Polynucleotides and Polypeptides Encoding Receptors

Abstract

Receptor polypeptides and polynucleotides and methods for producing such polypeptides by recombinant techniques are disclosed. Also disclosed are methods for utilizing receptor polypeptides and polynucleotides in the design of protocols for the treatment of diseases and diagnostic assays for such conditions.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of application Ser. No. 12/431,986, filed Apr. 29, 2009, which is a continuation of application Ser. No. 11/832,019, filed Aug. 1, 2007 (now abandoned), which is a continuation of application Ser. No. 11/041,419, filed Jan. 25, 2005 (now abandoned), which is a continuation of application Ser. No. 10/156,136, filed May 29, 2002 (now abandoned), which is a continuation of application Ser. No. 09/764,452, filed Jan. 19, 2001 (now abandoned), which is a continuation of application Ser. No. 09/010,146, filed Jan. 21, 1998 (now abandoned), which claims the benefit under 35 U.S.C. .sctn.119(e) of provisional Application No. 60/034,204, filed Jan. 21, 1997 and provisional Application No. 60/034,205, filed Jan. 21, 1997; each of which is hereby incorporated by reference in its entirety.

STATEMENT UNDER 37 C.F.R. .sctn.1.77(b)(5)

[0002] This application refers to a "Sequence Listing" listed below, which was provided as a text document in U.S. application Ser. No. 12/431,986, filed Apr. 29, 2009, entitled "PF354C5_SequenceList.txt". Applicants request the use of the computer readable "Sequence Listing" filed in connection with U.S. application Ser. No. 12/431,986 on Apr. 29, 2009, as the computer readable form for the instant application. Applicants hereby state that the paper copy of the "Sequence Listing" filed in the instant application on Nov. 23, 2010, is identical to the computer readable copy filed on Apr. 29, 2009, in U.S. application Ser. No. 12/431,986, and is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0003] Receptor proteins are found on the membrane of the cells and are generally involved in signal transduction. There are many types of receptor proteins, and for convenience, these proteins are grouped in families based on similarity in structure and function.

[0004] Receptor proteins are found on the membrane of the cells and are generally involved in signal transduction. There are many types of receptor proteins, and for convenience, these proteins are grouped in families based on similarity in structure and function.

[0005] For example, the TM4SF superfamily of cell surface proteins, also known as the tetraspan receptor superfamily, is comprised of at least seventeen individual gene products (these include CD9, CD20, CD37, CD53, CD63, CD81, CD82, A15, CO-029, Sm23, RDS, Uro B, Uro A, SAS, Rom-1, PETA3, and YKK8). The TM4SF superfamily is the second largest group in the CD antigen superfamily. Each member of the TM4SF superfamily can be characterized by several putative physical features including four highly conserved transmembrane domains, two divergent extracellular loops, and two short and highly divergent cytoplasmic tails. Expression patterns for members of the TM4SF superfamily tend to be rather broad and can vary widely between members. The functional roles of TM4SF superfamily members are primarily associated with signal transduction events and pathways, but also include cell adhesion in platelets and other lymphocytic and non-lymphocytic cell lines, as well as cell motility, proliferation, and metastasis. In addition, recent evidence suggests that a subset of the members of the TM4SF superfamily may function as potassium channel molecules.

[0006] One member of the TM4SF family, CD20, is a four membrane spanning domain cell surface phosphoprotein expressed exclusively on B lymphocytes. Although the precise functional role of CD20 has yet to be determined, it is thought to function primarily as a receptor during B-cell activation. Furthermore, a large number of experimental observations suggest several additional speculative roles for the CD20 molecule. For example, CD20-specific immunoprecipitation of biochemically cross-linked plasma membrane proteins suggests that CD20 assumes a multimeric structural conformation characteristic of other previously described membrane channel proteins. Further experimentation has revealed that expression of exogenous CD20 on the cell surface specifically increases Ca.sup.2+ conductance across the plasma membrane. Together, these results suggest that CD20 complexes may function as B-cell specific Ca.sup.2+ ion channels. In addition, monoclonal antibodies raised against CD20 have been used to stimulate resting B-cells to transition out of the G0/G1 segment of the cell cycle. It has also been demonstrated that CD20 is associated with both serine and tyrosine kinases and, more specifically, that CD20 is associated, although not directly, with the Src family of tyrosine kinases including p56/53lyn, p56lck, and p59fyn.

[0007] A second example of a receptor subfamily, called sialoadhesin molecules, belongs to the Ig superfamily of receptor-like molecules. The more than 100 members of the Ig superfamily are generally considered to engage in specific cell-cell interactions through which intercellular communication may occur. In addition to classical protein-protein interactions, intercellular communication may also be mediated through protein-carbohydrate interactions. In fact, all members of the sialoadhesin family of the Ig superfamily are capable of mediating protein-sialic acid binding interactions. To date, only a small number of proteins have been assigned to the sialoadhesin family including sialoadhesin, CD33, CD22, the myelin-associated glycoprotein (MAG), and the Schwann cell myelin protein (SMP). Each of these proteins is expressed in a restricted subset of cell types. For example, CD22 and CD33 are expressed exclusively by B-lymphocytes and cells of the myelomonocytic lineage, respectively.

[0008] Similarly, galectins are a family of the lectin superfamily of carbohydrate-binding proteins which have a high affinity for b-galactoside sugars. Although a large number of glycoproteins containing b-galactoside sugars are produced by the cell, only a few will bind to known galectins in vitro. Such apparent binding specificity suggests a highly specific functional role for the galectins. Galectin 1 (conventionally termed LGALS1 for lectin, galactoside-binding, soluble-1) is thought to specifically bind laminin, a highly polylactosaminated cellular glycoprotein, as well as the highly polylactosaminated lysosome-associated membrane proteins (LAMPs). Galectin 1 has also been shown to bind specifically to a lactosamine-containing glycolipid found on olfactory neurons and to integrin a.sub.7b.sub.1 on skeletal muscle cells. Galectin 3 has also been observed to bind specifically to laminin, immunoglobulin E and its receptor, and bacterial lipopolysaccharides.

[0009] Various galectins have been shown to function in the mechanisms of intercellular communication. For example, depending on cell type, galectin 1 has been observed to modulate cell adhesion either positively or negatively. More specifically, galectin 1 appears to inhibit cell adhesion of skeletal muscle presumably by galectin 1-mediated disruption of laminin-integrin a.sub.7b.sub.1 interactions. Alternatively, galectin 1 appears to promote cell adhesion in several non-skeletal muscle cell types examined presumably by a glycoconjugate cross-linking mechanism. Galectin 3 has also been observed to function in modulating cell-adhesion, as well as in the activation of certain immune cells by cross-linking IgE and IgE receptors. In addition, galectins have been observed to be involved in the regulation of immune cell activity, as well as in such diverse processes as cell adhesion, proliferation, inflammation, autoimmunity, and metastasis of tumor cells. Furthermore, a galectin-like antigen designated HOM-HD-21 was recently found to be highly expressed in a Hodgkin's Disease cDNA library. Very recently, a novel galectin, termed PCTA-1, was identified as a specific cell surface marker on human prostate cancer cell lines and patient-derived carcinomas. Galectins have also been found to function intracellularly as a component of ribonucleoprotein complexes. Finally, galectins 1 and 3 have each been found to modulate T-cell growth and apoptosis by interaction with CD45 and possibly Bcl2, respectively.

[0010] A relatively new family of cell-surface proteins has been identified and termed the Ly6 superfamily. The members of this family include murine and human SCA-2, rat Ly-6 (also termed ThB), human CD59 [also known as protectin or membrane attack complex inhibition factor (MACIF)], and E48 antigen. The determination of an initial functional role for SCA-2 may lie in an analysis of its expression profile with regard to the complex process of hematopoiesis. SCA-2 is highly expressed in early thymic precusor cells. In turn, progeny of the intrathymic precusor population continue to express SCA-2, but only until the point of transition occurs from blast cell to small cell. Further experimental evidence demonstrates that mature thymocytes and peripheral T-cells do not express detectable levels of SCA-2, whereas mature, peripheral B-cells do continue to express SCA-2. As a result, it seems very likely that SCA-2 plays an important role in thymocyte maturation and differentiation. A plausible explanation for this functional hypothesis is that SCA-2 may act as a receptor for a unknown cytokine which regulates thymocyte maturation and differentiation.

[0011] In addition, CD59 is a recently identified integral membrane protein which appears to be involved in the regulation of complement. Recent studies show that the CD59 antigen may prevent damage from complement C5b-9 and protect astrocytes during inflammatory and infectious disorders of the nervous system. Expression of recombinant human CD59 on porcine donor organs have been shown to prevent complement-mediated lysis and activation of endothelial cells that leads to hyperacute rejection. Recently, researchers at Alexion Pharmaceuticals (New Haven, Conn.) reported on the production of transgenic pigs which expressed human CD59. In these animals, xenogeneic organs were resistant to hyperacute rejection. (Fodor, et al., "Expression of a functional human complement inhibitor in a transgenic pig as a model for the prevention of xenogeneic hyperacute organ rejection," Proc. Natl. Acad. Sci., 91:1153-11157 (1994).) The same company also reported that expression of recombinant transmembrane CD59 in paroxysmal nocturnal hemoglobinuria (PNH) B-cells confers resistance to human complement. (Rother et al., "Expression of recombinant transmembrane CD59 in paroxysmal nocturnal hemoglobinuria B-cells confers resistance to human complement," Blood, 84:2604-2611 (1994).) PNH is an acquired hematopoietic disorder characterized by complement-mediated hemolytic anemia, pancytopenia, and venous thrombosis. It is thought that retroviral gene therapy with this molecule could provide a treatment for PNH patients.

[0012] A final Ly6 superfamily member, the E48 antigen, is involved in intercellular adhesion between keratinocyte cells of the squamous epithelium. Such keratinocytes are attached to adjoining cells by large numbers of desmosomes, which are thought to play a role in the transition of transformed keratinocytes to metastatic tumor cells. Treatment with a monoclonal antibody raised against the E48 antigen has been successful in the eradication of residual, postoperative squamous cell carcinoma cells of the upper aerodigestive tract in several in vivo models and, to some degree, in humans. (van Dongen, et al., "Progress in radioimmunotherapy of head and neck cancer," Oncol. Rep. 1:259-264 (1994).) The gene encoding the E48 antigen has been mapped to the q24-qter region of human chromosome 8. Interestingly, a number of human diseases have been mapped to this region of chromosome 8 including Langer-Giedion syndrome, brachio-otorhinolaryngeal syndrome, trichorhinolaryngeal syndrome, and epidermolysis bullosa simplex.

[0013] A further example of a receptor family includes the prohibitin receptors. The prohibitin gene product is expressed in a wide variety of tissues and has been implicated as a component of a number of anti-proliferative mechanisms. The prohibitin gene encodes a 30 kD postsynthetically modified polypeptide located primarily in the mitochondria, but also may be associated with the IgM receptor on the B-cell plasma membrane. The protein functionally inhibits DNA synthesis and entry into S phase of the cell cycle by an unknown mechanism. Interestingly, although the prohibitin gene product is hypothesized to be involved in the maintenance of senescence and the prevention of cancer, one study found that, although somatic mutations in the prohibitin gene were present in a small number of breast cancers, no mutations were identified in any other breast, ovary, liver, and lung cancers examined. (Sato et al., Genomics 17:762-764 (1993).) However, the prohibitin gene has been mapped to human chromosome 17q12-21, the same region thought to contain the gene involved in sporadic breast cancer. Furthermore, DNA sequence analysis of the prohibitin gene identified somatic mutation in 4 of 23 cases of sporadic breast cancer examined. Thus, prohibitin family members may be involved in the development of cancer.

