ggcgggatca gtcgcgtcgg ggtctgtaag gtcatgcacc 180ccgaaggcaa tggacgaagc ggctttctca tccatggtga acgacagaaa gacaaactgg 240tggtattgga atgctatgta agaaaggact tggtctacac caaagccaat ccaacgtttc 300atcactggaa ggtcgataat aggaagtttg gacttacttt ccaaagccct gctgatgccc 360gagcctttga caggggagta aggaaagcaa tcgaagacct tatagaaggt tcaacaacgt 420catcttccac catccataat gaagctgagc ttggcgatga tgacgttttt acaacagcta 480cagacagttc ttctaattcc tctcagaaga gagagcaacc tactcggaca atctcctctc 540ccacatcctg tgagcaccgg aggatttata ccctgggcca cctccacgac tcatacccca 600cagaccacta tcacctcgat cagccgatgc caaggcccta ccgccaggtg agcttcccgg 660acgacgacga ggagatcgtg cgcatcaacc cccgggagaa gatctggatg acggggtacg 720aggattaccg gcacgcaccc gtcaggggca agtacccgga cccctcggag gacgcggact 780cctcctacgt gcgcttcgcc aagggcgagg tccccaagca tgactacaac tacccctacg 840tggactcctc agactttggc ctaggcgagg accccaaagg ccgcgggggc agcgtgatca 900agacgcagcc ctcccggggc aagtcgcggc ggcggaagga ggacggagag cgctcgcggt 960gcgtgtactg cagggacatg ttcaaccacg aggagaaccg ccggggccac tgccaggacg 1020cgcccgactc cgtgagaact tgcatccgcc gggtgagctg catgtggtgc gcggacagca 1080tgctctatca ctgtatgtcg gaccccgagg gagactatac agacccttgc tcgtgcgata 1140ctagcgacga gaagttttgc ctccggtgga tggctcttat tgccttgtct ttcctggccc 1200cctgtatgtg ctgttacctg ccccttcggg cctgctacca ctgcggagtg atgtgcaggt 1260gctgtggcgg gaagcacaaa gcggccgcgt gactcagttt ccctcccttc tccctccatc 1320cgcagccaca ggggaactcg tctcttacat actctcatct tctcccccgc tcccttccac 1380tccaaggagc gaggagggca agcggcctcc cagctccctg gtacctcgag gcaccattcc 1440agccagggac gctgccgggt agactctcca ctccccctgc cgcccacact gcagcagcca 1500catccataca cacacgctcg cacagtgttc tgaggaagga accttcgcca cagactcctg 1560tactattaac aatctgtaac caagctaact gtctcatcca tgtgttgatt tcctgtttcc 1620tcctcccccg cctcttccag ttcaaaggag tctgcaattg gaactgctga ttttcggtgg 1680gttttgtagt tgatttttcc aagagcgtcg aagactctct ttctcttggt tcaccttgcc 1740tgtcgctagc aagcatctgg ttcagcggaa atgggatgtg agaatgatga aacccgacag 1800571800DNAHomo sapiensCDS(45)..(1292) 57aataatgcta atacccagca ctcgggctcc acaatgtaga ggaa atg gca tcg cct 56 Met Ala Ser Pro 1ggc agt gac agc tat att gtg cgt gtc aag gct gtg gtt atg acc aga 104Gly Ser Asp Ser Tyr Ile Val Arg Val Lys Ala Val Val Met Thr Arg5 10 15 20gat gac tcc agc ggg gga tgg ttc cca cgg gaa gga ggc ggg atc agt 152Asp Asp Ser Ser Gly Gly Trp Phe Pro Arg Glu Gly Gly Gly Ile Ser 25 30 35cgc gtc ggg gtc tgt aag gtc atg cac ccc gaa ggc aat gga cga agc 200Arg Val Gly Val Cys Lys Val Met His Pro Glu Gly Asn Gly Arg Ser 40 45 50ggc ttt ctc atc cat ggt gaa cga cag aaa gac aaa ctg gtg gta ttg 248Gly Phe Leu Ile His Gly Glu Arg Gln Lys Asp Lys Leu Val Val Leu 55 60 65gaa tgc tat gta aga aag gac ttg gtc tac acc aaa gcc aat cca acg 296Glu Cys Tyr Val Arg Lys Asp Leu Val Tyr Thr Lys Ala Asn Pro Thr 70 75 80ttt cat cac tgg aag gtc gat aat agg aag ttt gga ctt act ttc caa 344Phe His His Trp Lys Val Asp Asn Arg Lys Phe Gly Leu Thr Phe Gln85 90 95 100agc cct gct gat gcc cga gcc ttt gac agg gga gta agg aaa gca atc 392Ser Pro Ala Asp Ala Arg Ala Phe Asp Arg Gly Val Arg Lys Ala Ile 105 110 115gaa gac ctt ata gaa ggt tca aca acg tca tct tcc acc atc cat aat 440Glu Asp Leu Ile Glu Gly Ser Thr Thr Ser Ser Ser Thr Ile His Asn 120 125 130gaa gct gag ctt ggc gat gat gac gtt ttt aca aca gct aca gac agt 488Glu Ala Glu Leu Gly Asp Asp Asp Val Phe Thr Thr Ala Thr Asp Ser 135 140 145tct tct aat tcc tct cag aag aga gag caa cct act cgg aca atc tcc 536Ser Ser Asn Ser Ser Gln Lys Arg Glu Gln Pro Thr Arg Thr Ile Ser 150 155 160tct ccc aca tcc tgt gag cac cgg agg att tat acc ctg ggc cac ctc 584Ser Pro Thr Ser Cys Glu His Arg Arg Ile Tyr Thr Leu Gly His Leu165 170 175 180cac gac tca tac ccc aca gac cac tat cac ctc gat cag ccg atg cca 632His Asp Ser Tyr Pro Thr Asp His Tyr His Leu Asp Gln Pro Met Pro 185 190 195agg ccc tac cgc cag gtg agc ttc ccg gac gac gac gag gag atc gtg 680Arg Pro Tyr Arg Gln Val Ser Phe Pro Asp Asp Asp Glu Glu Ile Val 200 205 210cgc atc aac ccc cgg gag aag atc tgg atg acg ggg tac gag gat tac 728Arg Ile Asn Pro Arg Glu Lys Ile Trp Met Thr Gly Tyr Glu Asp Tyr 215 220 225cgg cac gca ccc gtc agg ggc aag tac ccg gac ccc tcg gag gac gcg 776Arg His Ala Pro Val Arg Gly Lys Tyr Pro Asp Pro Ser Glu Asp Ala 230 235 240gac tcc tcc tac gtg cgc ttc gcc aag ggc gag gtc ccc aag cat gac 824Asp Ser Ser Tyr Val Arg Phe Ala Lys Gly Glu Val Pro Lys His Asp245 250 255 260tac aac tac ccc tac gtg gac tcc tca gac ttt ggc cta ggc gag gac 872Tyr Asn Tyr Pro Tyr Val Asp Ser Ser Asp Phe Gly Leu Gly Glu Asp 265 270 275ccc aaa ggc cgc ggg ggc agc gtg atc aag acg cag ccc tcc cgg ggc 920Pro Lys Gly Arg Gly Gly Ser Val Ile Lys Thr Gln Pro Ser Arg Gly 280 285 290aag tcg cgg cgg cgg aag gag gac gga gag cgc tcg cgg tgc gtg tac 968Lys Ser Arg Arg Arg Lys Glu Asp Gly Glu Arg Ser Arg Cys Val Tyr 295 300 305tgc agg gac atg ttc aac cac gag gag aac cgc cgg ggc cac tgc cag 1016Cys Arg Asp Met Phe Asn His Glu Glu Asn Arg Arg Gly His Cys Gln 310 315 320gac gcg ccc gac tcc gtg aga act tgc atc cgc cgg gtg agc tgc atg 1064Asp Ala Pro Asp Ser Val Arg Thr Cys Ile Arg Arg Val Ser Cys Met325 330 335 340tgg tgc gcg gac agc atg ctc tat cac tgt atg tcg gac ccc gag gga 1112Trp Cys Ala Asp Ser Met Leu Tyr His Cys Met Ser Asp Pro Glu Gly 345 350 355gac tat aca gac cct tgc tcg tgc gat act agc gac gag aag ttt tgc 1160Asp Tyr Thr Asp Pro Cys Ser Cys Asp Thr Ser Asp Glu Lys Phe Cys 360 365 370ctc cgg tgg atg gct ctt att gcc ttg tct ttc ctg gcc ccc tgt atg 1208Leu Arg Trp Met Ala Leu Ile Ala Leu Ser Phe Leu Ala Pro Cys Met 375 380 385tgc tgt tac ctg ccc ctt cgg gcc tgc tac cac tgc gga gtg atg tgc 1256Cys Cys Tyr Leu Pro Leu Arg Ala Cys Tyr His Cys Gly Val Met Cys 390 395 400agg tgc tgt ggc ggg aag cac aaa gcg gcc gcg tga ctcagtttcc 1302Arg Cys Cys Gly Gly Lys His Lys Ala Ala Ala405 410 415ctcccttctc cctccatccg cagccacagg ggaactcgtc tcttacatac tctcatcttc 1362tcccccgctc ccttccactc caaggagcga ggagggcaag cggcctccca gctccctggt 1422acctcgaggc accattccag ccagggacgc tgccgggtag actctccact ccccctgccg 1482cccacactgc agcagccaca tccatacaca cacgctcgca cagtgttctg aggaaggaac 1542cttcgccaca gactcctgta ctattaacaa tctgtaacca agctaactgt ctcatccatg 1602tgttgatttc ctgtttcctc ctcccccgcc tcttccagtt caaaggagtc tgcaattgga 1662actgctgatt ttcggtgggt tttgtagttg atttttccaa gagcgtcgaa gactctcttt 1722ctcttggttc accttgcctg tcgctagcaa gcatctggtt cagcggaaat gggatgtgag 1782aatgatgaaa cccgacag 180058415PRTHomo sapiens 58Met Ala Ser Pro Gly Ser Asp Ser Tyr Ile Val Arg Val Lys Ala Val1 5 10 15Val Met Thr Arg Asp Asp Ser Ser Gly Gly Trp Phe Pro Arg Glu Gly 20 25 30Gly Gly Ile Ser Arg Val Gly Val Cys Lys Val Met His Pro Glu Gly 35 40 45Asn Gly Arg Ser Gly Phe Leu Ile His Gly Glu Arg Gln Lys Asp Lys 50 55 60Leu Val Val Leu Glu Cys Tyr Val Arg Lys Asp Leu Val Tyr Thr Lys65 70 75 80Ala Asn Pro Thr Phe His His Trp Lys Val Asp Asn Arg Lys Phe Gly 85 90 95Leu Thr Phe Gln Ser Pro Ala Asp Ala Arg Ala Phe Asp Arg Gly Val 100 105 110Arg Lys Ala Ile Glu Asp Leu Ile Glu Gly Ser Thr Thr Ser Ser Ser 115 120 125Thr Ile His Asn Glu Ala Glu Leu Gly Asp Asp Asp Val Phe Thr Thr 130 135 140Ala Thr Asp Ser Ser Ser Asn Ser Ser Gln Lys Arg Glu Gln Pro Thr145 150 155 160Arg Thr Ile Ser Ser Pro Thr Ser Cys Glu His Arg Arg Ile Tyr Thr 165 170 175Leu Gly His Leu His Asp Ser Tyr Pro Thr Asp His Tyr His Leu Asp 180 185 190Gln Pro Met Pro Arg Pro Tyr Arg Gln Val Ser Phe Pro Asp Asp Asp 195 200 205Glu Glu Ile Val Arg Ile Asn Pro Arg Glu Lys Ile Trp Met Thr Gly 210 215 220Tyr Glu Asp Tyr Arg His Ala Pro Val Arg Gly Lys Tyr Pro Asp Pro225 230 235 240Ser Glu Asp Ala Asp Ser Ser Tyr Val Arg Phe Ala Lys Gly Glu Val 245 250 255Pro Lys His Asp Tyr Asn Tyr Pro Tyr Val Asp Ser Ser Asp Phe Gly 260 265 270Leu Gly Glu Asp Pro Lys Gly Arg Gly Gly Ser Val Ile Lys Thr Gln 275 280 285Pro Ser Arg Gly Lys Ser Arg Arg Arg Lys Glu Asp Gly Glu Arg Ser 290 295 300Arg Cys Val Tyr Cys Arg Asp Met Phe Asn His Glu Glu Asn Arg Arg305 310 315 320Gly His Cys Gln Asp Ala Pro Asp Ser Val Arg Thr Cys Ile Arg Arg 325 330 335Val Ser Cys Met Trp Cys Ala Asp Ser Met Leu Tyr His Cys Met Ser 340 345 350Asp Pro Glu Gly Asp Tyr Thr Asp Pro Cys Ser Cys Asp Thr Ser Asp 355 360 365Glu Lys Phe Cys Leu Arg Trp Met Ala Leu Ile Ala Leu Ser Phe Leu 370 375 380Ala Pro Cys Met Cys Cys Tyr Leu Pro Leu Arg Ala Cys Tyr His Cys385 390 395 400Gly Val Met Cys Arg Cys Cys Gly Gly Lys His Lys Ala Ala Ala 405 410 4155961DNAHomo sapiens 59aataatgcta atacccagca ctcgggctcc acaatgtaga ggaaatggca tcgcctggca 60g 61606PRTHomo sapiens 60Met Ala Ser Pro Gly Ser1 56117DNAHomo sapiens 61atggcatcgc ctggcag 176222DNAArtificial Sequenceforward primer used for specifically detecting the variant of the present invention 62ggctccacaa tgtagaggaa at 226322DNAArtificial Sequencereverse primer used for specifically detecting the variant of the present invention 63ggtcataacc acagccttga ca 226477DNAArtificial Sequencepartial polynucleotide specific to the variant of the present invention, which is obtained by PCR using forward primer (SEQ ID NO62) and reverse primer (SEQ ID NO63) 64ggctccacaa tgtagaggaa atggcatcgc ctggcagtga cagctatatt gtgcgtgtca 60aggctgtggt tatgacc 776523DNAArtificial Sequenceforward primer used for specifically detecting the known variant of the gene of the present invention 65acaggcgtct aggtaacaag aaa 236620DNAArtificial Sequencereverse primer used for specifically detecting the known variant of the gene of the present invention 66cagccttgac acgcacaata 206778DNAArtificial Sequencepartial polynucleotide specific to the known variant of the gene of the present invention, which is obtained by PCR using forward primer (SEQ ID NO65) and reverse primer (SEQ ID NO66) 67acaggcgtct aggtaacaag aaaatgaccg aagaaacaca cccagacgat gacagctata 60ttgtgcgtgt caaggctg 786823DNAArtificial Sequenceforward primer used for detecting the variants of the gene of the present invention 68gaccccgagg gagactatac aga 236919DNAArtificial Sequencereverse primer used for detecting the variants of the gene of the present invention 69atccaccgga ggcaaaact 197071DNAArtificial Sequencepartial polynucleotide common to the variants of the gene of the present invention, which is obtained by PCR using forward primer (SEQ ID NO68) and reverse primer (SEQ ID NO69) 70gaccccgagg gagactatac agacccttgc tcgtgcgata ctagcgacga gaagttttgc 60ctccggtgga t 7171101DNAHomo sapiens 71aataatgcta atacccagca ctcgggctcc acaatgtaga ggaaatggca tcgcctggca 60gtgacagcta tattgtgcgt gtcaaggctg tggttatgac c 101721420DNAHomo sapiens 72agagctggag catctcgcag ccctacaact tctttgcggc gcttggtctg tctttgcgtt 60gcgagatcag gatcggtgtg ttgctcagac accggccgaa cgccaccggc acgtctagga 120gtctcctgtg cctggaagag gctggtttca ttcgattcta aaagaaacgg atgttgaaac 180atttgtagca gatatactga aaggagaaaa tttatccaag aaagcaaagg aaaagagaga 240atcccttatt aagaagataa aagatgtaaa gtctatctat cttcaggaat ttcaagacaa 300aggtgatgca gaagatgggg aagaatatga tgaccctttt gctgggcctc cagacactat 360ttcattagcc tcagaacgat atgataaaga cgatgaagcc ccctctgatg gagcccagtt 420tcctccaatt gcagcacaag accttccttt tgttctaaag gctggctacc ttgaaaaacg 480cagaaaagat cacagctttc tgggatttga atggcagaaa cggtggtgtg ctctcagtaa 540aacggtattc tattattatg gaagtgataa

agacaaacaa cagaaaggtg aatttgcaat 600agatggctac agtgtcagaa tgaataacac tctaagaaag gatggaaaga aagattgctg 660ttttgaaatc tctgctcctg ataaacgtat atatcagttt acagcagctt ctcccaaaga 720tgctgaagaa tgggtacagc agctgaaatt tgtattgcaa gatatggaat ctgatattat 780tcctgaggat tatgatgaga gaggagaatt atatgatgat gttgatcatc ctctaccaat 840aagcaatcca ctaacaagca gtcaaccaat agatgatgaa atttatgaag aacttccaga 900agaagaagag gacagtgctc cagtgaaagt ggaagaacaa aggaagatga gtcaggatag 960tgtccatcac acctcagggg ataagagcac tgattatgct aatttttacc agggattgtg 1020ggattgtact ggagcttttt ctgatgagtt gtcatttaag cgtggtgatg tgatttacat 1080tcttagcaag gaatacaata gatatggctg gtgggtagga gaaatgaagg gagccattgg 1140cttggtgcct aaagcctaca taatggagat gtatgatatt tgagagtcct ggaaaaggaa 1200aattcttctg cttgtctgca aatgctctgg atttagaagc gtcatgaaag cacgagtgac 1260agctcctaac ctctccttgt tttattaaac attacttatc tttgactgtt attttatgca 1320gtcgctcatt aaaatattcc tctgatgtga aattaaatga aggatattaa tgtaaattag 1380atgcaaccag ttaagttata cctgttgcta ttttgcaaag 1420731420DNAHomo sapiensCDS(620)..(1183) 73agagctggag catctcgcag ccctacaact tctttgcggc gcttggtctg tctttgcgtt 60gcgagatcag gatcggtgtg ttgctcagac accggccgaa cgccaccggc acgtctagga 120gtctcctgtg cctggaagag gctggtttca ttcgattcta aaagaaacgg atgttgaaac 180atttgtagca gatatactga aaggagaaaa tttatccaag aaagcaaagg aaaagagaga 240atcccttatt aagaagataa aagatgtaaa gtctatctat cttcaggaat ttcaagacaa 300aggtgatgca gaagatgggg aagaatatga tgaccctttt gctgggcctc cagacactat 360ttcattagcc tcagaacgat atgataaaga cgatgaagcc ccctctgatg gagcccagtt 420tcctccaatt gcagcacaag accttccttt tgttctaaag gctggctacc ttgaaaaacg 480cagaaaagat cacagctttc tgggatttga atggcagaaa cggtggtgtg ctctcagtaa 540aacggtattc tattattatg gaagtgataa agacaaacaa cagaaaggtg aatttgcaat 600agatggctac agtgtcaga atg aat aac act cta aga aag gat gga aag aaa 652 Met Asn Asn Thr Leu Arg Lys Asp Gly Lys Lys 1 5 10gat tgc tgt ttt gaa atc tct gct cct gat aaa cgt ata tat cag ttt 700Asp Cys Cys Phe Glu Ile Ser Ala Pro Asp Lys Arg Ile Tyr Gln Phe 15 20 25aca gca gct tct ccc aaa gat gct gaa gaa tgg gta cag cag ctg aaa 748Thr Ala Ala Ser Pro Lys Asp Ala Glu Glu Trp Val Gln Gln Leu Lys 30 35 40ttt gta ttg caa gat atg gaa tct gat att att cct gag gat tat gat 796Phe Val Leu Gln Asp Met Glu Ser Asp Ile Ile Pro Glu Asp Tyr Asp 45 50 55gag aga gga gaa tta tat gat gat gtt gat cat cct cta cca ata agc 844Glu Arg Gly Glu Leu Tyr Asp Asp Val Asp His Pro Leu Pro Ile Ser60 65 70 75aat cca cta aca agc agt caa cca ata gat gat gaa att tat gaa gaa 892Asn Pro Leu Thr Ser Ser Gln Pro Ile Asp Asp Glu Ile Tyr Glu Glu 80 85 90ctt cca gaa gaa gaa gag gac agt gct cca gtg aaa gtg gaa gaa caa 940Leu Pro Glu Glu Glu Glu Asp Ser Ala Pro Val Lys Val Glu Glu Gln 95 100 105agg aag atg agt cag gat agt gtc cat cac acc tca ggg gat aag agc 988Arg Lys Met Ser Gln Asp Ser Val His His Thr Ser Gly Asp Lys Ser 110 115 120act gat tat gct aat ttt tac cag gga ttg tgg gat tgt act gga gct 1036Thr Asp Tyr Ala Asn Phe Tyr Gln Gly Leu Trp Asp Cys Thr Gly Ala 125 130 135ttt tct gat gag ttg tca ttt aag cgt ggt gat gtg att tac att ctt 1084Phe Ser Asp Glu Leu Ser Phe Lys Arg Gly Asp Val Ile Tyr Ile Leu140 145 150 155agc aag gaa tac aat aga tat ggc tgg tgg gta gga gaa atg aag gga 1132Ser Lys Glu Tyr Asn Arg Tyr Gly Trp Trp Val Gly Glu Met Lys Gly 160 165 170gcc att ggc ttg gtg cct aaa gcc tac ata atg gag atg tat gat att 1180Ala Ile Gly Leu Val Pro Lys Ala Tyr Ile Met Glu Met Tyr Asp Ile 175 180 185tga gagtcctgga aaaggaaaat tcttctgctt gtctgcaaat gctctggatt 1233tagaagcgtc atgaaagcac gagtgacagc tcctaacctc tccttgtttt attaaacatt 1293 acttatcttt gactgttatt ttatgcagtc gctcattaaa atattcctct gatgtgaaat 1353taaatgaagg atattaatgt aaattagatg caaccagtta agttatacct gttgctattt 1413 tgcaaag 142074187PRTHomo sapiens 74Met Asn Asn Thr Leu Arg Lys Asp Gly Lys Lys Asp Cys Cys Phe Glu1 5 10 15Ile Ser Ala Pro Asp Lys Arg Ile Tyr Gln Phe Thr Ala Ala Ser Pro 20 25 30Lys Asp Ala Glu Glu Trp Val Gln Gln Leu Lys Phe Val Leu Gln Asp 35 40 45Met Glu Ser Asp Ile Ile Pro Glu Asp Tyr Asp Glu Arg Gly Glu Leu 50 55 60Tyr Asp Asp Val Asp His Pro Leu Pro Ile Ser Asn Pro Leu Thr Ser65 70 75 80Ser Gln Pro Ile Asp Asp Glu Ile Tyr Glu Glu Leu Pro Glu Glu Glu 85 90 95Glu Asp Ser Ala Pro Val Lys Val Glu Glu Gln Arg Lys Met Ser Gln 100 105 110Asp Ser Val His His Thr Ser Gly Asp Lys Ser Thr Asp Tyr Ala Asn 115 120 125Phe Tyr Gln Gly Leu Trp Asp Cys Thr Gly Ala Phe Ser Asp Glu Leu 130 135 140Ser Phe Lys Arg Gly Asp Val Ile Tyr Ile Leu Ser Lys Glu Tyr Asn145 150 155 160Arg Tyr Gly Trp Trp Val Gly Glu Met Lys Gly Ala Ile Gly Leu Val 165 170 175Pro Lys Ala Tyr Ile Met Glu Met Tyr Asp Ile 180 18575169DNAHomo sapiens 75agagctggag catctcgcag ccctacaact tctttgcggc gcttggtctg tctttgcgtt 60gcgagatcag gatcggtgtg ttgctcagac accggccgaa cgccaccggc acgtctagga 120gtctcctgtg cctggaagag gctggtttca ttcgattcta aaagaaacg 16976619DNAHomo sapiens 76agagctggag catctcgcag ccctacaact tctttgcggc gcttggtctg tctttgcgtt 60gcgagatcag gatcggtgtg ttgctcagac accggccgaa cgccaccggc acgtctagga 120gtctcctgtg cctggaagag gctggtttca ttcgattcta aaagaaacgg atgttgaaac 180atttgtagca gatatactga aaggagaaaa tttatccaag aaagcaaagg aaaagagaga 240atcccttatt aagaagataa aagatgtaaa gtctatctat cttcaggaat ttcaagacaa 300aggtgatgca gaagatgggg aagaatatga tgaccctttt gctgggcctc cagacactat 360ttcattagcc tcagaacgat atgataaaga cgatgaagcc ccctctgatg gagcccagtt 420tcctccaatt gcagcacaag accttccttt tgttctaaag gctggctacc ttgaaaaacg 480cagaaaagat cacagctttc tgggatttga atggcagaaa cggtggtgtg ctctcagtaa 540aacggtattc tattattatg gaagtgataa agacaaacaa cagaaaggtg aatttgcaat 600agatggctac agtgtcaga 6197720DNAArtificial Sequenceforward primer used for specifically detecting the variant of the present invention 77tctcgcagcc ctacaacttc 207820DNAArtificial Sequencereverse primer used for specifically detecting the variant of the present invention 78gcaacacacc gatcctgatc 207972DNAArtificial Sequencepartial polynucleotide specific to the variant of the present invention, which is obtained by PCR using forward primer (SEQ ID NO77) and reverse primer (SEQ ID NO78) 79tctcgcagcc ctacaacttc tttgcggcgc ttggtctgtc tttgcgttgc gagatcagga 60tcggtgtgtt gc 728018DNAArtificial Sequenceforward primer used for specifically detecting the known variant of the gene of the present invention 80cctgcgctcc ctaacatg 188122DNAArtificial Sequencereverse primer used for specifically detecting the known variant of the gene of the present invention 81tgccaacagg ttcctaattt cc 228281DNAArtificial Sequencepartial polynucleotide specific to the known variant of the gene of the present invention, which is obtained by PCR using forward primer (SEQ ID NO80) and reverse primer (SEQ ID NO81) 82cctgcgctcc ctaacatgcc caaccccagc agcacctcct ctccctaccc cctccctgag 60gaaattagga acctgttggc a 818324DNAArtificial Sequenceforward primer used for detecting the variants of the gene of the present invention 83catcctctac caataagcaa tcca 248427DNAArtificial Sequencereverse primer used for detecting the variants of the gene of the present invention 84ctatcctgac tcatcttcct ttgttct 2785134DNAArtificial Sequencepartial polynucleotide common to the variants of the gene of the present invention, which is obtained by PCR using forward primer (SEQ ID NO83) and reverse primer (SEQ ID NO84) 85catcctctac caataagcaa tccactaaca agcagtcaac caatagatga tgaaatttat 60gaagaacttc cagaagaaga agaggacagt gctccagtga aagtggaaga acaaaggaag 120atgagtcagg atag 1348684DNAHomo sapiens 86agagctggag catctcgcag ccctacaact tctttgcggc gcttggtctg tctttgcgtt 60gcgagatcag gatcggtgtg ttgc 84871660DNAHomo sapiens 87aagccagttt gaacttcagg aggaggaact atttggccaa aacacctcct aatatgtagt 60tcagtagaga tgccctggag aatgctgcac tgttccacat gcctgcaaat attcctctaa 120tgatacagtc ccaaggcttt ggacattgat agactccagg tatggcagca gccaaacttc 180tgcatgactc tggactgaat gtggttgttc tggaagcccg ggaccgtgtg ggaggcagga 240cttacactct taggaaccaa aaggttaaat atgtggacct tggaggatcc tatgttggac 300caacccagaa tcgtatcttg agattagcca aggagctagg attggagacc tacaaagtga 360atgaggttga gcgtctgatc caccatgtaa agggcaaatc ataccccttc agggggccat 420tcccacctgt atggaatcca attacctact tagatcataa caacttttgg aggacaatgg 480atgacatggg gcgagagatt ccgagtgatg ccccatggaa ggctcccctt gcagaagagt 540gggacaacat gacaatgaag gagctactgg acaagctctg ctggactgaa tctgcaaagc 600agcttgccac tctctttgtg aacctgtgtg tcactgcaga gacccatgag gtctctgctc 660tctggttcct gtggtatgtg aagcagtgtg gaggcacaac aagaatcatc tcgacaacaa 720atggaggaca ggagaggaaa tttgtgggcg gatctggtca agtgagtgag cggataatgg 780acctccttgg agaccgagtg aagctggaga ggcctgtgat ctacattgac cagacaagag 840aaaatgtcct tgtggagacc ctaaaccatg agatgtatga ggctaaatat gtgattagtg 900ctattcctcc tactctgggc atgaagattc acttcaatcc ccctctgcca atgatgagaa 960accagatgat cactcgtgtg cctttgggtt cagtcatcaa gtgtatagtt tattataaag 1020agcctttctg gaggaaaaag gattactgtg gaaccatgat tattgatgga gaagaagctc 1080cagttgccta cacgttggat gataccaaac ctgaaggcaa ctatgctgcc ataatgggat 1140ttatcctggc ccacaaagcc agaaaactgg cacgtcttac caaagaggaa aggttgaaga 1200aactttgtga actctatgcc aaggttctgg gttccctaga agctctggag ggttctacgc 1260cagccagtgg acaggattta ctttgcaggc accgagactg ccacacactg gagcggctac 1320atggaggggg ctgtagaggc cggggagaga gcagcccgag agatcctgca tgccatgggg 1380aagattccag aggatgaaat ctggcagtca gaaccagagt ctgtggatgt ccctgcacag 1440cccatcacca ccaccttttt ggagagacat ttgccctccg tgccaggcct gctcaggctg 1500attggattga ccaccatctt ttcagcaacg gctcttggct tcctggccca caaaaggggg 1560ctacttgtga gagtctaaag agagagggtg tctgtaatca cactctcttc ttactgtatt 1620tgggatatga gtttggggaa agagttgcag taaagttcca 1660881660DNAHomo sapiensCDS(162)..(1397) 88aagccagttt gaacttcagg aggaggaact atttggccaa aacacctcct aatatgtagt 60tcagtagaga tgccctggag aatgctgcac tgttccacat gcctgcaaat attcctctaa 120tgatacagtc ccaaggcttt ggacattgat agactccagg t atg gca gca gcc aaa 176 Met Ala Ala Ala Lys 1 5ctt ctg cat gac tct gga ctg aat gtg gtt gtt ctg gaa gcc cgg gac 224Leu Leu His Asp Ser Gly Leu Asn Val Val Val Leu Glu Ala Arg Asp 10 15 20cgt gtg gga ggc agg act tac act ctt agg aac caa aag gtt aaa tat 272Arg Val Gly Gly Arg Thr Tyr Thr Leu Arg Asn Gln Lys Val Lys Tyr 25 30 35gtg gac ctt gga gga tcc tat gtt gga cca acc cag aat cgt atc ttg 320Val Asp Leu Gly Gly Ser Tyr Val Gly Pro Thr Gln Asn Arg Ile Leu 40 45 50aga tta gcc aag gag cta gga ttg gag acc tac aaa gtg aat gag gtt 368Arg Leu Ala Lys Glu Leu Gly Leu Glu Thr Tyr Lys Val Asn Glu Val 55 60 65gag cgt ctg atc cac cat gta aag ggc aaa tca tac ccc ttc agg ggg 416Glu Arg Leu Ile His His Val Lys Gly Lys Ser Tyr Pro Phe Arg Gly70 75 80 85cca ttc cca cct gta tgg aat cca att acc tac tta gat cat aac aac 464Pro Phe Pro Pro Val Trp Asn Pro Ile Thr Tyr Leu Asp His Asn Asn 90 95 100ttt tgg agg aca atg gat gac atg ggg cga gag att ccg agt gat gcc 512Phe Trp Arg Thr Met Asp Asp Met Gly Arg Glu Ile Pro Ser Asp Ala 105 110 115cca tgg aag gct ccc ctt gca gaa gag tgg gac aac atg aca atg aag 560Pro Trp Lys Ala Pro Leu Ala Glu Glu Trp Asp Asn Met Thr Met Lys 120 125 130gag cta ctg gac aag ctc tgc tgg act gaa tct gca aag cag ctt gcc 608Glu Leu Leu Asp Lys Leu Cys Trp Thr Glu Ser Ala Lys Gln Leu Ala 135 140 145act ctc ttt gtg aac ctg tgt gtc act gca gag acc cat gag gtc tct 656Thr Leu Phe Val Asn Leu Cys Val Thr Ala Glu Thr His Glu Val Ser150 155 160 165gct ctc tgg ttc ctg tgg tat gtg aag cag tgt gga ggc aca aca aga 704Ala Leu Trp Phe Leu Trp Tyr Val Lys Gln Cys Gly Gly Thr Thr Arg 170 175 180atc atc tcg aca aca aat gga gga cag gag agg aaa ttt gtg ggc gga 752Ile Ile Ser Thr Thr Asn Gly Gly Gln Glu Arg Lys Phe Val Gly Gly 185 190 195tct ggt caa gtg agt gag cgg ata atg gac ctc ctt gga gac cga gtg 800Ser Gly Gln Val Ser Glu Arg Ile Met Asp Leu Leu Gly Asp Arg Val 200 205 210aag ctg gag agg cct gtg atc tac att gac cag aca aga gaa aat gtc 848Lys Leu Glu Arg Pro Val Ile Tyr Ile Asp Gln Thr Arg Glu Asn Val 215 220 225ctt gtg gag acc cta aac cat gag atg tat gag gct aaa tat gtg att 896Leu Val Glu Thr Leu Asn His Glu Met Tyr Glu Ala Lys Tyr Val Ile230 235 240 245agt gct att cct cct act ctg ggc atg aag att cac ttc aat ccc cct 944Ser Ala Ile Pro Pro Thr Leu Gly Met Lys Ile His Phe Asn Pro Pro 250 255 260ctg cca atg atg aga aac cag atg atc act cgt gtg cct ttg ggt tca 992Leu Pro Met Met Arg Asn Gln Met Ile Thr Arg Val Pro Leu Gly Ser 265 270 275gtc atc aag tgt ata gtt tat tat aaa gag cct ttc tgg agg aaa aag 1040Val Ile Lys Cys Ile Val Tyr Tyr Lys Glu Pro Phe Trp Arg Lys Lys 280 285 290gat tac tgt gga acc atg att att gat gga gaa gaa gct cca gtt gcc 1088Asp Tyr Cys Gly Thr Met Ile Ile Asp Gly Glu Glu Ala Pro Val Ala 295 300 305tac acg ttg gat gat acc aaa cct gaa ggc aac tat gct gcc ata atg 1136Tyr Thr Leu Asp Asp Thr Lys Pro Glu Gly Asn Tyr Ala Ala Ile Met310 315 320 325gga ttt atc ctg gcc cac aaa gcc aga aaa ctg gca cgt ctt acc aaa 1184Gly Phe Ile Leu Ala His Lys Ala Arg Lys Leu Ala Arg Leu Thr Lys 330 335 340gag gaa agg ttg aag aaa ctt tgt gaa ctc tat gcc aag gtt ctg ggt 1232Glu Glu Arg Leu Lys Lys Leu Cys Glu Leu Tyr Ala Lys Val Leu Gly 345 350 355tcc cta gaa gct ctg gag ggt tct acg cca gcc agt gga cag gat tta 1280Ser Leu Glu Ala Leu Glu Gly Ser Thr Pro Ala Ser Gly Gln Asp Leu 360 365 370ctt tgc agg cac cga gac tgc cac aca ctg gag cgg cta cat gga ggg 1328Leu Cys Arg His Arg Asp Cys His Thr Leu Glu Arg Leu His Gly Gly 375 380 385ggc tgt aga ggc cgg gga gag agc agc ccg aga gat cct gca tgc cat 1376Gly Cys Arg Gly Arg Gly Glu Ser Ser Pro Arg Asp Pro Ala Cys His390 395 400 405ggg gaa gat tcc aga gga tga aatctggcag tcagaaccag agtctgtgga 1427Gly Glu Asp Ser Arg Gly 410tgtccctgca cagcccatca ccaccacctt tttggagaga catttgccct ccgtgccagg 1487cctgctcagg ctgattggat tgaccaccat cttttcagca acggctcttg gcttcctggc 1547ccacaaaagg gggctacttg tgagagtcta aagagagagg gtgtctgtaa tcacactctc 1607ttcttactgt atttgggata tgagtttggg gaaagagttg cagtaaagtt cca 166089411PRTHomo sapiens 89Met Ala Ala Ala Lys Leu Leu His Asp Ser Gly Leu Asn Val Val Val1 5 10 15Leu Glu Ala Arg Asp Arg Val Gly Gly Arg Thr Tyr Thr Leu Arg Asn 20 25 30Gln Lys Val Lys Tyr Val Asp Leu Gly Gly Ser Tyr Val Gly Pro Thr 35 40 45Gln Asn Arg Ile Leu Arg Leu Ala Lys Glu Leu Gly Leu Glu Thr Tyr 50 55 60Lys Val Asn Glu Val Glu Arg Leu Ile His His Val Lys Gly Lys Ser65 70 75 80Tyr Pro Phe Arg Gly Pro Phe Pro Pro Val Trp Asn Pro Ile Thr Tyr 85 90 95Leu Asp His Asn Asn Phe Trp Arg Thr Met Asp Asp Met Gly Arg Glu 100 105 110Ile Pro Ser Asp Ala Pro Trp Lys Ala Pro Leu Ala Glu Glu Trp Asp 115 120 125Asn Met Thr Met Lys Glu Leu Leu Asp Lys Leu Cys Trp Thr Glu Ser 130 135 140Ala Lys Gln Leu Ala

Thr Leu Phe Val Asn Leu Cys Val Thr Ala Glu145 150 155 160Thr His Glu Val Ser Ala Leu Trp Phe Leu Trp Tyr Val Lys Gln Cys 165 170 175Gly Gly Thr Thr Arg Ile Ile Ser Thr Thr Asn Gly Gly Gln Glu Arg 180 185 190Lys Phe Val Gly Gly Ser Gly Gln Val Ser Glu Arg Ile Met Asp Leu 195 200 205Leu Gly Asp Arg Val Lys Leu Glu Arg Pro Val Ile Tyr Ile Asp Gln 210 215 220Thr Arg Glu Asn Val Leu Val Glu Thr Leu Asn His Glu Met Tyr Glu225 230 235 240Ala Lys Tyr Val Ile Ser Ala Ile Pro Pro Thr Leu Gly Met Lys Ile 245 250 255His Phe Asn Pro Pro Leu Pro Met Met Arg Asn Gln Met Ile Thr Arg 260 265 270Val Pro Leu Gly Ser Val Ile Lys Cys Ile Val Tyr Tyr Lys Glu Pro 275 280 285Phe Trp Arg Lys Lys Asp Tyr Cys Gly Thr Met Ile Ile Asp Gly Glu 290 295 300Glu Ala Pro Val Ala Tyr Thr Leu Asp Asp Thr Lys Pro Glu Gly Asn305 310 315 320Tyr Ala Ala Ile Met Gly Phe Ile Leu Ala His Lys Ala Arg Lys Leu 325 330 335Ala Arg Leu Thr Lys Glu Glu Arg Leu Lys Lys Leu Cys Glu Leu Tyr 340 345 350Ala Lys Val Leu Gly Ser Leu Glu Ala Leu Glu Gly Ser Thr Pro Ala 355 360 365Ser Gly Gln Asp Leu Leu Cys Arg His Arg Asp Cys His Thr Leu Glu 370 375 380Arg Leu His Gly Gly Gly Cys Arg Gly Arg Gly Glu Ser Ser Pro Arg385 390 395 400Asp Pro Ala Cys His Gly Glu Asp Ser Arg Gly 405 41090156DNAHomo sapiens 90aagccagttt gaacttcagg aggaggaact atttggccaa aacacctcct aatatgtagt 60tcagtagaga tgccctggag aatgctgcac tgttccacat gcctgcaaat attcctctaa 120tgatacagtc ccaaggcttt ggacattgat agactc 15691161DNAHomo sapiens 91aagccagttt gaacttcagg aggaggaact atttggccaa aacacctcct aatatgtagt 60tcagtagaga tgccctggag aatgctgcac tgttccacat gcctgcaaat attcctctaa 120tgatacagtc ccaaggcttt ggacattgat agactccagg t 1619242DNAHomo sapiens 92ggttccctag aagctctgga gggttctacg ccagccagtg ga 429348PRTHomo sapiens 93Gly Ser Thr Pro Ala Ser Gly Gln Asp Leu Leu Cys Arg His Arg Asp1 5 10 15Cys His Thr Leu Glu Arg Leu His Gly Gly Gly Cys Arg Gly Arg Gly 20 25 30Glu Ser Ser Pro Arg Asp Pro Ala Cys His Gly Glu Asp Ser Arg Gly 35 40 459414PRTHomo sapiens 94Gly Ser Leu Glu Ala Leu Glu Gly Ser Thr Pro Ala Ser Gly1 5 109598DNAHomo sapiens 95ccagtgcatt atgaagaaaa gaactggtgt gaggagcagt actctggggg ctgctacaca 60acttatttcc cccctgggat cctgactcaa tatggaag 989633PRTHomo sapiens 96Pro Val His Tyr Glu Glu Lys Asn Trp Cys Glu Glu Gln Tyr Ser Gly1 5 10 15Gly Cys Tyr Thr Thr Tyr Phe Pro Pro Gly Ile Leu Thr Gln Tyr Gly 20 25 30Arg971864DNAHomo sapiens 97aaagaaaacg gagcagcggg caccagggag gcctggaacg gggcgagcgc catgagcaac 60aaatgcgacg tggtcgtggt ggggggcggc atctcagaaa catcagactc tgggcctcta 120ttgacaaacc gtatccactt gtatggcagc agccaaactt ctgcatgact ctggactgaa 180tgtggttgtt ctggaagccc gggaccgtgt gggaggcagg acttacactc ttaggaacca 240aaaggttaaa tatgtggacc ttggaggatc ctatgttgga ccaacccaga atcgtatctt 300gagattagcc aaggagctag gattggagac ctacaaagtg aatgaggttg agcgtctgat 360ccaccatgta aagggcaaat catacccctt cagggggcca ttcccacctg tatggaatcc 420aattacctac ttagatcata acaacttttg gaggacaatg gatgacatgg ggcgagagat 480tccgagtgat gccccatgga aggctcccct tgcagaagag tgggacaaca tgacaatgaa 540ggagctactg gacaagctct gctggactga atctgcaaag cagcttgcca ctctctttgt 600gaacctgtgt gtcactgcag agacccatga ggtctctgct ctctggttcc tgtggtatgt 660gaagcagtgt ggaggcacaa caagaatcat ctcgacaaca aatggaggac aggagaggaa 720atttgtgggc ggatctggtc aagtgagtga gcggataatg gacctccttg gagaccgagt 780gaagctggag aggcctgtga tctacattga ccagacaaga gaaaatgtcc ttgtggagac 840cctaaaccat gagatgtatg aggctaaata tgtgattagt gctattcctc ctactctggg 900catgaagatt cacttcaatc cccctctgcc aatgatgaga aaccagatga tcactcgtgt 960gcctttgggt tcagtcatca agtgtatagt ttattataaa gagcctttct ggaggaaaaa 1020ggattactgt ggaaccatga ttattgatgg agaagaagct ccagttgcct acacgttgga 1080tgacaccaaa cctgaaggca actatgctgc cataatggga tttatcctgg cccacaaagc 1140cagaaaactg gcacgtctta ccaaagagga aaggttgaag aaactttgtg aactctatgc 1200caaggttctg ggttccctag aagctctgga gccagtgcat tatgaagaaa agaactggtg 1260tgaggagcag tactctgggg gctgctacac aacttatttc ccccctggga tcctgactca 1320atatggaagg gttctacgcc agccagtgga caggatttac tttgcaggca ccgagactgc 1380cacacactgg agcggctaca tggagggggc tgtagaggcc ggggagagag cagcccgaga 1440gatcctgcat gccatgggga agattccaga ggatgaaatc tggcagtcag aaccagagtc 1500tgtggatgtc cctgcacagc ccatcaccac cacctttttg gagagacatt tgccctccgt 1560gccaggcctg ctcaggctga ttggattgac caccatcttt tcagcaacgg ctcttggctt 1620cctggcccac aaaagggggc tacttgtgag agtctaaaga gagagggtgt ctgtaatcac 1680actctcttct tactgtattt gggatatgag tttggggaaa gagttgcagt aaagttccat 1740gaagacaaat agtgtggagt gaggcgggga gcatgaagat aaatccaact ctgactgtaa 1800aatacatggt atctctttct ccgttgtggc ccctgcttag tgtcccttac ctggcttagc 1860gttc 1864981864DNAHomo sapiensCDS(143)..(1657) 98aaagaaaacg gagcagcggg caccagggag gcctggaacg gggcgagcgc catgagcaac 60aaatgcgacg tggtcgtggt ggggggcggc atctcagaaa catcagactc tgggcctcta 120ttgacaaacc gtatccactt gt atg gca gca gcc aaa ctt ctg cat gac tct 172 Met Ala Ala Ala Lys Leu Leu His Asp Ser 1 5 10gga ctg aat gtg gtt gtt ctg gaa gcc cgg gac cgt gtg gga ggc agg 220Gly Leu Asn Val Val Val Leu Glu Ala Arg Asp Arg Val Gly Gly Arg 15 20 25act tac act ctt agg aac caa aag gtt aaa tat gtg gac ctt gga gga 268Thr Tyr Thr Leu Arg Asn Gln Lys Val Lys Tyr Val Asp Leu Gly Gly 30 35 40tcc tat gtt gga cca acc cag aat cgt atc ttg aga tta gcc aag gag 316Ser Tyr Val Gly Pro Thr Gln Asn Arg Ile Leu Arg Leu Ala Lys Glu 45 50 55cta gga ttg gag acc tac aaa gtg aat gag gtt gag cgt ctg atc cac 364Leu Gly Leu Glu Thr Tyr Lys Val Asn Glu Val Glu Arg Leu Ile His 60 65 70cat gta aag ggc aaa tca tac ccc ttc agg ggg cca ttc cca cct gta 412His Val Lys Gly Lys Ser Tyr Pro Phe Arg Gly Pro Phe Pro Pro Val75 80 85 90tgg aat cca att acc tac tta gat cat aac aac ttt tgg agg aca atg 460Trp Asn Pro Ile Thr Tyr Leu Asp His Asn Asn Phe Trp Arg Thr Met 95 100 105gat gac atg ggg cga gag att ccg agt gat gcc cca tgg aag gct ccc 508Asp Asp Met Gly Arg Glu Ile Pro Ser Asp Ala Pro Trp Lys Ala Pro 110 115 120ctt gca gaa gag tgg gac aac atg aca atg aag gag cta ctg gac aag 556Leu Ala Glu Glu Trp Asp Asn Met Thr Met Lys Glu Leu Leu Asp Lys 125 130 135ctc tgc tgg act gaa tct gca aag cag ctt gcc act ctc ttt gtg aac 604Leu Cys Trp Thr Glu Ser Ala Lys Gln Leu Ala Thr Leu Phe Val Asn 140 145 150ctg tgt gtc act gca gag acc cat gag gtc tct gct ctc tgg ttc ctg 652Leu Cys Val Thr Ala Glu Thr His Glu Val Ser Ala Leu Trp Phe Leu155 160 165 170tgg tat gtg aag cag tgt gga ggc aca aca aga atc atc tcg aca aca 700Trp Tyr Val Lys Gln Cys Gly Gly Thr Thr Arg Ile Ile Ser Thr Thr 175 180 185aat gga gga cag gag agg aaa ttt gtg ggc gga tct ggt caa gtg agt 748Asn Gly Gly Gln Glu Arg Lys Phe Val Gly Gly Ser Gly Gln Val Ser 190 195 200gag cgg ata atg gac ctc ctt gga gac cga gtg aag ctg gag agg cct 796Glu Arg Ile Met Asp Leu Leu Gly Asp Arg Val Lys Leu Glu Arg Pro 205 210 215gtg atc tac att gac cag aca aga gaa aat gtc ctt gtg gag acc cta 844Val Ile Tyr Ile Asp Gln Thr Arg Glu Asn Val Leu Val Glu Thr Leu 220 225 230aac cat gag atg tat gag gct aaa tat gtg att agt gct att cct cct 892Asn His Glu Met Tyr Glu Ala Lys Tyr Val Ile Ser Ala Ile Pro Pro235 240 245 250act ctg ggc atg aag att cac ttc aat ccc cct ctg cca atg atg aga 940Thr Leu Gly Met Lys Ile His Phe Asn Pro Pro Leu Pro Met Met Arg 255 260 265aac cag atg atc act cgt gtg cct ttg ggt tca gtc atc aag tgt ata 988Asn Gln Met Ile Thr Arg Val Pro Leu Gly Ser Val Ile Lys Cys Ile 270 275 280gtt tat tat aaa gag cct ttc tgg agg aaa aag gat tac tgt gga acc 1036Val Tyr Tyr Lys Glu Pro Phe Trp Arg Lys Lys Asp Tyr Cys Gly Thr 285 290 295atg att att gat gga gaa gaa gct cca gtt gcc tac acg ttg gat gac 1084Met Ile Ile Asp Gly Glu Glu Ala Pro Val Ala Tyr Thr Leu Asp Asp 300 305 310acc aaa cct gaa ggc aac tat gct gcc ata atg gga ttt atc ctg gcc 1132Thr Lys Pro Glu Gly Asn Tyr Ala Ala Ile Met Gly Phe Ile Leu Ala315 320 325 330cac aaa gcc aga aaa ctg gca cgt ctt acc aaa gag gaa agg ttg aag 1180His Lys Ala Arg Lys Leu Ala Arg Leu Thr Lys Glu Glu Arg Leu Lys 335 340 345aaa ctt tgt gaa ctc tat gcc aag gtt ctg ggt tcc cta gaa gct ctg 1228Lys Leu Cys Glu Leu Tyr Ala Lys Val Leu Gly Ser Leu Glu Ala Leu 350 355 360gag cca gtg cat tat gaa gaa aag aac tgg tgt gag gag cag tac tct 1276Glu Pro Val His Tyr Glu Glu Lys Asn Trp Cys Glu Glu Gln Tyr Ser 365 370 375ggg ggc tgc tac aca act tat ttc ccc cct ggg atc ctg act caa tat 1324Gly Gly Cys Tyr Thr Thr Tyr Phe Pro Pro Gly Ile Leu Thr Gln Tyr 380 385 390gga agg gtt cta cgc cag cca gtg gac agg att tac ttt gca ggc acc 1372Gly Arg Val Leu Arg Gln Pro Val Asp Arg Ile Tyr Phe Ala Gly Thr395 400 405 410gag act gcc aca cac tgg agc ggc tac atg gag ggg gct gta gag gcc 1420Glu Thr Ala Thr His Trp Ser Gly Tyr Met Glu Gly Ala Val Glu Ala 415 420 425ggg gag aga gca gcc cga gag atc ctg cat gcc atg ggg aag att cca 1468Gly Glu Arg Ala Ala Arg Glu Ile Leu His Ala Met Gly Lys Ile Pro 430 435 440gag gat gaa atc tgg cag tca gaa cca gag tct gtg gat gtc cct gca 1516Glu Asp Glu Ile Trp Gln Ser Glu Pro Glu Ser Val Asp Val Pro Ala 445 450 455cag ccc atc acc acc acc ttt ttg gag aga cat ttg ccc tcc gtg cca 1564Gln Pro Ile Thr Thr Thr Phe Leu Glu Arg His Leu Pro Ser Val Pro 460 465 470ggc ctg ctc agg ctg att gga ttg acc acc atc ttt tca gca acg gct 1612Gly Leu Leu Arg Leu Ile Gly Leu Thr Thr Ile Phe Ser Ala Thr Ala475 480 485 490ctt ggc ttc ctg gcc cac aaa agg ggg cta ctt gtg aga gtc taa 1657Leu Gly Phe Leu Ala His Lys Arg Gly Leu Leu Val Arg Val 495 500agagagaggg tgtctgtaat cacactctct tcttactgta tttgggatat gagtttgggg 1717aaagagttgc agtaaagttc catgaagaca aatagtgtgg agtgaggcgg ggagcatgaa 1777gataaatcca actctgactg taaaatacat ggtatctctt tctccgttgt ggcccctgct 1837tagtgtccct tacctggctt agcgttc 186499504PRTHomo sapiens 99Met Ala Ala Ala Lys Leu Leu His Asp Ser Gly Leu Asn Val Val Val1 5 10 15Leu Glu Ala Arg Asp Arg Val Gly Gly Arg Thr Tyr Thr Leu Arg Asn 20 25 30Gln Lys Val Lys Tyr Val Asp Leu Gly Gly Ser Tyr Val Gly Pro Thr 35 40 45Gln Asn Arg Ile Leu Arg Leu Ala Lys Glu Leu Gly Leu Glu Thr Tyr 50 55 60Lys Val Asn Glu Val Glu Arg Leu Ile His His Val Lys Gly Lys Ser65 70 75 80Tyr Pro Phe Arg Gly Pro Phe Pro Pro Val Trp Asn Pro Ile Thr Tyr 85 90 95Leu Asp His Asn Asn Phe Trp Arg Thr Met Asp Asp Met Gly Arg Glu 100 105 110Ile Pro Ser Asp Ala Pro Trp Lys Ala Pro Leu Ala Glu Glu Trp Asp 115 120 125Asn Met Thr Met Lys Glu Leu Leu Asp Lys Leu Cys Trp Thr Glu Ser 130 135 140Ala Lys Gln Leu Ala Thr Leu Phe Val Asn Leu Cys Val Thr Ala Glu145 150 155 160Thr His Glu Val Ser Ala Leu Trp Phe Leu Trp Tyr Val Lys Gln Cys 165 170 175Gly Gly Thr Thr Arg Ile Ile Ser Thr Thr Asn Gly Gly Gln Glu Arg 180 185 190Lys Phe Val Gly Gly Ser Gly Gln Val Ser Glu Arg Ile Met Asp Leu 195 200 205Leu Gly Asp Arg Val Lys Leu Glu Arg Pro Val Ile Tyr Ile Asp Gln 210 215 220Thr Arg Glu Asn Val Leu Val Glu Thr Leu Asn His Glu Met Tyr Glu225 230 235 240Ala Lys Tyr Val Ile Ser Ala Ile Pro Pro Thr Leu Gly Met Lys Ile 245 250 255His Phe Asn Pro Pro Leu Pro Met Met Arg Asn Gln Met Ile Thr Arg 260 265 270Val Pro Leu Gly Ser Val Ile Lys Cys Ile Val Tyr Tyr Lys Glu Pro 275 280 285Phe Trp Arg Lys Lys Asp Tyr Cys Gly Thr Met Ile Ile Asp Gly Glu 290 295 300Glu Ala Pro Val Ala Tyr Thr Leu Asp Asp Thr Lys Pro Glu Gly Asn305 310 315 320Tyr Ala Ala Ile Met Gly Phe Ile Leu Ala His Lys Ala Arg Lys Leu 325 330 335Ala Arg Leu Thr Lys Glu Glu Arg Leu Lys Lys Leu Cys Glu Leu Tyr 340 345 350Ala Lys Val Leu Gly Ser Leu Glu Ala Leu Glu Pro Val His Tyr Glu 355 360 365Glu Lys Asn Trp Cys Glu Glu Gln Tyr Ser Gly Gly Cys Tyr Thr Thr 370 375 380Tyr Phe Pro Pro Gly Ile Leu Thr Gln Tyr Gly Arg Val Leu Arg Gln385 390 395 400Pro Val Asp Arg Ile Tyr Phe Ala Gly Thr Glu Thr Ala Thr His Trp 405 410 415Ser Gly Tyr Met Glu Gly Ala Val Glu Ala Gly Glu Arg Ala Ala Arg 420 425 430Glu Ile Leu His Ala Met Gly Lys Ile Pro Glu Asp Glu Ile Trp Gln 435 440 445Ser Glu Pro Glu Ser Val Asp Val Pro Ala Gln Pro Ile Thr Thr Thr 450 455 460Phe Leu Glu Arg His Leu Pro Ser Val Pro Gly Leu Leu Arg Leu Ile465 470 475 480Gly Leu Thr Thr Ile Phe Ser Ala Thr Ala Leu Gly Phe Leu Ala His 485 490 495Lys Arg Gly Leu Leu Val Arg Val 50010043DNAHomo sapiens 100aaacatcaga ctctgggcct ctattgacaa accgtatcca ctt 43101142DNAHomo sapiens 101aaagaaaacg gagcagcggg caccagggag gcctggaacg gggcgagcgc catgagcaac 60aaatgcgacg tggtcgtggt ggggggcggc atctcagaaa catcagactc tgggcctcta 120ttgacaaacc gtatccactt gt 14210223DNAArtificial Sequenceforward primer used for specifically detecting the variant of the present invention 102tggccaaaac acctcctaat atg 2310326DNAArtificial Sequencereverse primer used for specifically detecting the variant of the present invention 103atacctggag tctatcaatg tccaaa 26104130DNAArtificial Sequencepartial polynucleotide specific to the variant of the present invention, which is obtained by PCR using forward primer (SEQ ID NO102) and reverse primer (SEQ ID NO103) 104tggccaaaac acctcctaat atgtagttca gtagagatgc cctggagaat gctgcactgt 60tccacatgcc tgcaaatatt cctctaatga tacagtccca aggctttgga cattgataga 120ctccaggtat 13010524DNAArtificial Sequenceforward primer used for specifically detecting the variant of the present invention 105ggcatctcag aaacatcaga ctct 2410622DNAArtificial Sequencereverse primer used for specifically detecting the variant of the present invention 106gcttccagaa caaccacatt ca 22107111DNAArtificial Sequencepartial polynucleotide specific to the variant of the present invention, which is obtained by PCR using forward primer (SEQ ID NO105) and reverse primer (SEQ ID NO106) 107ggcatctcag aaacatcaga ctctgggcct ctattgacaa accgtatcca cttgtatggc 60agcagccaaa cttctgcatg actctggact gaatgtggtt gttctggaag c 11110818DNAArtificial Sequenceforward primer used for specifically detecting the known variant of the gene of the present invention

108gagcgccatg agcaacaa 1810922DNAArtificial Sequencereverse primer used for specifically detecting the known variant of the gene of the present invention 109tccagagtca tgcagaagtt tg 2211088DNAArtificial Sequencepartial polynucleotide specific to the known variant of the gene of the present invention, which is obtained by PCR using forward primer (SEQ ID NO108) and reverse primer (SEQ ID NO109) 110gagcgccatg agcaacaaat gcgacgtggt cgtggtgggg ggcggcatct caggtatggc 60agcagccaaa cttctgcatg actctgga 8811123DNAArtificial Sequenceforward primer used for detecting the variants of the gene of the present invention 111gctctctggt tcctgtggta tgt 2311220DNAArtificial Sequencereverse primer used for detecting the variants of the gene of the present invention 112gatccgccca caaatttcct 2011398DNAArtificial Sequencepartial polynucleotide common to the variants of the gene of the present invention, which is obtained by PCR using forward primer (SEQ ID NO111) and reverse primer (SEQ ID NO112) 113gctctctggt tcctgtggta tgtgaagcag tgtggaggca caacaagaat catctcgaca 60acaaatggag gacaggagag gaaatttgtg ggcggatc 98114162DNAHomo sapiens 114aagccagttt gaacttcagg aggaggaact atttggccaa aacacctcct aatatgtagt 60tcagtagaga tgccctggag aatgctgcac tgttccacat gcctgcaaat attcctctaa 120tgatacagtc ccaaggcttt ggacattgat agactccagg ta 162115198DNAHomo sapiens 115aaagaaaacg gagcagcggg caccagggag gcctggaacg gggcgagcgc catgagcaac 60aaatgcgacg tggtcgtggt ggggggcggc atctcagaaa catcagactc tgggcctcta 120ttgacaaacc gtatccactt gtatggcagc agccaaactt ctgcatgact ctggactgaa 180tgtggttgtt ctggaagc 1981161422DNAHomo sapiens 116ctgcgcggcg cggcgggcga tccgagccgg gacgggctgc aggcgggggt gctgcagagg 60acacgaggcg gcgggctgga gacatggacc gcggcgagca aggtctgctg agaacagacc 120cagtccctga ggaaggagaa gatgttgctg ccacgatcag tgccacagag accctctcgg 180aagaggagca ggaagagcta agaagagaac ttgcaaaggt agaagaagaa atccagactc 240tgtctcaagt gttagcagca aaagagaagc atctagcaga gatcaagcgg aaacttggaa 300tcaattctct acaggaacta aaacagaaca ttgccaaagg gtggcaagac gtgacagcaa 360catctgctta caagaagaca tctgaaacct tatcccaggc tggacagaag gcctcagctg 420ctttttcgtc tgttggctca gtcatcacca aaaagctgga agatgtaaaa ttgcaagcct 480tttcacattc ctttagtata cgttccattc agcattcaat tagcatgcct gctatgagaa 540actccccaac ttttaaatca tttgaagaaa aggtcgaaaa cttaaagtct aaagtagggg 600gaaccaagcc tgctggtggt gattttggag aagtcttgaa ttcggctgca aatgctagtg 660ccaccaccac ggagcctctt ccagaaaaga cacaggagag cctgtgagat tcctaccttt 720gttctgctac ccactgccag atgctgcaag cgaggtccaa gcacatcttg tcaacatgca 780ttgccatgaa tttctaccag atgtgctttt atttagcttt acatattcct ttgaccaaat 840agtttgtggg ttaaacaaaa tgaaaatatc ttcacctcta ttcttgggaa acacccttta 900gtgtacattt atgttccttt atttaggaaa caccattata aaaacactta tagtaaatgg 960ggacattcac tataatgatc taagaagcta cagattgtca tagttgtttt cctgctttac 1020aaaattgctc cagatctgga atgccagttt gacctttgtc ttctataata tttccttttt 1080ttcccctctt tgaatctctg tatatttgat tcttaactaa aattgttctc ttaaatattc 1140tgaatcctgg taattaaaag tttgggtgta ttttctttac ctccaaggaa agaactacta 1200gctacaaaaa atattttgga ataagcattg ttttggtata aggtacatat tttggttgaa 1260gacaccagac tgaagtaaac agctgtgcat ccaatttatt atagttttgt aagtaacaat 1320atgtaatcaa acttctaggt gacttgagag tggaacctcc tatatcatta tttagcaccg 1380tttgtgacag taaccatttc agtgtattgt ttattatacc ac 14221171422DNAHomo sapiensCDS(84)..(707) 117ctgcgcggcg cggcgggcga tccgagccgg gacgggctgc aggcgggggt gctgcagagg 60acacgaggcg gcgggctgga gac atg gac cgc ggc gag caa ggt ctg ctg aga 113 Met Asp Arg Gly Glu Gln Gly Leu Leu Arg 1 5 10aca gac cca gtc cct gag gaa gga gaa gat gtt gct gcc acg atc agt 161Thr Asp Pro Val Pro Glu Glu Gly Glu Asp Val Ala Ala Thr Ile Ser 15 20 25gcc aca gag acc ctc tcg gaa gag gag cag gaa gag cta aga aga gaa 209Ala Thr Glu Thr Leu Ser Glu Glu Glu Gln Glu Glu Leu Arg Arg Glu 30 35 40ctt gca aag gta gaa gaa gaa atc cag act ctg tct caa gtg tta gca 257Leu Ala Lys Val Glu Glu Glu Ile Gln Thr Leu Ser Gln Val Leu Ala 45 50 55gca aaa gag aag cat cta gca gag atc aag cgg aaa ctt gga atc aat 305Ala Lys Glu Lys His Leu Ala Glu Ile Lys Arg Lys Leu Gly Ile Asn 60 65 70tct cta cag gaa cta aaa cag aac att gcc aaa ggg tgg caa gac gtg 353Ser Leu Gln Glu Leu Lys Gln Asn Ile Ala Lys Gly Trp Gln Asp Val75 80 85 90aca gca aca tct gct tac aag aag aca tct gaa acc tta tcc cag gct 401Thr Ala Thr Ser Ala Tyr Lys Lys Thr Ser Glu Thr Leu Ser Gln Ala 95 100 105gga cag aag gcc tca gct gct ttt tcg tct gtt ggc tca gtc atc acc 449Gly Gln Lys Ala Ser Ala Ala Phe Ser Ser Val Gly Ser Val Ile Thr 110 115 120aaa aag ctg gaa gat gta aaa ttg caa gcc ttt tca cat tcc ttt agt 497Lys Lys Leu Glu Asp Val Lys Leu Gln Ala Phe Ser His Ser Phe Ser 125 130 135ata cgt tcc att cag cat tca att agc atg cct gct atg aga aac tcc 545Ile Arg Ser Ile Gln His Ser Ile Ser Met Pro Ala Met Arg Asn Ser 140 145 150cca act ttt aaa tca ttt gaa gaa aag gtc gaa aac tta aag tct aaa 593Pro Thr Phe Lys Ser Phe Glu Glu Lys Val Glu Asn Leu Lys Ser Lys155 160 165 170gta ggg gga acc aag cct gct ggt ggt gat ttt gga gaa gtc ttg aat 641Val Gly Gly Thr Lys Pro Ala Gly Gly Asp Phe Gly Glu Val Leu Asn 175 180 185tcg gct gca aat gct agt gcc acc acc acg gag cct ctt cca gaa aag 689Ser Ala Ala Asn Ala Ser Ala Thr Thr Thr Glu Pro Leu Pro Glu Lys 190 195 200aca cag gag agc ctg tga gattcctacc tttgttctgc tacccactgc 737Thr Gln Glu Ser Leu 205cagatgctgc aagcgaggtc caagcacatc ttgtcaacat gcattgccat gaatttctac 797cagatgtgct tttatttagc tttacatatt cctttgacca aatagtttgt gggttaaaca 857aaatgaaaat atcttcacct ctattcttgg gaaacaccct ttagtgtaca tttatgttcc 917tttatttagg aaacaccatt ataaaaacac ttatagtaaa tggggacatt cactataatg 977atctaagaag ctacagattg tcatagttgt tttcctgctt tacaaaattg ctccagatct 1037ggaatgccag tttgaccttt gtcttctata atatttcctt tttttcccct ctttgaatct 1097ctgtatattt gattcttaac taaaattgtt ctcttaaata ttctgaatcc tggtaattaa 1157aagtttgggt gtattttctt tacctccaag gaaagaacta ctagctacaa aaaatatttt 1217ggaataagca ttgttttggt ataaggtaca tattttggtt gaagacacca gactgaagta 1277aacagctgtg catccaattt attatagttt tgtaagtaac aatatgtaat caaacttcta 1337ggtgacttga gagtggaacc tcctatatca ttatttagca ccgtttgtga cagtaaccat 1397ttcagtgtat tgtttattat accac 1422118207PRTHomo sapiens 118Met Asp Arg Gly Glu Gln Gly Leu Leu Arg Thr Asp Pro Val Pro Glu1 5 10 15Glu Gly Glu Asp Val Ala Ala Thr Ile Ser Ala Thr Glu Thr Leu Ser 20 25 30Glu Glu Glu Gln Glu Glu Leu Arg Arg Glu Leu Ala Lys Val Glu Glu 35 40 45Glu Ile Gln Thr Leu Ser Gln Val Leu Ala Ala Lys Glu Lys His Leu 50 55 60Ala Glu Ile Lys Arg Lys Leu Gly Ile Asn Ser Leu Gln Glu Leu Lys65 70 75 80Gln Asn Ile Ala Lys Gly Trp Gln Asp Val Thr Ala Thr Ser Ala Tyr 85 90 95Lys Lys Thr Ser Glu Thr Leu Ser Gln Ala Gly Gln Lys Ala Ser Ala 100 105 110Ala Phe Ser Ser Val Gly Ser Val Ile Thr Lys Lys Leu Glu Asp Val 115 120 125Lys Leu Gln Ala Phe Ser His Ser Phe Ser Ile Arg Ser Ile Gln His 130 135 140Ser Ile Ser Met Pro Ala Met Arg Asn Ser Pro Thr Phe Lys Ser Phe145 150 155 160Glu Glu Lys Val Glu Asn Leu Lys Ser Lys Val Gly Gly Thr Lys Pro 165 170 175Ala Gly Gly Asp Phe Gly Glu Val Leu Asn Ser Ala Ala Asn Ala Ser 180 185 190Ala Thr Thr Thr Glu Pro Leu Pro Glu Lys Thr Gln Glu Ser Leu 195 200 20511969DNAHomo sapiens 119ttgcaagcct tttcacattc ctttagtata cgttccattc agcattcaat tagcatgcct 60gctatgaga 6912023PRTHomo sapiens 120Leu Gln Ala Phe Ser His Ser Phe Ser Ile Arg Ser Ile Gln His Ser1 5 10 15Ile Ser Met Pro Ala Met Arg 2012121DNAArtificial Sequenceforward primer used for specifically detecting the variant of the present invention 121tcagctgctt tttcgtctgt t 2112220DNAArtificial Sequencereverse primer used for specifically detecting the variant of the present invention 122ggaatgtgaa aaggcttgca 2012378DNAArtificial Sequencepartial polynucleotide specific to the variant of the present invention, which is obtained by PCR using forward primer (SEQ ID NO121) and reverse primer (SEQ ID NO122) 123tcagctgctt tttcgtctgt tggctcagtc atcaccaaaa agctggaaga tgtaaaattg 60caagcctttt cacattcc 7812420DNAArtificial Sequenceforward primer used for specifically detecting the known variant of the gene of the present invention 124cctcagctgc tttttcgtct 2012525DNAArtificial Sequencereverse primer used for specifically detecting the known variant of the gene of the present invention 125aaaagttggg gagtttttta catct 2512674DNAArtificial Sequencepartial polynucleotide specific to the known variant of the gene of the present invention, which is obtained by PCR using forward primer (SEQ ID NO124) and reverse primer (SEQ ID NO125) 126cctcagctgc tttttcgtct gttggctcag tcatcaccaa aaagctggaa gatgtaaaaa 60actccccaac tttt 7412725DNAArtificial Sequenceforward primer used for detecting the variants of the gene of the present invention 127gacagcaaca tctgcttaca agaag 2512822DNAArtificial Sequencereverse primer used for detecting the variants of the gene of the present invention 128atgactgagc caacagacga aa 2212993DNAArtificial Sequencepartial polynucleotide common to the variants of the gene of the present invention, which is obtained by PCR using forward primer (SEQ ID NO127) and reverse primer (SEQ ID NO128) 129gacagcaaca tctgcttaca agaagacatc tgaaacctta tcccaggctg gacagaaggc 60ctcagctgct ttttcgtctg ttggctcagt cat 93130491DNAHomo sapiens 130ctgcgcggcg cggcgggcga tccgagccgg gacgggctgc aggcgggggt gctgcagagg 60acacgaggcg gcgggctgga gacatggacc gcggcgagca aggtctgctg agaacagacc 120cagtccctga ggaaggagaa gatgttgctg ccacgatcag tgccacagag accctctcgg 180aagaggagca ggaagagcta agaagagaac ttgcaaaggt agaagaagaa atccagactc 240tgtctcaagt gttagcagca aaagagaagc atctagcaga gatcaagcgg aaacttggaa 300tcaattctct acaggaacta aaacagaaca ttgccaaagg gtggcaagac gtgacagcaa 360catctgctta caagaagaca tctgaaacct tatcccaggc tggacagaag gcctcagctg 420ctttttcgtc tgttggctca gtcatcacca aaaagctgga agatgtaaaa ttgcaagcct 480tttcacattc c 4911311926DNAHomo sapiens 131aaaagtcggc tcgagtactc cccgtaacga ggaggtgttc tcggccgtcc cacccttcac 60tgccgtctcc gggctgcgcc gccggagccg ggacgcgcct ccgcagccct cgccgcctcc 120atccccgcgg ccgcagctcc tctcgccgtc cgcgcgcaca ccatgacgaa gaacgagaag 180aagtccctca accagagcct ggccgagtgg aagctcttca tctacaaccc gaccaccgga 240gaattcctgg ggcgcaccgc caagagctgg ggatcgcagt atgtggtagg gaagtgatgc 300tgtctgaagg tgacatcctg ttctcctctc ttctgtcctc tccatcctta ttttggccac 360ctggtttgat cttgctcttc tacctagttt tttatgggtt cctggctgca ctcttctcat 420tcacgatgtg ggttatgctt cagactctca acgatgaggt tccaaaatac cgtgaccaga 480ttcctagccc aggactcatg gtttttccaa aaccagtgac cgcattggaa tatacattca 540gtaggtctga tccaacttcg tatgcagggt acattgaaga ccttaagaag tttctaaaac 600catatacttt agaagaacag aagaacctca cagtctgtcc tgatggagca ctttttgaac 660agaagggtcc agtttatgtt gcatgtcagt ttcctatttc attacttcaa gcatgcagtg 720gtatgaatga tcctgatttt ggctattctc aaggaaaccc ttgtattctt gtgaaaatga 780acagaataat tggattaaag cctgaaggag tgccaaggat agattgtgtt tcaaagacaa 840ataatgtaaa agatggaatg aagatatacc aaatgtagca gtttatcctc ataatggaat 900gatagactta aaatatttcc catattatgg gaaaaaactg catgttgggt atctacagcc 960attggttgct gttcaggtca gctttgctcc taacaacact gggaaagaag taacagttga 1020gtgcaagatt gatggatcag ccaacctaaa aagtcaggat gatcgtgaca agtttttggg 1080acgagttatg ttcaaaatca cagcacgtgc atagtatgag taggatatct ccacagagta 1140aatgttgtgt tgtctgtctt cattttgtaa cagctggacc ttccattcta gaattatgag 1200accaccttgg agaaaggtgt gtggtacatg acattgggtt acatcataac gtgcttccag 1260atcatagtgt tcagtgtcct ctgaagtaac tgcctgttgc ctctgctgcc ctttgaacca 1320gtgtacagtc gccagatagg gaccggtgaa cacctgattc caaacatgta ggatgggggt 1380cttgtcctct ttttatgtgg tttaattgcc aagtgtctaa agcttaatat gccgtgctat 1440gtaaatattt tatggatata acaactgtca tattttgatg tcaacagagt tttagggata 1500aaatggtacc cggccaacat caagtgactt tatagctgca agaaatgtgg tatgtggaga 1560agttctgtat gtgaggaagg aaaaaaagaa aataaaagtg tgtttgaaaa atattatctt 1620gggttctttg taaaatttat tttttacatg ctgaattagc ctcgatcttt ttgattaaga 1680gcacaaactt ttttttgtaa aacatgtaaa aaaaaaactg ggattaattt ttagtgttgg 1740aactgcctct tattttaggc tgtagataaa atagcatttt taggttagcc agtgtgacta 1800tgcacctaat tttttatgag attaaattca taagacttaa tttgtacaat agtttgtgaa 1860atatcttgtt actgctttta tttagcagac tgtggactgt aataaagtat ataaattgtg 1920aaatat 19261321926DNAHomo sapiensCDS(297)..(878) 132aaaagtcggc tcgagtactc cccgtaacga ggaggtgttc tcggccgtcc cacccttcac 60tgccgtctcc gggctgcgcc gccggagccg ggacgcgcct ccgcagccct cgccgcctcc 120atccccgcgg ccgcagctcc tctcgccgtc cgcgcgcaca ccatgacgaa gaacgagaag 180aagtccctca accagagcct ggccgagtgg aagctcttca tctacaaccc gaccaccgga 240gaattcctgg ggcgcaccgc caagagctgg ggatcgcagt atgtggtagg gaagtg atg 299 Met 1ctg tct gaa ggt gac atc ctg ttc tcc tct ctt ctg tcc tct cca tcc 347Leu Ser Glu Gly Asp Ile Leu Phe Ser Ser Leu Leu Ser Ser Pro Ser 5 10 15tta ttt tgg cca cct ggt ttg atc ttg ctc ttc tac cta gtt ttt tat 395Leu Phe Trp Pro Pro Gly Leu Ile Leu Leu Phe Tyr Leu Val Phe Tyr 20 25 30ggg ttc ctg gct gca ctc ttc tca ttc acg atg tgg gtt atg ctt cag 443Gly Phe Leu Ala Ala Leu Phe Ser Phe Thr Met Trp Val Met Leu Gln 35 40 45act ctc aac gat gag gtt cca aaa tac cgt gac cag att cct agc cca 491Thr Leu Asn Asp Glu Val Pro Lys Tyr Arg Asp Gln Ile Pro Ser Pro50 55 60 65gga ctc atg gtt ttt cca aaa cca gtg acc gca ttg gaa tat aca ttc 539Gly Leu Met Val Phe Pro Lys Pro Val Thr Ala Leu Glu Tyr Thr Phe 70 75 80agt agg tct gat cca act tcg tat gca ggg tac att gaa gac ctt aag 587Ser Arg Ser Asp Pro Thr Ser Tyr Ala Gly Tyr Ile Glu Asp Leu Lys 85 90 95aag ttt cta aaa cca tat act tta gaa gaa cag aag aac ctc aca gtc 635Lys Phe Leu Lys Pro Tyr Thr Leu Glu Glu Gln Lys Asn Leu Thr Val 100 105 110tgt cct gat gga gca ctt ttt gaa cag aag ggt cca gtt tat gtt gca 683Cys Pro Asp Gly Ala Leu Phe Glu Gln Lys Gly Pro Val Tyr Val Ala 115 120 125tgt cag ttt cct att tca tta ctt caa gca tgc agt ggt atg aat gat 731Cys Gln Phe Pro Ile Ser Leu Leu Gln Ala Cys Ser Gly Met Asn Asp130 135 140 145cct gat ttt ggc tat tct caa gga aac cct tgt att ctt gtg aaa atg 779Pro Asp Phe Gly Tyr Ser Gln Gly Asn Pro Cys Ile Leu Val Lys Met 150 155 160aac aga ata att gga tta aag cct gaa gga gtg cca agg ata gat tgt 827Asn Arg Ile Ile Gly Leu Lys Pro Glu Gly Val Pro Arg Ile Asp Cys 165 170 175gtt tca aag aca aat aat gta aaa gat gga atg aag ata tac caa atg 875Val Ser Lys Thr Asn Asn Val Lys Asp Gly Met Lys Ile Tyr Gln Met 180 185 190tag cagtttatcc tcataatgga atgatagact taaaatattt cccatattat 928gggaaaaaac tgcatgttgg gtatctacag ccattggttg ctgttcaggt cagctttgct 988cctaacaaca ctgggaaaga agtaacagtt gagtgcaaga ttgatggatc agccaaccta 1048aaaagtcagg atgatcgtga caagtttttg ggacgagtta tgttcaaaat cacagcacgt 1108gcatagtatg agtaggatat ctccacagag taaatgttgt gttgtctgtc ttcattttgt 1168aacagctgga ccttccattc tagaattatg agaccacctt ggagaaaggt gtgtggtaca 1228tgacattggg ttacatcata acgtgcttcc agatcatagt gttcagtgtc ctctgaagta 1288actgcctgtt gcctctgctg ccctttgaac cagtgtacag tcgccagata gggaccggtg 1348aacacctgat tccaaacatg taggatgggg gtcttgtcct