[0014] Moreover, the EGFR family of plasma membrane proteins are an integral component of normal cellular proliferation and in the pathogenesis of the cancerous state. The family is relatively small and includes the EGFR, c-erbB-2, c-erbB-3, and others. Various cancers are correlated with aberrant expression of one or more of these genes. A number of ligands have been identified which bind to the EGFR-like receptors listed above including TGF-a, heparin-binding EGF, amphiregulin, criptoregulin, hercgulin, and others. A large fraction of adenocarcinomas examined to date, especially those of the breast, colon, and pancreas, are typified by the amplification or overexpression of the c-erbB-2 gene. EGF, or an analogous ligand, initiates the cellular growth factor response by binding to the EGFR, or EGFR-related, receptor. Following the binding event, the receptor molecule dimerizes activating its intracellular tyrosine kinase domain. This event results in the phosphorylation of specific tyrosine residues near the carboxy terminus of the receptor. The diversity of signals able to be transduced through the relatively small number of EGFR-related receptor molecules is amplified considerably by the recent finding that EGFR-like receptor molecules can function when dimerized with other EGFR family members forming heterodimers.

[0015] Members of the EGFR-related family of integral membrane proteins have been implicated in the pathogenesis of a number of human disease-states. For example, a mutation in the EGFR itself appears to play an important role in the development of glioblastomas. (Sang et al., J. Neurosurg 82:841-846 (1995).) The EGFR gene is amplified or overexpressed in the majority of primary human glioblastomas. Although not conferring a distinct advantage on cell growth, an increase in EGFR expression was found to confer an increase in the ability of glioma cells to maintain anchorage-independent growth in soft agar especially in response to EGF and retinoic acid. Anchorage-independent growth in vitro correlates highly with tumorigenicity in vivo, therefore, it is likely that cells which express abnormally high levels of EGFR in human glioblastoma cells may be involved in the high potential for these cells to cause tumors in vivo.

[0016] Moreover, overexpression or amplification of c-erbB-2 has been reported to be involved in a high number adenocarcinomas, particularly of the breast, colon, and pancreas, and in a small proportion of ovarian carcinomas.

[0017] Thus, there is a clear need for identifying and exploiting novel members of the receptor families, such as those described above. Although structurally related, these receptors will likely possess diverse and multifaceted functions in a variety of cell and tissue types. Receptor type molecules should prove useful in target based screens for small molecules and other such pharmacologically valuable factors. Monoclonal antibodies raised against such receptors may prove useful as therapeutics in an anti-tumor, diagnostic, or other capacity. Furthermore, receptors described here may prove useful in an active or passive immunotherapeutical role in patients with cancer or other immunocompromised disease states.

BRIEF SUMMARY OF THE INVENTION

[0018] This invention relates to newly identified polynucleotides and the polypeptides encoded by them, the use of such polynucleotides and polypeptides, and their production. More particularly, the polynucleotides and polypeptides of the present invention relate to specific receptor families described in the specification and known in the art. The invention also relates to inhibiting or activating the action of such polynucleotides and polypeptides.

[0019] In one aspect, the invention relates to receptor polypeptides and polynucleotides, as well as the methods for their production. Another aspect of the invention relates to methods for using such receptor polypeptides and polynucleotides. Such uses include the treatment of the specified diseases, among others. In still another aspect, the invention relates to methods to identify agonists and antagonists using the materials provided by the invention, and treating conditions associated with receptor imbalance with the identified compounds. Yet another aspect of the invention relates to diagnostic assays for detecting diseases associated with inappropriate receptor activity or levels.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1A-1B shows an amino acid sequence alignment of Clone ID HMACR70 (SEQ ID NO:18) versus OB-1 (SEQ ID NO:33) (shaded boxes indicate identical amino acid residues, non-shaded boxes indicate conservative substitutions).

[0021] FIG. 2 shows an amino acid sequence alignment of Clone ID HTEDK48 (SEQ ID NO:19) versus MRC-OX44 (SEQ ID NO:34) and PETA-3 (SEQ ID NO:35) (shaded boxes indicate identical amino acid residues, non-shaded boxes indicate conservative substitutions).

[0022] FIG. 3 shows an amino acid sequence alignment of Clone ID HPWAE25 (SEQ ID NO:20) versus NAG-2 (SEQ ID NO:36) and TALLA-1 (SEQ ID NO:37) (shaded boxes indicate identical amino acid residues, non-shaded boxes indicate conservative substitutions).

[0023] FIG. 4 shows an amino acid sequence alignment of Clone ID HTPEF86 (SEQ ID NO:21) versus B1 (SEQ ID NO:38) (shaded boxes indicate identical amino acid residues, non-shaded boxes indicate conservative substitutions).

[0024] FIG. 5 shows an amino acid sequence alignment of Clone ID HSBBF02 (SEQ ID NO:22) versus TALLA-1 (SEQ ID NO:37) (shaded boxes indicate identical amino acid residues, non-shaded boxes indicate conservative substitutions).

[0025] FIG. 6 shows an amino acid sequence alignment of Clone ID HLTAH80 (SEQ ID NO:23) versus TALLA-1 (SEQ ID NO:37) (shaded boxes indicate identical amino acid residues, non-shaded boxes indicate conservative substitutions).

[0026] FIG. 7 shows an amino acid sequence alignment of Clone ID HTPBA27 (SEQ ID NO:24) versus NAG-2 (SEQ ID NO:36)(shaded boxes indicate identical amino acid residues, non-shaded boxes indicate conservative substitutions).

[0027] FIG. 8 shows an amino acid sequence alignment of Clone ID HAIDQ59 (SEQ ID NO:25) versus CD9 (SEQ ID NO:39) (shaded boxes indicate identical amino acid residues, non-shaded boxes indicate conservative substitutions).

[0028] FIG. 9 shows an amino acid sequence alignment of Clone ID HHFEK40 (SEQ ID NO:26) versus PETA-3 (SEQ ID NO:35) (shaded boxes indicate identical amino acid residues, non-shaded boxes indicate conservative substitutions).

[0029] FIG. 10 shows an amino acid sequence alignment of Clone ID HGBGV89 (SEQ ID NO:27) versus L6H (SEQ ID NO:40) (shaded boxes indicate identical amino acid residues, non-shaded boxes indicate conservative substitutions).

[0030] FIG. 11 shows an amino acid sequence alignment of Clone ID HUVBB80 (SEQ ID NO:28) versus L6 (SEQ ID NO:41) (shaded boxes indicate identical amino acid residues, non-shaded boxes indicate conservative substitutions).

[0031] FIG. 12 shows an amino acid sequence alignment of Clone ID HJACE54 (SEQ ID NO:29) versus rGALECTIN-5 (SEQ ID NO:42) and hGALECTN-8 (SEQ ID NO:43) (shaded boxes indicate identical amino acid residues, non-shaded boxes indicate conservative substitutions).

[0032] FIG. 13 shows an amino acid sequence alignment of Clone ID HROAD63 (SEQ ID NO:30) versus E48 (SEQ ID NO:44) (shaded boxes indicate identical amino acid residues, non-shaded boxes indicate conservative substitutions).

[0033] FIG. 14 shows an amino acid sequence alignment of Clone ID HMWGS46 (SEQ ID NO:31) versus B-cell Receptor Associated Protein (shaded boxes indicate identical amino acid residues, non-shaded boxes indicate conservative substitutions).

[0034] FIG. 15 shows an amino acid sequence alignment of Clone ID HNFGW06 (SEQ ID NO:32) versus EGFR (SEQ ID NO:46) (shaded boxes indicate identical amino acid residues, non-shaded boxes indicate conservative substitutions).

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0035] The following definitions are provided to facilitate understanding of certain terms used frequently herein.

[0036] "Receptor" refers, among others, to a polypeptide comprising the amino acid sequence set forth in SEQ ID NO:Y, or an allelic variant thereof.

[0037] "Receptor Activity" or "Biological Activity of the Receptor" refers to the metabolic or physiologic function of said receptor including similar activities or improved activities or these activities with decreased undesirable side-effects. Also included are antigenic and immunogenic activities of said receptor.

[0038] "Receptor gene" refers to a polynucleotide comprising the nucleotide sequence set forth in SEQ ID NO:X or allelic variants thereof and/or their complements.

[0039] "SEQ ID NO:X" comprises all or a substantial portion of the polynucleotide encoding each receptor of the invention. The value X for the nucleotide sequence is an integer specified in Table 1. This nucleotide sequence was translated into the receptor polypeptide identified in Table 1 as "SEQ ID NO:Y," where the value of Y for each receptor polypeptide is an integer defined in Table 1.

[0040] The invention further provides a composition of matter comprising a nucleic acid molecule which comprises a human cDNA clone identified by a cDNA Clone ID (Identifier) in Table 1, which DNA molecule is contained in the material deposited with the American Type Culture Collection ("ATCC.TM.") and given the ATCC.TM. Deposit Number shown in Table 1 for that cDNA clone. The ATCC.TM. is located at American Type Culture Collection (ATCC.TM.), 10801 University Boulevard, Manassas, Va. 20110-2209, USA. The deposit has been made under the terms of the Budapest Treaty on the international recognition of the deposit of micro-organisms for purposes of patent procedure. The strain will be irrevocably and without restriction or condition released to the public upon the issuance of a patent. The deposit is provided merely as convenience to those of skill in the art and is not an admission that a deposit is required for enablement, such as that required under 35 U.S.C. .sctn.112. The nucleotide sequence of the polynucleotides contained in the deposited material, as well as the amino acid sequence of the polypeptide encoded thereby, are controlling in the event of any conflict with any description of sequences herein.

[0041] "Antibodies" as used herein includes polyclonal and monoclonal antibodies, chimeric, single chain, and humanized antibodies, as well as Fab fragments, including the products of an Fab or other immunoglobulin expression library.

[0042] "Isolated" means altered "by the hand of man" from the natural state. If an "isolated" composition or substance occurs in nature, it has been changed or removed from its original environment, or both. For example, a polynucleotide or a polypeptide naturally present in a living animal is not "isolated," but the same polynucleotide or polypeptide separated from the coexisting materials of its natural state is "isolated", as the term is employed herein.

[0043] "Polynucleotide" generally refers to any polyribonucleotide or polydeoxyribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. "Polynucleotides" include, without limitation single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, and RNA that is mixture of single- and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or a mixture of single- and double-stranded regions. In addition, "polynucleotide" refers to triple-stranded regions comprising RNA or DNA or both RNA and DNA. The term polynucleotide also includes DNAs or RNAs containing one or more modified bases and DNAs or RNAs with backbones modified for stability or for other reasons. "Modified" bases include, for example, tritylated bases and unusual bases such as inosine. A variety of modifications has been made to DNA and RNA; thus, "polynucleotide" embraces chemically, enzymatically or metabolically modified forms of polynucleotides as typically found in nature, as well as the chemical forms of DNA and RNA characteristic of viruses and cells. "Polynucleotide" also embraces relatively short polynucleotides, often referred to as oligonucleotides.

[0044] "Polypeptide" refers to any peptide or protein comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres. "Polypeptide" refers to both short chains, commonly referred to as peptides, oligopeptides or oligomers, and to longer chains, generally referred to as proteins. Polypeptides may contain amino acids other than the 20 gene-encoded amino acids. "Polypeptides" include amino acid sequences modified either by natural processes, such as posttranslational processing, or by chemical modification techniques which are well known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature. Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. It will be appreciated that the same type of modification may be present in the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide may contain many types of modifications. Polypeptides may be branched as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched and branched cyclic polypeptides may result from posttranslation natural processes or may be made by synthetic methods. Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cystine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination. (See, for instance, PROTEINS--STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W.H. Freeman and Company, New York, 1993 and Wold, F., Posttranslational Protein Modifications: Perspectives and Prospects, pgs. 1-12 in POSTTRANSLATIONAL COVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press, New York, 1983; Seifter et al., "Analysis for protein modifications and nonprotein cofactors", Meth Enzymol (1990) 182:626-646 and Rattan et al., "Protein Synthesis: Posttranslational Modifications and Aging", Ann NY Acad Sci (1992) 663:48-62.)

[0045] "Variant" as the term is used herein, is a polynucleotide or polypeptide that differs from a reference polynucleotide or polypeptide respectively, but retains essential properties. A typical variant of a polynucleotide differs in nucleotide sequence from another, reference polynucleotide. Changes in the nucleotide sequence of the variant may or may not alter the amino acid sequence of a polypeptide encoded by the reference polynucleotide. Nucleotide changes may result in amino acid substitutions, additions, deletions, fusions and truncations in the polypeptide encoded by the reference sequence, as discussed below. A typical variant of a polypeptide differs in amino acid sequence from another, reference polypeptide. Generally, differences are limited so that the sequences of the reference polypeptide and the variant are closely similar overall and, in many regions, identical. A variant and reference polypeptide may differ in amino acid sequence by one or more substitutions, additions, deletions in any combination. A substituted or inserted amino acid residue may or may not be one encoded by the genetic code. A variant of a polynucleotide or polypeptide may be a naturally occurring such as an allelic variant, or it may be a variant that is not known to occur naturally. Non-naturally occurring variants of polynucleotides and polypeptides may be made by mutagenesis techniques or by direct synthesis.

[0046] "Identity" is a measure of the identity of nucleotide sequences or amino acid sequences. In general, the sequences are aligned so that the highest order match is obtained. "Identity" per se has an art-recognized meaning and can be calculated using published techniques. (See, e.g.: COMPUTATIONAL MOLECULAR BIOLOGY, Lesk, A. M., ed., Oxford University Press, New York, 1988; BIOCOMPUTING: INFORMATICS AND GENOME PROJECTS, Smith, D. W., ed., Academic Press, New York, 1993; COMPUTER ANALYSIS OF SEQUENCE DATA, PART I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; SEQUENCE ANALYSIS IN MOLECULAR BIOLOGY, von Heinje, G., Academic Press, 1987; and SEQUENCE ANALYSIS PRIMER, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991.) While there exist a number of methods to measure identity between two polynucleotide or polypeptide sequences, the term "identity" is well known to skilled artisans. (Carillo, H., and Lipton, D., SIAM J Applied Math (1988) 48:1073.) Methods commonly employed to determine identity or similarity between two sequences include, but are not limited to, those disclosed in Guide to Huge Computers, Martin J. Bishop, ed., Academic Press, San Diego, 1994, and Carillo, H., and Lipton, D., SIAM J Applied Math (1988) 48:1073. Methods to determine identity and similarity are codified in computer programs. Preferred computer program methods to determine identity and similarity between two sequences include, but are not limited to, GCS program package (Devereux, J., et al., Nucleic Acids Research (1984) 12(1):387), BLASTP, BLASTN, FASTA (Atschul, S. F. et al., J Molec Biol (1990) 215:403.)

[0047] As an illustration, by a polynucleotide having a nucleotide sequence having at least, for example, 95% "identity" to a reference nucleotide sequence of SEQ ID NO:X is intended that the nucleotide sequence of the polynucleotide is identical to the reference sequence except that the polynucleotide sequence may include up to five point mutations per each 100 nucleotides of the reference nucleotide sequence of SEQ ID NO: X. In other words, to obtain a polynucleotide having a nucleotide sequence at least 95% identical to a reference nucleotide sequence, up to 5% of the nucleotides in the reference sequence may be deleted or substituted with another nucleotide, or a number of nucleotides up to 5% of the total nucleotides in the reference sequence may be inserted into the reference sequence. These mutations of the reference sequence may occur at the 5 or 3' terminal positions of the reference nucleotide sequence or anywhere between those terminal positions, interspersed either individually among nucleotides in the reference sequence or in one or more contiguous groups within the reference sequence.

[0048] Similarly, by a polypeptide having an amino acid sequence having at least, for example, 95% "identity" to a reference amino acid sequence of SEQ ID NO:Y is intended that the amino acid sequence of the polypeptide is identical to the reference sequence except that the polypeptide sequence may include up to five amino acid alterations per each 100 amino acids of the reference amino acid of SEQ ID NO:Y. In other words, to obtain a polypeptide having an amino acid sequence at least 95% identical to a reference amino acid sequence, up to 5% of the amino acid residues in the reference sequence may be deleted or substituted with another amino acid, or a number of amino acids up to 5% of the total amino acid residues in the reference sequence may be inserted into the reference sequence. These alterations of the reference sequence may occur at the amino or carboxy terminal positions of the reference amino acid sequence or anywhere between those terminal positions, interspersed either individually among residues in the reference sequence or in one or more contiguous groups within the reference sequence.

Polypeptides of the Invention

[0049] In one aspect, the present invention relates to receptor polypeptides (or receptor proteins). The receptor polypeptides include the polypeptide of SEQ ID NO:Y; as well as polypeptides comprising the amino acid sequence of SEQ ID NO:Y; and polypeptides comprising the amino acid sequence which have at least 80% identity to that of SEQ ID NO:Y over its entire length, and still more preferably at least 90% identity, and even still more preferably at least 95% identity to SEQ ID NO:Y. Furthermore, those with at least 97-99% identity to SEQ ID NO:Y are highly preferred. Also included within receptor polypeptides are polypeptides having the amino acid sequence which have at least 80% identity to the polypeptide having the amino acid sequence of SEQ ID NO:Y over its entire length, and still more preferably at least 90% identity, and even still more preferably at least 95% identity to SEQ ID NO:Y. Furthermore, those with at least 97-99% are highly preferred. Preferably receptor polypeptides exhibit at least one biological activity of the receptor.

[0050] The receptor polypeptides may be in the form of the "mature" protein or may be a part of a larger protein such as a fusion protein. It is often advantageous to include an additional amino acid sequence which contains secretory or leader sequences, pro-sequences, sequences which aid in purification such as multiple histidine residues, or an additional sequence for stability during recombinant production.

[0051] Fragments of the receptor polypeptides are also included in the invention. A "fragment" is a polypeptide having an amino acid sequence that entirely is the same as part, but not all, of the amino acid sequence of the aforementioned receptor polypeptides. As with receptor polypeptides, fragments may be "free-standing," or comprised within a larger polypeptide of which they form a part or region, most preferably as a single continuous region. Representative examples of polypeptide fragments of the invention, include, for example, fragments from about amino acid number 1-20, 21-40, 41-60, 61-80, 81-100, and 101 to the end of receptor polypeptide. In this context "about" includes the particularly recited ranges larger or smaller by several, 5, 4, 3, 2 or 1 amino acid at either extreme or at both extremes.

[0052] Preferred fragments include, for example, truncation polypeptides having the amino acid sequence of receptor polypeptides, except for deletion of a continuous series of residues that includes the amino terminus, or a continuous series of residues that includes the carboxyl terminus or deletion of two continuous series of residues, one including the amino terminus and one including the carboxyl terminus.

[0053] Also preferred are fragments characterized by structural or functional domains, such as fragments that comprise alpha-helix and alpha-helix forming regions, beta-sheet and beta-sheet-forming regions, turn and turn-forming regions, coil and coil-forming regions, hydrophilic regions, hydrophobic regions, alpha amphipathic regions, beta amphipathic regions, flexible regions, surface-forming regions, substrate binding region, and high antigenic index regions. The "domains" of each receptor polypeptide are illustrated in the Figures. The Figures compare SEQ ID NO:Y to the closest know homologue. Identical amino acids shared between the two polypeptides are shaded, while conservative amino acid changes are boxed. By examining the regions or amino acids shaded and/or boxed, the skilled artisan can readily identify conserved domains between the two polypeptides. The amino acids sequences of SEQ ID NO:Y falling within these conserved domains are "fragments" and are specifically contemplated by the present invention. Especially preferred is the extracellular domains of a receptor of the invention. Soluble extracellular domains have antagonist activity mediated by competition with a receptor ligand.

[0054] Other preferred fragments are biologically active fragments. Biologically active fragments are those that mediate receptor activity, including those with a similar activity or an improved activity, or with a decreased undesirable activity. Also included are those that are antigenic or immunogenic in an animal, especially in a human.

[0055] Preferably, all of these polypeptide fragments retain a biological activity of the receptor, including antigenic activity. Variants of the defined sequence and fragments also form part of the present invention. Preferred variants are those that vary from the referents by conservative amino acid substitutions--i.e., those that substitute a residue with another of like characteristics. Typical such substitutions are among Ala, Val, Leu and Ile; among Ser and Thr; among the acidic residues Asp and Glu; among Asn and Gln; and among the basic residues Lys and Arg; or aromatic residues Phe and Tyr. Particularly preferred are variants in which several, 5-10, 1-5, or 1-2 amino acids are substituted, deleted, or added in any combination.

[0056] The receptor polypeptides of the invention can be prepared in any suitable manner. Such polypeptides include isolated naturally occurring polypeptides, recombinantly produced polypeptides, synthetically produced polypeptides, or polypeptides produced by a combination of these methods. Means for preparing such polypeptides are well understood in the art.

Polynucleotides of the Invention

[0057] Another aspect of the invention relates to receptor polynucleotides. Receptor polynucleotides include isolated polynucleotides which encode the receptor polypeptides and fragments, and polynucleotides closely related thereto. More specifically, a receptor polynucleotide of the invention includes a polynucleotide comprising the nucleotide sequence contained in SEQ ID NO:X encoding a receptor polypeptide of SEQ ID NO:Y, and polynucleotide having the particular sequence of SEQ ID NO:X.