ctttttatgt ggtttaattg 1408ccaagtgtct aaagcttaat atgccgtgct atgtaaatat tttatggata taacaactgt 1468catattttga tgtcaacaga gttttaggga taaaatggta cccggccaac atcaagtgac 1528tttatagctg caagaaatgt ggtatgtgga gaagttctgt atgtgaggaa ggaaaaaaag 1588aaaataaaag tgtgtttgaa aaatattatc ttgggttctt tgtaaaattt attttttaca 1648tgctgaatta gcctcgatct ttttgattaa gagcacaaac ttttttttgt aaaacatgta 1708aaaaaaaaac tgggattaat ttttagtgtt ggaactgcct cttattttag gctgtagata 1768aaatagcatt tttaggttag ccagtgtgac tatgcaccta attttttatg agattaaatt 1828cataagactt aatttgtaca atagtttgtg aaatatcttg ttactgcttt tatttagcag 1888actgtggact gtaataaagt atataaattg tgaaatat 1926133193PRTHomo sapiens 133Met Leu Ser Glu Gly Asp Ile Leu Phe Ser Ser Leu Leu Ser Ser Pro1 5 10 15Ser Leu Phe Trp Pro Pro Gly Leu Ile Leu Leu Phe Tyr Leu Val Phe 20 25 30Tyr Gly Phe Leu Ala Ala Leu Phe Ser Phe Thr Met Trp Val Met Leu 35 40 45Gln Thr Leu Asn Asp Glu Val Pro Lys Tyr Arg Asp Gln Ile Pro Ser 50 55 60Pro Gly Leu Met Val Phe Pro Lys Pro Val Thr Ala Leu Glu Tyr Thr65 70 75 80Phe Ser Arg Ser Asp Pro Thr Ser Tyr Ala Gly Tyr Ile Glu Asp Leu 85 90 95Lys Lys Phe Leu Lys Pro Tyr Thr Leu Glu Glu Gln Lys Asn Leu Thr 100 105 110Val Cys Pro Asp Gly Ala Leu Phe Glu Gln Lys Gly Pro Val Tyr Val 115 120 125Ala Cys Gln Phe Pro Ile Ser Leu Leu Gln Ala Cys Ser Gly Met Asn 130 135 140Asp Pro Asp Phe Gly Tyr Ser Gln Gly Asn Pro Cys Ile Leu Val Lys145 150 155 160Met Asn Arg Ile Ile Gly Leu Lys Pro Glu Gly Val Pro Arg Ile Asp 165 170 175Cys Val Ser Lys Thr Asn Asn Val Lys Asp Gly Met Lys Ile Tyr Gln 180 185 190Met13492DNAHomo sapiens 134gatcgcagta tgtggtaggg aagtgatgct gtctgaaggt gacatcctgt tctcctctct 60tctgtcctct ccatccttat tttggccacc tg 9213523PRTHomo sapiens 135Met Leu Ser Glu Gly Asp Ile Leu Phe Ser Ser Leu Leu Ser Ser Pro1 5 10 15Ser Leu Phe Trp Pro Pro Gly 2013667DNAHomo sapiens 136atgctgtctg aaggtgacat cctgttctcc tctcttctgt cctctccatc cttattttgg 60ccacctg 6713720DNAHomo sapiens 137acaaataatg taaaagatgg 2013813PRTHomo sapiens 138Thr Asn Asn Val Lys Asp Gly Met Lys Ile Tyr Gln Met1 5 101397PRTHomo sapiens 139Thr Asn Asn Val Lys Asp Gly1 514022DNAArtificial Sequenceforward primer used for specifically detecting the variant of the present invention 140cgcagtatgt ggtagggaag tg 2214128DNAArtificial Sequencereverse primer used for specifically detecting the variant of the present invention 141aaactaggta gaagagcaag atcaaacc 28142116DNAArtificial Sequencepartial polynucleotide specific to the variant of the present invention, which is obtained by PCR using forward primer (SEQ ID NO141) and reverse primer (SEQ ID NO142) 142cgcagtatgt ggtagggaag tgatgctgtc tgaaggtgac atcctgttct cctctcttct 60gtcctctcca tccttatttt ggccacctgg tttgatcttg ctcttctacc tagttt 11614322DNAArtificial Sequenceforward primer used for specifically detecting the known variant of the gene of the present invention 143ccgagtggaa gctcttcatc ta 2214421DNAArtificial Sequencereverse primer used for specifically detecting the known variant of the gene of the present invention 144aagatcaaac cccagctctt g 2114579DNAArtificial Sequencepartial polynucleotide specific to the known variant of the gene of the present invention, which is obtained by PCR using forward primer (SEQ ID NO143) and reverse primer (SEQ ID NO144) 145ccgagtggaa gctcttcatc tacaacccga ccaccggaga attcctgggg cgcaccgcca 60agagctgggg tttgatctt 7914623DNAArtificial Sequenceforward primer used for detecting the variants of the gene of the present invention 146tcgtatgcag ggtacattga aga 2314723DNAArtificial Sequencereverse primer used for detecting the variants of the gene of the present invention 147tgcaacataa actggaccct tct 23148126DNAArtificial Sequencepartial polynucleotide common to the variants of the gene of the present invention, which is obtained by PCR using forward primer (SEQ ID NO146) and reverse primer (SEQ ID NO147) 148tcgtatgcag ggtacattga agaccttaag aagtttctaa aaccatatac tttagaagaa 60cagaagaacc tcacagtctg tcctgatgga gcactttttg aacagaaggg tccagtttat 120gttgca 126149390DNAHomo sapiens 149aaaagtcggc tcgagtactc cccgtaacga ggaggtgttc tcggccgtcc cacccttcac 60tgccgtctcc gggctgcgcc gccggagccg ggacgcgcct ccgcagccct cgccgcctcc 120atccccgcgg ccgcagctcc tctcgccgtc cgcgcgcaca ccatgacgaa gaacgagaag 180aagtccctca accagagcct ggccgagtgg aagctcttca tctacaaccc gaccaccgga 240gaattcctgg ggcgcaccgc caagagctgg ggatcgcagt atgtggtagg gaagtgatgc 300tgtctgaagg tgacatcctg ttctcctctc ttctgtcctc tccatcctta ttttggccac 360ctggtttgat cttgctcttc tacctagttt 3901501120DNAHomo sapiens 150tattcggcgc ggaggggcgg cggccgggga ggcggcggcg gcggcaggat tcccaggagc 60catgttgtca gaagtcctac tggtgtctgc tccggggaaa gtcatccttc atggagaaca 120tgccgtggta catggcaagg tagcactggc tgtatccttg aacttgagaa cattcctccg 180gcttcaaccc cacagcaatg ggaaagtgga cctcagctta cccaacattg gtatcaagcg 240ggcctgggat gtggccaggc ttcagtcact ggacacaagc tttctgggtg gaccaaggag 300gatttggagc taattaacaa gtgggccttc caaggggaga gaatgattca cgggaacccc 360tccggagtgg acaatgctgt cagcacctgg ggaggagccc tccgatacca tcaagggaag 420atttcatcct taaagaggtc gccagctctc cagatcctgc tgaccaacac caaagtccct 480cgcaatacca gggcccttgt ggctggcgtc agaaacaggc tgctcaagtt cccagagatc 540gtggcccccc tcctgacctc aatagatgcc atctccctgg agtgtgagcg cgtgctggga 600gagatggggg aagccccagc cccggagcag tacctcgtgc tggaagagct cattgacatg 660aaccagcacc atctgaatgc cctcggcgtg ggccacgcct ctctggacca gctctgccag 720gtgaccaggg cccgcggact tcacagcaag ctgactggcg caggcggtgg tggctgtggc 780atcacactcc tcaagccagg gctggagcag ccagaagtgg aggccacgaa gcaggccctg 840accagctgtg gctttgactg cttggaaacc agcatcggtg cccccggcgt ctccatccac 900tcagccacct ccctggacag ccgagtccag caagccctgg atggcctctg agaggagccc 960acgacactgc agccccaccc agatgcccct ttctggatta ttctgggggc tgcagttcga 1020ctctgtgctg gccagcgagc gcccagctcc tgacactgct ggagaggccc cagccgcttg 1080gcgatgccag ccaagctctg cagtcccagc ggtgggacct 11201511120DNAHomo sapiensCDS(343)..(951) 151tattcggcgc ggaggggcgg cggccgggga ggcggcggcg gcggcaggat tcccaggagc 60catgttgtca gaagtcctac tggtgtctgc tccggggaaa gtcatccttc atggagaaca 120tgccgtggta catggcaagg tagcactggc tgtatccttg aacttgagaa cattcctccg 180gcttcaaccc cacagcaatg ggaaagtgga cctcagctta cccaacattg gtatcaagcg 240ggcctgggat gtggccaggc ttcagtcact ggacacaagc tttctgggtg gaccaaggag 300gatttggagc taattaacaa gtgggccttc caaggggaga ga atg att cac ggg 354 Met Ile His Gly 1aac ccc tcc gga gtg gac aat gct gtc agc acc tgg gga gga gcc ctc 402Asn Pro Ser Gly Val Asp Asn Ala Val Ser Thr Trp Gly Gly Ala Leu5 10 15 20cga tac cat caa ggg aag att tca tcc tta aag agg tcg cca gct ctc 450Arg Tyr His Gln Gly Lys Ile Ser Ser Leu Lys Arg Ser Pro Ala Leu 25 30 35cag atc ctg ctg acc aac acc aaa gtc cct cgc aat acc agg gcc ctt 498Gln Ile Leu Leu Thr Asn Thr Lys Val Pro Arg Asn Thr Arg Ala Leu 40 45 50gtg gct ggc gtc aga aac agg ctg ctc aag ttc cca gag atc gtg gcc 546Val Ala Gly Val Arg Asn Arg Leu Leu Lys Phe Pro Glu Ile Val Ala 55 60 65ccc ctc ctg acc tca ata gat gcc atc tcc ctg gag tgt gag cgc gtg 594Pro Leu Leu Thr Ser Ile Asp Ala Ile Ser Leu Glu Cys Glu Arg Val 70 75 80ctg gga gag atg ggg gaa gcc cca gcc ccg gag cag tac ctc gtg ctg 642Leu Gly Glu Met Gly Glu Ala Pro Ala Pro Glu Gln Tyr Leu Val Leu85 90 95 100gaa gag ctc att gac atg aac cag cac cat ctg aat gcc ctc ggc gtg 690Glu Glu Leu Ile Asp Met Asn Gln His His Leu Asn Ala Leu Gly Val 105 110 115ggc cac gcc tct ctg gac cag ctc tgc cag gtg acc agg gcc cgc gga 738Gly His Ala Ser Leu Asp Gln Leu Cys Gln Val Thr Arg Ala Arg Gly 120 125 130ctt cac agc aag ctg act ggc gca ggc ggt ggt ggc tgt ggc atc aca 786Leu His Ser Lys Leu Thr Gly Ala Gly Gly Gly Gly Cys Gly Ile Thr 135 140 145ctc ctc aag cca ggg ctg gag cag cca gaa gtg gag gcc acg aag cag 834Leu Leu Lys Pro Gly Leu Glu Gln Pro Glu Val Glu Ala Thr Lys Gln 150 155 160gcc ctg acc agc tgt ggc ttt gac tgc ttg gaa acc agc atc ggt gcc 882Ala Leu Thr Ser Cys Gly Phe Asp Cys Leu Glu Thr Ser Ile Gly Ala165 170 175 180ccc ggc gtc tcc atc cac tca gcc acc tcc ctg gac agc cga gtc cag 930Pro Gly Val Ser Ile His Ser Ala Thr Ser Leu Asp Ser Arg Val Gln 185 190 195caa gcc ctg gat ggc ctc tga gaggagccca cgacactgca gccccaccca 981Gln Ala Leu Asp Gly Leu 200gatgcccctt tctggattat tctgggggct gcagttcgac tctgtgctgg ccagcgagcg 1041cccagctcct gacactgctg gagaggcccc agccgcttgg cgatgccagc caagctctgc 1101agtcccagcg gtgggacct 1120152202PRTHomo sapiens 152Met Ile His Gly Asn Pro Ser Gly Val Asp Asn Ala Val Ser Thr Trp1 5 10 15Gly Gly Ala Leu Arg Tyr His Gln Gly Lys Ile Ser Ser Leu Lys Arg 20 25 30Ser Pro Ala Leu Gln Ile Leu Leu Thr Asn Thr Lys Val Pro Arg Asn 35 40 45Thr Arg Ala Leu Val Ala Gly Val Arg Asn Arg Leu Leu Lys Phe Pro 50 55 60Glu Ile Val Ala Pro Leu Leu Thr Ser Ile Asp Ala Ile Ser Leu Glu65 70 75 80Cys Glu Arg Val Leu Gly Glu Met Gly Glu Ala Pro Ala Pro Glu Gln 85 90 95Tyr Leu Val Leu Glu Glu Leu Ile Asp Met Asn Gln His His Leu Asn 100 105 110Ala Leu Gly Val Gly His Ala Ser Leu Asp Gln Leu Cys Gln Val Thr 115 120 125Arg Ala Arg Gly Leu His Ser Lys Leu Thr Gly Ala Gly Gly Gly Gly 130 135 140Cys Gly Ile Thr Leu Leu Lys Pro Gly Leu Glu Gln Pro Glu Val Glu145 150 155 160Ala Thr Lys Gln Ala Leu Thr Ser Cys Gly Phe Asp Cys Leu Glu Thr 165 170 175Ser Ile Gly Ala Pro Gly Val Ser Ile His Ser Ala Thr Ser Leu Asp 180 185 190Ser Arg Val Gln Gln Ala Leu Asp Gly Leu 195 20015342DNAHomo sapiens 153cactggacac aagctttctg ggtggaccaa ggaggatttg ga 42154342DNAHomo sapiens 154tattcggcgc ggaggggcgg cggccgggga ggcggcggcg gcggcaggat tcccaggagc 60catgttgtca gaagtcctac tggtgtctgc tccggggaaa gtcatccttc atggagaaca 120tgccgtggta catggcaagg tagcactggc tgtatccttg aacttgagaa cattcctccg 180gcttcaaccc cacagcaatg ggaaagtgga cctcagctta cccaacattg gtatcaagcg 240ggcctgggat gtggccaggc ttcagtcact ggacacaagc tttctgggtg gaccaaggag 300gatttggagc taattaacaa gtgggccttc caaggggaga ga 342155301DNAHomo sapiens 155agcaaggtga tgtcacaaca cccacctcag agcaagtgga gaagctaaag gaggttgcag 60gcttgcctga cgactgtgct gtcaccgagc gcctggctgt gctggccttt ctttacttat 120acctgtccat ctgccggaag cagagggccc tgccgagcct ggatatcgta gtgtggtcgg 180agctgccccc cggggcgggc ttgggctcca gcgccgccta ctcggtgtgt ctggcagcag 240ccctcctgac tgtgtgcgag gagatcccaa acccgctgaa ggacggggat tgcgtcaaca 300g 301156101PRTHomo sapiens 156Glu Gln Gly Asp Val Thr Thr Pro Thr Ser Glu Gln Val Glu Lys Leu1 5 10 15Lys Glu Val Ala Gly Leu Pro Asp Asp Cys Ala Val Thr Glu Arg Leu 20 25 30Ala Val Leu Ala Phe Leu Tyr Leu Tyr Leu Ser Ile Cys Arg Lys Gln 35 40 45Arg Ala Leu Pro Ser Leu Asp Ile Val Val Trp Ser Glu Leu Pro Pro 50 55 60Gly Ala Gly Leu Gly Ser Ser Ala Ala Tyr Ser Val Cys Leu Ala Ala65 70 75 80Ala Leu Leu Thr Val Cys Glu Glu Ile Pro Asn Pro Leu Lys Asp Gly 85 90 95Asp Cys Val Asn Arg 1001571130DNAHomo sapiens 157ggaggggcgg cggccgggga ggcggcggcg gcggcaggat tcccaggagc catgttgtca 60gaagtcctac tggtgtctgc tccggggaaa gtcatccttc atggagaaca tgccgtggta 120catggcaagg tagcactggc tgtatccttg aacttgagaa cattcctccg gcttcaaccc 180cacagcaatg ggaaagtgga cctcagctta cccaacattg gtatcaagcg ggcctgggat 240gtggccaggc ttcagtcact ggacacaagc tttctggagc aaggtgatgt cacaacaccc 300acctcagagc aagtggagaa gctaaaggag gttgcaggct tgcctgacga ctgtgctgtc 360accgagcgcc tggctgtgct ggcctttctt tacttatacc tgtccatctg ccggaagcag 420aggtggacca aggaggattt ggagctaatt aacaagtggg ccttccaagg ggagagaatg 480attcacggga acccctccgg agtggacaat gctgtcagca cctggggagg agccctccga 540taccatcaag ggaagatttc atccttaaag aggtcgccag ctctcctgat cctgctgacc 600aacaccaaag tccctcgcaa taccagggcc cttgtggctg gcgtcagaaa caggctgctc 660aagttcccag agatcgtggc ccccctcctg acctcaatag atgccatctc cctggagtgt 720gagcgcgtgc tgggagagat gggggaagcc ccagccccgg agcagtacct cgtgctggaa 780gagctcatcg acatgaacca gcaccatctg aatgccctcg gcgtgggcca cgcctctctg 840gaccagctct gccaggtgac cagggcccgc ggacttcaca gcaagctgac tggcgcaggc 900ggtggtggct gtggcatcac actcctcaag ccagggctgg agcagccaga agtggaggcc 960acgaagcagg ccctgaccag ctgtggcttt gactgcttgg aaaccagcat cggtgccccc 1020ggcgtctcca tccactcagc cacctccctg gacagccgag tccagcaagc cctggatggc 1080ctctgagagg agcccacgac actgcagccc cacccagatg cccctttctg 11301581130DNAHomo sapiensCDS(52)..(1086) 158ggaggggcgg cggccgggga ggcggcggcg gcggcaggat tcccaggagc c atg ttg 57 Met Leu 1tca gaa gtc cta ctg gtg tct gct ccg ggg aaa gtc atc ctt cat gga 105Ser Glu Val Leu Leu Val Ser Ala Pro Gly Lys Val Ile Leu His Gly 5 10 15gaa cat gcc gtg gta cat ggc aag gta gca ctg gct gta tcc ttg aac 153Glu His Ala Val Val His Gly Lys Val Ala Leu Ala Val Ser Leu Asn 20 25 30ttg aga aca ttc ctc cgg ctt caa ccc cac agc aat ggg aaa gtg gac 201Leu Arg Thr Phe Leu Arg Leu Gln Pro His Ser Asn Gly Lys Val Asp35 40 45 50ctc agc tta ccc aac att ggt atc aag cgg gcc tgg gat gtg gcc agg 249Leu Ser Leu Pro Asn Ile Gly Ile Lys Arg Ala Trp Asp Val Ala Arg 55 60 65ctt cag tca ctg gac aca agc ttt ctg gag caa ggt gat gtc aca aca 297Leu Gln Ser Leu Asp Thr Ser Phe Leu Glu Gln Gly Asp Val Thr Thr 70 75 80ccc acc tca gag caa gtg gag aag cta aag gag gtt gca ggc ttg cct 345Pro Thr Ser Glu Gln Val Glu Lys Leu Lys Glu Val Ala Gly Leu Pro 85 90 95gac gac tgt gct gtc acc gag cgc ctg gct gtg ctg gcc ttt ctt tac 393Asp Asp Cys Ala Val Thr Glu Arg Leu Ala Val Leu Ala Phe Leu Tyr 100 105 110tta tac ctg tcc atc tgc cgg aag cag agg tgg acc aag gag gat ttg 441Leu Tyr Leu Ser Ile Cys Arg Lys Gln Arg Trp Thr Lys Glu Asp Leu115 120 125 130gag cta att aac aag tgg gcc ttc caa ggg gag aga atg att cac ggg 489Glu Leu Ile Asn Lys Trp Ala Phe Gln Gly Glu Arg Met Ile His Gly 135 140 145aac ccc tcc gga gtg gac aat gct gtc agc acc tgg gga gga gcc ctc 537Asn Pro Ser Gly Val Asp Asn Ala Val Ser Thr Trp Gly Gly Ala Leu 150 155 160cga tac cat caa ggg aag att tca tcc tta aag agg tcg cca gct ctc 585Arg Tyr His Gln Gly Lys Ile Ser Ser Leu Lys Arg Ser Pro Ala Leu 165 170 175ctg atc ctg ctg acc aac acc aaa gtc cct cgc aat acc agg gcc ctt 633Leu Ile Leu Leu Thr Asn Thr Lys Val Pro Arg Asn Thr Arg Ala Leu 180 185 190gtg gct ggc gtc aga aac agg ctg ctc aag ttc cca gag atc gtg gcc 681Val Ala Gly Val Arg Asn Arg Leu Leu Lys Phe Pro Glu Ile Val Ala195 200 205 210ccc ctc ctg acc tca ata gat gcc atc tcc ctg gag tgt gag cgc gtg 729Pro Leu Leu Thr Ser Ile Asp Ala Ile Ser Leu Glu Cys Glu Arg Val 215 220 225ctg gga gag atg ggg gaa gcc cca gcc ccg gag cag tac ctc gtg ctg 777Leu Gly Glu Met Gly

Glu Ala Pro Ala Pro Glu Gln Tyr Leu Val Leu 230 235 240gaa gag ctc atc gac atg aac cag cac cat ctg aat gcc ctc ggc gtg 825Glu Glu Leu Ile Asp Met Asn Gln His His Leu Asn Ala Leu Gly Val 245 250 255ggc cac gcc tct ctg gac cag ctc tgc cag gtg acc agg gcc cgc gga 873Gly His Ala Ser Leu Asp Gln Leu Cys Gln Val Thr Arg Ala Arg Gly 260 265 270ctt cac agc aag ctg act ggc gca ggc ggt ggt ggc tgt ggc atc aca 921Leu His Ser Lys Leu Thr Gly Ala Gly Gly Gly Gly Cys Gly Ile Thr275 280 285 290ctc ctc aag cca ggg ctg gag cag cca gaa gtg gag gcc acg aag cag 969Leu Leu Lys Pro Gly Leu Glu Gln Pro Glu Val Glu Ala Thr Lys Gln 295 300 305gcc ctg acc agc tgt ggc ttt gac tgc ttg gaa acc agc atc ggt gcc 1017Ala Leu Thr Ser Cys Gly Phe Asp Cys Leu Glu Thr Ser Ile Gly Ala 310 315 320ccc ggc gtc tcc atc cac tca gcc acc tcc ctg gac agc cga gtc cag 1065Pro Gly Val Ser Ile His Ser Ala Thr Ser Leu Asp Ser Arg Val Gln 325 330 335caa gcc ctg gat ggc ctc tga gaggagccca cgacactgca gccccaccca 1116Gln Ala Leu Asp Gly Leu 340gatgcccctt tctg 1130159344PRTHomo sapiens 159Met Leu Ser Glu Val Leu Leu Val Ser Ala Pro Gly Lys Val Ile Leu1 5 10 15His Gly Glu His Ala Val Val His Gly Lys Val Ala Leu Ala Val Ser 20 25 30Leu Asn Leu Arg Thr Phe Leu Arg Leu Gln Pro His Ser Asn Gly Lys 35 40 45Val Asp Leu Ser Leu Pro Asn Ile Gly Ile Lys Arg Ala Trp Asp Val 50 55 60Ala Arg Leu Gln Ser Leu Asp Thr Ser Phe Leu Glu Gln Gly Asp Val65 70 75 80Thr Thr Pro Thr Ser Glu Gln Val Glu Lys Leu Lys Glu Val Ala Gly 85 90 95Leu Pro Asp Asp Cys Ala Val Thr Glu Arg Leu Ala Val Leu Ala Phe 100 105 110Leu Tyr Leu Tyr Leu Ser Ile Cys Arg Lys Gln Arg Trp Thr Lys Glu 115 120 125Asp Leu Glu Leu Ile Asn Lys Trp Ala Phe Gln Gly Glu Arg Met Ile 130 135 140His Gly Asn Pro Ser Gly Val Asp Asn Ala Val Ser Thr Trp Gly Gly145 150 155 160Ala Leu Arg Tyr His Gln Gly Lys Ile Ser Ser Leu Lys Arg Ser Pro 165 170 175Ala Leu Leu Ile Leu Leu Thr Asn Thr Lys Val Pro Arg Asn Thr Arg 180 185 190Ala Leu Val Ala Gly Val Arg Asn Arg Leu Leu Lys Phe Pro Glu Ile 195 200 205Val Ala Pro Leu Leu Thr Ser Ile Asp Ala Ile Ser Leu Glu Cys Glu 210 215 220Arg Val Leu Gly Glu Met Gly Glu Ala Pro Ala Pro Glu Gln Tyr Leu225 230 235 240Val Leu Glu Glu Leu Ile Asp Met Asn Gln His His Leu Asn Ala Leu 245 250 255Gly Val Gly His Ala Ser Leu Asp Gln Leu Cys Gln Val Thr Arg Ala 260 265 270Arg Gly Leu His Ser Lys Leu Thr Gly Ala Gly Gly Gly Gly Cys Gly 275 280 285Ile Thr Leu Leu Lys Pro Gly Leu Glu Gln Pro Glu Val Glu Ala Thr 290 295 300Lys Gln Ala Leu Thr Ser Cys Gly Phe Asp Cys Leu Glu Thr Ser Ile305 310 315 320Gly Ala Pro Gly Val Ser Ile His Ser Ala Thr Ser Leu Asp Ser Arg 325 330 335Val Gln Gln Ala Leu Asp Gly Leu 34016042DNAHomo sapiens 160gtccatctgc cggaagcaga ggtggaccaa ggaggatttg ga 4216115PRTHomo sapiens 161Leu Ser Ile Cys Arg Lys Gln Arg Trp Thr Lys Glu Asp Leu Glu1 5 10 15162156DNAHomo sapiens 162ggccctgccg agcctggata tcgtagtgtg gtcggagctg ccccccgggg cgggcttggg 60ctccagcgcc gcctactcgg tgtgtctggc agcagccctc ctgactgtgt gcgaggagat 120cccaaacccg ctgaaggacg gggattgcgt caacag 15616353PRTHomo sapiens 163Arg Ala Leu Pro Ser Leu Asp Ile Val Val Trp Ser Glu Leu Pro Pro1 5 10 15Gly Ala Gly Leu Gly Ser Ser Ala Ala Tyr Ser Val Cys Leu Ala Ala 20 25 30Ala Leu Leu Thr Val Cys Glu Glu Ile Pro Asn Pro Leu Lys Asp Gly 35 40 45Asp Cys Val Asn Arg 5016419DNAArtificial Sequenceforward primer used for specifically detecting the variant of the present invention 164tggccaggct tcagtcact 1916523DNAArtificial Sequencereverse primer used for specifically detecting the variant of the present invention 165gcccacttgt taattagctc caa 2316675DNAArtificial Sequencepartial polynucleotide specific to the variant of the present invention, which is obtained by PCR using forward primer (SEQ ID NO164) and reverse primer (SEQ ID NO165) 166tggccaggct tcagtcactg gacacaagct ttctgggtgg accaaggagg atttggagct 60aattaacaag tgggc 7516729DNAArtificial Sequenceprobe used for detecting the variants of the present invention 167acacaagctt tctgggtgga ccaaggagg 2916819DNAArtificial Sequenceforward primer used for specifically detecting the variant of the present invention 168aggcttgcct gacgactgt 1916923DNAArtificial Sequencereverse primer used for specifically detecting the variant of the present invention 169ggaaggccca cttgttaatt agc 23170131DNAArtificial Sequencepartial polynucleotide specific to the variant of the present invention, which is obtained by PCR using forward primer (SEQ ID NO168) and reverse primer (SEQ ID NO169) 170aggcttgcct gacgactgtg ctgtcaccga gcgcctggct gtgctggcct ttctttactt 60atacctgtcc atctgccgga agcagaggtg gaccaaggag gatttggagc taattaacaa 120gtgggccttc c 13117127DNAArtificial Sequenceprobe used for detecting the variants of the present invention 171agcagaggtg gaccaaggag gatttgg 2717219DNAArtificial Sequenceforward primer used for specifically detecting the known variant of the gene of the present invention 172gatcccaaac ccgctgaag 1917322DNAArtificial Sequencereverse primer used for specifically detecting the known variant of the gene of the present invention 173gaatcattct ctccccttgg aa 22174101DNAArtificial Sequencepartial polynucleotide specific to the known variant of the gene of the present invention, which is obtained by PCR using forward primer (SEQ ID NO172) and reverse primer (SEQ ID NO173) 174gatcccaaac ccgctgaagg acggggattg cgtcaacagg tggaccaagg aggatttgga 60gctaattaac aagtgggcct tccaagggga gagaatgatt c 10117527DNAArtificial Sequenceprobe used for specifically detecting the known variant of the gene of the present invention 175cgtcaacagg tggaccaagg aggattt 2717619DNAArtificial Sequenceforward primer used for detecting the variants of the gene of the present invention 176cgccagctct ccagatcct 1917721DNAArtificial Sequencereverse primer used for detecting the variants of the gene of the present invention 177gggaacttga gcagcctgtt t 2117894DNAArtificial Sequencepartial polynucleotide common to the variants of the gene of the present invention, which is obtained by PCR using forward primer (SEQ ID NO176) and reverse primer (SEQ ID NO177) 178cgccagctct ccagatcctg ctgaccaaca ccaaagtccc tcgcaatacc agggcccttg 60tggctggcgt cagaaacagg ctgctcaagt tccc 9417925DNAArtificial Sequenceprobe used for detecting the variants of the gene of the present invention 179ctgaccaaca ccaaagtccc tcgca 25180326DNAHomo sapiens 180tattcggcgc ggaggggcgg cggccgggga ggcggcggcg gcggcaggat tcccaggagc 60catgttgtca gaagtcctac tggtgtctgc tccggggaaa gtcatccttc atggagaaca 120tgccgtggta catggcaagg tagcactggc tgtatccttg aacttgagaa cattcctccg 180gcttcaaccc cacagcaatg ggaaagtgga cctcagctta cccaacattg gtatcaagcg 240ggcctgggat gtggccaggc ttcagtcact ggacacaagc tttctgggtg gaccaaggag 300gatttggagc taattaacaa gtgggc 326181466DNAHomo sapiens 181ggaggggcgg cggccgggga ggcggcggcg gcggcaggat tcccaggagc catgttgtca 60gaagtcctac tggtgtctgc tccggggaaa gtcatccttc atggagaaca tgccgtggta 120catggcaagg tagcactggc tgtatccttg aacttgagaa cattcctccg gcttcaaccc 180cacagcaatg ggaaagtgga cctcagctta cccaacattg gtatcaagcg ggcctgggat 240gtggccaggc ttcagtcact ggacacaagc tttctggagc aaggtgatgt cacaacaccc 300acctcagagc aagtggagaa gctaaaggag gttgcaggct tgcctgacga ctgtgctgtc 360accgagcgcc tggctgtgct ggcctttctt tacttatacc tgtccatctg ccggaagcag 420aggtggacca aggaggattt ggagctaatt aacaagtggg ccttcc 4661821872DNAHomo sapiens 182acaacctgac ttttgtccac aatgcaaaga ctccaactgt tgagagtaga agtactgctg 60ggtgtgaaac aaggagatga aatgcggcat ttcttttttt cttctcagac ctccactctg 120gagaagagtc agaatggggg cgtcggggag gaggtcaccc cagctctgat ctttgccatc 180acagttgcta caatcggctc tttccagttt ggctacaaca ctggggtcat caatgctcct 240gagacgatca taaaggaatt tatcaataaa actttgacgg acaaggcaaa tgcccctccc 300tctgaggtgc tgctcacgaa tctctggtcc ttgtctgtgg ccatattttc cgtcgggggt 360atgatcggct ccttttccgt cggactcttt gttaaccgct ttggcaggcg caattcaatg 420ctgattgtca acctgttggc tgccactggt ggctgcctta tgggactgtg taaaatagct 480gagtcagttg aaatgctgat cctgggccgc ttggttattg gcctcttctg cggactctgc 540acaggttttg tgcccatgta cattggagag atctcgccta ctgccctgag gggtgccttt 600ggcactctca accagctggg catagttatt ggaattctgg tggcccagat ctttggtctg 660gaactcatcc ttgggtctaa agagctatgg ccggtgctat taggctttac catccttcca 720gctatcctgc aaagtgcagc ccttccatgt tgccctgaaa gtcccagatt tttgctcatt 780aacagaaaaa aagaggagaa tgctacgcgg atcctccagc ggttgtgggg cacccaggat 840gtatcccaag acatccagga gatgaaagat gagagtgcaa ggatgtcaca agaaaagcaa 900gtcaccgtgc tggagctctt tagagtgtcc agctaccgac agcccatcat catttccatt 960gtgctccagc tctctcagca gctctctggg atcaatgctg tgttctatta ctcaacagga 1020atcttcaagg atgcaggtgt tcaacagccc atctatgcca ccatcagcgc gggtgtggtt 1080aatactatct tcactttact ttctctattt ctggtggaaa gggcaggaag aaggactctg 1140catatgatag gccttggagg gatggctttt tgttccacgc tcatgactgt ttctttgtta 1200ttaaagaatc actataatgg gatgagcttt gtctgtattg gggctatctt ggtctttgtg 1260gcctgttttg aaattggacc aggccccatt ccctggttta ttgtggccga actcttcagc 1320cagggccccc gcccagctgc gatggcagtg gccggctgct ccaactggac ctccaacttc 1380ctagtcggat tgctcttccc ctctgctgct tactatttag gagcctacgt ttttattatc 1440ttcaccggct tcctcattac cttcctggcc tttaccttct tcaaagtccc tgagacccgt 1500ggcaggactt ttgaggatat cacacgggcc tttgaagggc aggcacacgg tgcagataga 1560tctggaaagg acggcgtcat ggggatgaac agcatcgagc ctgctaagga gaccaccacc 1620aatgtctaag tcgtgcctcc ttccacctcc ctcccggcat gggaaggcca cctctccctc 1680aacaagggag agacctcatc aggatgaacc caggacgctt ctgaatgctg ctacttgatt 1740tctttctcat cccacgcact ccatgagcac cccaaggctg cagtttgttg gatcttcaat 1800ggctttttaa attttatttc ctggacatcc tcttctgctt aggagagacc gagtgaacct 1860accttcattt ca 18721831872DNAHomo sapiensCDS(22)..(1629) 183acaacctgac ttttgtccac a atg caa aga ctc caa ctg ttg aga gta gaa 51 Met Gln Arg Leu Gln Leu Leu Arg Val Glu 1 5 10gta ctg ctg ggt gtg aaa caa gga gat gaa atg cgg cat ttc ttt ttt 99Val Leu Leu Gly Val Lys Gln Gly Asp Glu Met Arg His Phe Phe Phe 15 20 25tct tct cag acc tcc act ctg gag aag agt cag aat ggg ggc gtc ggg 147Ser Ser Gln Thr Ser Thr Leu Glu Lys Ser Gln Asn Gly Gly Val Gly 30 35 40gag gag gtc acc cca gct ctg atc ttt gcc atc aca gtt gct aca atc 195Glu Glu Val Thr Pro Ala Leu Ile Phe Ala Ile Thr Val Ala Thr Ile 45 50 55ggc tct ttc cag ttt ggc tac aac act ggg gtc atc aat gct cct gag 243Gly Ser Phe Gln Phe Gly Tyr Asn Thr Gly Val Ile Asn Ala Pro Glu 60 65 70acg atc ata aag gaa ttt atc aat aaa act ttg acg gac aag gca aat 291Thr Ile Ile Lys Glu Phe Ile Asn Lys Thr Leu Thr Asp Lys Ala Asn75 80 85 90gcc cct ccc tct gag gtg ctg ctc acg aat ctc tgg tcc ttg tct gtg 339Ala Pro Pro Ser Glu Val Leu Leu Thr Asn Leu Trp Ser Leu Ser Val 95 100 105gcc ata ttt tcc gtc ggg ggt atg atc ggc tcc ttt tcc gtc gga ctc 387Ala Ile Phe Ser Val Gly Gly Met Ile Gly Ser Phe Ser Val Gly Leu 110 115 120ttt gtt aac cgc ttt ggc agg cgc aat tca atg ctg att gtc aac ctg 435Phe Val Asn Arg Phe Gly Arg Arg Asn Ser Met Leu Ile Val Asn Leu 125 130 135ttg gct gcc act ggt ggc tgc ctt atg gga ctg tgt aaa ata gct gag 483Leu Ala Ala Thr Gly Gly Cys Leu Met Gly Leu Cys Lys Ile Ala Glu 140 145 150tca gtt gaa atg ctg atc ctg ggc cgc ttg gtt att ggc ctc ttc tgc 531Ser Val Glu Met Leu Ile Leu Gly Arg Leu Val Ile Gly Leu Phe Cys155 160 165 170gga ctc tgc aca ggt ttt gtg ccc atg tac att gga gag atc tcg cct 579Gly Leu Cys Thr Gly Phe Val Pro Met Tyr Ile Gly Glu Ile Ser Pro 175 180 185act gcc ctg agg ggt gcc ttt ggc act ctc aac cag ctg ggc ata gtt 627Thr Ala Leu Arg Gly Ala Phe Gly Thr Leu Asn Gln Leu Gly Ile Val 190 195 200att gga att ctg gtg gcc cag atc ttt ggt ctg gaa ctc atc ctt ggg 675Ile Gly Ile Leu Val Ala Gln Ile Phe Gly Leu Glu Leu Ile Leu Gly 205 210 215tct aaa gag cta tgg ccg gtg cta tta ggc ttt acc atc ctt cca gct 723Ser Lys Glu Leu Trp Pro Val Leu Leu Gly Phe Thr Ile Leu Pro Ala 220 225 230atc ctg caa agt gca gcc ctt cca tgt tgc cct gaa agt ccc aga ttt 771Ile Leu Gln Ser Ala Ala Leu Pro Cys Cys Pro Glu Ser Pro Arg Phe235 240 245 250ttg ctc att aac aga aaa aaa gag gag aat gct acg cgg atc ctc cag 819Leu Leu Ile Asn Arg Lys Lys Glu Glu Asn Ala Thr Arg Ile Leu Gln 255 260 265cgg ttg tgg ggc acc cag gat gta tcc caa gac atc cag gag atg aaa 867Arg Leu Trp Gly Thr Gln Asp Val Ser Gln Asp Ile Gln Glu Met Lys 270 275 280gat gag agt gca agg atg tca caa gaa aag caa gtc acc gtg ctg gag 915Asp Glu Ser Ala Arg Met Ser Gln Glu Lys Gln Val Thr Val Leu Glu 285 290 295ctc ttt aga gtg tcc agc tac cga cag ccc atc atc att tcc att gtg 963Leu Phe Arg Val Ser Ser Tyr Arg Gln Pro Ile Ile Ile Ser Ile Val 300 305 310ctc cag ctc tct cag cag ctc tct ggg atc aat gct gtg ttc tat tac 1011Leu Gln Leu Ser Gln Gln Leu Ser Gly Ile Asn Ala Val Phe Tyr Tyr315 320 325 330tca aca gga atc ttc aag gat gca ggt gtt caa cag ccc atc tat gcc 1059Ser Thr Gly Ile Phe Lys Asp Ala Gly Val Gln Gln Pro Ile Tyr Ala 335 340 345acc atc agc gcg ggt gtg gtt aat act atc ttc act tta ctt tct cta 1107Thr Ile Ser Ala Gly Val Val Asn Thr Ile Phe Thr Leu Leu Ser Leu 350 355 360ttt ctg gtg gaa agg gca gga aga agg act ctg cat atg ata ggc ctt 1155Phe Leu Val Glu Arg Ala Gly Arg Arg Thr Leu His Met Ile Gly Leu 365 370 375gga ggg atg gct ttt tgt tcc acg ctc atg act gtt tct ttg tta tta 1203Gly Gly Met Ala Phe Cys Ser Thr Leu Met Thr Val Ser Leu Leu Leu 380 385 390aag aat cac tat aat ggg atg agc ttt gtc tgt att ggg gct atc ttg 1251Lys Asn His Tyr Asn Gly Met Ser Phe Val Cys Ile Gly Ala Ile Leu395 400 405 410gtc ttt gtg gcc tgt ttt gaa att gga cca ggc ccc att ccc tgg ttt 1299Val Phe Val Ala Cys Phe Glu Ile Gly Pro Gly Pro Ile Pro Trp Phe 415 420 425att gtg gcc gaa ctc ttc agc cag ggc ccc cgc cca gct gcg atg gca 1347Ile Val Ala Glu Leu Phe Ser Gln Gly Pro Arg Pro Ala Ala Met Ala 430 435 440gtg gcc ggc tgc tcc aac tgg acc tcc aac ttc cta gtc gga ttg ctc 1395Val Ala Gly Cys Ser Asn Trp Thr Ser Asn Phe Leu Val Gly Leu Leu 445 450 455ttc ccc tct gct gct tac tat tta gga gcc tac gtt ttt att atc ttc 1443Phe Pro Ser Ala Ala Tyr Tyr Leu Gly Ala Tyr Val Phe Ile Ile Phe 460 465 470acc ggc ttc ctc att acc ttc ctg gcc ttt acc ttc ttc aaa gtc cct 1491Thr Gly Phe Leu Ile Thr Phe Leu Ala Phe Thr Phe Phe Lys Val Pro475 480 485 490gag acc cgt ggc agg act ttt gag gat atc aca cgg gcc ttt gaa ggg 1539Glu Thr Arg Gly Arg Thr Phe Glu Asp Ile