[0058] Receptor polynucleotides further include a polynucleotide comprising a nucleotide sequence that has at least 80% identity over its entire length to a nucleotide sequence encoding the receptor polypeptide of SEQ ID NO:Y, and a polynucleotide comprising a nucleotide sequence that is at least 80% identical to that of SEQ ID NO:X over its entire length. In this regard, polynucleotides at least 90% identical are particularly preferred, and those with at least 95% are especially preferred. Furthermore, those with at least 97% are highly preferred and those with at least 98-99% are most highly preferred, with at least 99% being the most preferred. Also included under receptor polynucleotides are a nucleotide sequence which has sufficient identity to a nucleotide sequence contained in SEQ ID NO:X, or contained in the cDNA insert in the plasmid deposited with ATCC.TM., to hybridize under conditions useable for amplification or for use as a probe or marker. Moreover, the receptor polynucleotide includes a nucleotide sequence having at least 80% identity to a nucleotide sequence encoding the receptor polypeptide expressed by the cDNA insert deposited at the ATCC.TM., and a nucleotide sequence comprising at least 15 contiguous nucleotides of such cDNA insert. In this regard, polynucleotides at least 90% identical are particularly preferred, and those with at least 95% are especially preferred. Furthermore, those with at least 97% are highly preferred and those with at least 98-99% are most highly preferred, with at least 99% being the most preferred. The invention also provides polynucleotides which are complementary to all the above receptor polynucleotides.

[0059] The receptors of the invention are structurally related to other proteins of specified receptor families, as shown by the results in the Figures. The cDNA sequence of SEQ ID NO:X encodes a polypeptide as described in Table 1 as SEQ ID NO:Y. Because the receptor polypeptides contain domains similar in structure to other receptor family members, the receptors of the present invention are expected to have, inter alia, similar biological functions/properties to their homologous polypeptides and polynucleotides, and their utility is obvious to anyone skilled in the art.

TABLE-US-00001 TABLE 1 SEQ ID SEQ ID ATCC .TM. ATCC .TM. Receptor Clone ID Name NO: X NO: Y Deposit No. Deposit Date Family Homology HMACR70 1 18 209054 May 16, 1997 Ig Sialoadhesin ##### Jan. 21, 1998 OB-1 HTEDK48 209054 May 16, 1997 TM4SF MRC-OX44 PETA-3 1-1849 bp 2 160-900 bp 3 19 HTPED39 4 20 209054 May 16, 1997 TM4SF NAG-2 HPWAE25 ##### Jan. 21, 1998 TALLA-1 HTPEF86 5 21 209053 May 16, 1997 TM4SF CD20 B1 Antigen HSBBF02 6 22 209054 May 16, 1997 TM4SF TALLA-1 HLTAH80 7 23 97242 Aug. 02, 1995 TM4SF TALLA-1 209054 May 16, 1997 HTPBA27 8 24 97242 Aug. 02, 1995 TM4SF NAG-2 209054 May 16, 1997 HAIDQ59 209054 May 16, 1997 TM4SF CD9 Antigen 5' Sequence 9 25 3' Sequence 10 - HHFEK40 11 26 209054 May 16, 1997 TM4SF PETA-3 HGBGV89 12 27 209125 Jun. 09, 1997 TM4SF L6H 209054 May 16, 1997 HUVBB80 13 28 209054 May 16, 1997 TM4SF L6 HJACE54 14 29 209053 May 16, 1997 Lectin Galectin-3 Galectin-5 Galectin-8 HROAD63 15 30 209053 May 16, 1997 Ly6 E48 splice variant HMWGS46 16 31 209053 May 16, 1997 Prohibitin BAP-37 HNFGW06 17 32 209053 May 16, 1997 EGFR EGFR

[0060] The novel full-length cDNA clone designated HMACR70 (SEQ ID NO:1) may be a member of the sialoadhesin family of the Ig superfamily of receptor-like molecules and a CD33 homologue. HMACR70 contains a 1497 nucleotide cDNA insert (SEQ ID NO:1) encoding a 315 amino acid ORF (SEQ ID NO:18) and was cloned from a GM-CSF-treated human macrophage cDNA library. The only additional cDNA libraries in the HGS database which include this clone are human eosinophils and possibly human gall bladder. A BLAST analysis of the amino acid sequence of HMACR70 (SEQ ID NO:18) demonstrates that this clone exhibits approximately 50% identity and 69% similarity over a 300 amino acids stretch of a gene termed human differentiation antigen, and 38% identity and 62% similarity of the human myelin-associated glycoprotein precursor CD33 gene.

[0061] A more recent BLAST analysis confirms HMACR70's (SEQ ID NO:18) designation as a sialoadhesin family member. HMACR70 (SEQ ID NO:18) is homologous to two recently identified sialoadhesin family members, human OB binding protein (OB) 1 (SEQ ID NO:33) and 2. (See, Genbank Accession No. U71382; see FIG. 1.) It is thought that OB-1 (SEQ ID NO:33) and OB-2 may bind leptin. Thus, HMACR70 (SEQ ID NO:18), as a sialoadhesin family member, may act to attenuate or even amplify intercellular routes of communication, including binding to leptin or modulating the activity of immune cells, such as macrophages. Clearly, any diseases affected by these processes could be treated by the polypeptide or fragment of HMACR70 (SEQ ID NO:18).

[0062] The full-length nucleotide sequences of ten novel human cDNA clones which potentially belong to the TM4SF superfamily are disclosed in the table above and will be addressed sequentially.

[0063] The cDNA clone HTEDK48 contains a 1849 nucleotide cDNA insert (SEQ ID NO:2) encoding a 245 amino acid ORF that was cloned from a human testes cDNA library. The coding sequence of HTEDK48 (SEQ ID NO: 3) may be fused to other human proteins, such as 3-hydroxyacyl-CoA dehydrogenase. BLAST analysis of the amino acid sequence of HTEDK48 (SEQ ID NO:19) demonstrates that this clone exhibits approximately 30% identity and 51% similarity over a 245 amino acid stretch of the CD82 molecule. Recent studies have shown that CD82 can associate with CD4 or CD8 and deliver costimulatory signals for the TCR/CD3 pathway. CD82 has also been found to be involved in syncytium formation in HTLV-1-infected T-cells. And finally, in a recently published study in which the expression of the CD82 gene by tumors of the lung was examined retrospectively, it was reported that CD82 may be linked to the suppression of tumor metastasis of prostate cancer. The study also reported that decreased CD82 expression may be involved in malignant progression of such cancers. Thus, HTEDK48 (SEQ ID NO:2, NO:3, NO:19) may also be involved in the development of cancer.

[0064] A more recent BLAST analysis shows that HTEDK48 (SEQ ID NO:19) is homologous the rat leukocyte antigen, MRC OX-44 (SEQ ID NO:34), and the platelet endothelial tetraspan antigen-3 (PETA-3) (SEQ ID NO:35). (See FIG. 2X.) MRC OX-44 (SEQ ID NO:34), a member of a new family of cell surface proteins, appears to be involved in growth regulation. (See, Bellacosa, A., et al., "The Rat Leukocyte antigen MRC OX-44 is a Member of a New Family of Cell Surface Proteins which Appear to be Involved in Growth Regulation," Mol. Cell. Bio. 11: 2864-2872 (1991).) Similarly, PETA-3 (SEQ ID NO:35) has been located to platelet endothelial cells, and an anti-PETA-3 antigen monoclonal antibody can stimulate platelet aggregation and mediator release. (See, Fitter, S., "Molecular Cloning of cDNA Encoding a Novel Platelet-Endothelial Cell Tetra-Span Antigen, PETA-3," Blood, 86(4):1348-1355 (1995).) Thus, HTEDK48 (SEQ ID NO:19) may function similar to MRC OX-44 (SEQ ID NO:34) or PETA-3 (SEQ ID NO:35) to affect growth of blood cells. Administering polypeptides or fragments of HTEDK48 (SEQ ID NO:19) may be an effective treatment of blood disorders.

[0065] The cDNA clone HPWAE25 contains a 1288 nucleotide cDNA insert (SEQ ID NO:4) encoding a 273 amino acid ORF (SEQ ID NO:20) that was cloned from a human pancreas tumor cDNA library, while clone HTPED39 represents a truncated cDNA sequence. This clone also appears in a number of other cDNA libraries constructed from a variety of human cell and tissue types including keratinocytes, ulcerative colitis, striatum depression, lymph node breast cancer, ovarian cancer, stage B2 prostate cancer, kidney medulla, and others. Northern blot analysis of HLTAH80 (SEQ ID NO:23) also shows expression in a variety of human cell lines including U937, MM96, WM115, and MDAMB231. A BLAST analysis of the amino acid sequence of HTPED39 demonstrates that this clone exhibits approximately 35% identity and 50% similarity over the entire length of the CD37 molecule. The CD37 antigen is expressed on B cells and on a subpopulation of T cells, but not on pre-B or plasma cells. It has been reported that CD37 expression is downregulated in conjunction with B-cell activation, suggesting that CD37 may be involved in the processes which dictate the activation state of the B-cell.

[0066] Moreover, HPWAE25 (SEQ ID NO:20) is also homologous to recently identified TM4SF members, NAG-2 (SEQ ID NO:36) and TALLA-1 (SEQ ID NO:37). (See FIG. 3.) NAG-2 (SEQ ID NO:36) is thought to complex with integrins and other TM4SF proteins, while TALLA-1 (SEQ ID NO:37) is a highly specific marker of T-cell acute lymphoblastic leukemia and neuroblastoma. (See, Tachibana, I., et al., "NAG-2, A Novel Transmembrane-4 Superfamily (TM4SF) Protein that Complexs with Integrins and Other TM4SF Proteins," J. Biol. Chem., 272:29181-29189 (1997); Takagi, S., "Identification of a Highly Specific Surface Marker of T-cell Acute Lymphoblastic Leukemia and Neuroblastoma as a New Member of the Transmembrane 4 Superfamily," Int. J. Cancer 61(5):706-715 (1995).) Thus, HPWAE25 (SEQ ID NO:20) may be involved the development of cancer, particularly leukemia, lymphoma, and neuroblastoma. HPWAE25 (SEQ ID NO:4 and NO:20) may be used as an effective treatment of these cancers, as well as a diagnostic marker.

[0067] A subfamily of TM4SF receptors include CD20 proteins. A CD20-like cDNA clone was obtained from a human pancreas tumor cDNA library and contains a 1236 nucleotide insert which encodes a 250 amino acid ORF. A BLAST analysis of the deduced amino acid sequence of HTPEF86 (SEQ ID NO:21) exhibits approximately 41% identity and 61% similarity to the CD20 gene, also known as B1 antigen (SEQ ID NO:38). (See FIG. 4.) Expression of this gene is detected in only two additional HGS human cDNA libraries; amygdala depression and 9 week early stage human. Although the precise functional role of CD20 has yet to be determined, it is clear that CD20 plays a key role in the regulation of B-cell activation. Based primarily on sequence identity, the novel CD20-like molecule presented herein may also be involved in cell cycle activation. Potential therapeutic and/or diagnostic applications for HTPEF86 (SEQ ID NO:21) may include such clinical presentations as juvenile rheumatoid arthritis, Graves' Disease, and a number of B-cell lymphomas or other lymphoid tumors.

[0068] The clone HSBBF02 contains a 1115 nucleotide cDNA insert (SEQ ID NO:6) encoding a 245 amino acid ORF (SEQ ID NO:22) and was cloned from an HSC 172 cell line cDNA library. This clone also appears in a number of other cDNA libraries constructed from a variety of human cell and tissue types including brain amygdala depression, endothelial cells, fetal liver and heart, osteoblasts, testes, and others. A BLAST analysis of the amino acid sequence of HSBBF02 (SEQ ID NO:22) demonstrates that this clone exhibits approximately 64% identity and 80% similarity with the A15 molecule over a 131 amino acid stretch (A15 is composed of 244 amino acids). A more recent BLAST search shows that HSBBF02 (SEQ ID NO:22) is similar to the TALLA-1 protein (SEQ ID NO:37) and may in fact be a closely related family member. (See FIG. 5.)

[0069] In addition, a second cDNA clone, designated HLTAH80 (SEQ ID NO:23), exhibits sequence similarity to the A15 molecule and TALLA-1 (SEQ ID NO:37). (See FIG. 6.) This clone contains a 1662 nucleotide cDNA insert encoding a 253 amino acid ORF and was cloned from a human T-cell lymphoma cDNA library. This clone also appears in a number of other cDNA libraries constructed from a variety of human cell and tissue types including B-cell lymphoma, corpus collosum, endometrial tumor, osteosarcoma, testes, and others. Northern blot analysis of HLTAH80 (SEQ ID NO:7) also shows expression in a variety of human tissues including spleen, lymph node, thymus, PBLs, heart, and a particularly strong signal in skeletal muscle and pancreas. A BLAST analysis of the amino acid sequence of HLTAH80 (SEQ ID NO:23) demonstrates that this clone exhibits approximately 35% identity and 55% similarity over the entire length of the A15 molecule.

[0070] Since expression of A15 drops to undetectable levels when comparing immature T-cells to peripheral blood lymphocytes, it is thought that A15 may play a role in the development of T-cells. Furthermore, the MXS1(CCG-B7) gene which codes for A15 contains a number of triplet nucleotide repeats which have been associated with neuropsychiatric diseases such as Huntington's chorea, fragile X syndrome, and myotonic dystrophy. In addition, A15 appears to be expressed exclusively on T-cell acute lymphoblastic leukemia cell lines, including several derived from adult T-cell leukemia and those established by immortalization with human T-cell leukemia virus type 1 or Herpesvirus saimiri. Thus, clones HLTAH80 (SEQ ID NO:7 and NO:23) and/or HSBBF02 (SEQ ID NO:6 and NO:22) may also be involved in diseases caused by the expansion of repeats or chromosomal instability.

[0071] The cDNA clone HTPBA27 contains a 1345 nucleotide cDNA insert (SEQ ID NO:8) encoding a 238 amino acid ORF (SEQ ID NO:24) and was cloned from a human tumor pancreas cDNA library. This clone also appears in a number of other cDNA libraries constructed from a variety of human cell and tissue types including cerebellum, breast lymph node, osteosarcoma, adult testes, RS4; 11 bone marrow cell line, microvascular endothelial cells, and others. A BLAST analysis of the amino acid sequence of HTPBA27 (SEQ ID NO:24) demonstrates that this clone exhibits approximately 40% identity and 64% similarity with a glycoprotein termed CD53 over its entire length. CD53 is thought to be involved in thymopoiesis, since rat CD53 can be detected on immature CD4-8-thymocytes and the functionally mature single-positive subset, but cannot be detected on the intermediate CD4+8+ thymocytic subset of cells. The CD53 molecule has also been implicated as a component of signal transduction pathways in B cells, monocytes and granulocytes, rat macrophages, NK, and T cells. Moreover, as illustrated in FIG. 7, HTPBA27 (SEQ ID NO:24) was recently confirmed as a TM4SF receptor. (See, Tachibana, I., et al., "NAG-2, A Novel Transmembrane-4 Superfamily (TM4SF) Protein that with Integrins and Other TM4SF Proteins," J. Biol. Chem., 272:29181-29189 (1997).) Calling the HTPBA27 polypeptide (SEQ ID NO:24) NAG-2 (SEQ ID NO:36), this group confirmed HTPBA27's status as a TM4SF receptor by showing that NAG-2 (SEQ ID NO:36) complexes with integrin and other TM4SF receptors. Thus, diseases caused by the failure of HTPBA27 (SEQ ID NO:24) to complex with integrin and other TM4SF receptors can be treated by administering HTPBA27(SEQ ID NO:24). HTPBA27 (SEQ ID NO:8 and NO:24) can also be used to diagnose these diseases.

[0072] The cDNA clone HAIDQ59 contains cDNA insert encoding a 221 amino acid ORF (SEQ ID NO:25) that was cloned from a human epithelial cell induced with TNFa and INF cDNA library. The 5' end of HAIDQ59 is represented by the SEQ ID NO: 9, while the 3' end is represented by SEQ ID NO: 10. This clone appears in only two additional cDNA libraries in the HGS database. These two libraries were constructed from the human Jurkat T-cell line and human microvascular endothelial cells. A BLAST analysis of the amino acid sequence of HAIDQ59 (SEQ ID NO:25) demonstrates that this clone exhibits approximately 53% identity and 69% similarity over 226 amino acids of the CD9 TM4SF molecule (SEQ ID NO:39). (See FIG. 8.) It has been demonstrated that the CD9 molecule (SEQ ID NO:39) is involved in signal transduction pathways in platelets, as well as in cell adhesion in both platelets and pre-B-cell lines. Intriguingly, a monoclonal antibody (vpg15), which recognizes the feline homologue of CD9, has been shown to block infection by feline immunodeficiency virus (FIV). Furthermore, a recent study shows that cells expressing high levels of CD9 (SEQ ID NO:39) exhibited suppressed cell motility. Thus, HAIDQ59 (SEQ ID NO:25) may also be involved in signal transduction of blood cells.

[0073] The cDNA clone HHFEK40 contains a 936 nucleotide cDNA insert (SEQ ID NO:11) encoding a 252 amino acid ORE (SEQ ID NO:26) and was cloned from a human fetal heart cDNA library. This clone appears once in the human fetal heart cDNA library and possibly in a hemangiopericytoma cDNA library. A BLAST analysis of the amino acid sequence of HHFEK40 (SEQ ID NO:26) demonstrated that this clone exhibits approximately 60% identity and 75% similarity over the entire length of a molecule designated PETA-3 (SEQ ID NO:35). (See FIG. 9.) PETA-3 (SEQ ID NO:35) was originally identified as a novel human platelet surface glycoprotein termed gp27. Although PETA-3 (SEQ ID NO:35) is present in low abundance on the platelet surface, an anti-PETA-3 monoclonal antibody can stimulate platelet aggregation and mediator release. Thus, HHFEK40 (SEQ ID NO:26) may function similar to PETA-3 (SEQ ID NO:35) to affect growth of blood cells. Administering polypeptides or fragments of HHFEK40 (SEQ ID NO:26) may be an effective treatment of blood disorders.

[0074] The cDNA clone HGBGV89 contains a 738 nucleotide cDNA insert (SEQ ID NO:12) encoding a 197 amino acid ORF (SEQ ID NO:27) and was cloned from a human gall bladder cDNA library. The only two additional appearances of this clone in the HGS database are in a normalized fetal liver cDNA library and in a fetal liver/spleen cDNA library. The cDNA clone HUVBB80 contains a 1071 nucleotide cDNA insert (SEQ ID NO:13) encoding a 201 amino acid ORF (SEQ ID NO:28) and was cloned from a human umbilical vein cDNA library. This clone appears in several additional cDNA libraries in the HGS database including prostate BPH, thyroid, and fetal liver/spleen. BLAST analyses of the amino acid sequences of HGBGV89 (SEQ ID NO:27) and HUVBB80 (SEQ ID NO:28) demonstrate that these clones exhibit approximately 49% identity and 65% similarity and 47% identity and 68% similarity, respectively, over the entire length of a molecule designated L6 surface protein (SEQ ID NO:41) or human tumor-associated antigen L6 (SEQ ID NO:41) (See FIGS. 10 & 11.) Moreover, another group has confirmed the TM4SF receptor homology of HGBGV89 (SEQ ID NO:27) by describing the protein as a putative transmembrane protein L6H (SEQ ID NO:40). (See Genbank Accession No 2587054; see FIG. 10.) The L6 cell surface antigen (SEQ ID NO:41) is highly expressed on lung, breast, colon, and ovarian carcinomas. Promising results of phase 1 clinical studies have been reported with an anti-L6 monoclonal antibody, or its humanized counterpart, suggesting that the L6 antigen (SEQ ID NO:41) may be an attractive target for monoclonal antibody-based cancer therapy.

[0075] In summary, there is a clear need for identifying and exploiting novel members of the TM4SF superfamily such as those described herein. Although structurally related, these factors will likely possess diverse and multifaceted functions in a variety of cell and tissue types. Receptor type molecules, such as the novel potential members of the TM4SF superfamily detailed here, should prove useful in target based screens for small molecules and other such pharmacologically valuable factors. Monoclonal antibodies raised against such factors may prove useful as therapeutics in an anti-tumor, diagnostic, or other capacity. Furthermore, factors such as the nine novel TM4SF superfamily-like molecules described here may prove useful in an active or passive immunotherapeutical role in patients with cancer or other immunocompromised disease states.

[0076] Besides TM4SF receptors, receptors from other families are also described. For example, clone HJACE54 (SEQ ID NO:14 and NO:29), also called galectin 11, exhibits significant sequence identity to the rat galectin 5 (SEQ ID NO:42), the chicken galectin 3 gene, and the human galectin 8 (SEQ ID NO:43) genes. (See FIG. 12.) The galectin 11 cDNA clone contains an 865 nucleotide insert (SEQ ID NO:14) which encodes a 133 amino acid ORF (SEQ ID NO:29). The clone was obtained from a Jurkat T-cell G1 phase cDNA library. A BLAST analysis of the deduced amino acid sequence of HJACE54 (SEQ ID NO:29) demonstrates approximately 35% identity and 57% similarity to the amino acid sequence of the rat galectin 5 (SEQ ID NO:42) gene. Expression of galectin 11 (SEQ ID NO:14) is quite limited in the HGS database. In fact, the only two additional ESTs in the HGS database which contain the HJACE54 sequence (SEQ ID NO:14) were found in human neutrophil and human infant adrenal gland cDNA libraries. Northern blot analyses have not been performed to examine expression patterns of the galectin 11 gene (SEQ ID NO:14).

[0077] Various galectins have been shown to function in the mechanisms of intercellular communication. For example, depending on cell type, galectin 1 has been observed to modulate cell adhesion either positively or negatively. More specifically, galectin 1 appears to inhibit cell adhesion of skeletal muscle presumably by galectin 1-mediated disruption of laminin-integrin a.sub.7b.sub.1 interactions. Alternatively, galectin 1 appears to promote cell adhesion in several non-skeletal muscle cell types examined presumably by a glycoconjugate cross-linking mechanism. Galectin 3 has also been observed to function in modulating cell-adhesion, as well as in the activation of certain immune cells by cross-linking IgE and IgE receptors. In addition, galectins have been observed to be involved in the regulation of immune cell activity, as well as in such diverse processes as cell adhesion, proliferation, inflammation, autoimmunity, and metastasis of tumor cells. Furthermore, a galectin-like antigen designated HOM-HD-21 was recently found to be highly expressed in a Hodgkin's Disease cDNA library. Very recently, a novel galectin, termed PCTA-1, was identified as a specific cell surface marker on human prostate cancer cell lines and patient-derived carcinomas. Galectins have also been found to function intracellularly as a component of ribonucleoprotein complexes. Finally, galectins 1 and 3 have each been found to modulate T-cell growth and apoptosis by interaction with CD45 and possibly Bcl2, respectively. As a result, the discovery of a novel galectin (SEQ ID NO:29), such as that encoded by HJACE54 (SEQ ID NO:14), is likely to be a valuable asset both diagnostically and therapeutically.