Thr Arg Ala Phe Glu Gly 495 500 505cag gca cac ggt gca gat aga tct gga aag gac ggc gtc atg ggg atg 1587Gln Ala His Gly Ala Asp Arg Ser Gly Lys Asp Gly Val Met Gly Met 510 515 520aac agc atc gag cct gct aag gag acc acc acc aat gtc taa 1629Asn Ser Ile Glu Pro Ala Lys Glu Thr Thr Thr Asn Val 525 530 535gtcgtgcctc cttccacctc cctcccggca tgggaaggcc acctctccct caacaaggga 1689gagacctcat caggatgaac ccaggacgct tctgaatgct gctacttgat ttctttctca 1749tcccacgcac tccatgagca ccccaaggct gcagtttgtt ggatcttcaa tggcttttta 1809aattttattt cctggacatc ctcttctgct taggagagac cgagtgaacc taccttcatt 1869tca 1872184535PRTHomo sapiens 184Met Gln Arg Leu Gln Leu Leu Arg Val Glu Val Leu Leu Gly Val Lys1 5 10 15Gln Gly Asp Glu Met Arg His Phe Phe Phe Ser Ser Gln Thr Ser Thr 20 25 30Leu Glu Lys Ser Gln Asn Gly Gly Val Gly Glu Glu Val Thr Pro Ala 35 40 45Leu Ile Phe Ala Ile Thr Val Ala Thr Ile Gly Ser Phe Gln Phe Gly 50 55 60Tyr Asn Thr Gly Val Ile Asn Ala Pro Glu Thr Ile Ile Lys Glu Phe65 70 75 80Ile Asn Lys Thr Leu Thr Asp Lys Ala Asn Ala Pro Pro Ser Glu Val 85 90 95Leu Leu Thr Asn Leu Trp Ser Leu Ser Val Ala Ile Phe Ser Val Gly 100 105 110Gly Met Ile Gly Ser Phe Ser Val Gly Leu Phe Val Asn Arg Phe Gly 115 120 125Arg Arg Asn Ser Met Leu Ile Val Asn Leu Leu Ala Ala Thr Gly Gly 130 135 140Cys Leu Met Gly Leu Cys Lys Ile Ala Glu Ser Val Glu Met Leu Ile145 150 155 160Leu Gly Arg Leu Val Ile Gly Leu Phe Cys Gly Leu Cys Thr Gly Phe 165 170 175Val Pro Met Tyr Ile Gly Glu Ile Ser Pro Thr Ala Leu Arg Gly Ala 180 185 190Phe Gly Thr Leu Asn Gln Leu Gly Ile Val Ile Gly Ile Leu Val Ala 195 200 205Gln Ile Phe Gly Leu Glu Leu Ile Leu Gly Ser Lys Glu Leu Trp Pro 210 215 220Val Leu Leu Gly Phe Thr Ile Leu Pro Ala Ile Leu Gln Ser Ala Ala225 230 235 240Leu Pro Cys Cys Pro Glu Ser Pro Arg Phe Leu Leu Ile Asn Arg Lys 245 250 255Lys Glu Glu Asn Ala Thr Arg Ile Leu Gln Arg Leu Trp Gly Thr Gln 260 265 270Asp Val Ser Gln Asp Ile Gln Glu Met Lys Asp Glu Ser Ala Arg Met 275 280 285Ser Gln Glu Lys Gln Val Thr Val Leu Glu Leu Phe Arg Val Ser Ser 290 295 300Tyr Arg Gln Pro Ile Ile Ile Ser Ile Val Leu Gln Leu Ser Gln Gln305 310 315 320Leu Ser Gly Ile Asn Ala Val Phe Tyr Tyr Ser Thr Gly Ile Phe Lys 325 330 335Asp Ala Gly Val Gln Gln Pro Ile Tyr Ala Thr Ile Ser Ala Gly Val 340 345 350Val Asn Thr Ile Phe Thr Leu Leu Ser Leu Phe Leu Val Glu Arg Ala 355 360 365Gly Arg Arg Thr Leu His Met Ile Gly Leu Gly Gly Met Ala Phe Cys 370 375 380Ser Thr Leu Met Thr Val Ser Leu Leu Leu Lys Asn His Tyr Asn Gly385 390 395 400Met Ser Phe Val Cys Ile Gly Ala Ile Leu Val Phe Val Ala Cys Phe 405 410 415Glu Ile Gly Pro Gly Pro Ile Pro Trp Phe Ile Val Ala Glu Leu Phe 420 425 430Ser Gln Gly Pro Arg Pro Ala Ala Met Ala Val Ala Gly Cys Ser Asn 435 440 445Trp Thr Ser Asn Phe Leu Val Gly Leu Leu Phe Pro Ser Ala Ala Tyr 450 455 460Tyr Leu Gly Ala Tyr Val Phe Ile Ile Phe Thr Gly Phe Leu Ile Thr465 470 475 480Phe Leu Ala Phe Thr Phe Phe Lys Val Pro Glu Thr Arg Gly Arg Thr 485 490 495Phe Glu Asp Ile Thr Arg Ala Phe Glu Gly Gln Ala His Gly Ala Asp 500 505 510Arg Ser Gly Lys Asp Gly Val Met Gly Met Asn Ser Ile Glu Pro Ala 515 520 525Lys Glu Thr Thr Thr Asn Val 530 535185153DNAHomo sapiens 185acaacctgac ttttgtccac aatgcaaaga ctccaactgt tgagagtaga agtactgctg 60ggtgtgaaac aaggagatga aatgcggcat ttcttttttt cttctcagac ctccactctg 120gagaagagtc agaatggggg cgtcggggag gag 15318644PRTHomo sapiens 186Met Gln Arg Leu Gln Leu Leu Arg Val Glu Val Leu Leu Gly Val Lys1 5 10 15Gln Gly Asp Glu Met Arg His Phe Phe Phe Ser Ser Gln Thr Ser Thr 20 25 30Leu Glu Lys Ser Gln Asn Gly Gly Val Gly Glu Glu 35 40187132DNAHomo sapiens 187atgcaaagac tccaactgtt gagagtagaa gtactgctgg gtgtgaaaca aggagatgaa 60atgcggcatt tctttttttc ttctcagacc tccactctgg agaagagtca gaatgggggc 120gtcggggagg ag 1321881872DNAHomo sapiens 188acaacctgac ttttgttcac aatgcaaaga ctccaactgt tgagagtaga agtactgctg 60ggtgtgaaac aaggagatga aatgcggcat ttcttttttt cttctcagac ctccactctg 120gagaagagtc agaatggggg cgtcggggag gaggtcaccc cagctctgat ctttgccatc 180acagttgcta caatcggctc tttccagttt ggctacaaca ctggggtcat caatgctcct 240gagacgatca taaaggaatt tatcaataaa actttgacgg acaaggcaaa tgcccctccc 300tctgaggtgc tgctcacgaa tctctggtcc ttgtctgtgg ccatattttc cgtcgggggt 360atgatcggct ccttttccgt cggactcttt gttaaccgct ttggcaggcg caattcaatg 420ctgattgtca acctgttggc tgccactggt ggctgcctta tgggactgtg taaaatagct 480gagtcagttg aaatgctgat cctgggccgc ttggttattg gcctcttctg cggactctgc 540acaggttttg tgcccatgta cattggagag atctcgccta ctgccctgag gggtgccttt 600ggcactctca accagctggg catagttatt ggaattctgg tggcccagat ctttggtctg 660gaactcatcc ttgggtctga agagctatgg ccggtgctat taggctttac catccttcca 720gctatcctgc aaagtgcagc ccttccatgt tgccctgaaa gtcccagatt tttgctcatt 780aacagaaaaa aagaggagaa tgctacgcgg atcctccagc ggttgtgggg cacccaggat 840gtatcccaag acatccagga gatgaaagat gagagtgcaa ggatgtcaca agaaaagcaa 900gtcaccgtgc tggagctctt tagagtgtcc agctaccgac agcccatcat catttccatt 960gtgctccagc tctctcagca gctctctggg atcaatgctg tgttctatta ctcaacagga 1020atcttcaagg atgcaggtgt tcaacagccc atctatgcca ccatcagcgc gggtgtggtt 1080aatactatct tcactttact ttctctattt ctggtggaaa gggcaggaag aaggactctg 1140catatgatag gccttggagg gatggctttt tgttccacgc tcatgactgt ttctttgtta 1200ttaaagaatc actataatgg gatgagcttt gtctgtattg gggctatctt ggtctttgtg 1260gcctgttttg aaattggacc aggccccatt ccctggttta ttgtggccga actcttcagc 1320cagggccccc gcccagctgc gatggcagtg gccggctgct ccaactggac ctccaacttc 1380ctagtcggat tgctcttccc ctctgctgct tactatttag gagcctacgt ttttattatc 1440ttcaccggct tcctcattac cttcctggcc tttaccttct tcaaagtccc tgagacccgt 1500ggcaggactt ttgaggatat cacacgggcc tttgaagggc aggcacacgg tgcagataga 1560tctggaaagg acggcgtcat ggggatgaac agcatcgagc ctgctaagga gaccaccacc 1620aatgtctaag tcgtgcctcc ttccacctcc ctcccggcat gggaaagcca cctctccctc 1680aacaagggag agacctcatc aggatgaacc caggacgctt ctgaatgctg ctacttgatt 1740tctttctcat cccacgcact ccatgagcac cccaaggctg cagtttgttg gatcttcaat 1800ggctttttaa attttatttc ctggacatcc tcttctgctt aggagagacc gagtgaacct 1860accttcattt ca 18721891872DNAHomo sapiensCDS(22)..(1629) 189acaacctgac ttttgttcac a atg caa aga ctc caa ctg ttg aga gta gaa 51 Met Gln Arg Leu Gln Leu Leu Arg Val Glu 1 5 10gta ctg ctg ggt gtg aaa caa gga gat gaa atg cgg cat ttc ttt ttt 99Val Leu Leu Gly Val Lys Gln Gly Asp Glu Met Arg His Phe Phe Phe 15 20 25tct tct cag acc tcc act ctg gag aag agt cag aat ggg ggc gtc ggg 147Ser Ser Gln Thr Ser Thr Leu Glu Lys Ser Gln Asn Gly Gly Val Gly 30 35 40gag gag gtc acc cca gct ctg atc ttt gcc atc aca gtt gct aca atc 195Glu Glu Val Thr Pro Ala Leu Ile Phe Ala Ile Thr Val Ala Thr Ile 45 50 55ggc tct ttc cag ttt ggc tac aac act ggg gtc atc aat gct cct gag 243Gly Ser Phe Gln Phe Gly Tyr Asn Thr Gly Val Ile Asn Ala Pro Glu 60 65 70acg atc ata aag gaa ttt atc aat aaa act ttg acg gac aag gca aat 291Thr Ile Ile Lys Glu Phe Ile Asn Lys Thr Leu Thr Asp Lys Ala Asn75 80 85 90gcc cct ccc tct gag gtg ctg ctc acg aat ctc tgg tcc ttg tct gtg 339Ala Pro Pro Ser Glu Val Leu Leu Thr Asn Leu Trp Ser Leu Ser Val 95 100 105gcc ata ttt tcc gtc ggg ggt atg atc ggc tcc ttt tcc gtc gga ctc 387Ala Ile Phe Ser Val Gly Gly Met Ile Gly Ser Phe Ser Val Gly Leu 110 115 120ttt gtt aac cgc ttt ggc agg cgc aat tca atg ctg att gtc aac ctg 435Phe Val Asn Arg Phe Gly Arg Arg Asn Ser Met Leu Ile Val Asn Leu 125 130 135ttg gct gcc act ggt ggc tgc ctt atg gga ctg tgt aaa ata gct gag 483Leu Ala Ala Thr Gly Gly Cys Leu Met Gly Leu Cys Lys Ile Ala Glu 140 145 150tca gtt gaa atg ctg atc ctg ggc cgc ttg gtt att ggc ctc ttc tgc 531Ser Val Glu Met Leu Ile Leu Gly Arg Leu Val Ile Gly Leu Phe Cys155 160 165 170gga ctc tgc aca ggt ttt gtg ccc atg tac att gga gag atc tcg cct 579Gly Leu Cys Thr Gly Phe Val Pro Met Tyr Ile Gly Glu Ile Ser Pro 175 180 185act gcc ctg agg ggt gcc ttt ggc act ctc aac cag ctg ggc ata gtt 627Thr Ala Leu Arg Gly Ala Phe Gly Thr Leu Asn Gln Leu Gly Ile Val 190 195 200att gga att ctg gtg gcc cag atc ttt ggt ctg gaa ctc atc ctt ggg 675Ile Gly Ile Leu Val Ala Gln Ile Phe Gly Leu Glu Leu Ile Leu Gly 205 210 215tct gaa gag cta tgg ccg gtg cta tta ggc ttt acc atc ctt cca gct 723Ser Glu Glu Leu Trp Pro Val Leu Leu Gly Phe Thr Ile Leu Pro Ala 220 225 230atc ctg caa agt gca gcc ctt cca tgt tgc cct gaa agt ccc aga ttt 771Ile Leu Gln Ser Ala Ala Leu Pro Cys Cys Pro Glu Ser Pro Arg Phe235 240 245 250ttg ctc att aac aga aaa aaa gag gag aat gct acg cgg atc ctc cag 819Leu Leu Ile Asn Arg Lys Lys Glu Glu Asn Ala Thr Arg Ile Leu Gln 255 260 265cgg ttg tgg ggc acc cag gat gta tcc caa gac atc cag gag atg aaa 867Arg Leu Trp Gly Thr Gln Asp Val Ser Gln Asp Ile Gln Glu Met Lys 270 275 280gat gag agt gca agg atg tca caa gaa aag caa gtc acc gtg ctg gag 915Asp Glu Ser Ala Arg Met Ser Gln Glu Lys Gln Val Thr Val Leu Glu 285 290 295ctc ttt aga gtg tcc agc tac cga cag ccc atc atc att tcc att gtg 963Leu Phe Arg Val Ser Ser Tyr Arg Gln Pro Ile Ile Ile Ser Ile Val 300 305 310ctc cag ctc tct cag cag ctc tct ggg atc aat gct gtg ttc tat tac 1011Leu Gln Leu Ser Gln Gln Leu Ser Gly Ile Asn Ala Val Phe Tyr Tyr315 320 325 330tca aca gga atc ttc aag gat gca ggt gtt caa cag ccc atc tat gcc 1059Ser Thr Gly Ile Phe Lys Asp Ala Gly Val Gln Gln Pro Ile Tyr Ala 335 340 345acc atc agc gcg ggt gtg gtt aat act atc ttc act tta ctt tct cta 1107Thr Ile Ser Ala Gly Val Val Asn Thr Ile Phe Thr Leu Leu Ser Leu 350 355 360ttt ctg gtg gaa agg gca gga aga agg act ctg cat atg ata ggc ctt 1155Phe Leu Val Glu Arg Ala Gly Arg Arg Thr Leu His Met Ile Gly Leu 365 370 375gga ggg atg gct ttt tgt tcc acg ctc atg act gtt tct ttg tta tta 1203Gly Gly Met Ala Phe Cys Ser Thr Leu Met Thr Val Ser Leu Leu Leu 380 385 390aag aat cac tat aat ggg atg agc ttt gtc tgt att ggg gct atc ttg 1251Lys Asn His Tyr Asn Gly Met Ser Phe Val Cys Ile Gly Ala Ile Leu395 400 405 410gtc ttt gtg gcc tgt ttt gaa att gga cca ggc ccc att ccc tgg ttt 1299Val Phe Val Ala Cys Phe Glu Ile Gly Pro Gly Pro Ile Pro Trp Phe 415 420 425att gtg gcc gaa ctc ttc agc cag ggc ccc cgc cca gct gcg atg gca 1347Ile Val Ala Glu Leu Phe Ser Gln Gly Pro Arg Pro Ala Ala Met Ala 430 435 440gtg gcc ggc tgc tcc aac tgg acc tcc aac ttc cta gtc gga ttg ctc 1395Val Ala Gly Cys Ser Asn Trp Thr Ser Asn Phe Leu Val Gly Leu Leu 445 450 455ttc ccc tct gct gct tac tat tta gga gcc tac gtt ttt att atc ttc 1443Phe Pro Ser Ala Ala Tyr Tyr Leu Gly Ala Tyr Val Phe Ile Ile Phe 460 465 470acc ggc ttc ctc att acc ttc ctg gcc ttt acc ttc ttc aaa gtc cct 1491Thr Gly Phe Leu Ile Thr Phe Leu Ala Phe Thr Phe Phe Lys Val Pro475 480 485 490gag acc cgt ggc agg act ttt gag gat atc aca cgg gcc ttt gaa ggg 1539Glu Thr Arg Gly Arg Thr Phe Glu Asp Ile Thr Arg Ala Phe Glu Gly 495 500 505cag gca cac ggt gca gat aga tct gga aag gac ggc gtc atg ggg atg 1587Gln Ala His Gly Ala Asp Arg Ser Gly Lys Asp Gly Val Met Gly Met 510 515 520aac agc atc gag cct gct aag gag acc acc acc aat gtc taa 1629Asn Ser Ile Glu Pro Ala Lys Glu Thr Thr Thr Asn Val 525 530 535gtcgtgcctc cttccacctc cctcccggca tgggaaagcc acctctccct caacaaggga 1689gagacctcat caggatgaac ccaggacgct tctgaatgct gctacttgat ttctttctca 1749tcccacgcac tccatgagca ccccaaggct gcagtttgtt ggatcttcaa tggcttttta 1809aattttattt cctggacatc ctcttctgct taggagagac cgagtgaacc taccttcatt 1869tca 1872190535PRTHomo sapiens 190Met Gln Arg Leu Gln Leu Leu Arg Val Glu Val Leu Leu Gly Val Lys1 5 10 15Gln Gly Asp Glu Met Arg His Phe Phe Phe Ser Ser Gln Thr Ser Thr 20 25 30Leu Glu Lys Ser Gln Asn Gly Gly Val Gly Glu Glu Val Thr Pro Ala 35 40 45Leu Ile Phe Ala Ile Thr Val Ala Thr Ile Gly Ser Phe Gln Phe Gly 50 55 60Tyr Asn Thr Gly Val Ile Asn Ala Pro Glu Thr Ile Ile Lys Glu Phe65 70 75 80Ile Asn Lys Thr Leu Thr Asp Lys Ala Asn Ala Pro Pro Ser Glu Val 85 90 95Leu Leu Thr Asn Leu Trp Ser Leu Ser Val Ala Ile Phe Ser Val Gly 100 105 110Gly Met Ile Gly Ser Phe Ser Val Gly Leu Phe Val Asn Arg Phe Gly 115 120 125Arg Arg Asn Ser Met Leu Ile Val Asn Leu Leu Ala Ala Thr Gly Gly 130 135 140Cys Leu Met Gly Leu Cys Lys Ile Ala Glu Ser Val Glu Met Leu Ile145 150 155 160Leu Gly Arg Leu Val Ile Gly Leu Phe Cys Gly Leu Cys Thr Gly Phe 165 170 175Val Pro Met Tyr Ile Gly Glu Ile Ser Pro Thr Ala Leu Arg Gly Ala 180 185 190Phe Gly Thr Leu Asn Gln Leu Gly Ile Val Ile Gly Ile Leu Val Ala 195 200 205Gln Ile Phe Gly Leu Glu Leu Ile Leu Gly Ser Glu Glu Leu Trp Pro 210 215 220Val Leu Leu Gly Phe Thr Ile Leu Pro Ala Ile Leu Gln Ser Ala Ala225 230 235 240Leu Pro Cys Cys Pro Glu Ser Pro Arg Phe Leu Leu Ile Asn Arg Lys 245 250 255Lys Glu Glu Asn Ala Thr Arg Ile Leu Gln Arg Leu Trp Gly Thr Gln 260 265 270Asp Val Ser Gln Asp Ile Gln Glu Met Lys Asp Glu Ser Ala Arg Met 275 280 285Ser Gln Glu Lys Gln Val Thr Val Leu Glu Leu Phe Arg Val Ser Ser 290 295 300Tyr Arg Gln Pro Ile Ile Ile Ser Ile Val Leu Gln Leu Ser Gln Gln305 310 315 320Leu Ser Gly Ile Asn Ala Val Phe Tyr Tyr Ser Thr Gly Ile Phe Lys 325 330 335Asp Ala Gly Val Gln Gln Pro Ile Tyr Ala Thr Ile Ser Ala Gly Val 340 345 350Val Asn Thr Ile Phe Thr Leu Leu Ser Leu Phe Leu Val Glu Arg Ala 355 360 365Gly Arg Arg Thr Leu His Met Ile Gly Leu Gly Gly Met Ala Phe Cys 370 375 380Ser Thr Leu Met Thr Val Ser Leu Leu Leu Lys Asn His Tyr Asn Gly385 390 395 400Met Ser Phe Val Cys Ile Gly Ala Ile Leu Val Phe Val Ala Cys Phe 405 410 415Glu Ile Gly Pro Gly Pro Ile Pro Trp Phe Ile Val Ala Glu Leu Phe 420 425 430Ser Gln Gly Pro Arg Pro Ala Ala Met Ala Val Ala Gly Cys Ser Asn 435 440 445Trp Thr Ser Asn Phe Leu Val Gly Leu Leu Phe Pro Ser Ala Ala Tyr 450 455 460Tyr Leu Gly Ala Tyr Val Phe Ile

Ile Phe Thr Gly Phe Leu Ile Thr465 470 475 480Phe Leu Ala Phe Thr Phe Phe Lys Val Pro Glu Thr Arg Gly Arg Thr 485 490 495Phe Glu Asp Ile Thr Arg Ala Phe Glu Gly Gln Ala His Gly Ala Asp 500 505 510Arg Ser Gly Lys Asp Gly Val Met Gly Met Asn Ser Ile Glu Pro Ala 515 520 525Lys Glu Thr Thr Thr Asn Val 530 535191153DNAHomo sapiens 191acaacctgac ttttgttcac aatgcaaaga ctccaactgt tgagagtaga agtactgctg 60ggtgtgaaac aaggagatga aatgcggcat ttcttttttt cttctcagac ctccactctg 120gagaagagtc agaatggggg cgtcggggag gag 15319244PRTHomo sapiens 192Met Gln Arg Leu Gln Leu Leu Arg Val Glu Val Leu Leu Gly Val Lys1 5 10 15Gln Gly Asp Glu Met Arg His Phe Phe Phe Ser Ser Gln Thr Ser Thr 20 25 30Leu Glu Lys Ser Gln Asn Gly Gly Val Gly Glu Glu 35 40193132DNAHomo sapiens 193atgcaaagac tccaactgtt gagagtagaa gtactgctgg gtgtgaaaca aggagatgaa 60atgcggcatt tctttttttc ttctcagacc tccactctgg agaagagtca gaatgggggc 120gtcggggagg ag 1321944115DNAHomo sapiens 194agtcgcgggg tctgggagga gacctgaatg aaatgaggga gccttgggag catgatccag 60gcggagggaa ctggattcgg gaggaggaac tgccttggcc ttgaaagata cctaccagga 120gttcaagtgc tgtgcgggtg catcagcttt gtagatttgt gcaagatgaa aattggaatt 180gtcttaggaa attatggatc attcatttat tcagtgctgg attcattcag tgatttatgt 240ctgaagtgtg acagaagggg agtaaggcca agtgtccttg ccctctattg gagattctgc 300ctcccctggg acagatggct tcttgagcac actcccacga tgggtggctg ctctggtaca 360tctcatccac ttcttcatct gtgaagctgt cacccatggt ggtgagcagc tcctggaggt 420ggtcctcatg agtgaaacct gaggattcct cgttgaagca ggtattcatc catggggttc 480ttccgcggtg aagccagctt gtcgtgctgt cccccttgtc aatgaagcca tcatggttct 540ggtcaatcat gttgaaagcc tccttaaact cctggatgtg gaactggtca aacatcacga 600agacattgga tgtggccccc tgtgctgtgg tcgcttcttg gtcttggctt tggtccactt 660gctgaacatt ttggcttcag gaagcagtac cttgaagaga aattggagag ggagtcaatt 720cctaggatag cagagagatg gacaacagac agaatagatg gagtttcaca atggtggcca 780tgtgtctgga attggtgggt tcttggtctc actgacttca agaatgaagc cgcacaccct 840cgcagtcacc ccagctctga tctttgccat cacagttgct acaatcggct ctttccagtt 900tggctacaac actggggtca tcaatgctcc tgagacgatc ataaaggaat ttatcaataa 960aactttgacg gacaaggcaa atgcccctcc ctctgaggtg ctgctcacga atctctggtc 1020cttgtctgtg gccatatttt ccgtcggggg tatgatcggc tccttttccg tcggactctt 1080tgttaaccgc tttggcaggc gcaattcaat gctgattgtc aacctgttgg ctgccactgg 1140tggctgcctt atgggactgt gtaaaatagc tgagtcagtt gaaatgctga tcctgggccg 1200cttggttatt ggcctcttct gcggactctg cacaggtttt gtgcccatgt acattggaga 1260gatctcgcct actgccctga ggggtgcctt tggcactctc aaccagctgg gcatagttat 1320tggaattctg gtggcccaga tctttggtct ggaactcatc cttgggtctg aagagctatg 1380gccggtgcta ttaggcttta ccatccttcc agctatcctg caaagtgcag cccttccatg 1440ttgccctgaa agtcccagat ttttgctcat taacagaaaa aaagaggaga atgctacgcg 1500gatcctccag cggttgtggg gcacccagga tgtatcccaa gacatccagg agatgaaaga 1560tgagagtgca aggatgtcac aagaaaagca agtcaccgtg ctggagctct ttagagtgtc 1620cagctaccga cagcccatca tcatttccat tgtgctccag ctctctcagc agctctctgg 1680gatcaatgct gtgttctatt actcaacagg aatcttcaag gatgcaggtg ttcaacagcc 1740catctatgcc accatcagcg cgggtgtggt taatactatc ttcactttac tttctctatt 1800tctggtggaa agggcaggaa gaaggactct gcatatgata ggccttggag ggatggcttt 1860ttgttccacg ctcatgactg tttctttgtt attaaagaat cactataatg ggatgagctt 1920tgtctgtatt ggggctatct tggtctttgt ggcctgtttt gaaattggac caggccccat 1980tccctggttt attgtggccg aactcttcag ccagggcccc cgcccagctg cgatggcagt 2040ggccggctgc tccaactgga cctccaactt cctagtcgga ttgctcttcc cctctgctgc 2100ttactattta ggagcctacg tttttattat cttcaccggc ttcctcatta ccttcttggc 2160ctttaccttc ttcaaagtcc ctgagacccg tggcaggact tttgaggata tcacacgggc 2220ctttgaaggg caggcacacg gtgcagatag atctggaaag gacggcgtca tggggatgaa 2280cagcatcgag cctgctaagg agaccaccac caatgtctaa gtcgtgcctc cttccacctc 2340cctcccggca tgggaaagcc acctctccct caacaaggga gagactttat caggatgaac 2400ccaggacgct tctgaatgct gctacttgat ttctttctca tcccacgcac tccatgagca 2460ccccaaggct gcagtttgtt ggatcttcaa tggcttttta aattttattt cctggacatc 2520ctcttctgct taggagagac cgagtgaacc taccttcatt tcaggaggga ttggccgctt 2580ggcacatgac aactttgcca gcttttcctc ccttgggttc tgatattgcc gcactagggg 2640atataggaga ggaaaagtaa ggtgcagttg ccccaacctc agacttacca ggaagcagat 2700acatgtgagt gtggaaggca gagggggttt atgtaagagc accttcctca cttccataca 2760gctctacgcg gcaaattaac ttgagtttta tttatcttat cctctggttt aattacataa 2820atatttattt tttaagtgta attttgccaa ataataacaa cagaaggaaa ttgagattag 2880agggaggtgt ttaaagagag gttatagagt aaaagatttg atgctggaga ggttaaggtg 2940caataagaat tcagggagaa atgttgttca ttattggagg gtaaatgatg tggtgcctga 3000ggtctgtaca ttacctctta acaatttctg tccttcagat gaaaactctt tgatttctca 3060gaaaagttgt atgcctattt aataaagcta ctcatttcct ttggaacttt atctttaaga 3120taatagttta catgtagtag tacttgaaat ctaggattat taactaatat gggcattgta 3180gttaatggcg gttgatgggt tctaattttg gatggagtcc agggaagaga aagtgatttc 3240tagaaagcct gttcccctca ctggacgaaa taactccttg tagtagtctc attacttttg 3300aagtaatccc gccacctatc tagtgggaga gccatccaaa tgagaaacct aaaataattg 3360gttcttggta gagattcatt atttctccac tttgttcttt aggagatttt aggtgttgat 3420tttctgtttt attttaactc atacctttaa aggaattccc caaagaatgt ttatagcaaa 3480cttggaattt gtaacctcag ctctgggaga ggattttttt ctgagcgatt attatctaaa 3540gtgtgttgtt gctttaggct cacggcacgc ttgcgtatgt ctgttaccat gtcactgtgg 3600tcctatgccg aatgccctca ggggacttga atctttccaa taaaccaggt ttagacagta 3660tgagtcaatg tgcagtgcag cccacacttg agaggatgaa tgtatgtgca ctgtcacttt 3720gctctgggtg gaagtatgtt attgttgact tattttctct gtgtttgttc ctacagcccc 3780tttttcatat gttgctcagt ctccctttcc cttcttggtg cttacacatc tcagaccctt 3840tagccaaacc cttgccagtg acagtatttt ggttctcagt tctcactgtt ccctctgctc 3900ctggagcctt tgaataaaaa tgcacgtagc tatggagtgg ggtttagctg gaaaggtggc 3960cttccaactt cacgtcaact tctggctcct cagtttggca gtaaggcagg gaagttgttt 4020tcctatttct cactgagaag attgtgaata tttccatatg gattttccat tattgtttgt 4080ttgattcttt gttttaaaat aaaaattctg aatgt 41151954115DNAHomo sapiensCDS(758)..(2320) 195agtcgcgggg tctgggagga gacctgaatg aaatgaggga gccttgggag catgatccag 60gcggagggaa ctggattcgg gaggaggaac tgccttggcc ttgaaagata cctaccagga 120gttcaagtgc tgtgcgggtg catcagcttt gtagatttgt gcaagatgaa aattggaatt 180gtcttaggaa attatggatc attcatttat tcagtgctgg attcattcag tgatttatgt 240ctgaagtgtg acagaagggg agtaaggcca agtgtccttg ccctctattg gagattctgc 300ctcccctggg acagatggct tcttgagcac actcccacga tgggtggctg ctctggtaca 360tctcatccac ttcttcatct gtgaagctgt cacccatggt ggtgagcagc tcctggaggt 420ggtcctcatg agtgaaacct gaggattcct cgttgaagca ggtattcatc catggggttc 480ttccgcggtg aagccagctt gtcgtgctgt cccccttgtc aatgaagcca tcatggttct 540ggtcaatcat gttgaaagcc tccttaaact cctggatgtg gaactggtca aacatcacga 600agacattgga tgtggccccc tgtgctgtgg tcgcttcttg gtcttggctt tggtccactt 660gctgaacatt ttggcttcag gaagcagtac cttgaagaga aattggagag ggagtcaatt 720cctaggatag cagagagatg gacaacagac agaatag atg gag ttt cac aat ggt 775 Met Glu Phe His Asn Gly 1 5ggc cat gtg tct gga att ggt ggg ttc ttg gtc tca ctg act tca aga 823Gly His Val Ser Gly Ile Gly Gly Phe Leu Val Ser Leu Thr Ser Arg 10 15 20atg aag ccg cac acc ctc gca gtc acc cca gct ctg atc ttt gcc atc 871Met Lys Pro His Thr Leu Ala Val Thr Pro Ala Leu Ile Phe Ala Ile 25 30 35aca gtt gct aca atc ggc tct ttc cag ttt ggc tac aac act ggg gtc 919Thr Val Ala Thr Ile Gly Ser Phe Gln Phe Gly Tyr Asn Thr Gly Val 40 45 50atc aat gct cct gag acg atc ata aag gaa ttt atc aat aaa act ttg 967Ile Asn Ala Pro Glu Thr Ile Ile Lys Glu Phe Ile Asn Lys Thr Leu55 60 65 70acg gac aag gca aat gcc cct ccc tct gag gtg ctg ctc acg aat ctc 1015Thr Asp Lys Ala Asn Ala Pro Pro Ser Glu Val Leu Leu Thr Asn Leu 75 80 85tgg tcc ttg tct gtg gcc ata ttt tcc gtc ggg ggt atg atc ggc tcc 1063Trp Ser Leu Ser Val Ala Ile Phe Ser Val Gly Gly Met Ile Gly Ser 90 95 100ttt tcc gtc gga ctc ttt gtt aac cgc ttt ggc agg cgc aat tca atg 1111Phe Ser Val Gly Leu Phe Val Asn Arg Phe Gly Arg Arg Asn Ser Met 105 110 115ctg att gtc aac ctg ttg gct gcc act ggt ggc tgc ctt atg gga ctg 1159Leu Ile Val Asn Leu Leu Ala Ala Thr Gly Gly Cys Leu Met Gly Leu 120 125 130tgt aaa ata gct gag tca gtt gaa atg ctg atc ctg ggc cgc ttg gtt 1207Cys Lys Ile Ala Glu Ser Val Glu Met Leu Ile Leu Gly Arg Leu Val135 140 145 150att ggc ctc ttc tgc gga ctc tgc aca ggt ttt gtg ccc atg tac att 1255Ile Gly Leu Phe Cys Gly Leu Cys Thr Gly Phe Val Pro Met Tyr Ile 155 160 165gga gag atc tcg cct act gcc ctg agg ggt gcc ttt ggc act ctc aac 1303Gly Glu Ile Ser Pro Thr Ala Leu Arg Gly Ala Phe Gly Thr Leu Asn 170 175 180cag ctg ggc ata gtt att gga att ctg gtg gcc cag atc ttt ggt ctg 1351Gln Leu Gly Ile Val Ile Gly Ile Leu Val Ala Gln Ile Phe Gly Leu 185 190 195gaa ctc atc ctt ggg tct gaa gag cta tgg ccg gtg cta tta ggc ttt 1399Glu Leu Ile Leu Gly Ser Glu Glu Leu Trp Pro Val Leu Leu Gly Phe 200 205 210acc atc ctt cca gct atc ctg caa agt gca gcc ctt cca tgt tgc cct 1447Thr Ile Leu Pro Ala Ile Leu Gln Ser Ala Ala Leu Pro Cys Cys Pro215 220 225 230gaa agt ccc aga ttt ttg ctc att aac aga aaa aaa gag gag aat gct 1495Glu Ser Pro Arg Phe Leu Leu Ile Asn Arg Lys Lys Glu Glu Asn Ala 235 240 245acg cgg atc ctc cag cgg ttg tgg ggc acc cag gat gta tcc caa gac 1543Thr Arg Ile Leu Gln Arg Leu Trp Gly Thr Gln Asp Val Ser Gln Asp 250 255 260atc cag gag atg aaa gat gag agt gca agg atg tca caa gaa aag caa 1591Ile Gln Glu Met Lys Asp Glu Ser Ala Arg Met Ser Gln Glu Lys Gln 265 270 275gtc acc gtg ctg gag ctc ttt aga gtg tcc agc tac cga cag ccc atc 1639Val Thr Val Leu Glu Leu Phe Arg Val Ser Ser Tyr Arg Gln Pro Ile 280 285 290atc att tcc att gtg ctc cag ctc tct cag cag ctc tct ggg atc aat 1687Ile Ile Ser Ile Val Leu Gln Leu Ser Gln Gln Leu Ser Gly Ile Asn295 300 305 310gct gtg ttc tat tac tca aca gga atc ttc aag gat gca ggt gtt caa 1735Ala Val Phe Tyr Tyr Ser Thr Gly Ile Phe Lys Asp Ala Gly Val Gln 315 320 325cag ccc atc tat gcc acc atc agc gcg ggt gtg gtt aat act atc ttc 1783Gln Pro Ile Tyr Ala Thr Ile Ser Ala Gly Val Val Asn Thr Ile Phe 330 335 340act tta ctt tct cta ttt ctg gtg gaa agg gca gga aga agg act ctg 1831Thr Leu Leu Ser Leu Phe Leu Val Glu Arg Ala Gly Arg Arg Thr Leu 345 350 355cat atg ata ggc ctt gga ggg atg gct ttt tgt tcc acg ctc atg act 1879His Met Ile Gly Leu Gly Gly Met Ala Phe Cys Ser Thr Leu Met Thr 360 365 370gtt tct ttg tta tta aag aat cac tat aat ggg atg agc ttt gtc tgt 1927Val Ser Leu Leu Leu Lys Asn His Tyr Asn Gly Met Ser Phe Val Cys375 380 385 390att ggg gct atc ttg gtc ttt gtg gcc tgt ttt gaa att gga cca ggc 1975Ile Gly Ala Ile Leu Val Phe Val Ala Cys Phe Glu Ile Gly Pro Gly 395 400 405ccc att ccc tgg ttt att gtg gcc gaa ctc ttc agc cag ggc ccc cgc 2023Pro Ile Pro Trp Phe Ile Val Ala Glu Leu Phe Ser Gln Gly Pro Arg 410 415 420cca gct gcg atg gca gtg gcc ggc tgc tcc aac tgg acc tcc aac ttc 2071Pro Ala Ala Met Ala Val Ala Gly Cys Ser Asn Trp Thr Ser Asn Phe 425 430 435cta gtc gga ttg ctc ttc ccc tct gct gct tac tat tta gga gcc tac 2119Leu Val Gly Leu Leu Phe Pro Ser Ala Ala Tyr Tyr Leu Gly Ala Tyr 440 445 450gtt ttt att atc ttc acc ggc ttc ctc att acc ttc ttg gcc ttt acc 2167Val Phe Ile Ile Phe Thr Gly Phe Leu Ile Thr Phe Leu Ala Phe Thr455 460 465 470ttc ttc aaa gtc cct gag acc cgt ggc agg act ttt gag gat atc aca 2215Phe Phe Lys Val Pro Glu Thr Arg Gly Arg Thr Phe Glu Asp Ile Thr 475 480 485cgg gcc ttt gaa ggg cag gca cac ggt gca gat aga tct gga aag gac 2263Arg Ala Phe Glu Gly Gln Ala His Gly Ala Asp Arg Ser Gly Lys Asp 490 495 500ggc gtc atg ggg atg aac agc atc gag cct gct aag gag acc acc acc 2311Gly Val Met Gly Met Asn Ser Ile Glu Pro Ala Lys Glu Thr Thr Thr 505 510 515aat gtc taa gtcgtgcctc cttccacctc cctcccggca tgggaaagcc 2360Asn Val 520acctctccct caacaaggga gagactttat caggatgaac ccaggacgct tctgaatgct 2420gctacttgat ttctttctca tcccacgcac tccatgagca ccccaaggct gcagtttgtt 2480ggatcttcaa tggcttttta aattttattt cctggacatc ctcttctgct taggagagac 2540cgagtgaacc taccttcatt tcaggaggga ttggccgctt ggcacatgac aactttgcca 2600gcttttcctc ccttgggttc tgatattgcc gcactagggg atataggaga ggaaaagtaa 2660ggtgcagttg ccccaacctc agacttacca ggaagcagat acatgtgagt gtggaaggca 2720gagggggttt atgtaagagc accttcctca cttccataca gctctacgcg gcaaattaac 2780ttgagtttta tttatcttat cctctggttt aattacataa atatttattt tttaagtgta 2840attttgccaa ataataacaa cagaaggaaa ttgagattag agggaggtgt ttaaagagag 2900gttatagagt aaaagatttg atgctggaga ggttaaggtg caataagaat tcagggagaa 2960atgttgttca ttattggagg gtaaatgatg tggtgcctga ggtctgtaca ttacctctta 3020acaatttctg tccttcagat gaaaactctt tgatttctca gaaaagttgt atgcctattt 3080aataaagcta ctcatttcct ttggaacttt atctttaaga taatagttta catgtagtag 3140tacttgaaat ctaggattat taactaatat gggcattgta gttaatggcg gttgatgggt 3200tctaattttg gatggagtcc agggaagaga aagtgatttc tagaaagcct gttcccctca 3260ctggacgaaa taactccttg tagtagtctc attacttttg aagtaatccc gccacctatc 3320tagtgggaga gccatccaaa tgagaaacct aaaataattg gttcttggta gagattcatt 3380atttctccac tttgttcttt aggagatttt aggtgttgat tttctgtttt attttaactc 3440atacctttaa aggaattccc caaagaatgt ttatagcaaa cttggaattt gtaacctcag 3500ctctgggaga ggattttttt ctgagcgatt attatctaaa gtgtgttgtt gctttaggct 3560cacggcacgc ttgcgtatgt ctgttaccat gtcactgtgg tcctatgccg aatgccctca 3620ggggacttga atctttccaa taaaccaggt ttagacagta tgagtcaatg tgcagtgcag 3680cccacacttg agaggatgaa tgtatgtgca ctgtcacttt gctctgggtg gaagtatgtt 3740attgttgact tattttctct gtgtttgttc ctacagcccc tttttcatat gttgctcagt 3800ctccctttcc cttcttggtg cttacacatc tcagaccctt tagccaaacc cttgccagtg 3860acagtatttt ggttctcagt tctcactgtt ccctctgctc ctggagcctt tgaataaaaa 3920tgcacgtagc tatggagtgg ggtttagctg gaaaggtggc cttccaactt cacgtcaact 3980tctggctcct cagtttggca gtaaggcagg gaagttgttt tcctatttct cactgagaag 4040attgtgaata tttccatatg gattttccat tattgtttgt ttgattcttt gttttaaaat 4100aaaaattctg aatgt 4115196520PRTHomo sapiens 196Met Glu Phe His Asn Gly Gly His Val Ser Gly Ile Gly Gly Phe Leu1 5 10 15Val Ser Leu Thr Ser Arg Met Lys Pro His Thr Leu Ala Val Thr Pro 20 25 30Ala Leu Ile Phe Ala Ile Thr Val Ala Thr Ile Gly Ser Phe Gln Phe 35 40 45Gly Tyr Asn Thr Gly Val Ile Asn Ala Pro Glu Thr Ile Ile Lys Glu 50 55 60Phe Ile Asn Lys Thr Leu Thr Asp Lys Ala Asn Ala Pro Pro Ser Glu65 70 75 80Val Leu Leu Thr Asn Leu Trp Ser Leu Ser Val Ala Ile Phe Ser Val 85 90 95Gly Gly Met Ile Gly Ser Phe Ser Val Gly Leu Phe Val Asn Arg Phe 100 105 110Gly Arg Arg Asn Ser Met Leu Ile Val Asn Leu Leu Ala Ala Thr Gly 115 120 125Gly Cys Leu Met Gly Leu Cys Lys Ile Ala Glu Ser Val Glu Met Leu 130 135 140Ile Leu Gly Arg Leu Val Ile Gly Leu Phe Cys Gly Leu Cys Thr Gly145 150 155 160Phe Val Pro Met Tyr Ile Gly Glu Ile Ser Pro Thr Ala Leu Arg Gly 165 170 175Ala Phe Gly Thr Leu Asn Gln Leu Gly Ile Val Ile Gly Ile Leu Val 180 185 190Ala Gln Ile Phe Gly Leu Glu Leu Ile Leu Gly Ser Glu Glu Leu Trp 195 200 205Pro Val Leu Leu Gly Phe Thr Ile Leu Pro Ala Ile Leu Gln Ser Ala 210 215 220Ala Leu Pro Cys Cys Pro Glu Ser Pro Arg Phe Leu Leu Ile Asn Arg225 230 235 240Lys Lys Glu Glu Asn Ala Thr Arg Ile Leu Gln Arg Leu Trp Gly Thr 245 250 255Gln Asp Val Ser Gln Asp Ile Gln Glu Met Lys Asp Glu Ser Ala Arg 260 265 270Met Ser Gln Glu Lys Gln Val Thr Val Leu Glu Leu Phe Arg Val Ser 275 280 285Ser Tyr Arg Gln Pro Ile Ile Ile Ser Ile Val Leu Gln Leu Ser Gln 290 295 300Gln Leu Ser Gly Ile Asn Ala Val Phe Tyr Tyr Ser Thr Gly Ile Phe305 310 315 320Lys Asp Ala Gly Val Gln Gln Pro Ile Tyr Ala Thr Ile Ser Ala Gly

325 330 335Val Val Asn Thr Ile Phe Thr Leu Leu Ser Leu Phe Leu Val Glu Arg 340 345 350Ala Gly Arg Arg Thr Leu His Met Ile Gly Leu Gly Gly Met Ala Phe 355 360 365Cys Ser Thr Leu Met Thr Val Ser Leu Leu Leu Lys Asn His Tyr Asn 370 375 380Gly Met Ser Phe Val Cys Ile Gly Ala Ile Leu Val Phe Val Ala Cys385 390 395 400Phe Glu Ile Gly Pro Gly Pro Ile Pro Trp Phe Ile Val Ala Glu Leu 405 410 415Phe Ser Gln Gly Pro Arg Pro Ala Ala Met Ala Val Ala Gly Cys Ser 420 425 430Asn Trp Thr Ser Asn Phe Leu Val Gly Leu Leu Phe Pro Ser Ala Ala 435 440 445Tyr Tyr Leu Gly Ala Tyr Val Phe Ile Ile Phe Thr Gly Phe Leu Ile 450 455 460Thr Phe Leu Ala Phe Thr Phe Phe Lys Val Pro Glu Thr Arg Gly Arg465 470 475 480Thr Phe Glu Asp Ile Thr Arg Ala Phe Glu Gly Gln Ala His Gly Ala 485 490 495Asp Arg Ser Gly Lys Asp Gly Val Met Gly Met Asn Ser Ile Glu Pro 500 505 510Ala Lys Glu Thr Thr Thr Asn Val 515 52019723DNAArtificial Sequenceforward primer used for specifically detecting the variant of the present invention 197ggcatttctt tttttcttct cag 2319817DNAArtificial Sequencereverse primer used for specifically detecting the variant of the present invention 198ggtgacctcc tccccga 1719974DNAArtificial Sequencepartial polynucleotide specific to the variant of the present invention, which is obtained by PCR using forward primer (SEQ ID NO197) and reverse primer (SEQ ID NO198) 199ggcatttctt tttttcttct cagacctcca ctctggagaa gagtcagaat gggggcgtcg 60gggaggaggt cacc 7420022DNAArtificial Sequenceforward primer used for detecting the variants of the gene of the present invention 200tttattgtgg ccgaactctt ca 2220122DNAArtificial Sequencereverse primer used for detecting the variants of the gene of the present invention 201gcaatccgac taggaagttg ga 2220297DNAArtificial Sequencepartial polynucleotide common to the variants of the gene of the present invention, which is obtained by PCR using forward primer (SEQ ID NO200) and reverse primer (SEQ ID NO201) 202tttattgtgg ccgaactctt cagccagggc ccccgcccag ctgcgatggc agtggccggc 60tgctccaact ggacctccaa cttcctagtc ggattgc 97203159DNAHomo sapiens 203acaacctgac ttttgtccac aatgcaaaga ctccaactgt tgagagtaga agtactgctg 60ggtgtgaaac aaggagatga aatgcggcat ttcttttttt cttctcagac ctccactctg 120gagaagagtc agaatggggg cgtcggggag gaggtcacc 159204159DNAHomo sapiens 204acaacctgac ttttgttcac aatgcaaaga ctccaactgt tgagagtaga agtactgctg 60ggtgtgaaac aaggagatga aatgcggcat ttcttttttt cttctcagac ctccactctg 120gagaagagtc agaatggggg cgtcggggag gaggtcacc 1592052724DNAHomo sapiens 205gagagcagcg ccaatgtgaa gcgttgcagt cgcttgactc acctgaggct ctccaaggat 60accttcaatg cctgcactgt aagggagctg cttttcccgg gtgctggcga gaacggaagc 120cttcctttga cgtttttcta aacatgggat gcagtctgtg cagcctgcag aagcaagagg 180agcagtacaa attactctat gaagtttgtc aggtcaacgg cagagactta tccagagcaa 240ctcatgacca ggctgtggaa gctttcaaga cagccaagga gcccatagtg gtgcaggtgt 300tgagaagaac accaaggacc aaaatgttca cgcctccatc agagtctcag ctggtggaca 360cgggaaccca aaccgacatc acctttgaac atatcatggc cctcactaag atgtcctctc 420ccagcccacc cgtgctggat ccctatctct tgccagagga gcatccctca gcccatgaat 480actacgatcc aaatgactac attggagaca tccatcagga gatggacagg gaggagctgg 540agctggagga agtggacctc tacagaatga acagccagga caagctgggc ctcactgtgt 600gctaccggac ggacgatgaa gacgacattg ggatttatat cagtgagatt gaccctaaca 660gcattgcagc caaggatggg cgcatccgag aaggagactg cattatccag attaatggga 720tagaggtgca gaaccgtgaa gaggctgtgg ctcttctaac cagtgaagaa aataaaaact 780tttcattgct gattgcaagg cctgaactcc agctggatga gggctggatg gatgatgaca 840ggaacgactt tctggatgac ctgcacatgg acatgctgga ggagcagcac caccaggcca 900tgcaattcac agctagcgtg ctgcagcaga agaagcacga cgaagacggt gggaccacag 960atacagccac catcttgtcc aaccagcacg agaaggacag cggtgtgggg cggaccgacg 1020agagcacccg taatgacgag agctcggagc aagagaacaa tggcgacgac gccaccgcat 1080cctccaaccc gctggcgggg cagaggaagc tcacctgcag ccaggacacc ttgggcagcg 1140gcgacctgcc cttcagcaac gagtctttca tttcggccga ctgcacggac gccgactacc 1200tggggatccc ggtggacgag tgcgagcgct tccgcgagct cctggagctc aagtgccagg 1260tgaagagcgc caccccttac ggcctgtact accctagcgg ccccctggac gccggcaaga 1320gtgaccctga gagcgtggac aaggagctgg agctgctgaa cgaagagctg cgcagcatcg 1380agctggagtg cctgagcatc gtgcgcgccc acaagatgca gcagctcaag gagcagtacc 1440gcgagtcctg gatgctgcac aacagcggct tccgcaacta caacaccagc atcgacgtgc 1500gcagacgcga gctctcagat atcaccgagc tcccggagaa atccgacaag gacagctcga 1560gcgcctacaa cacaggcgag agctgccgca gcaccccgct caccctggag atctcccccg 1620acaactcctt gaggagagcg gcggagggca tcagctgccc gagcagcgaa ggggctgtgg 1680ggaccacgga agcctacggg ccagcctcca agaatctgct ctccatcacg gaagatcccg 1740aagtgggcac ccctacctat agcccgtccc tgaaggagct ggaccccaac cagcccctgg 1800aaagcaaaga gcggagagcc agcgacggga gccggagccc cacgcccagc cagaagctgg 1860gcagcgccta cctgccctcc tatcaccact ccccatacaa gcacgcgcac atcccggcgc 1920acgcccagca ctaccagagc tacatgcagc tgatccagca gaagtcggcc gtggagtacg 1980cgcaaagcca gatgagcctg gtgagcatgt gcaaggacct gagctctccc accccgtcgg 2040agccgcgcat ggagtggaag gtgaagatcc gcagcgacgg gacgcgctac atcaccaaga 2100ggcccgtgcg ggaccgcctg ctgcgggagc gcgccctgaa gatccgggaa gagcgcagcg 2160gcatgaccac cgacgacgac gcggtgagcg agatgaagat ggggcgctac tggagcaagg 2220aggagaggaa gcagcacttg gtgaaggcca aggagcagcg gcggcggcgc gagttcatga 2280tgcagagcag gttggattgt ctcaaggagc agcaagcagc cgatgacagg aaggagatga 2340acattctcga actgagccac aaaaagatga tgaagaagag gaataagaaa atcttcgata 2400actggatgac gatccaagaa ctcttaaccc acggcacaaa atccccggac ggcactagag 2460tatacaattc cttcctatcg gtgactactg tataattttc acttctgcat tatgtacata 2520aaggagacca ctaccactgg ggtagaaatt cctgcctcgt tcaatgcggc aagtttttgt 2580atataagata agtacggtct tcatgtttat agtccaaatt tgcaaaccct acaactctgg 2640gtgtcatagg tctattttaa gggaagagag agaaaaacac ccttactatc ttggaaggca 2700atattaacaa acagagcttt tttc 27242062724DNAHomo sapiensCDS(144)..(2495) 206gagagcagcg ccaatgtgaa gcgttgcagt cgcttgactc acctgaggct ctccaaggat 60accttcaatg cctgcactgt aagggagctg cttttcccgg gtgctggcga gaacggaagc 120cttcctttga cgtttttcta aac atg gga tgc agt ctg tgc agc ctg cag aag 173 Met Gly Cys Ser Leu Cys Ser Leu Gln Lys 1 5 10caa gag gag cag tac aaa tta ctc tat gaa gtt tgt cag gtc aac ggc 221Gln Glu Glu Gln Tyr Lys Leu Leu Tyr Glu Val Cys Gln Val Asn Gly 15 20 25aga gac tta tcc aga gca act cat gac cag gct gtg gaa gct ttc aag 269Arg Asp Leu Ser Arg Ala Thr His Asp Gln Ala Val Glu Ala Phe Lys 30 35 40aca gcc aag gag ccc ata gtg gtg cag gtg ttg aga aga aca cca agg 317Thr Ala Lys Glu Pro Ile Val Val Gln Val Leu Arg Arg Thr Pro Arg 45 50 55acc aaa atg ttc acg cct cca tca gag tct cag ctg gtg gac acg gga 365Thr Lys Met Phe Thr Pro Pro Ser Glu Ser Gln Leu Val Asp Thr Gly 60 65 70acc caa acc gac atc acc ttt gaa cat atc atg gcc ctc act aag atg 413Thr Gln Thr Asp Ile Thr Phe Glu His Ile Met Ala Leu Thr Lys Met75 80 85 90tcc tct ccc agc cca ccc gtg ctg gat ccc tat ctc ttg cca gag gag 461Ser Ser Pro Ser Pro Pro Val Leu Asp Pro Tyr Leu Leu Pro Glu Glu 95 100 105cat ccc tca gcc cat gaa tac tac gat cca aat gac tac att gga gac 509His Pro Ser Ala His Glu Tyr Tyr Asp Pro Asn Asp Tyr Ile Gly Asp 110 115 120atc cat cag gag atg gac agg gag gag ctg gag ctg gag gaa gtg gac 557Ile His Gln Glu Met Asp Arg Glu Glu Leu Glu Leu Glu Glu Val Asp 125 130 135ctc tac aga atg aac agc cag gac aag ctg ggc ctc act gtg tgc tac 605Leu Tyr Arg Met Asn Ser Gln Asp Lys Leu Gly Leu Thr Val Cys Tyr 140 145 150cgg acg gac gat gaa gac gac att ggg att tat atc agt gag att gac 653Arg Thr Asp Asp Glu Asp Asp Ile Gly Ile Tyr Ile Ser Glu Ile Asp155 160 165 170cct aac agc att gca gcc aag gat ggg cgc atc cga gaa gga gac tgc 701Pro Asn Ser Ile Ala Ala Lys Asp Gly Arg Ile Arg Glu Gly Asp Cys 175 180 185att atc cag att aat ggg ata gag gtg cag aac cgt gaa gag gct gtg 749Ile Ile Gln Ile Asn Gly Ile Glu Val Gln Asn Arg Glu Glu Ala Val 190 195 200gct ctt cta acc agt gaa gaa aat aaa aac ttt tca ttg ctg att gca 797Ala Leu Leu Thr Ser Glu Glu Asn Lys Asn Phe Ser Leu Leu Ile Ala 205 210 215agg cct gaa ctc cag ctg gat gag ggc tgg atg gat gat gac agg aac 845Arg Pro Glu Leu Gln Leu Asp Glu Gly Trp Met Asp Asp Asp Arg Asn 220 225 230gac ttt ctg gat gac ctg cac atg gac atg ctg gag gag cag cac cac 893Asp Phe Leu Asp Asp Leu His Met Asp Met Leu Glu Glu Gln His His235 240 245 250cag gcc atg caa ttc aca gct agc gtg ctg cag cag aag aag cac gac 941Gln Ala Met Gln Phe Thr Ala Ser Val Leu Gln Gln Lys Lys His Asp 255 260 265gaa gac ggt ggg acc aca gat aca gcc acc atc ttg tcc aac cag cac 989Glu Asp Gly Gly Thr Thr Asp Thr Ala Thr Ile Leu Ser Asn Gln His 270 275 280gag aag gac agc ggt gtg ggg cgg acc gac gag agc acc cgt aat gac 1037Glu Lys Asp Ser Gly Val Gly Arg Thr Asp Glu Ser Thr Arg Asn Asp 285 290 295gag agc tcg gag caa gag aac aat ggc gac gac gcc acc gca tcc tcc 1085Glu Ser Ser Glu Gln Glu Asn Asn Gly Asp Asp Ala Thr Ala Ser Ser 300 305 310aac ccg ctg gcg ggg cag agg aag ctc acc tgc agc cag gac acc ttg 1133Asn Pro Leu Ala Gly Gln Arg Lys Leu Thr Cys Ser Gln Asp Thr Leu315 320 325 330ggc agc ggc gac ctg ccc ttc agc aac gag tct ttc att tcg gcc gac 1181Gly Ser Gly Asp Leu Pro Phe Ser Asn Glu Ser Phe Ile Ser Ala Asp 335 340 345tgc acg gac gcc gac tac ctg ggg atc ccg gtg gac gag tgc gag cgc 1229Cys Thr Asp Ala Asp Tyr Leu Gly Ile Pro Val Asp Glu Cys Glu Arg 350 355 360ttc cgc gag ctc ctg gag ctc aag tgc cag gtg aag agc gcc acc cct 1277Phe Arg Glu Leu Leu Glu Leu Lys Cys Gln Val Lys Ser Ala Thr Pro 365 370 375tac ggc ctg tac tac cct agc ggc ccc ctg gac gcc ggc aag agt gac 1325Tyr Gly Leu Tyr Tyr Pro Ser Gly Pro Leu Asp Ala Gly Lys Ser Asp 380 385 390cct gag agc gtg gac aag gag ctg gag ctg ctg aac gaa gag ctg cgc 1373Pro Glu Ser Val Asp Lys Glu Leu Glu Leu Leu Asn Glu Glu Leu Arg395 400 405 410agc atc gag ctg gag tgc ctg agc atc gtg cgc gcc cac aag atg cag 1421Ser Ile Glu Leu Glu Cys Leu Ser Ile Val Arg Ala His Lys Met Gln 415 420 425cag ctc aag gag cag tac cgc gag tcc tgg atg ctg cac aac agc ggc 1469Gln Leu Lys Glu Gln Tyr Arg Glu Ser Trp Met Leu His Asn Ser Gly 430 435 440ttc cgc aac tac aac acc agc atc gac gtg cgc aga cgc gag ctc tca 1517Phe Arg Asn Tyr Asn Thr Ser Ile Asp Val Arg Arg Arg Glu Leu Ser 445 450 455gat atc acc gag ctc ccg gag aaa tcc gac aag gac agc tcg agc gcc 1565Asp Ile Thr Glu Leu Pro Glu Lys Ser Asp Lys Asp Ser Ser Ser Ala 460 465 470tac aac aca ggc gag agc tgc cgc agc acc ccg ctc acc ctg gag atc 1613Tyr Asn Thr Gly Glu Ser Cys Arg Ser Thr Pro Leu Thr Leu Glu Ile475 480 485 490tcc ccc gac aac tcc ttg agg aga gcg gcg gag ggc atc agc tgc ccg 1661Ser Pro Asp Asn Ser Leu Arg Arg Ala Ala Glu Gly Ile Ser Cys Pro 495 500 505agc agc gaa ggg gct gtg ggg acc acg gaa gcc tac ggg cca gcc tcc 1709Ser Ser Glu Gly Ala Val Gly Thr Thr Glu Ala Tyr Gly Pro Ala Ser 510 515 520aag aat ctg ctc tcc atc acg gaa gat ccc gaa gtg ggc acc cct acc 1757Lys Asn Leu Leu Ser Ile Thr Glu Asp Pro Glu Val Gly Thr Pro Thr 525 530 535tat agc ccg tcc ctg aag gag ctg gac ccc aac cag ccc ctg gaa agc 1805Tyr Ser Pro Ser Leu Lys Glu Leu Asp Pro Asn Gln Pro Leu Glu Ser 540 545 550aaa gag cgg aga gcc agc gac ggg agc cgg agc ccc acg ccc agc cag 1853Lys Glu Arg Arg Ala Ser Asp Gly Ser Arg Ser Pro Thr Pro Ser Gln555 560 565 570aag ctg ggc agc gcc tac ctg ccc tcc tat cac cac tcc cca tac aag 1901Lys Leu Gly Ser Ala Tyr Leu Pro Ser Tyr His His Ser Pro Tyr Lys 575 580 585cac gcg cac atc ccg gcg cac gcc cag cac tac cag agc tac atg cag 1949His Ala His Ile Pro Ala His Ala Gln His Tyr Gln Ser Tyr Met Gln 590 595 600ctg atc cag cag aag tcg gcc gtg gag tac gcg caa agc cag atg agc 1997Leu Ile Gln Gln Lys Ser Ala Val Glu Tyr Ala Gln Ser Gln Met Ser 605 610 615ctg gtg agc atg tgc aag gac ctg agc tct ccc acc ccg tcg gag ccg 2045Leu Val Ser Met Cys Lys Asp Leu Ser Ser Pro Thr Pro Ser Glu Pro 620 625 630cgc atg gag tgg aag gtg aag atc cgc agc gac ggg acg cgc tac atc 2093Arg Met Glu Trp Lys Val Lys Ile Arg Ser Asp Gly Thr Arg Tyr Ile635 640 645 650acc aag agg ccc gtg cgg gac cgc ctg ctg cgg gag cgc gcc ctg aag 2141Thr Lys Arg Pro Val Arg Asp Arg Leu Leu Arg Glu Arg Ala Leu Lys 655 660 665atc cgg gaa gag cgc agc ggc atg acc acc gac gac gac gcg gtg agc 2189Ile Arg Glu Glu Arg Ser Gly Met Thr Thr Asp Asp Asp Ala Val Ser 670 675 680gag atg aag atg ggg cgc tac tgg agc aag gag gag agg aag cag cac 2237Glu Met Lys Met Gly Arg Tyr Trp Ser Lys Glu Glu Arg Lys Gln His 685 690 695ttg gtg aag gcc aag gag cag cgg cgg cgg cgc gag ttc atg atg cag 2285Leu Val Lys Ala Lys Glu Gln Arg Arg Arg Arg Glu Phe Met Met Gln 700 705 710agc agg ttg gat tgt ctc aag gag cag caa gca gcc gat gac agg aag 2333Ser Arg Leu Asp Cys Leu Lys Glu Gln Gln Ala Ala Asp Asp Arg Lys715 720 725 730gag atg aac att ctc gaa ctg agc cac aaa aag atg atg aag aag agg 2381Glu Met Asn Ile Leu Glu Leu Ser His Lys Lys Met Met Lys Lys Arg 735 740 745aat aag aaa atc ttc gat aac tgg atg acg atc caa gaa ctc tta acc 2429Asn Lys Lys Ile Phe Asp Asn Trp Met Thr Ile Gln Glu Leu Leu Thr 750 755 760cac ggc aca aaa tcc ccg gac ggc act aga gta tac aat tcc ttc cta 2477His Gly Thr Lys Ser Pro Asp Gly Thr Arg Val Tyr Asn Ser Phe Leu 765 770 775tcg gtg act act gta taa ttttcacttc tgcattatgt acataaagga 2525Ser Val Thr Thr Val 780gaccactacc actggggtag aaattcctgc ctcgttcaat gcggcaagtt tttgtatata 2585agataagtac ggtcttcatg tttatagtcc aaatttgcaa accctacaac tctgggtgtc 2645ataggtctat tttaagggaa gagagagaaa aacaccctta ctatcttgga aggcaatatt 2705aacaaacaga gcttttttc 2724207783PRTHomo sapiens 207Met Gly Cys Ser Leu Cys Ser Leu Gln Lys Gln Glu Glu Gln Tyr Lys1 5 10 15Leu Leu Tyr Glu Val Cys Gln Val Asn Gly Arg Asp Leu Ser Arg Ala 20 25 30Thr His Asp Gln Ala Val Glu Ala Phe Lys Thr Ala Lys Glu Pro Ile 35 40 45Val Val Gln Val Leu Arg Arg Thr Pro Arg Thr Lys Met Phe Thr Pro 50 55 60Pro Ser Glu Ser Gln Leu Val Asp Thr Gly Thr Gln Thr Asp Ile Thr65 70 75 80Phe Glu His Ile Met Ala Leu Thr Lys Met Ser Ser Pro Ser Pro Pro 85 90 95Val Leu Asp Pro Tyr Leu Leu Pro Glu Glu His Pro Ser Ala His Glu 100 105 110Tyr Tyr Asp Pro Asn Asp Tyr Ile Gly Asp Ile His Gln Glu Met Asp 115 120 125Arg Glu Glu Leu Glu Leu Glu Glu Val Asp Leu Tyr Arg Met Asn Ser 130 135 140Gln Asp Lys Leu Gly Leu Thr Val Cys Tyr Arg Thr Asp Asp Glu Asp145 150 155 160Asp Ile Gly Ile Tyr Ile Ser Glu Ile Asp Pro Asn Ser Ile Ala Ala 165 170 175Lys Asp Gly Arg Ile Arg Glu Gly Asp Cys Ile Ile Gln Ile Asn Gly 180 185 190Ile Glu Val Gln Asn Arg Glu Glu Ala Val Ala Leu Leu Thr Ser Glu 195