[0078] Additionally, a full-length nucleotide sequence of a novel human cDNA clone which encodes an apparent splice variant of the previously described human E48 antigen has recently been determined. (See FIG. 13.) Clone HROAD63 contains a 441 nucleotide cDNA (SEQ ID NO:15) which encodes a 70 amino acid polypeptide (SEQ ID NO:30). This novel clone exhibits significant sequence identity to several members of a relatively new family of cell-surface proteins termed the Ly6 superfamily. These members include murine and human SCA-2, rat Ly-6 (also termed ThB), and human CD59 [also known as protectin or membrane attack complex inhibition factor (MACIF)]. The novel E48 splice variant (SEQ ID NO:15) was obtained from the HGS human stomach cDNA library. The clone (SEQ ID NO:30) is present in only a limited number of other HGS cDNA libraries including kidney cancer, keratinocyte, and tongue. An alignment of the nucleotide sequences of the human E48 and HROAD63 (SEQ ID NO:15) cDNAs demonstrates that the initial 168 and 178 nucleotides of E48 and HROAD63, respectively, are identical, with the exception of an additional 10 nucleotides of sequence at the extreme 5' end of the HROAD63 sequence. The sequence of the two clones is also identical for an additional 229 nucleotides including the 3' end of the coding sequences and the entire 3' untranslated regions. The only divergence of nucleotide sequence in this region of the clones is the deletion of a single thymidine residue in the 3' UTR of the E48 cDNA. The major difference between the two nucleotide sequences is a 329 nucleotide deletion from the HROAD63 sequence. This deletion causes a shift in the HROAD63 reading frame and encompasses the translational stop signal used in the E48 clone. As a result, the carboxy terminal sequence of HROAD63 (SEQ ID NO:30) is radically altered with regard to that of E48 (SEQ ID NO:44) (as illustrated in FIG. 13 by the obvious differences between amino acids 56-128 of E48 and 56-70 of HROAD63 in the amino acid alignment). The clinical presentation of disorders, including abnormal skin and hair phenotypes, may be attributed, at least in part, to a non-functional Ly6 superfamily member such as E48 (SEQ ID NO:44) or HROAD63 (SEQ ID NO:30). HROAD63 (SEQ ID NO:30) may also be involved in blood disorders, as seen with its homologues SCA-2 and CD59.

[0079] A novel prohibitin cDNA clone (SEQ ID NO:16) presented herein was originally identified in a human bone marrow cell line (RS4; 11) cDNA library. The clone contains a 1066 nucleotide insert (SEQ ID NO:16) which encodes a 299 amino acid polypeptide (SEQ ID NO:31). BLAST and BestFit analyses of the predicted amino acid sequence of HMWGS46 (SEQ ID NO:31) demonstrate a highly significant sequence identity to a murine protein termed IgM B-cell receptor associated protein (BAP)-37 (SEQ ID NO:45) (Genbank accession number X78683). The HMWGS46 amino acid sequence (SEQ ID NO:31) exhibits nearly perfect identity and similarity over the entire length of the murine BAP-37 sequence (SEQ ID NO:45). (See FIG. 14.) In addition, the full-length nucleotide sequences of HMWGS46 (SEQ ID NO:16) and BAP-37 (SEQ ID NO:45) exhibit at least 87% identical. The HMWGS46 clone (SEQ ID NO:16) also exhibits approximately 49% sequence identity and 85% sequence similarity to a human gene designated prohibitin. Finally, the HMWGS46 cDNA (SEQ ID NO:16) appears in a substantial number of HGS human cDNA libraries in addition to the bone marrow cell line cDNA library from which it was cloned. Some of the cDNA libraries in which this clone appears include keratinocytes, induced endothelial cells, activated neutrophils, synovial sarcoma, colon carcinoma cell line, Jurkat cell line membrane bound polysomes, epileptic frontal cortex, primary dendritic cells, and a number of others. The novel gene related to prohibitin and BAP-37 (SEQ ID NO:45) may prove quite useful as a diagnostic for tumorigenesis, as well as a target for therapeutic intervention of such an event. Thus, although the precise functional role of the prohibitin family members are less than clear, it is quite likely that such homologues are involved in such complex processes as development, senescence, and tumor suppression. Therefore a novel gene, such as HMWGS46 (SEQ ID NO:16 and NO:31), may prove quite useful as a diagnostic for tumorigenesis, as well as a target for therapeutic intervention of such an event.

[0080] A human cDNA clone encoding a novel epidermal growth factor receptor (EGFR)-like molecule (SEQ ID NO:32) is also disclosed. The novel EGFR-like cDNA clone (SEQ ID NO:17) presented herein was originally identified in an activated human neutrophil cDNA library. The clone contains a 704 nucleotide insert (SEQ ID NO:17) which encodes a 168 amino acid polypeptide (SEQ ID NO:32). A BLAST analysis of the predicted amino acid sequence of HNFGW06 (SEQ ID NO:32) demonstrates that this novel clone exhibits approximately 85% identity and 90% similarity to a protein designated epidermal growth factor receptor-related protein [Homo sapiens] (SEQ ID NO:46). (See FIG. 15.) The expression profile of the HNFGW06 clone (SEQ ID NO:17) in the HGS database indicates the existence of a fairly highly restricted expression pattern. In addition to the activated neutrophil library from which this clone (SEQ ID NO:17) was obtained, it also appears in the following HGS human cDNA libraries: synovial sarcoma, smooth muscle, placenta, and possibly primary dendritic cells.

[0081] The novel EGFR-like cDNA clone HNFGW06 (SEQ ID NO:17) may lead to a number of exciting possibilities for therapeutic and/or diagnostic treatments or reagents. For example, HNFGW06 (SEQ ID NO:17 and NO:32) may be involved in the onset of human breast cancers as well. In addition, due to the fact that TGF-a acts through binding to the EGFR (SEQ ID NO:46), it is possible that HNFGW06 (SEQ ID NO:17 and NO:32) may also play a role in a variety of gastric processes including regulation of acid secretion, regulation of mucous cell growth, and protection against ethanol- and aspirin-induced injury to gastric tissues.

Generating Polynucleotides

[0082] Polynucleotides of the present invention encoding a receptor may be obtained using standard cloning and screening, from a cDNA library derived from mRNA in cells specified in Table 1 using the expressed sequence tag (EST) analysis (Adams, M. D., et al. Science (1991) 252:1651-1656; Adams, M. D. et al., Nature, (1992) 355:632-634; Adams, M. D., et al., Nature (1995) 377 Supp:3-174.) Polynucleotides of the invention can also be obtained from natural sources such as genomic DNA libraries or can be synthesized using well known and commercially available techniques.

[0083] The nucleotide sequence encoding a receptor polypeptide of SEQ ID NO:Y may be identical to the polynucleotide encoding SEQ ID NO:Y, or it may be a sequence, which as a result of the redundancy (degeneracy) of the genetic code, also encodes the polypeptide of SEQ ID NO:Y.

[0084] When the polynucleotides of the invention are used for the recombinant production of a receptor polypeptide, the polynucleotide may include the coding sequence for the mature polypeptide or a fragment thereof, by itself; the coding sequence for the mature polypeptide or fragment in reading frame with other coding sequences, such as those encoding a leader or secretory sequence, a pre-, or pro- or prepro-protein sequence, or other fusion peptide portions. For example, a marker sequence which facilitates purification of the fused polypeptide can be encoded. In certain preferred embodiments of this aspect of the invention, the marker sequence is a hexa-histidine peptide, as provided in the pQE vector (Qiagen, Inc.) and described in Gentz et al., Proc Natl Acad Sci USA (1989) 86:821-824, or is an HA tag. The polynucleotide may also contain non-coding 5' and 3' sequences, such as transcribed, non-translated sequences, splicing and polyadenylation signals, ribosome binding sites and sequences that stabilize mRNA.

[0085] Further preferred embodiments are polynucleotides encoding receptor variants comprising the amino acid sequence of receptor polypeptide of Table 1 (SEQ ID NO:Y) in which several, 5-10, 1-5, 1-3, 1-2 or 1 amino acid residues are substituted, deleted or added, in any combination.

[0086] The present invention further relates to polynucleotides that hybridize to the herein above-described sequences. In this regard, the present invention especially relates to polynucleotides which hybridize under stringent conditions to the herein above-described polynucleotides. As herein used, the term "stringent conditions" means hybridization will occur only if there is at least 80%, and preferably at least 90%, and more preferably at least 95%, yet even more preferably 97-99% identity between the sequences.

[0087] Polynucleotides of the invention, which are identical or sufficiently identical to a nucleotide sequence contained in SEQ ID NO:X or a fragment thereof, or to the cDNA insert in the plasmid deposited at the ATCC.TM., or a fragment thereof, may be used as hybridization probes for cDNA and genomic DNA, to isolate full-length cDNAs and genomic clones encoding the receptor and to isolate cDNA and genomic clones of other genes (including genes encoding homologs and orthologs) that have a high sequence similarity to the receptor gene. Such hybridization techniques are known to those of skill in the art. Typically these nucleotide sequences are 80% identical, preferably 90% identical, more preferably 95% identical to that of the referent. The probes generally will comprise at least 15 nucleotides. Preferably, such probes will have at least 30 nucleotides and may have at least 50 nucleotides. Particularly preferred probes will range between 30 and 50 nucleotides.

[0088] In one embodiment, to obtain a polynucleotide encoding the receptor polypeptide, including homologs and orthologs from other species, comprises the steps of screening an appropriate library under stringent hybridization conditions with a labeled probe having the SEQ ID NO:X or a fragment thereof; and isolating full-length cDNA and genomic clones containing said polynucleotide sequence. Such hybridization techniques are well known to those of skill in the art. Stringent hybridization conditions are as defined above or, alternatively, conditions under overnight incubation at 42.degree. C. in a solution comprising: 50% formamidc, 5.times.SSC (150 mM NaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH7.6), 5.times.Denhardt's solution, 10% dextran sulfate, and 20 microgram/ml denatured, sheared salmon sperm DNA, followed by washing the filters in 0.1.times.SSC at about 65.degree. C.

[0089] The polynucleotides and polypeptides of the present invention may be employed as research reagents and materials for discovery of treatments and diagnostics to animal and human disease.

Vectors, Host Cells, Expression

[0090] The present invention also relates to vectors which comprise a polynucleotide or polynucleotides of the present invention, and host cells which are genetically engineered with vectors of the invention and to the production of polypeptides of the invention by recombinant techniques. Cell-free translation systems can also be employed to produce such proteins using RNAs derived from the DNA constructs of the present invention.

[0091] For recombinant production, host cells can be genetically engineered to incorporate expression systems or portions thereof for polynucleotides of the present invention. Introduction of polynucleotides into host cells can be effected by methods described in many standard laboratory manuals, such as Davis et al., BASIC METHODS IN MOLECULAR BIOLOGY (1986) and Sambrook et al., MOLECULAR CLONING: A LABORATORY MANUAL, 2nd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989) such as calcium phosphate transfection, DEAE-dextran mediated transfection, transvection, microinjection, cationic lipid-mediated transfection, electroporation, transduction, scrape loading, ballistic introduction or infection.