200 205Glu Asn Lys Asn Phe Ser Leu Leu Ile Ala Arg Pro Glu Leu Gln Leu 210 215 220Asp Glu Gly Trp Met Asp Asp Asp Arg Asn Asp Phe Leu Asp Asp Leu225 230 235 240His Met Asp Met Leu Glu Glu Gln His His Gln Ala Met Gln Phe Thr 245 250 255Ala Ser Val Leu Gln Gln Lys Lys His Asp Glu Asp Gly Gly Thr Thr 260 265 270Asp Thr Ala Thr Ile Leu Ser Asn Gln His Glu Lys Asp Ser Gly Val 275 280 285Gly Arg Thr Asp Glu Ser Thr Arg Asn Asp Glu Ser Ser Glu Gln Glu 290 295 300Asn Asn Gly Asp Asp Ala Thr Ala Ser Ser Asn Pro Leu Ala Gly Gln305 310 315 320Arg Lys Leu Thr Cys Ser Gln Asp Thr Leu Gly Ser Gly Asp Leu Pro 325 330 335Phe Ser Asn Glu Ser Phe Ile Ser Ala Asp Cys Thr Asp Ala Asp Tyr 340 345 350Leu Gly Ile Pro Val Asp Glu Cys Glu Arg Phe Arg Glu Leu Leu Glu 355 360 365Leu Lys Cys Gln Val Lys Ser Ala Thr Pro Tyr Gly Leu Tyr Tyr Pro 370 375 380Ser Gly Pro Leu Asp Ala Gly Lys Ser Asp Pro Glu Ser Val Asp Lys385 390 395 400Glu Leu Glu Leu Leu Asn Glu Glu Leu Arg Ser Ile Glu Leu Glu Cys 405 410 415Leu Ser Ile Val Arg Ala His Lys Met Gln Gln Leu Lys Glu Gln Tyr 420 425 430Arg Glu Ser Trp Met Leu His Asn Ser Gly Phe Arg Asn Tyr Asn Thr 435 440 445Ser Ile Asp Val Arg Arg Arg Glu Leu Ser Asp Ile Thr Glu Leu Pro 450 455 460Glu Lys Ser Asp Lys Asp Ser Ser Ser Ala Tyr Asn Thr Gly Glu Ser465 470 475 480Cys Arg Ser Thr Pro Leu Thr Leu Glu Ile Ser Pro Asp Asn Ser Leu 485 490 495Arg Arg Ala Ala Glu Gly Ile Ser Cys Pro Ser Ser Glu Gly Ala Val 500 505 510Gly Thr Thr Glu Ala Tyr Gly Pro Ala Ser Lys Asn Leu Leu Ser Ile 515 520 525Thr Glu Asp Pro Glu Val Gly Thr Pro Thr Tyr Ser Pro Ser Leu Lys 530 535 540Glu Leu Asp Pro Asn Gln Pro Leu Glu Ser Lys Glu Arg Arg Ala Ser545 550 555 560Asp Gly Ser Arg Ser Pro Thr Pro Ser Gln Lys Leu Gly Ser Ala Tyr 565 570 575Leu Pro Ser Tyr His His Ser Pro Tyr Lys His Ala His Ile Pro Ala 580 585 590His Ala Gln His Tyr Gln Ser Tyr Met Gln Leu Ile Gln Gln Lys Ser 595 600 605Ala Val Glu Tyr Ala Gln Ser Gln Met Ser Leu Val Ser Met Cys Lys 610 615 620Asp Leu Ser Ser Pro Thr Pro Ser Glu Pro Arg Met Glu Trp Lys Val625 630 635 640Lys Ile Arg Ser Asp Gly Thr Arg Tyr Ile Thr Lys Arg Pro Val Arg 645 650 655Asp Arg Leu Leu Arg Glu Arg Ala Leu Lys Ile Arg Glu Glu Arg Ser 660 665 670Gly Met Thr Thr Asp Asp Asp Ala Val Ser Glu Met Lys Met Gly Arg 675 680 685Tyr Trp Ser Lys Glu Glu Arg Lys Gln His Leu Val Lys Ala Lys Glu 690 695 700Gln Arg Arg Arg Arg Glu Phe Met Met Gln Ser Arg Leu Asp Cys Leu705 710 715 720Lys Glu Gln Gln Ala Ala Asp Asp Arg Lys Glu Met Asn Ile Leu Glu 725 730 735Leu Ser His Lys Lys Met Met Lys Lys Arg Asn Lys Lys Ile Phe Asp 740 745 750Asn Trp Met Thr Ile Gln Glu Leu Leu Thr His Gly Thr Lys Ser Pro 755 760 765Asp Gly Thr Arg Val Tyr Asn Ser Phe Leu Ser Val Thr Thr Val 770 775 780208212DNAHomo sapiens 208gagagcagcg ccaatgtgaa gcgttgcagt cgcttgactc acctgaggct ctccaaggat 60accttcaatg cctgcactgt aagggagctg cttttcccgg gtgctggcga gaacggaagc 120cttcctttga cgtttttcta aacatgggat gcagtctgtg cagcctgcag aagcaagagg 180agcagtacaa attactctat gaagtttgtc ag 21220923PRTHomo sapiens 209Met Gly Cys Ser Leu Cys Ser Leu Gln Lys Gln Glu Glu Gln Tyr Lys1 5 10 15Leu Leu Tyr Glu Val Cys Gln 2021069DNAHomo sapiens 210atgggatgca gtctgtgcag cctgcagaag caagaggagc agtacaaatt actctatgaa 60gtttgtcag 692112570DNAHomo sapiens 211gtgaagcgtt gcagtcgctt gactcacctg aggctctcca aggatacctt caatgcctgc 60actgtaaggg agctgctttt cccgggtgct ggcgagaacg gaagccttcc tttgacgttt 120ttctaaacat gggatgcagt ctgtgcagcc tgcagaagca agaggagcag tacaaattac 180tctatgaagt ttgtcaggtc aacggcagag acttatccag agcaactcat gaccaggctg 240tggaagcttt caagacagcc aaggagccca tagtggtgca ggtgttgaga agaacaccaa 300ggaccaaaat gttcacgcct ccatcagagt ctcagctggt ggacacggga acccaaaccg 360acatcacctt tgaacatatc atggccctca ctaagatgtc ctctcccagc ccacccgtac 420tggatcccta tctcttgcca gaggagcatc cctcagccca tgaatactac gatccaaatg 480actacattgg agacatccat caggagatgg acagggagga gctggagctg gaggaagtgg 540acctctacag aatgaacagc caggacaagc tgggcctcac tgtgtgctac cggacggacg 600atgaagacga cattgggatt tatatcagtg agattgaccc taacagcatt gcagccaagg 660atgggcgcat ccgagaagga gaccgcatta tccagattaa tgggatagag gtgcagaacc 720gtgaagaggc tgtggctctt ctaaccagtg aagaaaataa aaacttttca ttgctgattg 780caaggcctga actccagctg gatgagggct ggatggatga tgacaggaac gactttctgg 840atgacctgca catggacatg ctggaggagc agcaccacca ggccatgcaa ttcacagcta 900gcgtgctgca gcagaagaag cacgacgaag acggtgggac cacagataca gccaccatct 960tgtccaacca gcacgagaag gacagtggtg tggggcggac cgacgagagc acccgtaatg 1020acgagagctc ggagcaagag aacaatggcg acgacgccac cgcatcctcc aacccgctgg 1080cggggcagag gaagctcacc tgcagccagg acaccttggg cagcggcgac ctgcccttca 1140gcaacgagtc tttcatttcg gccgactgca cggacgccga ctacctgggg atcccggtgg 1200acgagtgcga gcgcttccgc gagctcctgg agctcaagtg ccaggtgaag agcgccaccc 1260cttacggcct gtactaccct agcggccccc tggacgccgg caagagtgac cctgagagcg 1320tggacaagga gctggagctg ctgaacgaag agctgcgcag catcgagctg gagtgcctga 1380gcatcgtgcg cgcccacaag atgcagcagc tcaaggagca gtaccgcgag tcctggatgc 1440tgcacaacag cggcttccgc aactacaaca ccagcatcga cgtgcgcaga cacgagctct 1500cagatatcac cgagctcccg gagaaatccg acaaggacag ctcgagcgcc tacaacacag 1560gcgagagctg ccgcagcacc ccgctcaccc tggagatctc ccccgacaac tccttgagga 1620gagcggcgga gggcatcagc tgcccgagca gcgaaggggc tgtggggacc acggaagcct 1680acgggccagc ctccaagaat ctgctctcca tcacggaaga tcccgaagtg ggcaccccta 1740cctatagccc gtccctgaag gagctggacc ccaaccagcc cctggaaagc aaagagcgga 1800gagccagcga cgggagccgg agccccacgc ccagccagaa gctgggcagc gcctacctgc 1860cctcctatca ccactcccca tacaagcacg cgcacatccc ggcgcacgcc cagcactacc 1920agagctacat gcagctgatc cagcagaagt cggccgtgga gtacgcgcaa agccagatga 1980gcctggtgag catgtgcaag gacctgagct ctcccacccc gtcggagccg cgcatggagt 2040ggaaggtgaa gatccgcagc gacgggacgc gctacatcac caagaggccc gtgcgggacc 2100gcctgctgcg ggagcgcgcc ctgaagatcc gggaagagcg cagcggcatg accaccgacg 2160acgacgcggt gagcgagatg aagatggggc gctactggag caaggaggag aggaagcagc 2220acctggtgaa ggccaaggag cagcggcggc ggcgcgagtt catgatgcag agcaggttgg 2280attgtctcaa ggagcagcaa gcagccgatg acaggaagga gatgaacatt ctcgaactga 2340gccacaaaaa gatgatgaag aagaggaata agaaaatctt cgataactgg atgacgatcc 2400aagaactctt aacccacggc acaaaatccc cggacggcac tagagtatac aattccttcc 2460tatcggtgac tactgtataa ttttcacttc tgcattatgt acataaagga gaccactacc 2520actggggtag aaattcctgc ctcgttcaat gcggcaagtt tttgtatata 25702122570DNAHomo sapiensCDS(129)..(2480) 212gtgaagcgtt gcagtcgctt gactcacctg aggctctcca aggatacctt caatgcctgc 60actgtaaggg agctgctttt cccgggtgct ggcgagaacg gaagccttcc tttgacgttt 120ttctaaac atg gga tgc agt ctg tgc agc ctg cag aag caa gag gag cag 170 Met Gly Cys Ser Leu Cys Ser Leu Gln Lys Gln Glu Glu Gln 1 5 10tac aaa tta ctc tat gaa gtt tgt cag gtc aac ggc aga gac tta tcc 218Tyr Lys Leu Leu Tyr Glu Val Cys Gln Val Asn Gly Arg Asp Leu Ser15 20 25 30aga gca act cat gac cag gct gtg gaa gct ttc aag aca gcc aag gag 266Arg Ala Thr His Asp Gln Ala Val Glu Ala Phe Lys Thr Ala Lys Glu 35 40 45ccc ata gtg gtg cag gtg ttg aga aga aca cca agg acc aaa atg ttc 314Pro Ile Val Val Gln Val Leu Arg Arg Thr Pro Arg Thr Lys Met Phe 50 55 60acg cct cca tca gag tct cag ctg gtg gac acg gga acc caa acc gac 362Thr Pro Pro Ser Glu Ser Gln Leu Val Asp Thr Gly Thr Gln Thr Asp 65 70 75atc acc ttt gaa cat atc atg gcc ctc act aag atg tcc tct ccc agc 410Ile Thr Phe Glu His Ile Met Ala Leu Thr Lys Met Ser Ser Pro Ser 80 85 90cca ccc gta ctg gat ccc tat ctc ttg cca gag gag cat ccc tca gcc 458Pro Pro Val Leu Asp Pro Tyr Leu Leu Pro Glu Glu His Pro Ser Ala95 100 105 110cat gaa tac tac gat cca aat gac tac att gga gac atc cat cag gag 506His Glu Tyr Tyr Asp Pro Asn Asp Tyr Ile Gly Asp Ile His Gln Glu 115 120 125atg gac agg gag gag ctg gag ctg gag gaa gtg gac ctc tac aga atg 554Met Asp Arg Glu Glu Leu Glu Leu Glu Glu Val Asp Leu Tyr Arg Met 130 135 140aac agc cag gac aag ctg ggc ctc act gtg tgc tac cgg acg gac gat 602Asn Ser Gln Asp Lys Leu Gly Leu Thr Val Cys Tyr Arg Thr Asp Asp 145 150 155gaa gac gac att ggg att tat atc agt gag att gac cct aac agc att 650Glu Asp Asp Ile Gly Ile Tyr Ile Ser Glu Ile Asp Pro Asn Ser Ile 160 165 170gca gcc aag gat ggg cgc atc cga gaa gga gac cgc att atc cag att 698Ala Ala Lys Asp Gly Arg Ile Arg Glu Gly Asp Arg Ile Ile Gln Ile175 180 185 190aat ggg ata gag gtg cag aac cgt gaa gag gct gtg gct ctt cta acc 746Asn Gly Ile Glu Val Gln Asn Arg Glu Glu Ala Val Ala Leu Leu Thr 195 200 205agt gaa gaa aat aaa aac ttt tca ttg ctg att gca agg cct gaa ctc 794Ser Glu Glu Asn Lys Asn Phe Ser Leu Leu Ile Ala Arg Pro Glu Leu 210 215 220cag ctg gat gag ggc tgg atg gat gat gac agg aac gac ttt ctg gat 842Gln Leu Asp Glu Gly Trp Met Asp Asp Asp Arg Asn Asp Phe Leu Asp 225 230 235gac ctg cac atg gac atg ctg gag gag cag cac cac cag gcc atg caa 890Asp Leu His Met Asp Met Leu Glu Glu Gln His His Gln Ala Met Gln 240 245 250ttc aca gct agc gtg ctg cag cag aag aag cac gac gaa gac ggt ggg 938Phe Thr Ala Ser Val Leu Gln Gln Lys Lys His Asp Glu Asp Gly Gly255 260 265 270acc aca gat aca gcc acc atc ttg tcc aac cag cac gag aag gac agt 986Thr Thr Asp Thr Ala Thr Ile Leu Ser Asn Gln His Glu Lys Asp Ser 275 280 285ggt gtg ggg cgg acc gac gag agc acc cgt aat gac gag agc tcg gag 1034Gly Val Gly Arg Thr Asp Glu Ser Thr Arg Asn Asp Glu Ser Ser Glu 290 295 300caa gag aac aat ggc gac gac gcc acc gca tcc tcc aac ccg ctg gcg 1082Gln Glu Asn Asn Gly Asp Asp Ala Thr Ala Ser Ser Asn Pro Leu Ala 305 310 315ggg cag agg aag ctc acc tgc agc cag gac acc ttg ggc agc ggc gac 1130Gly Gln Arg Lys Leu Thr Cys Ser Gln Asp Thr Leu Gly Ser Gly Asp 320 325 330ctg ccc ttc agc aac gag tct ttc att tcg gcc gac tgc acg gac gcc 1178Leu Pro Phe Ser Asn Glu Ser Phe Ile Ser Ala Asp Cys Thr Asp Ala335 340 345 350gac tac ctg ggg atc ccg gtg gac gag tgc gag cgc ttc cgc gag ctc 1226Asp Tyr Leu Gly Ile Pro Val Asp Glu Cys Glu Arg Phe Arg Glu Leu 355 360 365ctg gag ctc aag tgc cag gtg aag agc gcc acc cct tac ggc ctg tac 1274Leu Glu Leu Lys Cys Gln Val Lys Ser Ala Thr Pro Tyr Gly Leu Tyr 370 375 380tac cct agc ggc ccc ctg gac gcc ggc aag agt gac cct gag agc gtg 1322Tyr Pro Ser Gly Pro Leu Asp Ala Gly Lys Ser Asp Pro Glu Ser Val 385 390 395gac aag gag ctg gag ctg ctg aac gaa gag ctg cgc agc atc gag ctg 1370Asp Lys Glu Leu Glu Leu Leu Asn Glu Glu Leu Arg Ser Ile Glu Leu 400 405 410gag tgc ctg agc atc gtg cgc gcc cac aag atg cag cag ctc aag gag 1418Glu Cys Leu Ser Ile Val Arg Ala His Lys Met Gln Gln Leu Lys Glu415 420 425 430cag tac cgc gag tcc tgg atg ctg cac aac agc ggc ttc cgc aac tac 1466Gln Tyr Arg Glu Ser Trp Met Leu His Asn Ser Gly Phe Arg Asn Tyr 435 440 445aac acc agc atc gac gtg cgc aga cac gag ctc tca gat atc acc gag 1514Asn Thr Ser Ile Asp Val Arg Arg His Glu Leu Ser Asp Ile Thr Glu 450 455 460ctc ccg gag aaa tcc gac aag gac agc tcg agc gcc tac aac aca ggc 1562Leu Pro Glu Lys Ser Asp Lys Asp Ser Ser Ser Ala Tyr Asn Thr Gly 465 470 475gag agc tgc cgc agc acc ccg ctc acc ctg gag atc tcc ccc gac aac 1610Glu Ser Cys Arg Ser Thr Pro Leu Thr Leu Glu Ile Ser Pro Asp Asn 480 485 490tcc ttg agg aga gcg gcg gag ggc atc agc tgc ccg agc agc gaa ggg 1658Ser Leu Arg Arg Ala Ala Glu Gly Ile Ser Cys Pro Ser Ser Glu Gly495 500 505 510gct gtg ggg acc acg gaa gcc tac ggg cca gcc tcc aag aat ctg ctc 1706Ala Val Gly Thr Thr Glu Ala Tyr Gly Pro Ala Ser Lys Asn Leu Leu 515 520 525tcc atc acg gaa gat ccc gaa gtg ggc acc cct acc tat agc ccg tcc 1754Ser Ile Thr Glu Asp Pro Glu Val Gly Thr Pro Thr Tyr Ser Pro Ser 530 535 540ctg aag gag ctg gac ccc aac cag ccc ctg gaa agc aaa gag cgg aga 1802Leu Lys Glu Leu Asp Pro Asn Gln Pro Leu Glu Ser Lys Glu Arg Arg 545 550 555gcc agc gac ggg agc cgg agc ccc acg ccc agc cag aag ctg ggc agc 1850Ala Ser Asp Gly Ser Arg Ser Pro Thr Pro Ser Gln Lys Leu Gly Ser 560 565 570gcc tac ctg ccc tcc tat cac cac tcc cca tac aag cac gcg cac atc 1898Ala Tyr Leu Pro Ser Tyr His His Ser Pro Tyr Lys His Ala His Ile575 580 585 590ccg gcg cac gcc cag cac tac cag agc tac atg cag ctg atc cag cag 1946Pro Ala His Ala Gln His Tyr Gln Ser Tyr Met Gln Leu Ile Gln Gln 595 600 605aag tcg gcc gtg gag tac gcg caa agc cag atg agc ctg gtg agc atg 1994Lys Ser Ala Val Glu Tyr Ala Gln Ser Gln Met Ser Leu Val Ser Met 610 615 620tgc aag gac ctg agc tct ccc acc ccg tcg gag ccg cgc atg gag tgg 2042Cys Lys Asp Leu Ser Ser Pro Thr Pro Ser Glu Pro Arg Met Glu Trp 625 630 635aag gtg aag atc cgc agc gac ggg acg cgc tac atc acc aag agg ccc 2090Lys Val Lys Ile Arg Ser Asp Gly Thr Arg Tyr Ile Thr Lys Arg Pro 640 645 650gtg cgg gac cgc ctg ctg cgg gag cgc gcc ctg aag atc cgg gaa gag 2138Val Arg Asp Arg Leu Leu Arg Glu Arg Ala Leu Lys Ile Arg Glu Glu655 660 665 670cgc agc ggc atg acc acc gac gac gac gcg gtg agc gag atg aag atg 2186Arg Ser Gly Met Thr Thr Asp Asp Asp Ala Val Ser Glu Met Lys Met 675 680 685ggg cgc tac tgg agc aag gag gag agg aag cag cac ctg gtg aag gcc 2234Gly Arg Tyr Trp Ser Lys Glu Glu Arg Lys Gln His Leu Val Lys Ala 690 695 700aag gag cag cgg cgg cgg cgc gag ttc atg atg cag agc agg ttg gat 2282Lys Glu Gln Arg Arg Arg Arg Glu Phe Met Met Gln Ser Arg Leu Asp 705 710 715tgt ctc aag gag cag caa gca gcc gat gac agg aag gag atg aac att 2330Cys Leu Lys Glu Gln Gln Ala Ala Asp Asp Arg Lys Glu Met Asn Ile 720 725 730ctc gaa ctg agc cac aaa aag atg atg aag aag agg aat aag aaa atc 2378Leu Glu Leu Ser His Lys Lys Met Met Lys Lys Arg Asn Lys Lys Ile735 740 745 750ttc gat aac tgg atg acg atc caa gaa ctc tta acc cac ggc aca aaa 2426Phe Asp Asn Trp Met Thr Ile Gln Glu Leu Leu Thr His Gly Thr Lys 755 760 765tcc ccg gac ggc act aga gta tac aat tcc ttc cta tcg gtg act act 2474Ser Pro Asp Gly Thr Arg Val Tyr Asn Ser Phe Leu Ser Val Thr Thr 770 775 780gta taa ttttcacttc tgcattatgt acataaagga gaccactacc actggggtag 2530Valaaattcctgc ctcgttcaat gcggcaagtt tttgtatata 2570213783PRTHomo sapiens 213Met Gly Cys Ser Leu Cys Ser Leu Gln Lys Gln Glu Glu Gln Tyr Lys1 5 10 15Leu Leu Tyr Glu Val Cys Gln Val Asn Gly Arg Asp Leu Ser Arg Ala 20 25 30Thr His Asp Gln Ala Val Glu Ala Phe Lys Thr Ala Lys Glu Pro Ile 35 40 45Val Val Gln Val Leu Arg Arg Thr Pro Arg Thr Lys Met Phe Thr Pro 50 55 60Pro Ser Glu Ser Gln Leu

Val Asp Thr Gly Thr Gln Thr Asp Ile Thr65 70 75 80Phe Glu His Ile Met Ala Leu Thr Lys Met Ser Ser Pro Ser Pro Pro 85 90 95Val Leu Asp Pro Tyr Leu Leu Pro Glu Glu His Pro Ser Ala His Glu 100 105 110Tyr Tyr Asp Pro Asn Asp Tyr Ile Gly Asp Ile His Gln Glu Met Asp 115 120 125Arg Glu Glu Leu Glu Leu Glu Glu Val Asp Leu Tyr Arg Met Asn Ser 130 135 140Gln Asp Lys Leu Gly Leu Thr Val Cys Tyr Arg Thr Asp Asp Glu Asp145 150 155 160Asp Ile Gly Ile Tyr Ile Ser Glu Ile Asp Pro Asn Ser Ile Ala Ala 165 170 175Lys Asp Gly Arg Ile Arg Glu Gly Asp Arg Ile Ile Gln Ile Asn Gly 180 185 190Ile Glu Val Gln Asn Arg Glu Glu Ala Val Ala Leu Leu Thr Ser Glu 195 200 205Glu Asn Lys Asn Phe Ser Leu Leu Ile Ala Arg Pro Glu Leu Gln Leu 210 215 220Asp Glu Gly Trp Met Asp Asp Asp Arg Asn Asp Phe Leu Asp Asp Leu225 230 235 240His Met Asp Met Leu Glu Glu Gln His His Gln Ala Met Gln Phe Thr 245 250 255Ala Ser Val Leu Gln Gln Lys Lys His Asp Glu Asp Gly Gly Thr Thr 260 265 270Asp Thr Ala Thr Ile Leu Ser Asn Gln His Glu Lys Asp Ser Gly Val 275 280 285Gly Arg Thr Asp Glu Ser Thr Arg Asn Asp Glu Ser Ser Glu Gln Glu 290 295 300Asn Asn Gly Asp Asp Ala Thr Ala Ser Ser Asn Pro Leu Ala Gly Gln305 310 315 320Arg Lys Leu Thr Cys Ser Gln Asp Thr Leu Gly Ser Gly Asp Leu Pro 325 330 335Phe Ser Asn Glu Ser Phe Ile Ser Ala Asp Cys Thr Asp Ala Asp Tyr 340 345 350Leu Gly Ile Pro Val Asp Glu Cys Glu Arg Phe Arg Glu Leu Leu Glu 355 360 365Leu Lys Cys Gln Val Lys Ser Ala Thr Pro Tyr Gly Leu Tyr Tyr Pro 370 375 380Ser Gly Pro Leu Asp Ala Gly Lys Ser Asp Pro Glu Ser Val Asp Lys385 390 395 400Glu Leu Glu Leu Leu Asn Glu Glu Leu Arg Ser Ile Glu Leu Glu Cys 405 410 415Leu Ser Ile Val Arg Ala His Lys Met Gln Gln Leu Lys Glu Gln Tyr 420 425 430Arg Glu Ser Trp Met Leu His Asn Ser Gly Phe Arg Asn Tyr Asn Thr 435 440 445Ser Ile Asp Val Arg Arg His Glu Leu Ser Asp Ile Thr Glu Leu Pro 450 455 460Glu Lys Ser Asp Lys Asp Ser Ser Ser Ala Tyr Asn Thr Gly Glu Ser465 470 475 480Cys Arg Ser Thr Pro Leu Thr Leu Glu Ile Ser Pro Asp Asn Ser Leu 485 490 495Arg Arg Ala Ala Glu Gly Ile Ser Cys Pro Ser Ser Glu Gly Ala Val 500 505 510Gly Thr Thr Glu Ala Tyr Gly Pro Ala Ser Lys Asn Leu Leu Ser Ile 515 520 525Thr Glu Asp Pro Glu Val Gly Thr Pro Thr Tyr Ser Pro Ser Leu Lys 530 535 540Glu Leu Asp Pro Asn Gln Pro Leu Glu Ser Lys Glu Arg Arg Ala Ser545 550 555 560Asp Gly Ser Arg Ser Pro Thr Pro Ser Gln Lys Leu Gly Ser Ala Tyr 565 570 575Leu Pro Ser Tyr His His Ser Pro Tyr Lys His Ala His Ile Pro Ala 580 585 590His Ala Gln His Tyr Gln Ser Tyr Met Gln Leu Ile Gln Gln Lys Ser 595 600 605Ala Val Glu Tyr Ala Gln Ser Gln Met Ser Leu Val Ser Met Cys Lys 610 615 620Asp Leu Ser Ser Pro Thr Pro Ser Glu Pro Arg Met Glu Trp Lys Val625 630 635 640Lys Ile Arg Ser Asp Gly Thr Arg Tyr Ile Thr Lys Arg Pro Val Arg 645 650 655Asp Arg Leu Leu Arg Glu Arg Ala Leu Lys Ile Arg Glu Glu Arg Ser 660 665 670Gly Met Thr Thr Asp Asp Asp Ala Val Ser Glu Met Lys Met Gly Arg 675 680 685Tyr Trp Ser Lys Glu Glu Arg Lys Gln His Leu Val Lys Ala Lys Glu 690 695 700Gln Arg Arg Arg Arg Glu Phe Met Met Gln Ser Arg Leu Asp Cys Leu705 710 715 720Lys Glu Gln Gln Ala Ala Asp Asp Arg Lys Glu Met Asn Ile Leu Glu 725 730 735Leu Ser His Lys Lys Met Met Lys Lys Arg Asn Lys Lys Ile Phe Asp 740 745 750Asn Trp Met Thr Ile Gln Glu Leu Leu Thr His Gly Thr Lys Ser Pro 755 760 765Asp Gly Thr Arg Val Tyr Asn Ser Phe Leu Ser Val Thr Thr Val 770 775 780214197DNAHomo sapiens 214gtgaagcgtt gcagtcgctt gactcacctg aggctctcca aggatacctt caatgcctgc 60actgtaaggg agctgctttt cccgggtgct ggcgagaacg gaagccttcc tttgacgttt 120ttctaaacat gggatgcagt ctgtgcagcc tgcagaagca agaggagcag tacaaattac 180tctatgaagt ttgtcag 19721523PRTHomo sapiens 215Met Gly Cys Ser Leu Cys Ser Leu Gln Lys Gln Glu Glu Gln Tyr Lys1 5 10 15Leu Leu Tyr Glu Val Cys Gln 2021669DNAHomo sapiens 216atgggatgca gtctgtgcag cctgcagaag caagaggagc agtacaaatt actctatgaa 60gtttgtcag 692172698DNAHomo sapiens 217agcatttgct cagtactctc aacataaacc aagcttagat cgcaatgaaa ctgcggacct 60gcaggctgcc ttgcttcact gagtcaattt ttaaatgaag atggaacaca agaggatgat 120cttattgttc agtaaattta ctctaataca taaaccccat ggtggaagat ggtatttggt 180caacggcaga gacttatcca gagcaactca tgaccaggct gtggaagctt tcaagacagc 240caaggagccc atagtggtgc aggtgttgag aagaacacca aggaccaaaa tgttcacgcc 300tccatcagag tctcagctgg tggacacggg aacccaaacc gacatcacct ttgaacatat 360catggccctc actaagatgt cctctcccag cccacccgta ctggatccct atctcttgcc 420agaggagcat ccctcagccc atgaatacta cgatccaaat gactacattg gagacatcca 480tcaggagatg gacagggagg agctggagct ggaggaagtg gacctctaca gaatgaacag 540ccaggacaag ctgggcctca ctgtgtgcta ccggacggac gatgaagacg acattgggat 600ttatatcagt gagattgacc ctaacagcat tgcagccaag gatgggcgca tccgagaagg 660agaccgcatt atccagatta atgggataga ggtgcagaac cgtgaagagg ctgtggctct 720tctaaccagt gaagaaaata aaaacttttc attgctgatt gcaaggcctg aactccagct 780ggatgagggc tggatggatg atgacaggaa cgactttctg gatgacctgc acatggacat 840gctggaggag cagcaccacc aggccatgca attcacagct agcgtgctgc agcagaagaa 900gcacgacgaa gacggtggga ccacagatac agccaccatc ttgtccaacc agcacgagaa 960ggacagcggt gtggggcgga ccgacgagag cacccgtaat gacgagagct cggagcaaga 1020gaacaatggc gacgacgcca ccgcatcctc caacccgctg gcggggcaga ggaagctcac 1080ctgcagccag gacaccttgg gcagcggcga cctgcccttc agcaacgagt ctttcatttc 1140ggccgactgc acggacgccg actacctggg gatcccggtg gacgagtgcg agcgcttccg 1200cgagctcctg gagctcaagt gccaggtgaa gagcgccacc ccttacggcc tgtactaccc 1260tagcggcccc ctggacgccg gcaagagtga ccctgagagc gtggacaagg agctggagct 1320gctgaacgaa gagctgcgca gcatcgagct ggagtgcctg agcatcgtgc gcgcccacaa 1380gatgcagcag ctcaaggagc agtaccgcga gtcctggatg ctgcacaaca gcggcttccg 1440caactacaac accagcatcg acgtgcgcag acacgagctc tcggatatca ccgagctccc 1500ggagaaatcc gacaaggaca gctcgagcgc ctacaacaca ggcgagagct gccgcagcac 1560cccgctcacc ctggagatct cccccgacaa ctccttgagg agagcggtgg agggcatcag 1620ctgcccgagc agcgaagggg ctgtggggac cacggaagcc tacgggccag cctccaagaa 1680tctgctctcc atcacggaag atcccgaagt gggcacccct acctatagcc cgtccctgaa 1740ggagctggac cccaaccagc ccctggaaag caaagagcgg agagccagcg acgggagccg 1800gagccccacg cccagccaga agctgggcag cgcctacctg ccctcctatc accactcccc 1860atacaagcac gcgcacatcc cggcgcacgc ccagcactac cagagctaca tgcagctgat 1920ccagcagaag tcggccgtgg agtacgcgca aagccagatg agcctggtga gcatgtgcaa 1980ggacctgagc tctcccaccc cgtcggagcc gcgcatggag tggaaggtga agatccgcag 2040cgacgggacg cgctacatca ccaagaggcc cgtgcgggac cgcctgctgc gggagcgcgc 2100cctgaagatc cgggaagagc gcagcggcat gaccaccgac gacgacgcgg tgagcgagat 2160gaagatgggg cgctactgga gcaaggagga gaggaagcag cacctggtga aggccaagga 2220gcagcggcgg cggcgcgagt tcatgatgca gagcaggttg gattgtctca aggagcagca 2280agcagccgat gacaggaagg agatgaacat tctcgaactg agccacaaaa agatgatgaa 2340gaagaggaat aagaaaatct tcgataactg gatgacgatc caagaactct taacccacgg 2400cacaaaatcc ccggacggca ctagagtata caattccttc ctatcggtga ctactgtata 2460attttcactt ctgcattatg tacataaagg agaccactac cactggggta gaaattcctg 2520cctcgttcaa tgcggcaagt ttttgtatat aagataagta cggtcttcat gtttatagtc 2580caaatttgca aaccctacaa ctctgggtgt cataggtcta ttttaaggga agagagagaa 2640aaacaccctt actatcttgg aaggcaatat taacaaacag agcttttttc aaatagca 26982182698DNAHomo sapiensCDS(95)..(2461) 218agcatttgct cagtactctc aacataaacc aagcttagat cgcaatgaaa ctgcggacct 60gcaggctgcc ttgcttcact gagtcaattt ttaa atg aag atg gaa cac aag agg 115 Met Lys Met Glu His Lys Arg 1 5atg atc tta ttg ttc agt aaa ttt act cta ata cat aaa ccc cat ggt 163Met Ile Leu Leu Phe Ser Lys Phe Thr Leu Ile His Lys Pro His Gly 10 15 20gga aga tgg tat ttg gtc aac ggc aga gac tta tcc aga gca act cat 211Gly Arg Trp Tyr Leu Val Asn Gly Arg Asp Leu Ser Arg Ala Thr His 25 30 35gac cag gct gtg gaa gct ttc aag aca gcc aag gag ccc ata gtg gtg 259Asp Gln Ala Val Glu Ala Phe Lys Thr Ala Lys Glu Pro Ile Val Val40 45 50 55cag gtg ttg aga aga aca cca agg acc aaa atg ttc acg cct cca tca 307Gln Val Leu Arg Arg Thr Pro Arg Thr Lys Met Phe Thr Pro Pro Ser 60 65 70gag tct cag ctg gtg gac acg gga acc caa acc gac atc acc ttt gaa 355Glu Ser Gln Leu Val Asp Thr Gly Thr Gln Thr Asp Ile Thr Phe Glu 75 80 85cat atc atg gcc ctc act aag atg tcc tct ccc agc cca ccc gta ctg 403His Ile Met Ala Leu Thr Lys Met Ser Ser Pro Ser Pro Pro Val Leu 90 95 100gat ccc tat ctc ttg cca gag gag cat ccc tca gcc cat gaa tac tac 451Asp Pro Tyr Leu Leu Pro Glu Glu His Pro Ser Ala His Glu Tyr Tyr 105 110 115gat cca aat gac tac att gga gac atc cat cag gag atg gac agg gag 499Asp Pro Asn Asp Tyr Ile Gly Asp Ile His Gln Glu Met Asp Arg Glu120 125 130 135gag ctg gag ctg gag gaa gtg gac ctc tac aga atg aac agc cag gac 547Glu Leu Glu Leu Glu Glu Val Asp Leu Tyr Arg Met Asn Ser Gln Asp 140 145 150aag ctg ggc ctc act gtg tgc tac cgg acg gac gat gaa gac gac att 595Lys Leu Gly Leu Thr Val Cys Tyr Arg Thr Asp Asp Glu Asp Asp Ile 155 160 165ggg att tat atc agt gag att gac cct aac agc att gca gcc aag gat 643Gly Ile Tyr Ile Ser Glu Ile Asp Pro Asn Ser Ile Ala Ala Lys Asp 170 175 180ggg cgc atc cga gaa gga gac cgc att atc cag att aat ggg ata gag 691Gly Arg Ile Arg Glu Gly Asp Arg Ile Ile Gln Ile Asn Gly Ile Glu 185 190 195gtg cag aac cgt gaa gag gct gtg gct ctt cta acc agt gaa gaa aat 739Val Gln Asn Arg Glu Glu Ala Val Ala Leu Leu Thr Ser Glu Glu Asn200 205 210 215aaa aac ttt tca ttg ctg att gca agg cct gaa ctc cag ctg gat gag 787Lys Asn Phe Ser Leu Leu Ile Ala Arg Pro Glu Leu Gln Leu Asp Glu 220 225 230ggc tgg atg gat gat gac agg aac gac ttt ctg gat gac ctg cac atg 835Gly Trp Met Asp Asp Asp Arg Asn Asp Phe Leu Asp Asp Leu His Met 235 240 245gac atg ctg gag gag cag cac cac cag gcc atg caa ttc aca gct agc 883Asp Met Leu Glu Glu Gln His His Gln Ala Met Gln Phe Thr Ala Ser 250 255 260gtg ctg cag cag aag aag cac gac gaa gac ggt ggg acc aca gat aca 931Val Leu Gln Gln Lys Lys His Asp Glu Asp Gly Gly Thr Thr Asp Thr 265 270 275gcc acc atc ttg tcc aac cag cac gag aag gac agc ggt gtg ggg cgg 979Ala Thr Ile Leu Ser Asn Gln His Glu Lys Asp Ser Gly Val Gly Arg280 285 290 295acc gac gag agc acc cgt aat gac gag agc tcg gag caa gag aac aat 1027Thr Asp Glu Ser Thr Arg Asn Asp Glu Ser Ser Glu Gln Glu Asn Asn 300 305 310ggc gac gac gcc acc gca tcc tcc aac ccg ctg gcg ggg cag agg aag 1075Gly Asp Asp Ala Thr Ala Ser Ser Asn Pro Leu Ala Gly Gln Arg Lys 315 320 325ctc acc tgc agc cag gac acc ttg ggc agc ggc gac ctg ccc ttc agc 1123Leu Thr Cys Ser Gln Asp Thr Leu Gly Ser Gly Asp Leu Pro Phe Ser 330 335 340aac gag tct ttc att tcg gcc gac tgc acg gac gcc gac tac ctg ggg 1171Asn Glu Ser Phe Ile Ser Ala Asp Cys Thr Asp Ala Asp Tyr Leu Gly 345 350 355atc ccg gtg gac gag tgc gag cgc ttc cgc gag ctc ctg gag ctc aag 1219Ile Pro Val Asp Glu Cys Glu Arg Phe Arg Glu Leu Leu Glu Leu Lys360 365 370 375tgc cag gtg aag agc gcc acc cct tac ggc ctg tac tac cct agc ggc 1267Cys Gln Val Lys Ser Ala Thr Pro Tyr Gly Leu Tyr Tyr Pro Ser Gly 380 385 390ccc ctg gac gcc ggc aag agt gac cct gag agc gtg gac aag gag ctg 1315Pro Leu Asp Ala Gly Lys Ser Asp Pro Glu Ser Val Asp Lys Glu Leu 395 400 405gag ctg ctg aac gaa gag ctg cgc agc atc gag ctg gag tgc ctg agc 1363Glu Leu Leu Asn Glu Glu Leu Arg Ser Ile Glu Leu Glu Cys Leu Ser 410 415 420atc gtg cgc gcc cac aag atg cag cag ctc aag gag cag tac cgc gag 1411Ile Val Arg Ala His Lys Met Gln Gln Leu Lys Glu Gln Tyr Arg Glu 425 430 435tcc tgg atg ctg cac aac agc ggc ttc cgc aac tac aac acc agc atc 1459Ser Trp Met Leu His Asn Ser Gly Phe Arg Asn Tyr Asn Thr Ser Ile440 445 450 455gac gtg cgc aga cac gag ctc tcg gat atc acc gag ctc ccg gag aaa 1507Asp Val Arg Arg His Glu Leu Ser Asp Ile Thr Glu Leu Pro Glu Lys 460 465 470tcc gac aag gac agc tcg agc gcc tac aac aca ggc gag agc tgc cgc 1555Ser Asp Lys Asp Ser Ser Ser Ala Tyr Asn Thr Gly Glu Ser Cys Arg 475 480 485agc acc ccg ctc acc ctg gag atc tcc ccc gac aac tcc ttg agg aga 1603Ser Thr Pro Leu Thr Leu Glu Ile Ser Pro Asp Asn Ser Leu Arg Arg 490 495 500gcg gtg gag ggc atc agc tgc ccg agc agc gaa ggg gct gtg ggg acc 1651Ala Val Glu Gly Ile Ser Cys Pro Ser Ser Glu Gly Ala Val Gly Thr 505 510 515acg gaa gcc tac ggg cca gcc tcc aag aat ctg ctc tcc atc acg gaa 1699Thr Glu Ala Tyr Gly Pro Ala Ser Lys Asn Leu Leu Ser Ile Thr Glu520 525 530 535gat ccc gaa gtg ggc acc cct acc tat agc ccg tcc ctg aag gag ctg 1747Asp Pro Glu Val Gly Thr Pro Thr Tyr Ser Pro Ser Leu Lys Glu Leu 540 545 550gac ccc aac cag ccc ctg gaa agc aaa gag cgg aga gcc agc gac ggg 1795Asp Pro Asn Gln Pro Leu Glu Ser Lys Glu Arg Arg Ala Ser Asp Gly 555 560 565agc cgg agc ccc acg ccc agc cag aag ctg ggc agc gcc tac ctg ccc 1843Ser Arg Ser Pro Thr Pro Ser Gln Lys Leu Gly Ser Ala Tyr Leu Pro 570 575 580tcc tat cac cac tcc cca tac aag cac gcg cac atc ccg gcg cac gcc 1891Ser Tyr His His Ser Pro Tyr Lys His Ala His Ile Pro Ala His Ala 585 590 595cag cac tac cag agc tac atg cag ctg atc cag cag aag tcg gcc gtg 1939Gln His Tyr Gln Ser Tyr Met Gln Leu Ile Gln Gln Lys Ser Ala Val600 605 610 615gag tac gcg caa agc cag atg agc ctg gtg agc atg tgc aag gac ctg 1987Glu Tyr Ala Gln Ser Gln Met Ser Leu Val Ser Met Cys Lys Asp Leu 620 625 630agc tct ccc acc ccg tcg gag ccg cgc atg gag tgg aag gtg aag atc 2035Ser Ser Pro Thr Pro Ser Glu Pro Arg Met Glu Trp Lys Val Lys Ile 635 640 645cgc agc gac ggg acg cgc tac atc acc aag agg ccc gtg cgg gac cgc 2083Arg Ser Asp Gly Thr Arg Tyr Ile Thr Lys Arg Pro Val Arg Asp Arg 650 655 660ctg ctg cgg gag cgc gcc ctg aag atc cgg gaa gag cgc agc ggc atg 2131Leu Leu Arg Glu Arg Ala Leu Lys Ile Arg Glu Glu Arg Ser Gly Met 665 670 675acc acc gac gac gac gcg gtg agc gag atg aag atg ggg cgc tac tgg 2179Thr Thr Asp Asp Asp Ala Val Ser Glu Met Lys Met Gly Arg Tyr Trp680 685 690 695agc aag gag gag agg aag cag cac ctg gtg aag gcc aag gag cag cgg 2227Ser Lys Glu Glu Arg Lys Gln His Leu Val Lys Ala Lys Glu Gln Arg 700 705 710cgg cgg cgc gag ttc atg atg cag agc agg ttg gat tgt ctc aag gag 2275Arg Arg Arg Glu Phe Met Met Gln Ser Arg Leu Asp Cys Leu Lys Glu 715 720 725cag caa gca gcc gat gac agg aag gag atg aac att ctc gaa ctg agc 2323Gln Gln Ala Ala Asp Asp Arg Lys Glu Met Asn Ile Leu Glu Leu Ser 730 735