[0092] Representative examples of appropriate hosts include bacterial cells, such as streptococci, staphylococci, E. coli, Streptomyces and Bacillus subtilis cells; fungal cells, such as yeast cells and Aspergillus cells; insect cells such as Drosophila S2 and Spodoptera Sf9 cells; animal cells such as CHO, COS, HeLa, C127, 3T3, BHK, HEK 293 and Bowes melanoma cells; and plant cells.

[0093] A great variety of expression systems can be used. Such systems include, among others, chromosomal, episomal and virus-derived systems, e.g., vectors derived from bacterial plasmids, from bacteriophage, from transposons, from yeast episomes, from insertion elements, from yeast chromosomal elements, from viruses such as baculoviruses, papova viruses, such as SV40, vaccinia viruses, adenoviruses, fowl pox viruses, pseudorabies viruses and retroviruses, and vectors derived from combinations thereof, such as those derived from plasmid and bacteriophage genetic elements, such as cosmids and phagemids. The expression systems may contain control regions that regulate as well as engender expression. Generally, any system or vector suitable to maintain, propagate or express polynucleotides to produce a polypeptide in a host may be used. The appropriate nucleotide sequence may be inserted into an expression system by any of a variety of well-known and routine techniques, such as, for example, those set forth in Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL (supra).

[0094] For secretion of the translated protein into the lumen of the endoplasmic reticulum, into the periplasmic space or into the extracellular environment, appropriate secretion signals may be incorporated into the desired polypeptide. These signals may be endogenous to the polypeptide or they may be heterologous signals.

[0095] If the receptor polypeptide is to be expressed for use in screening assays, generally, it is preferred that the polypeptide be produced at the surface of the cell. In this event, the cells may be harvested prior to use in the screening assay. If the receptor polypeptide is secreted into the medium, the medium can be recovered in order to recover and purify the polypeptide; if produced intracellularly, the cells must first be lysed before the polypeptide is recovered.

[0096] Receptor polypeptides can be recovered and purified from recombinant cell cultures by well-known methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Most preferably, high performance liquid chromatography is employed for purification. Well known techniques for refolding proteins may be employed to regenerate active conformation when the polypeptide is denatured during isolation and or purification.

Diagnostic Assays

[0097] This invention also relates to the use of receptor polynucleotides or polypeptides for use as diagnostic reagents. Detection of a mutated form of the receptor gene associated with a dysfunction will provide a diagnostic tool that can add to or define a diagnosis of a disease or susceptibility to a disease which results from under-expression, over-expression or altered expression of the receptor. Individuals carrying mutations in the receptor gene may be detected at the DNA level by a variety of techniques.

[0098] Nucleic acids for diagnosis may be obtained from a subject's cells, such as from blood, urine, saliva, tissue biopsy or autopsy material. The genomic DNA may be used directly for detection or may be amplified enzymatically by using PCR or other amplification techniques prior to analysis. RNA or cDNA may also be used in similar fashion. Deletions and insertions can be detected by a change in size of the amplified product in comparison to the normal genotype. Point mutations can be identified by hybridizing amplified DNA to labeled receptor nucleotide sequences. Perfectly matched sequences can be distinguished from mismatched duplexes by RNasc digestion or by differences in melting temperatures. DNA sequence differences may also be detected by alterations in electrophoretic mobility of DNA fragments in gels, with or without denaturing agents, or by direct DNA sequencing. (See, e.g., Myers et al., Science (1985) 230:1242.) Sequence changes at specific locations may also be revealed by nuclease protection assays, such as RNase and S1 protection or the chemical cleavage method. (See Cotton et al., Proc Natl Acad Sci USA (1985) 85: 4397-4401.) In another embodiment, an array of oligonucleotides probes comprising receptor nucleotide sequence or fragments thereof can be constructed to conduct efficient screening of e.g., genetic mutations. Array technology methods are well known and have general applicability and can be used to address a variety of questions in molecular genetics including gene expression, genetic linkage, and genetic variability. (See for example: M. Chee et al., Science, Vol 274, pp 610-613 (1996).)

[0099] The diagnostic assays offer a process for diagnosing or determining a susceptibility to specific diseases through detection of mutation in the receptor gene by the methods described.

[0100] In addition, specific diseases can be diagnosed by methods comprising determining from a sample derived from a subject an abnormally decreased or increased level of receptor polypeptide or receptor mRNA. Decreased or increased expression can be measured at the RNA level using any of the methods well known in the art for the quantitation of polynucleotides, such as, for example, PCR, RT-PCR, RNase protection, Northern blotting and other hybridization methods. Assay techniques that can be used to determine levels of a protein in a sample derived from a host are well-known to those of skill in the art. Such assay methods include radioimmunoassays, competitive-binding assays, Western Blot analysis and ELISA assays.

[0101] Thus in another aspect, the present invention relates to a diagnostic kit for a disease or susceptibility to a disease which comprises:

[0102] (a) a receptor polynucleotide, preferably the nucleotide sequence of SEQ ID NO:X, or a fragment thereof;

[0103] (b) a nucleotide sequence complementary to that of (a);

[0104] (c) a receptor polypeptide, preferably the polypeptide of SEQ ID NO:Y, or a fragment thereof; or

[0105] (d) an antibody to a receptor polypeptide, preferably to the polypeptide of SEQ ID NO: Y.

[0106] It will be appreciated that in any such kit, (a), (b), (c) or (d) may comprise a substantial component.

Chromosome Assays

[0107] The nucleotide sequences of the present invention are also valuable for chromosome identification. The sequence is specifically targeted to and can hybridize with a particular location on an individual human chromosome. The mapping of relevant sequences to chromosomes according to the present invention is an important first step in correlating those sequences with gene associated disease. Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be correlated with genetic map data. Such data are found, for example, in V. McKusick, Mendelian Inheritance in Man (available on line through Johns Hopkins University Welch Medical Library). The relationship between genes and diseases that have been mapped to the same chromosomal region are then identified through linkage analysis (coinheritance of physically adjacent genes).

[0108] The differences in the cDNA or genomic sequence between affected and unaffected individuals can also be determined. If a mutation is observed in some or all of the affected individuals but not in any normal individuals, then the mutation is likely to be the causative agent of the disease.

Antibodies

[0109] The polypeptides of the invention or their fragments or analogs thereof, or cells expressing them can also be used as immunogens to produce antibodies immunospecific for the receptor polypeptides. The term "immunospecific" means that the antibodies have substantially greater affinity for the polypeptides of the invention than their affinity for other related polypeptides in the prior art.

[0110] Antibodies generated against the receptor polypeptides can be obtained by administering the polypeptides or epitope-bearing fragments, analogs or cells to an animal, preferably a nonhuman, using routine protocols. For preparation of monoclonal antibodies, any technique which provides antibodies produced by continuous cell line cultures can be used. Examples include the hybridoma technique (Kohler, G. and Milstein, C., Nature (1975) 256:495-497), the trioma technique, the human B-cell hybridoma technique (Kozbor et al., Immunology Today (1983) 4:72) and the EBV-hybridoma technique (Cole et al., MONOCLONAL ANTIBODIES AND CANCER THERAPY, pp. 77-96, Alan R. Liss, Inc., 1985).

[0111] Techniques for the production of single chain antibodies (U.S. Pat. No. 4,946,778) can also be adapted to produce single chain antibodies to polypeptides of this invention. Also, transgenic mice, or other organisms including other mammals, may be used to express humanized antibodies.

[0112] The above-described antibodies may be employed to isolate or to identify clones expressing the polypeptide or to purify the polypeptides by affinity chromatography.

[0113] Antibodies against receptor polypeptides may also be employed to treat diseases.

Vaccines

[0114] Another aspect of the invention relates to a method for inducing an immunological response in a mammal which comprises inoculating the mammal with a receptor polypeptide, or a fragment thereof, adequate to produce antibody and/or T cell immune response to protect said animal from a disease. Yet another aspect of the invention relates to a method of inducing immunological response in a mammal which comprises, delivering a receptor polypeptide via a vector directing expression of the receptor polynucleotide in vivo in order to induce such an immunological response to produce antibody to protect said animal from diseases.

[0115] Further aspect of the invention relates to an immunological/vaccine formulation (composition) which, when introduced into a mammalian host, induces an immunological response in that mammal to a receptor polypeptide wherein the composition comprises a receptor polypeptide or receptor gene. The vaccine formulation may further comprise a suitable carrier. Since a receptor polypeptide may be broken down in the stomach, it is preferably administered parenterally (including subcutaneous, intramuscular, intravenous, intradermal etc. injection). Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation instonic with the blood of the recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents or thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials and may be stored in a freeze-dried condition requiring only the addition of the sterile liquid carrier immediately prior to use. The vaccine formulation may also include adjuvant systems for enhancing the immunogenicity of the formulation, such as oil-in water systems and other systems known in the art. The dosage will depend on the specific activity of the vaccine and can be readily determined by routine experimentation.

Screening Assays

[0116] The receptor polypeptide of the present invention may be employed in a screening process for compounds which bind the receptor and which activate (agonists) or inhibit activation of (antagonists) the receptor polypeptide of the present invention. Thus, polypeptides of the invention may also be used to assess the binding of small molecule substrates and ligands in, for example, cells, cell-free preparations, chemical libraries, and natural product mixtures. These substrates and ligands may be natural substrates and ligands or may be structural or functional mimetics. See Coligan et al., Current Protocols in Immunology 1(2):Chapter 5 (1991).

[0117] The receptor polypeptides are responsible for many biological functions, including many pathologies. Accordingly, it is desirous to find compounds and drugs which stimulate the receptor on the one hand and which can inhibit the function of the receptor on the other hand. In general, agonists are employed for therapeutic and prophylactic purposes for such conditions and diseases. Antagonists may be employed for a variety of therapeutic and prophylactic purposes for such conditions and diseases.

[0118] In general, such screening procedures involve producing appropriate cells which express the receptor polypeptide of the present invention on the surface thereof. Such cells include cells from mammals, yeast, Drosophila or E. coli. Cells expressing the receptor (or cell membrane containing the expressed receptor) are then contacted with a test compound to observe binding, or stimulation or inhibition of a functional response.

[0119] The assays may simply test binding of a candidate compound wherein adherence to the cells bearing the receptor is detected by means of a label directly or indirectly associated with the candidate compound or in an assay involving competition with a labeled competitor. Further, these assays may test whether the candidate compound results in a signal generated by activation of the receptor, using detection systems appropriate to the cells bearing the receptor at their surfaces. Inhibitors of activation are generally assayed in the presence of a known agonist and the effect on activation by the agonist by the presence of the candidate compound is observed.

[0120] Further, the assays may simply comprise the steps of mixing a candidate compound with a solution containing a receptor polypeptide to form a mixture, measuring receptor activity in the mixture, and comparing the receptor activity of the mixture to a standard.

[0121] The receptor cDNA, protein and antibodies to the protein may also be used to configure assays for detecting the effect of added compounds on the production of receptor mRNA and protein in cells. For example, an ELISA may be constructed for measuring secreted or cell associated levels of receptor protein using monoclonal and polyclonal antibodies by standard methods known in the art, and this can be used to discover agents which may inhibit or enhance the production of the receptor (also called antagonist or agonist, respectively) from suitably manipulated cells or tissues. Standard methods for conducting screening assays are well understood in the art.