740cac aaa aag atg atg aag aag agg aat aag aaa atc ttc gat aac tgg 2371His Lys Lys Met Met Lys Lys Arg Asn Lys Lys Ile Phe Asp Asn Trp 745 750 755atg acg atc caa gaa ctc tta acc cac ggc aca aaa tcc ccg gac ggc 2419Met Thr Ile Gln Glu Leu Leu Thr His Gly Thr Lys Ser Pro Asp Gly760 765 770 775act aga gta tac aat tcc ttc cta tcg gtg act act gta taa 2461Thr Arg Val Tyr Asn Ser Phe Leu Ser Val Thr Thr Val 780 785ttttcacttc tgcattatgt acataaagga gaccactacc actggggtag aaattcctgc 2521ctcgttcaat gcggcaagtt tttgtatata agataagtac ggtcttcatg tttatagtcc 2581aaatttgcaa accctacaac tctgggtgtc ataggtctat tttaagggaa gagagagaaa 2641aacaccctta ctatcttgga aggcaatatt aacaaacaga gcttttttca aatagca 2698219788PRTHomo sapiens 219Met Lys Met Glu His Lys Arg Met Ile Leu Leu Phe Ser Lys Phe Thr1 5 10 15Leu Ile His Lys Pro His Gly Gly Arg Trp Tyr Leu Val Asn Gly Arg 20 25 30Asp Leu Ser Arg Ala Thr His Asp Gln Ala Val Glu Ala Phe Lys Thr 35 40 45Ala Lys Glu Pro Ile Val Val Gln Val Leu Arg Arg Thr Pro Arg Thr 50 55 60Lys Met Phe Thr Pro Pro Ser Glu Ser Gln Leu Val Asp Thr Gly Thr65 70 75 80Gln Thr Asp Ile Thr Phe Glu His Ile Met Ala Leu Thr Lys Met Ser 85 90 95Ser Pro Ser Pro Pro Val Leu Asp Pro Tyr Leu Leu Pro Glu Glu His 100 105 110Pro Ser Ala His Glu Tyr Tyr Asp Pro Asn Asp Tyr Ile Gly Asp Ile 115 120 125His Gln Glu Met Asp Arg Glu Glu Leu Glu Leu Glu Glu Val Asp Leu 130 135 140Tyr Arg Met Asn Ser Gln Asp Lys Leu Gly Leu Thr Val Cys Tyr Arg145 150 155 160Thr Asp Asp Glu Asp Asp Ile Gly Ile Tyr Ile Ser Glu Ile Asp Pro 165 170 175Asn Ser Ile Ala Ala Lys Asp Gly Arg Ile Arg Glu Gly Asp Arg Ile 180 185 190Ile Gln Ile Asn Gly Ile Glu Val Gln Asn Arg Glu Glu Ala Val Ala 195 200 205Leu Leu Thr Ser Glu Glu Asn Lys Asn Phe Ser Leu Leu Ile Ala Arg 210 215 220Pro Glu Leu Gln Leu Asp Glu Gly Trp Met Asp Asp Asp Arg Asn Asp225 230 235 240Phe Leu Asp Asp Leu His Met Asp Met Leu Glu Glu Gln His His Gln 245 250 255Ala Met Gln Phe Thr Ala Ser Val Leu Gln Gln Lys Lys His Asp Glu 260 265 270Asp Gly Gly Thr Thr Asp Thr Ala Thr Ile Leu Ser Asn Gln His Glu 275 280 285Lys Asp Ser Gly Val Gly Arg Thr Asp Glu Ser Thr Arg Asn Asp Glu 290 295 300Ser Ser Glu Gln Glu Asn Asn Gly Asp Asp Ala Thr Ala Ser Ser Asn305 310 315 320Pro Leu Ala Gly Gln Arg Lys Leu Thr Cys Ser Gln Asp Thr Leu Gly 325 330 335Ser Gly Asp Leu Pro Phe Ser Asn Glu Ser Phe Ile Ser Ala Asp Cys 340 345 350Thr Asp Ala Asp Tyr Leu Gly Ile Pro Val Asp Glu Cys Glu Arg Phe 355 360 365Arg Glu Leu Leu Glu Leu Lys Cys Gln Val Lys Ser Ala Thr Pro Tyr 370 375 380Gly Leu Tyr Tyr Pro Ser Gly Pro Leu Asp Ala Gly Lys Ser Asp Pro385 390 395 400Glu Ser Val Asp Lys Glu Leu Glu Leu Leu Asn Glu Glu Leu Arg Ser 405 410 415Ile Glu Leu Glu Cys Leu Ser Ile Val Arg Ala His Lys Met Gln Gln 420 425 430Leu Lys Glu Gln Tyr Arg Glu Ser Trp Met Leu His Asn Ser Gly Phe 435 440 445Arg Asn Tyr Asn Thr Ser Ile Asp Val Arg Arg His Glu Leu Ser Asp 450 455 460Ile Thr Glu Leu Pro Glu Lys Ser Asp Lys Asp Ser Ser Ser Ala Tyr465 470 475 480Asn Thr Gly Glu Ser Cys Arg Ser Thr Pro Leu Thr Leu Glu Ile Ser 485 490 495Pro Asp Asn Ser Leu Arg Arg Ala Val Glu Gly Ile Ser Cys Pro Ser 500 505 510Ser Glu Gly Ala Val Gly Thr Thr Glu Ala Tyr Gly Pro Ala Ser Lys 515 520 525Asn Leu Leu Ser Ile Thr Glu Asp Pro Glu Val Gly Thr Pro Thr Tyr 530 535 540Ser Pro Ser Leu Lys Glu Leu Asp Pro Asn Gln Pro Leu Glu Ser Lys545 550 555 560Glu Arg Arg Ala Ser Asp Gly Ser Arg Ser Pro Thr Pro Ser Gln Lys 565 570 575Leu Gly Ser Ala Tyr Leu Pro Ser Tyr His His Ser Pro Tyr Lys His 580 585 590Ala His Ile Pro Ala His Ala Gln His Tyr Gln Ser Tyr Met Gln Leu 595 600 605Ile Gln Gln Lys Ser Ala Val Glu Tyr Ala Gln Ser Gln Met Ser Leu 610 615 620Val Ser Met Cys Lys Asp Leu Ser Ser Pro Thr Pro Ser Glu Pro Arg625 630 635 640Met Glu Trp Lys Val Lys Ile Arg Ser Asp Gly Thr Arg Tyr Ile Thr 645 650 655Lys Arg Pro Val Arg Asp Arg Leu Leu Arg Glu Arg Ala Leu Lys Ile 660 665 670Arg Glu Glu Arg Ser Gly Met Thr Thr Asp Asp Asp Ala Val Ser Glu 675 680 685Met Lys Met Gly Arg Tyr Trp Ser Lys Glu Glu Arg Lys Gln His Leu 690 695 700Val Lys Ala Lys Glu Gln Arg Arg Arg Arg Glu Phe Met Met Gln Ser705 710 715 720Arg Leu Asp Cys Leu Lys Glu Gln Gln Ala Ala Asp Asp Arg Lys Glu 725 730 735Met Asn Ile Leu Glu Leu Ser His Lys Lys Met Met Lys Lys Arg Asn 740 745 750Lys Lys Ile Phe Asp Asn Trp Met Thr Ile Gln Glu Leu Leu Thr His 755 760 765Gly Thr Lys Ser Pro Asp Gly Thr Arg Val Tyr Asn Ser Phe Leu Ser 770 775 780Val Thr Thr Val785220178DNAHomo sapiens 220agcatttgct cagtactctc aacataaacc aagcttagat cgcaatgaaa ctgcggacct 60gcaggctgcc ttgcttcact gagtcaattt ttaaatgaag atggaacaca agaggatgat 120cttattgttc agtaaattta ctctaataca taaaccccat ggtggaagat ggtatttg 17822128PRTHomo sapiens 221Met Lys Met Glu His Lys Arg Met Ile Leu Leu Phe Ser Lys Phe Thr1 5 10 15Leu Ile His Lys Pro His Gly Gly Arg Trp Tyr Leu 20 2522284DNAHomo sapiens 222atgaagatgg aacacaagag gatgatctta ttgttcagta aatttactct aatacataaa 60ccccatggtg gaagatggta tttg 842232927DNAHomo sapiens 223agcatttgct cagtactctc aacataaacc aagcttagat cgcaatgaaa ctgcggacct 60gcaggctgcc ttgcttcact gagtcaattt ttaaatgaag atggaacaca agaggatgat 120cttattgttc agtaaattta ctctaataca taaaccccat ggtggaagat ggtatttggt 180caacggcaga gacttatcca gagcaactca tgaccaggct gtggaagctt tcaagacagc 240caaggagccc atagtggtgc aggtgttgag aagaacacca aggaccaaaa tgttcacgcc 300tccatcagag tctcagctgg tggacacggg aacccaaacc gacatcacct ttgaacatat 360catggccctc actaagatgt cctctcccag cccacccgta ctggatccct atctcttgcc 420agaggagcat ccctcagccc atgaatacta cgatccaaat gactacattg gagacatcca 480tcaggagatg gacagggagg agctggagct ggaggaagtg gacctctaca gaatgaacag 540ccaggacaag ctgggcctca ctgtgtgcta ccggacggac gatgaagacg acattgggat 600ttacatcagt gagattgacc ctaacagcat tgcagccaag gatgggcgca tccgagaagg 660agaccgcatt atccagatta atgggataga ggtgcagaac cgtgaagagg ctgtggctct 720tctaaccagt gaagaaaata aaaacttttc attgctgatt gcaaggcctg aactccagct 780ggatgagggc tggatggatg atgacaggaa cgactttctg gatgacctgc acatggacat 840gctggaggag cagcaccacc aggccatgca attcacagct agcgtgctgc agcagaagaa 900gcacgacgaa gacggtggga ccacagatac agccaccatc ttgtccaacc agcacgagaa 960ggacagcggt gtggggcgga ccgacgagag cacccgtaac gacgagagct cggagcaaga 1020gaacaatggc gacgacgcca ccgcatcctc caacccgctg gcggggcaga ggaagctcac 1080ctgcagccag gacaccttgg gcagcggcga cctgcccttc agcaacgagt ctttcatttc 1140ggccgactgc acggacgccg actacctggg gatcacggtg gacgagtgcg agcgcttccg 1200cgagctcctg gagctcaagt gccaggtgaa gagcgccacc ccttacggcc tgtactaccc 1260tagcggcccc ctggacgccg gcaagagtga ccctgagagc gtggacaagg agctggagct 1320gctgaacgaa gagctgcgca gcatcgagct ggagtgcctg agcatcgtgc gcgcccacaa 1380gatgcagcag ctcaaggagc agtaccgcga gtcctggatg ctgcacaaca gcggcttccg 1440caactacaac accagcatcg acgtgcgcag acacgagctc tcagatatca ccgagctccc 1500ggagaaatcc gacaaggaca gctcgagcgc ctacaacaca ggcgagagct gccgcagcac 1560cccgctcacc ctggagatct cccccgacaa ctccttgagg agagcggcgg agggcatcag 1620ctgcccgagc agcgaagggg ctgtggggac cacggaagcc tacgggccag cctccaagaa 1680tctgctctcc atcacggaag atcccgaagt gggcacccct acctatagcc cgtccctgaa 1740ggagctggac cccaaccagc ccctggaaag caaagagcgg agagccagcg acgggagccg 1800gagccccacg cccagccaga agctgggcag cgcctacctg ccctcctatc accactcccc 1860atacaagcac gcgcacatcc cggcgcacgc ccagcactac cagagctaca tgcagctgat 1920ccagcagaag tcggccgtgg agtacgcgca aagccagatg agcctggtga gcatgtgcaa 1980ggacctgagc tctcccaccc cgtcggagcc gcgcatggag tggaaggtga agatccgcag 2040cgacgggacg cgctacatca ccaagaggcc cgtgcgggac cgcctgctgc gggagcgcgc 2100cctgaagatc cgggaagagc gcagcggcat gaccaccgac gacgacgcgg tgagcgagat 2160gaagatgggg cgctactgga gcaaggagga gaggaagcag cacctggtga aggccaagga 2220gcagcggcgg cggcgcgagt tcatgatgca gagcaggttg gattgtctca aggagcagca 2280agcagccgat gacaggaagg agatgaacat tctcgaactg agccacaaaa agatgatgaa 2340gaagaggaat aagaaaatct tcgataactg gatgacgatc caagaactct taacccacgg 2400cacaaaatcc ccggacggca ctagagtata caattccttc ctatcggtga ctactgtata 2460attttcactt ctgcattatg tacataaagg agaccactac cactggggta gaaattcctg 2520cctcgttcaa tgcggcaagt ttttgtatat aagataagta cggtcttcat gtttacagtc 2580caaatttgca aaccctacaa ctctgggtgt cataggtcta ttttaaggga agagagagaa 2640aaacaccctt actatcttgg aaggcaatat taacaaacag atcttttttc aaatagcaat 2700tgtacttttc tacctgtacc cttttacata aagtgtttaa atttcagaaa gatcttttat 2760taagcatact ttcacagaat aacttgttta aactatattc atataaaaaa gttaaacacg 2820ctttttttcc tgcctaaaac acaaatacaa ctgccagtat gtatttttaa tggaacccta 2880ttttataatg gtacgttact gaatgtgttt catatgcgtg accgtta 29272242927DNAHomo sapiensCDS(95)..(2461) 224agcatttgct cagtactctc aacataaacc aagcttagat cgcaatgaaa ctgcggacct 60gcaggctgcc ttgcttcact gagtcaattt ttaa atg aag atg gaa cac aag agg 115 Met Lys Met Glu His Lys Arg 1 5atg atc tta ttg ttc agt aaa ttt act cta ata cat aaa ccc cat ggt 163Met Ile Leu Leu Phe Ser Lys Phe Thr Leu Ile His Lys Pro His Gly 10 15 20gga aga tgg tat ttg gtc aac ggc aga gac tta tcc aga gca act cat 211Gly Arg Trp Tyr Leu Val Asn Gly Arg Asp Leu Ser Arg Ala Thr His 25 30 35gac cag gct gtg gaa gct ttc aag aca gcc aag gag ccc ata gtg gtg 259Asp Gln Ala Val Glu Ala Phe Lys Thr Ala Lys Glu Pro Ile Val Val40 45 50 55cag gtg ttg aga aga aca cca agg acc aaa atg ttc acg cct cca tca 307Gln Val Leu Arg Arg Thr Pro Arg Thr Lys Met Phe Thr Pro Pro Ser 60 65 70gag tct cag ctg gtg gac acg gga acc caa acc gac atc acc ttt gaa 355Glu Ser Gln Leu Val Asp Thr Gly Thr Gln Thr Asp Ile Thr Phe Glu 75 80 85cat atc atg gcc ctc act aag atg tcc tct ccc agc cca ccc gta ctg 403His Ile Met Ala Leu Thr Lys Met Ser Ser Pro Ser Pro Pro Val Leu 90 95 100gat ccc tat ctc ttg cca gag gag cat ccc tca gcc cat gaa tac tac 451Asp Pro Tyr Leu Leu Pro Glu Glu His Pro Ser Ala His Glu Tyr Tyr 105 110 115gat cca aat gac tac att gga gac atc cat cag gag atg gac agg gag 499Asp Pro Asn Asp Tyr Ile Gly Asp Ile His Gln Glu Met Asp Arg Glu120 125 130 135gag ctg gag ctg gag gaa gtg gac ctc tac aga atg aac agc cag gac 547Glu Leu Glu Leu Glu Glu Val Asp Leu Tyr Arg Met Asn Ser Gln Asp 140 145 150aag ctg ggc ctc act gtg tgc tac cgg acg gac gat gaa gac gac att 595Lys Leu Gly Leu Thr Val Cys Tyr Arg Thr Asp Asp Glu Asp Asp Ile 155 160 165ggg att tac atc agt gag att gac cct aac agc att gca gcc aag gat 643Gly Ile Tyr Ile Ser Glu Ile Asp Pro Asn Ser Ile Ala Ala Lys Asp 170 175 180ggg cgc atc cga gaa gga gac cgc att atc cag att aat ggg ata gag 691Gly Arg Ile Arg Glu Gly Asp Arg Ile Ile Gln Ile Asn Gly Ile Glu 185 190 195gtg cag aac cgt gaa gag gct gtg gct ctt cta acc agt gaa gaa aat 739Val Gln Asn Arg Glu Glu Ala Val Ala Leu Leu Thr Ser Glu Glu Asn200 205 210 215aaa aac ttt tca ttg ctg att gca agg cct gaa ctc cag ctg gat gag 787Lys Asn Phe Ser Leu Leu Ile Ala Arg Pro Glu Leu Gln Leu Asp Glu 220 225 230ggc tgg atg gat gat gac agg aac gac ttt ctg gat gac ctg cac atg 835Gly Trp Met Asp Asp Asp Arg Asn Asp Phe Leu Asp Asp Leu His Met 235 240 245gac atg ctg gag gag cag cac cac cag gcc atg caa ttc aca gct agc 883Asp Met Leu Glu Glu Gln His His Gln Ala Met Gln Phe Thr Ala Ser 250 255 260gtg ctg cag cag aag aag cac gac gaa gac ggt ggg acc aca gat aca 931Val Leu Gln Gln Lys Lys His Asp Glu Asp Gly Gly Thr Thr Asp Thr 265 270 275gcc acc atc ttg tcc aac cag cac gag aag gac agc ggt gtg ggg cgg 979Ala Thr Ile Leu Ser Asn Gln His Glu Lys Asp Ser Gly Val Gly Arg280 285 290 295acc gac gag agc acc cgt aac gac gag agc tcg gag caa gag aac aat 1027Thr Asp Glu Ser Thr Arg Asn Asp Glu Ser Ser Glu Gln Glu Asn Asn 300 305 310ggc gac gac gcc acc gca tcc tcc aac ccg ctg gcg ggg cag agg aag 1075Gly Asp Asp Ala Thr Ala Ser Ser Asn Pro Leu Ala Gly Gln Arg Lys 315 320 325ctc acc tgc agc cag gac acc ttg ggc agc ggc gac ctg ccc ttc agc 1123Leu Thr Cys Ser Gln Asp Thr Leu Gly Ser Gly Asp Leu Pro Phe Ser 330 335 340aac gag tct ttc att tcg gcc gac tgc acg gac gcc gac tac ctg ggg 1171Asn Glu Ser Phe Ile Ser Ala Asp Cys Thr Asp Ala Asp Tyr Leu Gly 345 350 355atc acg gtg gac gag tgc gag cgc ttc cgc gag ctc ctg gag ctc aag 1219Ile Thr Val Asp Glu Cys Glu Arg Phe Arg Glu Leu Leu Glu Leu Lys360 365 370 375tgc cag gtg aag agc gcc acc cct tac ggc ctg tac tac cct agc ggc 1267Cys Gln Val Lys Ser Ala Thr Pro Tyr Gly Leu Tyr Tyr Pro Ser Gly 380 385 390ccc ctg gac gcc ggc aag agt gac cct gag agc gtg gac aag gag ctg 1315Pro Leu Asp Ala Gly Lys Ser Asp Pro Glu Ser Val Asp Lys Glu Leu 395 400 405gag ctg ctg aac gaa gag ctg cgc agc atc gag ctg gag tgc ctg agc 1363Glu Leu Leu Asn Glu Glu Leu Arg Ser Ile Glu Leu Glu Cys Leu Ser 410 415 420atc gtg cgc gcc cac aag atg cag cag ctc aag gag cag tac cgc gag 1411Ile Val Arg Ala His Lys Met Gln Gln Leu Lys Glu Gln Tyr Arg Glu 425 430 435tcc tgg atg ctg cac aac agc ggc ttc cgc aac tac aac acc agc atc 1459Ser Trp Met Leu His Asn Ser Gly Phe Arg Asn Tyr Asn Thr Ser Ile440 445 450 455gac gtg cgc aga cac gag ctc tca gat atc acc gag ctc ccg gag aaa 1507Asp Val Arg Arg His Glu Leu Ser Asp Ile Thr Glu Leu Pro Glu Lys 460 465 470tcc gac aag gac agc tcg agc gcc tac aac aca ggc gag agc tgc cgc 1555Ser Asp Lys Asp Ser Ser Ser Ala Tyr Asn Thr Gly Glu Ser Cys Arg 475 480 485agc acc ccg ctc acc ctg gag atc tcc ccc gac aac tcc ttg agg aga 1603Ser Thr Pro Leu Thr Leu Glu Ile Ser Pro Asp Asn Ser Leu Arg Arg 490 495 500gcg gcg gag ggc atc agc tgc ccg agc agc gaa ggg gct gtg ggg acc 1651Ala Ala Glu Gly Ile Ser Cys Pro Ser Ser Glu Gly Ala Val Gly Thr 505 510 515acg gaa gcc tac ggg cca gcc tcc aag aat ctg ctc tcc atc acg gaa 1699Thr Glu Ala Tyr Gly Pro Ala Ser Lys Asn Leu Leu Ser Ile Thr Glu520 525 530 535gat ccc gaa gtg ggc acc cct acc tat agc ccg tcc ctg aag gag ctg 1747Asp Pro Glu Val Gly Thr Pro Thr Tyr Ser Pro Ser Leu Lys Glu Leu 540 545 550gac ccc aac cag ccc ctg gaa agc aaa gag cgg aga gcc agc gac ggg 1795Asp Pro Asn Gln Pro Leu Glu Ser Lys Glu Arg Arg Ala Ser Asp Gly 555 560 565agc cgg agc ccc acg ccc agc cag aag ctg ggc agc gcc tac ctg ccc 1843Ser Arg Ser Pro Thr Pro Ser Gln Lys Leu Gly Ser Ala Tyr Leu Pro 570 575 580tcc tat cac cac tcc cca tac aag cac gcg cac atc ccg gcg cac gcc 1891Ser Tyr His His Ser Pro Tyr Lys His Ala His Ile Pro Ala His Ala 585 590 595cag cac tac cag agc tac atg cag ctg atc cag

cag aag tcg gcc gtg 1939Gln His Tyr Gln Ser Tyr Met Gln Leu Ile Gln Gln Lys Ser Ala Val600 605 610 615gag tac gcg caa agc cag atg agc ctg gtg agc atg tgc aag gac ctg 1987Glu Tyr Ala Gln Ser Gln Met Ser Leu Val Ser Met Cys Lys Asp Leu 620 625 630agc tct ccc acc ccg tcg gag ccg cgc atg gag tgg aag gtg aag atc 2035Ser Ser Pro Thr Pro Ser Glu Pro Arg Met Glu Trp Lys Val Lys Ile 635 640 645cgc agc gac ggg acg cgc tac atc acc aag agg ccc gtg cgg gac cgc 2083Arg Ser Asp Gly Thr Arg Tyr Ile Thr Lys Arg Pro Val Arg Asp Arg 650 655 660ctg ctg cgg gag cgc gcc ctg aag atc cgg gaa gag cgc agc ggc atg 2131Leu Leu Arg Glu Arg Ala Leu Lys Ile Arg Glu Glu Arg Ser Gly Met 665 670 675acc acc gac gac gac gcg gtg agc gag atg aag atg ggg cgc tac tgg 2179Thr Thr Asp Asp Asp Ala Val Ser Glu Met Lys Met Gly Arg Tyr Trp680 685 690 695agc aag gag gag agg aag cag cac ctg gtg aag gcc aag gag cag cgg 2227Ser Lys Glu Glu Arg Lys Gln His Leu Val Lys Ala Lys Glu Gln Arg 700 705 710cgg cgg cgc gag ttc atg atg cag agc agg ttg gat tgt ctc aag gag 2275Arg Arg Arg Glu Phe Met Met Gln Ser Arg Leu Asp Cys Leu Lys Glu 715 720 725cag caa gca gcc gat gac agg aag gag atg aac att ctc gaa ctg agc 2323Gln Gln Ala Ala Asp Asp Arg Lys Glu Met Asn Ile Leu Glu Leu Ser 730 735 740cac aaa aag atg atg aag aag agg aat aag aaa atc ttc gat aac tgg 2371His Lys Lys Met Met Lys Lys Arg Asn Lys Lys Ile Phe Asp Asn Trp 745 750 755atg acg atc caa gaa ctc tta acc cac ggc aca aaa tcc ccg gac ggc 2419Met Thr Ile Gln Glu Leu Leu Thr His Gly Thr Lys Ser Pro Asp Gly760 765 770 775act aga gta tac aat tcc ttc cta tcg gtg act act gta taa 2461Thr Arg Val Tyr Asn Ser Phe Leu Ser Val Thr Thr Val 780 785ttttcacttc tgcattatgt acataaagga gaccactacc actggggtag aaattcctgc 2521ctcgttcaat gcggcaagtt tttgtatata agataagtac ggtcttcatg tttacagtcc 2581aaatttgcaa accctacaac tctgggtgtc ataggtctat tttaagggaa gagagagaaa 2641aacaccctta ctatcttgga aggcaatatt aacaaacaga tcttttttca aatagcaatt 2701gtacttttct acctgtaccc ttttacataa agtgtttaaa tttcagaaag atcttttatt 2761aagcatactt tcacagaata acttgtttaa actatattca tataaaaaag ttaaacacgc 2821tttttttcct gcctaaaaca caaatacaac tgccagtatg tatttttaat ggaaccctat 2881tttataatgg tacgttactg aatgtgtttc atatgcgtga ccgtta 2927225788PRTHomo sapiens 225Met Lys Met Glu His Lys Arg Met Ile Leu Leu Phe Ser Lys Phe Thr1 5 10 15Leu Ile His Lys Pro His Gly Gly Arg Trp Tyr Leu Val Asn Gly Arg 20 25 30Asp Leu Ser Arg Ala Thr His Asp Gln Ala Val Glu Ala Phe Lys Thr 35 40 45Ala Lys Glu Pro Ile Val Val Gln Val Leu Arg Arg Thr Pro Arg Thr 50 55 60Lys Met Phe Thr Pro Pro Ser Glu Ser Gln Leu Val Asp Thr Gly Thr65 70 75 80Gln Thr Asp Ile Thr Phe Glu His Ile Met Ala Leu Thr Lys Met Ser 85 90 95Ser Pro Ser Pro Pro Val Leu Asp Pro Tyr Leu Leu Pro Glu Glu His 100 105 110Pro Ser Ala His Glu Tyr Tyr Asp Pro Asn Asp Tyr Ile Gly Asp Ile 115 120 125His Gln Glu Met Asp Arg Glu Glu Leu Glu Leu Glu Glu Val Asp Leu 130 135 140Tyr Arg Met Asn Ser Gln Asp Lys Leu Gly Leu Thr Val Cys Tyr Arg145 150 155 160Thr Asp Asp Glu Asp Asp Ile Gly Ile Tyr Ile Ser Glu Ile Asp Pro 165 170 175Asn Ser Ile Ala Ala Lys Asp Gly Arg Ile Arg Glu Gly Asp Arg Ile 180 185 190Ile Gln Ile Asn Gly Ile Glu Val Gln Asn Arg Glu Glu Ala Val Ala 195 200 205Leu Leu Thr Ser Glu Glu Asn Lys Asn Phe Ser Leu Leu Ile Ala Arg 210 215 220Pro Glu Leu Gln Leu Asp Glu Gly Trp Met Asp Asp Asp Arg Asn Asp225 230 235 240Phe Leu Asp Asp Leu His Met Asp Met Leu Glu Glu Gln His His Gln 245 250 255Ala Met Gln Phe Thr Ala Ser Val Leu Gln Gln Lys Lys His Asp Glu 260 265 270Asp Gly Gly Thr Thr Asp Thr Ala Thr Ile Leu Ser Asn Gln His Glu 275 280 285Lys Asp Ser Gly Val Gly Arg Thr Asp Glu Ser Thr Arg Asn Asp Glu 290 295 300Ser Ser Glu Gln Glu Asn Asn Gly Asp Asp Ala Thr Ala Ser Ser Asn305 310 315 320Pro Leu Ala Gly Gln Arg Lys Leu Thr Cys Ser Gln Asp Thr Leu Gly 325 330 335Ser Gly Asp Leu Pro Phe Ser Asn Glu Ser Phe Ile Ser Ala Asp Cys 340 345 350Thr Asp Ala Asp Tyr Leu Gly Ile Thr Val Asp Glu Cys Glu Arg Phe 355 360 365Arg Glu Leu Leu Glu Leu Lys Cys Gln Val Lys Ser Ala Thr Pro Tyr 370 375 380Gly Leu Tyr Tyr Pro Ser Gly Pro Leu Asp Ala Gly Lys Ser Asp Pro385 390 395 400Glu Ser Val Asp Lys Glu Leu Glu Leu Leu Asn Glu Glu Leu Arg Ser 405 410 415Ile Glu Leu Glu Cys Leu Ser Ile Val Arg Ala His Lys Met Gln Gln 420 425 430Leu Lys Glu Gln Tyr Arg Glu Ser Trp Met Leu His Asn Ser Gly Phe 435 440 445Arg Asn Tyr Asn Thr Ser Ile Asp Val Arg Arg His Glu Leu Ser Asp 450 455 460Ile Thr Glu Leu Pro Glu Lys Ser Asp Lys Asp Ser Ser Ser Ala Tyr465 470 475 480Asn Thr Gly Glu Ser Cys Arg Ser Thr Pro Leu Thr Leu Glu Ile Ser 485 490 495Pro Asp Asn Ser Leu Arg Arg Ala Ala Glu Gly Ile Ser Cys Pro Ser 500 505 510Ser Glu Gly Ala Val Gly Thr Thr Glu Ala Tyr Gly Pro Ala Ser Lys 515 520 525Asn Leu Leu Ser Ile Thr Glu Asp Pro Glu Val Gly Thr Pro Thr Tyr 530 535 540Ser Pro Ser Leu Lys Glu Leu Asp Pro Asn Gln Pro Leu Glu Ser Lys545 550 555 560Glu Arg Arg Ala Ser Asp Gly Ser Arg Ser Pro Thr Pro Ser Gln Lys 565 570 575Leu Gly Ser Ala Tyr Leu Pro Ser Tyr His His Ser Pro Tyr Lys His 580 585 590Ala His Ile Pro Ala His Ala Gln His Tyr Gln Ser Tyr Met Gln Leu 595 600 605Ile Gln Gln Lys Ser Ala Val Glu Tyr Ala Gln Ser Gln Met Ser Leu 610 615 620Val Ser Met Cys Lys Asp Leu Ser Ser Pro Thr Pro Ser Glu Pro Arg625 630 635 640Met Glu Trp Lys Val Lys Ile Arg Ser Asp Gly Thr Arg Tyr Ile Thr 645 650 655Lys Arg Pro Val Arg Asp Arg Leu Leu Arg Glu Arg Ala Leu Lys Ile 660 665 670Arg Glu Glu Arg Ser Gly Met Thr Thr Asp Asp Asp Ala Val Ser Glu 675 680 685Met Lys Met Gly Arg Tyr Trp Ser Lys Glu Glu Arg Lys Gln His Leu 690 695 700Val Lys Ala Lys Glu Gln Arg Arg Arg Arg Glu Phe Met Met Gln Ser705 710 715 720Arg Leu Asp Cys Leu Lys Glu Gln Gln Ala Ala Asp Asp Arg Lys Glu 725 730 735Met Asn Ile Leu Glu Leu Ser His Lys Lys Met Met Lys Lys Arg Asn 740 745 750Lys Lys Ile Phe Asp Asn Trp Met Thr Ile Gln Glu Leu Leu Thr His 755 760 765Gly Thr Lys Ser Pro Asp Gly Thr Arg Val Tyr Asn Ser Phe Leu Ser 770 775 780Val Thr Thr Val785226178DNAHomo sapiens 226agcatttgct cagtactctc aacataaacc aagcttagat cgcaatgaaa ctgcggacct 60gcaggctgcc ttgcttcact gagtcaattt ttaaatgaag atggaacaca agaggatgat 120cttattgttc agtaaattta ctctaataca taaaccccat ggtggaagat ggtatttg 17822728PRTHomo sapiens 227Met Lys Met Glu His Lys Arg Met Ile Leu Leu Phe Ser Lys Phe Thr1 5 10 15Leu Ile His Lys Pro His Gly Gly Arg Trp Tyr Leu 20 2522884DNAHomo sapiens 228atgaagatgg aacacaagag gatgatctta ttgttcagta aatttactct aatacataaa 60ccccatggtg gaagatggta tttg 842292738DNAHomo sapiens 229atatataata gccttgcaag tgaacggata agcaaagtca gttgctgaga aataacactt 60ccgagctgac gcatccaaat gtttaggata cacctgagat gtctctctta ctgaatagaa 120acaacatccc tggaagctct agacttctga ggcaccccag ctttccctgg tcaacggcag 180agacttatcc agagcaactc atgaccaggc tgtggaagct ttcaagacag ccaaggagcc 240catagtggtg caggtgttga gaagaacacc aaggaccaaa atgttcacgc ctccatcaga 300gtctcagctg gtggacacgg gaacccaaac cgacatcacc tttgaacata tcatggccct 360cactaagatg tcctctccca gcccacccgt actggatccc tatctcttgc cagaggagca 420tccctcagcc catgaatact acgatccaaa tgactacatt ggagacatcc atcaggagat 480ggacagggag gagctggagc tggaggaagt ggacctctac agaatgaaca gccaggacaa 540gctgggcctc actgtgtgct accggacgga cgatgaagac gacattggga tttatatcag 600tgagattgac cctaacagca ttgcagccaa ggatgggcgc atccgagaag gagaccgcat 660tatccagatt aatgggatag aggtgcagaa ccgtgaagag gctgtggctc ttctaaccag 720tgaagaaaat aaaaactttt cattgctgat tgcaaggcct gaactccagc tggatgaggg 780ctggatggat gatgacagga acgactttct ggatgacctg cacatggaca tgctggagga 840gcagcaccac caggccatgc aattcacagc tagcgtgctg cagcagaaga agcacgacga 900agacggtggg accacagata cagccaccat cttgtccaac cagcacgaga aggacagcgg 960tgtggggcgg accgacgaga gcacccgtaa tgacgagagc tcggagcaag agaacaatgg 1020cgacgacgcc accgcatcct ccaacccgct ggcggggcag aggaagctca cctgcagcca 1080ggacaccttg ggcagcggcg acctgccctt cagcaacgag tctttcattt cggccgactg 1140cacggacgcc gactacctgg ggatcccggt ggacgagtgc gagcgcttcc gcgagctcct 1200ggagctcaag tgccaggtga agagcgccac cccttacggc ctgtactacc ctagcggccc 1260cctggacgcc ggcaagagtg accctgagag cgtggacaag gagctggagc tgctgaacga 1320agagctgcgc agcatcgagc tggagtgcct gagcatcgtg cgcgcccaca agatgcagca 1380gctcaaggag cagtaccgcg agtcctggat gctgcacaac agcggcttcc gcaactacaa 1440caccagcatc gacgtgcgca gacacgagct ctcggatatc accgagctcc cggagaaatc 1500cgacaaggac agctcgagcg cctacaacac aggcgagagc tgccgcagca ccccgctcac 1560cctggagatc tcccccgaca actccttgag gagagcggtg gagggcatca gctgcccgag 1620cagcgaaggg gctgtgggga ccacggaagc ctacgggcca gcctccaaga atctgctctc 1680catcacggaa gatcccgaag tgggcacccc tacctatagc ccgtccctga aggagctgga 1740ccccaaccag cccctggaaa gcaaagagcg gagagccagc gacgggagcc ggagccccac 1800gcccagccag aagctgggca gcgcctacct gccctcctat caccactccc catacaagca 1860cgcgcacatc ccggcgcacg cccagcacta ccagagctac atgcagctga tccagcagaa 1920gtcggccgtg gagtacgcgc aaagccagat gagcctggtg agcatgtgca aggacctgag 1980ctctcccacc ccgtcggagc cgcgcatgga gtggaaggtg aagatccgca gcgacgggac 2040gcgctacatc accaagaggc ccgtgcggga ccgcctgctg cgggagcgcg ccctgaagat 2100ccgggaagag cgcagcggca tgaccaccga cgacgacgcg gtgagcgaga tgaagatggg 2160gcgctactgg agcaaggagg agaggaagca gcacctggtg aaggccaagg agcagcggcg 2220gcggcgcgag ttcatgatgc agagcaggtt ggattgtctc aaggagcagc aagcagccga 2280tgacaggaag gagatgaaca ttctcgaact gagccacaaa aagatgatga agaagaggaa 2340taagaaaatc ttcgataact ggatgacgat ccaagaactc ttaacccacg gcacaaaatc 2400cccggacggc actagagtat acaattcctt cctatcggtg actactgtat aattttcact 2460tctgcattat gtacataaag gagaccacta ccactggggt agaaattcct gcctcgttca 2520atgcggcaag tttttgtata taagataagt acggtcttca tgtttacagt ccaaatttgc 2580aaaccccaca actctgggtg tcgtaggtct attttaaggg aagagagaga aaaacaccct 2640tactatcttg gaaggcaata ttaacaaaca gagctttttt caaatagcaa ttgtactttt 2700ctacctgtac ccttttacat aaagtgttta aatttcag 27382302738DNAHomo sapiensCDS(281)..(2452) 230atatataata gccttgcaag tgaacggata agcaaagtca gttgctgaga aataacactt 60ccgagctgac gcatccaaat gtttaggata cacctgagat gtctctctta ctgaatagaa 120acaacatccc tggaagctct agacttctga ggcaccccag ctttccctgg tcaacggcag 180agacttatcc agagcaactc atgaccaggc tgtggaagct ttcaagacag ccaaggagcc 240catagtggtg caggtgttga gaagaacacc aaggaccaaa atg ttc acg cct cca 295 Met Phe Thr Pro Pro 1 5tca gag tct cag ctg gtg gac acg gga acc caa acc gac atc acc ttt 343Ser Glu Ser Gln Leu Val Asp Thr Gly Thr Gln Thr Asp Ile Thr Phe 10 15 20gaa cat atc atg gcc ctc act aag atg tcc tct ccc agc cca ccc gta 391Glu His Ile Met Ala Leu Thr Lys Met Ser Ser Pro Ser Pro Pro Val 25 30 35ctg gat ccc tat ctc ttg cca gag gag cat ccc tca gcc cat gaa tac 439Leu Asp Pro Tyr Leu Leu Pro Glu Glu His Pro Ser Ala His Glu Tyr 40 45 50tac gat cca aat gac tac att gga gac atc cat cag gag atg gac agg 487Tyr Asp Pro Asn Asp Tyr Ile Gly Asp Ile His Gln Glu Met Asp Arg 55 60 65gag gag ctg gag ctg gag gaa gtg gac ctc tac aga atg aac agc cag 535Glu Glu Leu Glu Leu Glu Glu Val Asp Leu Tyr Arg Met Asn Ser Gln70 75 80 85gac aag ctg ggc ctc act gtg tgc tac cgg acg gac gat gaa gac gac 583Asp Lys Leu Gly Leu Thr Val Cys Tyr Arg Thr Asp Asp Glu Asp Asp 90 95 100att ggg att tat atc agt gag att gac cct aac agc att gca gcc aag 631Ile Gly Ile Tyr Ile Ser Glu Ile Asp Pro Asn Ser Ile Ala Ala Lys 105 110 115gat ggg cgc atc cga gaa gga gac cgc att atc cag att aat ggg ata 679Asp Gly Arg Ile Arg Glu Gly Asp Arg Ile Ile Gln Ile Asn Gly Ile 120 125 130gag gtg cag aac cgt gaa gag gct gtg gct ctt cta acc agt gaa gaa 727Glu Val Gln Asn Arg Glu Glu Ala Val Ala Leu Leu Thr Ser Glu Glu 135 140 145aat aaa aac ttt tca ttg ctg att gca agg cct gaa ctc cag ctg gat 775Asn Lys Asn Phe Ser Leu Leu Ile Ala Arg Pro Glu Leu Gln Leu Asp150 155 160 165gag ggc tgg atg gat gat gac agg aac gac ttt ctg gat gac ctg cac 823Glu Gly Trp Met Asp Asp Asp Arg Asn Asp Phe Leu Asp Asp Leu His 170 175 180atg gac atg ctg gag gag cag cac cac cag gcc atg caa ttc aca gct 871Met Asp Met Leu Glu Glu Gln His His Gln Ala Met Gln Phe Thr Ala 185 190 195agc gtg ctg cag cag aag aag cac gac gaa gac ggt ggg acc aca gat 919Ser Val Leu Gln Gln Lys Lys His Asp Glu Asp Gly Gly Thr Thr Asp 200 205 210aca gcc acc atc ttg tcc aac cag cac gag aag gac agc ggt gtg ggg 967Thr Ala Thr Ile Leu Ser Asn Gln His Glu Lys Asp Ser Gly Val Gly 215 220 225cgg acc gac gag agc acc cgt aat gac gag agc tcg gag caa gag aac 1015Arg Thr Asp Glu Ser Thr Arg Asn Asp Glu Ser Ser Glu Gln Glu Asn230 235 240 245aat ggc gac gac gcc acc gca tcc tcc aac ccg ctg gcg ggg cag agg 1063Asn Gly Asp Asp Ala Thr Ala Ser Ser Asn Pro Leu Ala Gly Gln Arg 250 255 260aag ctc acc tgc agc cag gac acc ttg ggc agc ggc gac ctg ccc ttc 1111Lys Leu Thr Cys Ser Gln Asp Thr Leu Gly Ser Gly Asp Leu Pro Phe 265 270 275agc aac gag tct ttc att tcg gcc gac tgc acg gac gcc gac tac ctg 1159Ser Asn Glu Ser Phe Ile Ser Ala Asp Cys Thr Asp Ala Asp Tyr Leu 280 285 290ggg atc ccg gtg gac gag tgc gag cgc ttc cgc gag ctc ctg gag ctc 1207Gly Ile Pro Val Asp Glu Cys Glu Arg Phe Arg Glu Leu Leu Glu Leu 295 300 305aag tgc cag gtg aag agc gcc acc cct tac ggc ctg tac tac cct agc 1255Lys Cys Gln Val Lys Ser Ala Thr Pro Tyr Gly Leu Tyr Tyr Pro Ser310 315 320 325ggc ccc ctg gac gcc ggc aag agt gac cct gag agc gtg gac aag gag 1303Gly Pro Leu Asp Ala Gly Lys Ser Asp Pro Glu Ser Val Asp Lys Glu 330 335 340ctg gag ctg ctg aac gaa gag ctg cgc agc atc gag ctg gag tgc ctg 1351Leu Glu Leu Leu Asn Glu Glu Leu Arg Ser Ile Glu Leu Glu Cys Leu 345 350 355agc atc gtg cgc gcc cac aag atg cag cag ctc aag gag cag tac cgc 1399Ser Ile Val Arg Ala His Lys Met Gln Gln Leu Lys Glu Gln Tyr Arg 360 365 370gag tcc tgg atg ctg cac aac agc ggc ttc cgc aac tac aac acc agc 1447Glu Ser Trp Met Leu His Asn Ser Gly Phe Arg Asn Tyr Asn Thr Ser 375 380 385atc gac gtg cgc aga cac gag ctc tcg gat atc acc gag ctc ccg gag 1495Ile Asp Val Arg Arg His Glu Leu Ser Asp Ile Thr Glu Leu Pro Glu390 395 400 405aaa tcc gac aag gac agc tcg agc gcc tac aac aca ggc gag agc tgc 1543Lys Ser Asp Lys Asp Ser Ser Ser Ala Tyr Asn Thr Gly Glu Ser Cys 410 415 420cgc agc acc ccg ctc acc ctg gag atc tcc ccc gac aac tcc ttg agg 1591Arg Ser Thr Pro Leu Thr Leu Glu Ile Ser Pro Asp Asn Ser Leu Arg 425

430 435aga gcg gtg gag ggc atc agc tgc ccg agc agc gaa ggg gct gtg ggg 1639Arg Ala Val Glu Gly Ile Ser Cys Pro Ser Ser Glu Gly Ala Val Gly 440 445 450acc acg gaa gcc tac ggg cca gcc tcc aag aat ctg ctc tcc atc acg 1687Thr Thr Glu Ala Tyr Gly Pro Ala Ser Lys Asn Leu Leu Ser Ile Thr 455 460 465gaa gat ccc gaa gtg ggc acc cct acc tat agc ccg tcc ctg aag gag 1735Glu Asp Pro Glu Val Gly Thr Pro Thr Tyr Ser Pro Ser Leu Lys Glu470 475 480 485ctg gac ccc aac cag ccc ctg gaa agc aaa gag cgg aga gcc agc gac 1783Leu Asp Pro Asn Gln Pro Leu Glu Ser Lys Glu Arg Arg Ala Ser Asp 490 495 500ggg agc cgg agc ccc acg ccc agc cag aag ctg ggc agc gcc tac ctg 1831Gly Ser Arg Ser Pro Thr Pro Ser Gln Lys Leu Gly Ser Ala Tyr Leu 505 510 515ccc tcc tat cac cac tcc cca tac aag cac gcg cac atc ccg gcg cac 1879Pro Ser Tyr His His Ser Pro Tyr Lys His Ala His Ile Pro Ala His 520 525 530gcc cag cac tac cag agc tac atg cag ctg atc cag cag aag tcg gcc 1927Ala Gln His Tyr Gln Ser Tyr Met Gln Leu Ile Gln Gln Lys Ser Ala 535 540 545gtg gag tac gcg caa agc cag atg agc ctg gtg agc atg tgc aag gac 1975Val Glu Tyr Ala Gln Ser Gln Met Ser Leu Val Ser Met Cys Lys Asp550 555 560 565ctg agc tct ccc acc ccg tcg gag ccg cgc atg gag tgg aag gtg aag 2023Leu Ser Ser Pro Thr Pro Ser Glu Pro Arg Met Glu Trp Lys Val Lys 570 575 580atc cgc agc gac ggg acg cgc tac atc acc aag agg ccc gtg cgg gac 2071Ile Arg Ser Asp Gly Thr Arg Tyr Ile Thr Lys Arg Pro Val Arg Asp 585 590 595cgc ctg ctg cgg gag cgc gcc ctg aag atc cgg gaa gag cgc agc ggc 2119Arg Leu Leu Arg Glu Arg Ala Leu Lys Ile Arg Glu Glu Arg Ser Gly 600 605 610atg acc acc gac gac gac gcg gtg agc gag atg aag atg ggg cgc tac 2167Met Thr Thr Asp Asp Asp Ala Val Ser Glu Met Lys Met Gly Arg Tyr 615 620 625tgg agc aag gag gag agg aag cag cac ctg gtg aag gcc aag gag cag 2215Trp Ser Lys Glu Glu Arg Lys Gln His Leu Val Lys Ala Lys Glu Gln630 635 640 645cgg cgg cgg cgc gag ttc atg atg cag agc agg ttg gat tgt ctc aag 2263Arg Arg Arg Arg Glu Phe Met Met Gln Ser Arg Leu Asp Cys Leu Lys 650 655 660gag cag caa gca gcc gat gac agg aag gag atg aac att ctc gaa ctg 2311Glu Gln Gln Ala Ala Asp Asp Arg Lys Glu Met Asn Ile Leu Glu Leu 665 670 675agc cac aaa aag atg atg aag aag agg aat aag aaa atc ttc gat aac 2359Ser His Lys Lys Met Met Lys Lys Arg Asn Lys Lys Ile Phe Asp Asn 680 685 690tgg atg acg atc caa gaa ctc tta acc cac ggc aca aaa tcc ccg gac 2407Trp Met Thr Ile Gln Glu Leu Leu Thr His Gly Thr Lys Ser Pro Asp 695 700 705ggc act aga gta tac aat tcc ttc cta tcg gtg act act gta taa 2452Gly Thr Arg Val Tyr Asn Ser Phe Leu Ser Val Thr Thr Val710 715 720ttttcacttc tgcattatgt acataaagga gaccactacc actggggtag aaattcctgc 2512ctcgttcaat gcggcaagtt tttgtatata agataagtac ggtcttcatg tttacagtcc 2572aaatttgcaa accccacaac tctgggtgtc gtaggtctat tttaagggaa gagagagaaa 2632aacaccctta ctatcttgga aggcaatatt aacaaacaga gcttttttca aatagcaatt 2692gtacttttct acctgtaccc ttttacataa agtgtttaaa tttcag 2738231723PRTHomo sapiens 231Met Phe Thr Pro Pro Ser Glu Ser Gln Leu Val Asp Thr Gly Thr Gln1 5 10 15Thr Asp Ile Thr Phe Glu His Ile Met Ala Leu Thr Lys Met Ser Ser 20 25 30Pro Ser Pro Pro Val Leu Asp Pro Tyr Leu Leu Pro Glu Glu His Pro 35 40 45Ser Ala His Glu Tyr Tyr Asp Pro Asn Asp Tyr Ile Gly Asp Ile His 50 55 60Gln Glu Met Asp Arg Glu Glu Leu Glu Leu Glu Glu Val Asp Leu Tyr65 70 75 80Arg Met Asn Ser Gln Asp Lys Leu Gly Leu Thr Val Cys Tyr Arg Thr 85 90 95Asp Asp Glu Asp Asp Ile Gly Ile Tyr Ile Ser Glu Ile Asp Pro Asn 100 105 110Ser Ile Ala Ala Lys Asp Gly Arg Ile Arg Glu Gly Asp Arg Ile Ile 115 120 125Gln Ile Asn Gly Ile Glu Val Gln Asn Arg Glu Glu Ala Val Ala Leu 130 135 140Leu Thr Ser Glu Glu Asn Lys Asn Phe Ser Leu Leu Ile Ala Arg Pro145 150 155 160Glu Leu Gln Leu Asp Glu Gly Trp Met Asp Asp Asp Arg Asn Asp Phe 165 170 175Leu Asp Asp Leu His Met Asp Met Leu Glu Glu Gln His His Gln Ala 180 185 190Met Gln Phe Thr Ala Ser Val Leu Gln Gln Lys Lys His Asp Glu Asp 195 200 205Gly Gly Thr Thr Asp Thr Ala Thr Ile Leu Ser Asn Gln His Glu Lys 210 215 220Asp Ser Gly Val Gly Arg Thr Asp Glu Ser Thr Arg Asn Asp Glu Ser225 230 235 240Ser Glu Gln Glu Asn Asn Gly Asp Asp Ala Thr Ala Ser Ser Asn Pro 245 250 255Leu Ala Gly Gln Arg Lys Leu Thr Cys Ser Gln Asp Thr Leu Gly Ser 260 265 270Gly Asp Leu Pro Phe Ser Asn Glu Ser Phe Ile Ser Ala Asp Cys Thr 275 280 285Asp Ala Asp Tyr Leu Gly Ile Pro Val Asp Glu Cys Glu Arg Phe Arg 290 295 300Glu Leu Leu Glu Leu Lys Cys Gln Val Lys Ser Ala Thr Pro Tyr Gly305 310 315 320Leu Tyr Tyr Pro Ser Gly Pro Leu Asp Ala Gly Lys Ser Asp Pro Glu 325 330 335Ser Val Asp Lys Glu Leu Glu Leu Leu Asn Glu Glu Leu Arg Ser Ile 340 345 350Glu Leu Glu Cys Leu Ser Ile Val Arg Ala His Lys Met Gln Gln Leu 355 360 365Lys Glu Gln Tyr Arg Glu Ser Trp Met Leu His Asn Ser Gly Phe Arg 370 375 380Asn Tyr Asn Thr Ser Ile Asp Val Arg Arg His Glu Leu Ser Asp Ile385 390 395 400Thr Glu Leu Pro Glu Lys Ser Asp Lys Asp Ser Ser Ser Ala Tyr Asn 405 410 415Thr Gly Glu Ser Cys Arg Ser Thr Pro Leu Thr Leu Glu Ile Ser Pro 420 425 430Asp Asn Ser Leu Arg Arg Ala Val Glu Gly Ile Ser Cys Pro Ser Ser 435 440 445Glu Gly Ala Val Gly Thr Thr Glu Ala Tyr Gly Pro Ala Ser Lys Asn 450 455 460Leu Leu Ser Ile Thr Glu Asp Pro Glu Val Gly Thr Pro Thr Tyr Ser465 470 475 480Pro Ser Leu Lys Glu Leu Asp Pro Asn Gln Pro Leu Glu Ser Lys Glu 485 490 495Arg Arg Ala Ser Asp Gly Ser Arg Ser Pro Thr Pro Ser Gln Lys Leu 500 505 510Gly Ser Ala Tyr Leu Pro Ser Tyr His His Ser Pro Tyr Lys His Ala 515 520 525His Ile Pro Ala His Ala Gln His Tyr Gln Ser Tyr Met Gln Leu Ile 530 535 540Gln Gln Lys Ser Ala Val Glu Tyr Ala Gln Ser Gln Met Ser Leu Val545 550 555 560Ser Met Cys Lys Asp Leu Ser Ser Pro Thr Pro Ser Glu Pro Arg Met 565 570 575Glu Trp Lys Val Lys Ile Arg Ser Asp Gly Thr Arg Tyr Ile Thr Lys 580 585 590Arg Pro Val Arg Asp Arg Leu Leu Arg Glu Arg Ala Leu Lys Ile Arg 595 600 605Glu Glu Arg Ser Gly Met Thr Thr Asp Asp Asp Ala Val Ser Glu Met 610 615 620Lys Met Gly Arg Tyr Trp Ser Lys Glu Glu Arg Lys Gln His Leu Val625 630 635 640Lys Ala Lys Glu Gln Arg Arg Arg Arg Glu Phe Met Met Gln Ser Arg 645 650 655Leu Asp Cys Leu Lys Glu Gln Gln Ala Ala Asp Asp Arg Lys Glu Met 660 665 670Asn Ile Leu Glu Leu Ser His Lys Lys Met Met Lys Lys Arg Asn Lys 675 680 685Lys Ile Phe Asp Asn Trp Met Thr Ile Gln Glu Leu Leu Thr His Gly 690 695 700Thr Lys Ser Pro Asp Gly Thr Arg Val Tyr Asn Ser Phe Leu Ser Val705 710 715 720Thr Thr Val232169DNAHomo sapiens 232atatataata gccttgcaag tgaacggata agcaaagtca gttgctgaga aataacactt 60ccgagctgac gcatccaaat gtttaggata cacctgagat gtctctctta ctgaatagaa 120acaacatccc tggaagctct agacttctga ggcaccccag ctttccctg 169233280DNAHomo sapiens 233atatataata gccttgcaag tgaacggata agcaaagtca gttgctgaga aataacactt 60ccgagctgac gcatccaaat gtttaggata cacctgagat gtctctctta ctgaatagaa 120acaacatccc tggaagctct agacttctga ggcaccccag ctttccctgg tcaacggcag 180agacttatcc agagcaactc atgaccaggc tgtggaagct ttcaagacag ccaaggagcc 240catagtggtg caggtgttga gaagaacacc aaggaccaaa 2802341574DNAHomo sapiens 234gtagacgcct cggggcttaa gagaacgtga catggaagag acaggaaata tgtactcttg 60tacaggtatg cggcacacat gtggccccct ccctcccagc ctcctcacta aagattatta 120acctgcttat tctcctggtt cacctgaggc tgttttgaga gaatctcagt atctcagtct 180tcatttcata cgacattctt cgggctcctc ttgttcatct ttgcagactg aagtatttat 240gaaggacctt cagaaatctg attcctcctg atgaatcaaa gagtaaagaa gaatcaaaca 300tgattaacca ggtcaacggc agagacttat ccagagcaac tcatgaccag gctgtggaag 360ctttcaagac agccaaggag cccatagtgg tgcaggtgtt gagaagaaca ccaaggacca 420aaatgttcac gcctccatca gagtctcagc tggtggacac gggaacccaa accgacatca 480cctttgaaca tatcatggcc ctcactaaga tgtcctctcc cagcccaccc gtactggatc 540cctatctctt gccagaggag catccctcag cccatgaata ctacgatcca aatgactaca 600ttggagacat ccatcaggag atggacaggg aggagctgga gctggaggaa gtggacctct 660acagaatgaa cagccaggac aagctgggcc tcactgtgtg ctaccggacg gacgatgaag 720acgacattgg gatttatatc agtgagattg accctaacag cattgcagcc aaggatgggc 780gcatccgaga aggagaccgc attatccaga ttaatgggat agaggtgcag aaccgtgaag 840aggctgtggc tcttctaacc agtgaagaaa ataaaaactt ttcattgctg attgcaaggc 900ctgaactcca gctggatgag ggctggatgg atgatgacag gaacgacttt ctggatgacc 960tgcacatgga catgctggag gagcagcacc accaggccat gcaattcaca gctagcgtgc 1020tgcagcagaa gaagcacgac gaagacggtg ggaccacaga tacagccacc atcttgtcca 1080accagcacga gaaggacagc ggtgtggggc ggaccgacga gagcacccgt aatgacgaga 1140gctcggagca agagagcaat ggcgacgacg ccaccgcatc ctccaacccg ctggcggggc 1200agaggaagct cacctgcagc caggacacct tgggcagcgg cgacctgccc ttcagcaacg 1260agtctttcat ttcggccgac tgcacggacg ccgactacct ggggatcccg gtggacgagt 1320gcgagcgctt ccgcgagctc ctggagctca agtgccaggt gaagagcgcc accccttacg 1380gcctgtacta ccctagcggc cccctggacg ccggcaagag tgaccctgag agcgtggaca 1440aggagctgga gctgctgaac gaagagctgc gcagcatcga gctggagtgc ctgagcatcg 1500tgcgcgccca caagatgcag cagctcaagg agcagtaccg cgagtcctgg atgctgcaca 1560acagcggctt ccgc 15742351574DNAHomo sapiensCDS(300)..(1574) 235gtagacgcct cggggcttaa gagaacgtga catggaagag acaggaaata tgtactcttg 60tacaggtatg cggcacacat gtggccccct ccctcccagc ctcctcacta aagattatta 120acctgcttat tctcctggtt cacctgaggc tgttttgaga gaatctcagt atctcagtct 180tcatttcata cgacattctt cgggctcctc ttgttcatct ttgcagactg aagtatttat 240gaaggacctt cagaaatctg attcctcctg atgaatcaaa gagtaaagaa gaatcaaac 299atg att aac cag gtc aac ggc aga gac tta tcc aga gca act cat gac 347Met Ile Asn Gln Val Asn Gly Arg Asp Leu Ser Arg Ala Thr His Asp1 5 10 15cag gct gtg gaa gct ttc aag aca gcc aag gag ccc ata gtg gtg cag 395Gln Ala Val Glu Ala Phe Lys Thr Ala Lys Glu Pro Ile Val Val Gln 20 25 30gtg ttg aga aga aca cca agg acc aaa atg ttc acg cct cca tca gag 443Val Leu Arg Arg Thr Pro Arg Thr Lys Met Phe Thr Pro Pro Ser Glu 35 40 45tct cag ctg gtg gac acg gga acc caa acc gac atc acc ttt gaa cat 491Ser Gln Leu Val Asp Thr Gly Thr Gln Thr Asp Ile Thr Phe Glu His 50 55 60atc atg gcc ctc act aag atg tcc tct ccc agc cca ccc gta ctg gat 539Ile Met Ala Leu Thr Lys Met Ser Ser Pro Ser Pro Pro Val Leu Asp65 70 75 80ccc tat ctc ttg cca gag gag cat ccc tca gcc cat gaa tac tac gat 587Pro Tyr Leu Leu Pro Glu Glu His Pro Ser Ala His Glu Tyr Tyr Asp 85 90 95cca aat gac tac att gga gac atc cat cag gag atg gac agg gag gag 635Pro Asn Asp Tyr Ile Gly Asp Ile His Gln Glu Met Asp Arg Glu Glu 100 105 110ctg gag ctg gag gaa gtg gac ctc tac aga atg aac agc cag gac aag 683Leu Glu Leu Glu Glu Val Asp Leu Tyr Arg Met Asn Ser Gln Asp Lys 115 120 125ctg ggc ctc act gtg tgc tac cgg acg gac gat gaa gac gac att ggg 731Leu Gly Leu Thr Val Cys Tyr Arg Thr Asp Asp Glu Asp Asp Ile Gly 130 135 140att tat atc agt gag att gac cct aac agc att gca gcc aag gat ggg 779Ile Tyr Ile Ser Glu Ile Asp Pro Asn Ser Ile Ala Ala Lys Asp Gly145 150 155 160cgc atc cga gaa gga gac cgc att atc cag att aat ggg ata gag gtg 827Arg Ile Arg Glu Gly Asp Arg Ile Ile Gln Ile Asn Gly Ile Glu Val 165 170 175cag aac cgt gaa gag gct gtg gct ctt cta acc agt gaa gaa aat aaa 875Gln Asn Arg Glu Glu Ala Val Ala Leu Leu Thr Ser Glu Glu Asn Lys 180 185 190aac ttt tca ttg ctg att gca agg cct gaa ctc cag ctg gat gag ggc 923Asn Phe Ser Leu Leu Ile Ala Arg Pro Glu Leu Gln Leu Asp Glu Gly 195 200 205tgg atg gat gat gac agg aac gac ttt ctg gat gac ctg cac atg gac 971Trp Met Asp Asp Asp Arg Asn Asp Phe Leu Asp Asp Leu His Met Asp 210 215 220atg ctg gag gag cag cac cac cag gcc atg caa ttc aca gct agc gtg 1019Met Leu Glu Glu Gln His His Gln Ala Met Gln Phe Thr Ala Ser Val225 230 235 240ctg cag cag aag aag cac gac gaa gac ggt ggg acc aca gat aca gcc 1067Leu Gln Gln Lys Lys His Asp Glu Asp Gly Gly Thr Thr Asp Thr Ala 245 250 255acc atc ttg tcc aac cag cac gag aag gac agc ggt gtg ggg cgg acc 1115Thr Ile Leu Ser Asn Gln His Glu Lys Asp Ser Gly Val Gly Arg Thr 260 265 270gac gag agc acc cgt aat gac gag agc tcg gag caa gag agc aat ggc 1163Asp Glu Ser Thr Arg Asn Asp Glu Ser Ser Glu Gln Glu Ser Asn Gly 275 280 285gac gac gcc acc gca tcc tcc aac ccg ctg gcg ggg cag agg aag ctc 1211Asp Asp Ala Thr Ala Ser Ser Asn Pro Leu Ala Gly Gln Arg Lys Leu 290 295 300acc tgc agc cag gac acc ttg ggc agc ggc gac ctg ccc ttc agc aac 1259Thr Cys Ser Gln Asp Thr Leu Gly Ser Gly Asp Leu Pro Phe Ser Asn305 310 315 320gag tct ttc att tcg gcc gac tgc acg gac gcc gac tac ctg ggg atc 1307Glu Ser Phe Ile Ser Ala Asp Cys Thr Asp Ala Asp Tyr Leu Gly Ile 325 330 335ccg gtg gac gag tgc gag cgc ttc cgc gag ctc ctg gag ctc aag tgc 1355Pro Val Asp Glu Cys Glu Arg Phe Arg Glu Leu Leu Glu Leu Lys Cys 340 345 350cag gtg aag agc gcc acc cct tac ggc ctg tac tac cct agc ggc ccc 1403Gln Val Lys Ser Ala Thr Pro Tyr Gly Leu Tyr Tyr Pro Ser Gly Pro 355 360 365ctg gac gcc ggc aag agt gac cct gag agc gtg gac aag gag ctg gag 1451Leu Asp Ala Gly Lys Ser Asp Pro Glu Ser Val Asp Lys Glu Leu Glu 370 375 380ctg ctg aac gaa gag ctg cgc agc atc gag ctg gag tgc ctg agc atc 1499Leu Leu Asn Glu Glu Leu Arg Ser Ile Glu Leu Glu Cys Leu Ser Ile385 390 395 400gtg cgc gcc cac aag atg cag cag ctc aag gag cag tac cgc gag tcc 1547Val Arg Ala His Lys Met Gln Gln Leu Lys Glu Gln Tyr Arg Glu Ser 405 410 415tgg atg ctg cac aac agc ggc ttc cgc 1574Trp Met Leu His Asn Ser Gly Phe Arg 420 425236425PRTHomo sapiens 236Met Ile Asn Gln Val Asn Gly Arg Asp Leu Ser Arg Ala Thr His Asp1 5 10 15Gln Ala Val Glu Ala Phe Lys Thr Ala Lys Glu Pro Ile Val Val Gln 20 25 30Val Leu Arg Arg Thr Pro Arg Thr Lys Met Phe Thr Pro Pro Ser Glu 35 40 45Ser Gln Leu Val Asp Thr Gly Thr Gln Thr Asp Ile Thr Phe Glu His 50 55 60Ile Met Ala Leu Thr Lys Met Ser Ser Pro Ser Pro Pro Val Leu Asp65 70 75 80Pro Tyr Leu Leu Pro Glu Glu His Pro Ser Ala His Glu Tyr Tyr Asp 85 90 95Pro Asn Asp Tyr Ile Gly Asp Ile His Gln Glu Met Asp Arg Glu Glu 100 105 110Leu Glu Leu Glu Glu Val Asp Leu Tyr Arg Met Asn Ser Gln Asp Lys 115 120 125Leu Gly Leu Thr Val Cys Tyr Arg Thr Asp Asp Glu Asp Asp

Ile Gly 130 135 140Ile Tyr Ile Ser Glu Ile Asp Pro Asn Ser Ile Ala Ala Lys Asp Gly145 150 155 160Arg Ile Arg Glu Gly Asp Arg Ile Ile Gln Ile Asn Gly Ile Glu Val 165 170 175Gln Asn Arg Glu Glu Ala Val Ala Leu Leu Thr Ser Glu Glu Asn Lys 180 185 190Asn Phe Ser Leu Leu Ile Ala Arg Pro Glu Leu Gln Leu Asp Glu Gly 195 200 205Trp Met Asp Asp Asp Arg Asn Asp Phe Leu Asp Asp Leu His Met Asp 210 215 220Met Leu Glu Glu Gln His His Gln Ala Met Gln Phe Thr Ala Ser Val225 230 235 240Leu Gln Gln Lys Lys His Asp Glu Asp Gly Gly Thr Thr Asp Thr Ala 245 250 255Thr Ile Leu Ser Asn Gln His Glu Lys Asp Ser Gly Val Gly Arg Thr 260 265 270Asp Glu Ser Thr Arg Asn Asp Glu Ser Ser Glu Gln Glu Ser Asn Gly 275 280 285Asp Asp Ala Thr Ala Ser Ser Asn Pro Leu Ala Gly Gln Arg Lys Leu 290 295 300Thr Cys Ser Gln Asp Thr Leu Gly Ser Gly Asp Leu Pro Phe Ser Asn305 310 315 320Glu Ser Phe Ile Ser Ala Asp Cys Thr Asp Ala Asp Tyr Leu Gly Ile 325 330 335Pro Val Asp Glu Cys Glu Arg Phe Arg Glu Leu Leu Glu Leu Lys Cys 340 345 350Gln Val Lys Ser Ala Thr Pro Tyr Gly Leu Tyr Tyr Pro Ser Gly Pro 355 360 365Leu Asp Ala Gly Lys Ser Asp Pro Glu Ser Val Asp Lys Glu Leu Glu 370 375 380Leu Leu Asn Glu Glu Leu Arg Ser Ile Glu Leu Glu Cys Leu Ser Ile385 390 395 400Val Arg Ala His Lys Met Gln Gln Leu Lys Glu Gln Tyr Arg Glu Ser 405 410 415Trp Met Leu His Asn Ser Gly Phe Arg 420 425237311DNAHomo sapiens 237gtagacgcct cggggcttaa gagaacgtga catggaagag acaggaaata tgtactcttg 60tacaggtatg cggcacacat gtggccccct ccctcccagc ctcctcacta aagattatta 120acctgcttat tctcctggtt cacctgaggc tgttttgaga gaatctcagt atctcagtct 180tcatttcata cgacattctt cgggctcctc ttgttcatct ttgcagactg aagtatttat 240gaaggacctt cagaaatctg attcctcctg atgaatcaaa gagtaaagaa gaatcaaaca 300tgattaacca g 3112384PRTHomo sapiens 238Met Ile Asn Gln123912DNAHomo sapiens 239atgattaacc ag 1224021DNAArtificial Sequenceforward primer used for specifically detecting the variant of the present invention 240gccttccttt gacgtttttc t 2124124DNAArtificial Sequencereverse primer used for specifically detecting the variant of the present invention 241cgttgacctg acaaacttca taga 24242101DNAArtificial Sequencepartial polynucleotide specific to the variant of the present invention, which is obtained by PCR using forward primer (SEQ ID NO240) and reverse primer (SEQ ID NO241) 242gccttccttt gacgtttttc taaacatggg atgcagtctg tgcagcctgc agaagcaaga 60ggagcagtac aaattactct atgaagtttg tcaggtcaac g 10124322DNAArtificial Sequenceforward primer used for specifically detecting the variant of the present invention 243gcttagatcg caatgaaact gc 2224422DNAArtificial Sequencereverse primer used for specifically detecting the variant of the present invention 244ccaaatacca tcttccacca tg 22245147DNAArtificial Sequencepartial polynucleotide specific to the variant of the present invention, which is obtained by PCR using forward primer (SEQ ID NO243) and reverse primer (SEQ ID NO244) 245gcttagatcg caatgaaact gcggacctgc aggctgcctt gcttcactga gtcaattttt 60aaatgaagat ggaacacaag aggatgatct tattgttcag taaatttact ctaatacata 120aaccccatgg tggaagatgg tatttgg 14724625DNAArtificial Sequenceforward primer used for specifically detecting the variant of the present invention 246ccaaatgttt aggatacacc tgaga 2524720DNAArtificial Sequencereverse primer used for specifically detecting the variant of the present invention 247ctgccgttga ccagggaaag 20248106DNAArtificial Sequencepartial polynucleotide specific to the variant of the present invention, which is obtained by PCR using forward primer (SEQ ID NO246) and reverse primer (SEQ ID NO247) 248ccaaatgttt aggatacacc tgagatgtct ctcttactga atagaaacaa catccctgga 60agctctagac ttctgaggca ccccagcttt ccctggtcaa cggcag 10624927DNAArtificial Sequenceforward primer used for specifically detecting the variant of the present invention 249cagtatctca gtcttcattt catacga 2725024DNAArtificial Sequencereverse primer used for specifically detecting the variant of the present invention 250ttgacctggt taatcatgtt tgat 24251150DNAArtificial Sequencepartial polynucleotide specific to the variant of the present invention, which is obtained by PCR using forward primer (SEQ ID NO249) and reverse primer (SEQ ID NO250) 251cagtatctca gtcttcattt catacgacat tcttcgggct cctcttgttc atctttgcag 60actgaagtat ttatgaagga ccttcagaaa tctgattcct cctgatgaat caaagagtaa 120agaagaatca aacatgatta accaggtcaa 15025219DNAArtificial Sequenceforward primer used for specifically detecting the known variant of the gene of the present invention 252gcaagggcga agaaaccaa 1925322DNAArtificial Sequencereverse primer used for specifically detecting the known variant of the gene of the present invention 253gatgatccat cgtggttatc ca 22254112DNAArtificial Sequencepartial polynucleotide specific to the known variant of the gene of the present invention, which is obtained by PCR using forward primer (SEQ ID NO252) and reverse primer (SEQ ID NO253) 254gcaagggcga agaaaccaaa agtctgactc ttgtcctgca tcgggactcc ggctccctgg 60gattcaatat tattggtggc cggccgagtg tggataacca cgatggatca tc 11225520DNAArtificial Sequenceforward primer used for detecting the variants of the gene of the present invention 255caccactccc catacaagca 2025620DNAArtificial Sequencereverse primer used for detecting the variants of the gene of the present invention 256catctggctt tgcgcgtact 20257111DNAArtificial Sequencepartial polynucleotide common to the variants of the gene of the present invention, which is obtained by PCR using forward primer (SEQ ID NO255) and reverse primer (SEQ ID NO256) 257caccactccc catacaagca cgcgcacatc ccggcgcacg cccagcacta ccagagctac 60atgcagctga tccagcagaa gtcggccgtg gagtacgcgc aaagccagat g 111258219DNAHomo sapiens 258gagagcagcg ccaatgtgaa gcgttgcagt cgcttgactc acctgaggct ctccaaggat 60accttcaatg cctgcactgt aagggagctg cttttcccgg gtgctggcga gaacggaagc 120cttcctttga cgtttttcta aacatgggat gcagtctgtg cagcctgcag aagcaagagg 180agcagtacaa attactctat gaagtttgtc aggtcaacg 219259204DNAHomo sapiens 259gtgaagcgtt gcagtcgctt gactcacctg aggctctcca aggatacctt caatgcctgc 60actgtaaggg agctgctttt cccgggtgct ggcgagaacg gaagccttcc tttgacgttt 120ttctaaacat gggatgcagt ctgtgcagcc tgcagaagca agaggagcag tacaaattac 180tctatgaagt ttgtcaggtc aacg 204260179DNAHomo sapiens 260agcatttgct cagtactctc aacataaacc aagcttagat cgcaatgaaa ctgcggacct 60gcaggctgcc ttgcttcact gagtcaattt ttaaatgaag atggaacaca agaggatgat 120cttattgttc agtaaattta ctctaataca taaaccccat ggtggaagat ggtatttgg 179261179DNAHomo sapiens 261agcatttgct cagtactctc aacataaacc aagcttagat cgcaatgaaa ctgcggacct 60gcaggctgcc ttgcttcact gagtcaattt ttaaatgaag atggaacaca agaggatgat 120cttattgttc agtaaattta ctctaataca taaaccccat ggtggaagat ggtatttgg 179262180DNAHomo sapiens 262atatataata gccttgcaag tgaacggata agcaaagtca gttgctgaga aataacactt 60ccgagctgac gcatccaaat gtttaggata cacctgagat gtctctctta ctgaatagaa 120acaacatccc tggaagctct agacttctga ggcaccccag ctttccctgg tcaacggcag 180263316DNAHomo sapiens 263gtagacgcct cggggcttaa gagaacgtga catggaagag acaggaaata tgtactcttg 60tacaggtatg cggcacacat gtggccccct ccctcccagc ctcctcacta aagattatta 120acctgcttat tctcctggtt cacctgaggc tgttttgaga gaatctcagt atctcagtct 180tcatttcata cgacattctt cgggctcctc ttgttcatct ttgcagactg aagtatttat 240gaaggacctt cagaaatctg attcctcctg atgaatcaaa gagtaaagaa gaatcaaaca 300tgattaacca ggtcaa 31626462PRTHomo sapiens 264Met Ser Asp Val Ala Ile Val Lys Glu Gly Trp Leu His Lys Arg Gly1 5 10 15Glu Tyr Ile Lys Thr Trp Arg Pro Arg Tyr Phe Leu Leu Lys Asn Asp 20 25 30Gly Thr Phe Ile Gly Tyr Lys Glu Arg Pro Gln Asp Val Asp Gln Arg 35 40 45Glu Ala Pro Leu Asn Asn Phe Ser Val Ala Gln Cys Gln Leu 50 55 60265172PRTHomo sapiens 265Met Pro Asn Pro Ser Ser Thr Ser Ser Pro Tyr Pro Leu Pro Glu Glu1 5 10 15Ile Arg Asn Leu Leu Ala Asp Val Glu Thr Phe Val Ala Asp Ile Leu 20 25 30Lys Gly Glu Asn Leu Ser Lys Lys Ala Lys Glu Lys Arg Glu Ser Leu 35 40 45Ile Lys Lys Ile Lys Asp Val Lys Ser Ile Tyr Leu Gln Glu Phe Gln 50 55 60Asp Lys Gly Asp Ala Glu Asp Gly Glu Glu Tyr Asp Asp Pro Phe Ala65 70 75 80Gly Pro Pro Asp Thr Ile Ser Leu Ala Ser Glu Arg Tyr Asp Lys Asp 85 90 95Asp Glu Ala Pro Ser Asp Gly Ala Gln Phe Pro Pro Ile Ala Ala Gln 100 105 110Asp Leu Pro Phe Val Leu Lys Ala Gly Tyr Leu Glu Lys Arg Arg Lys 115 120 125Asp His Ser Phe Leu Gly Phe Glu Trp Gln Lys Arg Trp Cys Ala Leu 130 135 140Ser Lys Thr Val Phe Tyr Tyr Tyr Gly Ser Asp Lys Asp Lys Gln Gln145 150 155 160Lys Gly Glu Phe Ala Ile Asp Gly Tyr Ser Val Arg 165 17026616PRTHomo sapiens 266Met Ser Asn Lys Cys Asp Val Val Val Val Gly Gly Gly Ile Ser Gly1 5 10 15

Claims

1.-27. (canceled)

28. An isolated peptide comprising the amino acid sequence of SEQ ID NO: 60.

29. A polynucleotide that encodes the peptide of claim 28.

30. An expression vector comprising the polynucleotide of claim 29 and a promoter operably linked thereto.

31. A transformant incorporating the expression vector of claim 30.

32. An aptamer that binds the peptide of claim 28.

33. An antibody that binds the peptide of claim 28.

34. The antibody of claim 33, wherein the antibody is any one of the (i) to (iii) below: (i) a polyclonal antibody; (ii) a monoclonal antibody or a portion thereof; (iii) a chimeric antibody, a humanized antibody or a human antibody.

35. A cell that produces the antibody of claim 33.

36. The cell of claim 35, wherein the cell is a hybridoma.

37. A composition comprising (a) the antibody of claim 33, or an expression vector therefor, and (b) a pharmaceutically acceptable carrier.

38. A reagent or kit for detection or quantification of any one of the polypeptides encoded by the brain/nerve-specific genes 1 to 10, which reagent or kit comprises one or more antibodies of claim 33.

39. The peptide of claim 28 consisting of the amino acid sequence of SEQ ID NO: 60.

40. A polynucleotide that encodes the peptide of claim 39.

41. An expression vector comprising the polynucleotide of claim 40 and a promoter operably linked thereto.

42. A transformant incorporating the expression vector of claim 41.

43. An aptamer that binds the peptide of claim 39.

44. An antibody that binds the peptide of claim 39.

45. The antibody of claim 44, wherein the antibody is any one of the (i) to (iii) below: (i) a polyclonal antibody; (ii) a monoclonal antibody or a portion thereof; (iii) a chimeric antibody, a humanized antibody or a human antibody.

46. A cell that produces the antibody of claim 44.

47. The cell of claim 46, wherein the cell is a hybridoma.

48. A composition comprising (a) the antibody of claim 44, or an expression vector therefor, and (b) a pharmaceutically acceptable carrier.

49. A reagent or kit for detection or quantification of any one of the polypeptides encoded by the brain/nerve-specific genes 1 to 10, which reagent or kit comprise one or more antibodies of claim 44.