[0122] Examples of potential receptor antagonists include antibodies or, in some cases, oligonucleotides or proteins which are closely related to the ligand of the receptor, e.g., a fragment of the ligand, or small molecules which bind to the receptor but do not elicit a response, so that the activity of the receptor is prevented.

[0123] Thus in another aspect, the present invention relates to a screening kit for identifying agonists, antagonists, ligands, receptors, substrates, enzymes, etc. for receptor polypeptides; or compounds which decrease or enhance the production of receptor, which comprises:

[0124] (a) a receptor polypeptide, preferably that of SEQ ID NO:Y;

[0125] (b) a recombinant cell expressing a receptor polypeptide, preferably that of SEQ ID NO:Y;

[0126] (c) a cell membrane expressing a receptor polypeptide; preferably that of SEQ ID NO: Y; or

[0127] (d) antibody to a receptor polypeptide, preferably that of SEQ ID NO: Y.

[0128] It will be appreciated that in any such kit, (a), (b), (c) or (d) may comprise a substantial component.

Prophylactic and Therapeutic Methods

[0129] This invention provides methods of treating an abnormal conditions related to both an excess of and insufficient amounts of receptor activity.

[0130] If the activity of the receptor is in excess, several approaches are available. One approach comprises administering to a subject an inhibitor compound (antagonist) as described along with a pharmaceutically acceptable carrier in an amount effective to inhibit activation by blocking the binding of ligands to the receptor or by inhibiting a second signal, and thereby alleviating the abnormal condition.

[0131] In another approach, soluble forms of the receptor polypeptides still capable of binding the ligand in competition with endogenous receptor may be administered. Typical embodiments of such competitors comprise fragments of the receptor polypeptide.

[0132] In still another approach, expression of the gene encoding endogenous receptor can be inhibited using expression blocking techniques. Known such techniques involve the use of antisense sequences, either internally generated or separately administered. (See, for example, O'Connor, J Neurochem (1991) 56:560 in Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988).) Alternatively, oligonucleotides which form triple helices with the gene can be supplied. (See, for example, Lee et al., Nucleic Acids Res (1979) 6:3073; Cooney et al., Science (1988) 241:456; Dervan et al., Science (1991) 251:1360.) These oligomers can be administered per se or the relevant oligomers can be expressed in vivo.

[0133] For treating abnormal conditions related to an under-expression of the receptor and its activity, several approaches are also available. One approach comprises administering to a subject a therapeutically effective amount of a compound which activates the receptor, i.e., an agonist as described above, in combination with a pharmaceutically acceptable carrier, to thereby alleviate the abnormal condition. Alternatively, gene therapy may be employed to effect the endogenous production of the receptor by the relevant cells in the subject. For example, a polynucleotide of the invention may be engineered for expression in a replication defective retroviral vector, as discussed above. The retroviral expression construct may then be isolated and introduced into a packaging cell transduced with a retroviral plasmid vector containing RNA encoding a polypeptide of the present invention such that the packaging cell now produces infectious viral particles containing the gene of interest. These producer cells may be administered to a subject for engineering cells in vivo and expression of the polypeptide in vivo. For overview of gene therapy, see Chapter 20, Gene Therapy and other Molecular Genetic-based Therapeutic Approaches, (and references cited therein) in Human Molecular Genetics, T Strachan and A P Read, BIOS Scientific Publishers Ltd (1996).

Formulation and Administration

[0134] Peptides, such as the soluble form of receptor polypeptides, and agonists and antagonist peptides or small molecules, may be formulated in combination with a suitable pharmaceutical carrier. Such formulations comprise a therapeutically effective amount of the polypeptide or compound, and a pharmaceutically acceptable carrier or excipient. Such carriers include but are not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. Formulation should suit the mode of administration, and is well within the skill of the art. The invention further relates to pharmaceutical packs and kits comprising one or more containers filled with one or more of the ingredients of the aforementioned compositions of the invention.

[0135] Polypeptides and other compounds of the present invention may be employed alone or in conjunction with other compounds, such as therapeutic compounds. Preferred forms of systemic administration of the pharmaceutical compositions include injection, typically by intravenous injection. Other injection routes, such as subcutaneous, intramuscular, or intraperitoneal, can be used. Alternative means for systemic administration include transmucosal and transdermal administration using penetrants such as bile salts or fusidic acids or other detergents. In addition, if properly formulated in enteric or encapsulated formulations, oral administration may also be possible. Administration of these compounds may also be topical and/or localized, in the form of salves, pastes, gels and the like.

[0136] The dosage range required depends on the choice of peptide, the route of administration, the nature of the formulation, the nature of the subject's condition, and the judgment of the attending practitioner. Suitable dosages, however, are in the range of 0.1-100 .mu.g/kg of subject. Wide variations in the needed dosage, however, are to be expected in view of the variety of compounds available and the differing efficiencies of various routes of administration. For example, oral administration would be expected to require higher dosages than administration by intravenous injection. Variations in these dosage levels can be adjusted using standard empirical routines for optimization, as is well understood in the art.

[0137] Polypeptides used in treatment can also be generated endogenously in the subject, in treatment modalities often referred to as "gene therapy" as described above. Thus, for example, cells from a subject may be engineered with a polynucleotide, such as a DNA or RNA, to encode a polypeptide ex vivo, and for example, by the use of a retroviral plasmid vector. The cells are then introduced into the subject.

[0138] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

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Sequence CWU 1

1

6311497DNAHomo sapiens 1gcagttcctg agagaagaac cctgaggaac agacgttccc tcgcggccct ggcacctcca 60accccagata tgctgctgct gctgctgctg cccctgctct gggggaggga gagggtggaa 120ggacagaaga gtaaccggaa ggattactcg ctgacgatgc agagttccgt gaccgtgcaa 180gagggcatgt gtgtccatgt gcgctgctcc ttctcctacc cagtggacag ccagactgac 240tctgacccag ttcatggcta ctggttccgg gcagggaatg atataagctg gaaggctcca 300gtggccacaa acaacccagc ttgggcagtg caggaggaaa ctcgggaccg attccacctc 360cttggggacc cacagaccaa aaattgcacc ctgagcatca gagatgccag aatgagtgat 420gcggggagat acttctttcg tatggagaaa ggaaatataa aatggaatta taaatatgac 480cagctctctg tgaacgtgac ataccctcct cagaacttga ctgtgactgt cttccaagga 540gaaggcacag catccacagc tctggggaac agctcatctc tttcagtcct agagggccag 600tctctgcgct tggtctgtgc tgttgacagc aatccccctg ccaggctgag ctggacctgg 660aggagtctga ccctgtaccc ctcacagccc tcaaaccctc tggtactgga gctgcaagtg 720cacctggggg atgaagggga attcacctgt cgagctcaga actctctggg ttcccagcac 780gtttccctga acctctccct gcaacaggag tacacaggca aaatgaagcc tgtatcagga 840gtgttgctgg gggcggtcgg gggaactgga gccacagccc tggtcttcct ctccttctgt 900gtcatcttca ttgtagtgag gtcctgcagg aagaaatcgg caagaccagc agcggacgtg 960ggagacatag gcatgaagga tgcaaacacc attcaggggc tcagcctctc agggtaactg 1020gatgagtcct gggcagatga taacccccga caccatggcc tggctgccca ctccctcagg 1080ggaggaaaga gagatcccag tatgcacccc tcagctttca taagggggag cctcaggacc 1140tatccaggtc aagaagccac caacaatgag tactcagaga tcaagatccc caagtaagaa 1200aatgcagagg ctcgggcttg tttgagggtt cacgacccct ccagcaaagg agtctgaggc 1260tgattccagt agaattagca gccctcaatg ctgtgcaaca agacatcaga acttattcct 1320cttgtctaac tgaaaatgca tgcctgatga ccaaactctc cctttcccca tccaatcggt 1380ccacactccc cgccctggcc tctgtaccca ccattctcct ctgtacttct ctaaggatga 1440ctactttaga ttccgaatat agtgagattg taacgtgaaa aaaaaaaaaa aaaaaaa 149721849DNAHomo sapiens 2cggcacgagt ggacaaccat cagggagcca ggacacagag gggcagagca agtcagcatt 60ggcgcccctt cctcagatcc ctatcatctt gggaaacagt agcccagagg ttcaggaaga 120tgttaactta aatgttcggg gtgccccagt ctgttcagca tggctgaaat ccacactccg 180tattcttcct tgaagaaact gttatcttta ctcaatggct tcgtggctgt gtctggcatc 240atcctagttg gcctgggcat tggtggtaaa tgtggagggg cctctctgac gaatgtcctc 300gggctgtcct ccgcatacct ccttcacgtt ggcaacctgt gcctggtgat gggatgcatc 360acggtactgc ttggctgtgc cgggtggtat ggagcgacta aagagagcag aggcacgctc 420ttgttttgca tcctgtcaat ggttattgtc ctcatcatgg aagttacagc tgccacagtg 480gtccttcttt tctttccaat tgttggagat gtggccttgg aacacacctt cgtgaccctg 540aggaagaatt acagaggtta caacgagcca gacgactatt ctacacagtg gaacttggtc 600atggagaagc taaagtgctg tggggtgaat aactacacag atttttctgg ctcttccttc 660gaaatgacaa cgggccacac ctaccccagg agttgctgta aatccatcgg aagtgtgtcc 720tgtgacggac gcgatgtgtc tccaaacgtc atccaccaga agggctgttt ccataaactc 780ctaaaaatca ccaagactca gagcttcacc ctgagtggga gctctctggg agctgcagtg 840atacagaggt gggggtctcg ctatgttgcg caggctggtc ttgaactgct ggcctaaagc 900gatccccccg cctaggcctc ccaaagtgct gggtttacca gcgtgagcca ccacgctggg 960cttcctgcat ccttttaagg ttcctgaggg tctgcctgag aggagctgtc cctgaatctc 1020catgcagccc cacctgccac atcaccaaga catacaatct ttgccagcaa cacttcctcc 1080ttgcagatta caagcatagc taatgccacc accagacaag accgattcgc tggcctccat 1140ttcttcaacc cagtgcctgt catgaaactt gtggaggtca ttaaaacacc aatgaccagc 1200cagaagacat ttgaatcttt ggtagacttt agcaaaaccc taggaaagca tcctgtttct 1260tgcaaggaca ctcctgggtt tattgtgaac cgcctcctgg ttccatacct catggaagca 1320atcaggctgt atgaacgagg gcctcctggc tttccctgtg ggcttctgag aaaggtttct 1380ggaactccca ccacccccac tacagtccca gccagagcaa ttgcatggcc ggcccagatt 1440gatatcctgg atctctgctt ttgattaaaa ggtgacgcat ccaaagaaga cattgacact 1500gctatgaaat taggagccgg ttaccccatg ggcccatttg agcttctaga ttatgtcgga 1560ctggatacta cgaagttcat cgtggatggg tggcatgaaa tggatgcaga gaacccatta 1620catcagccca gcccatcctt aaataagctg gtagcagaga acaagttcgg caagaagact 1680ggagaaggat tttacaaata caagtgatgt gcagcttctc cggttctgag aagaacacct 1740gagagcgctt tccagccagt gccccgagtg cctgtgggaa tgctctttgg tcagacattc 1800cctcacacag tacagtttaa taaatgtgca ttttgattgt aaaaaaaaa 18493741DNAHomo sapiens 3atggctgaaa tccacactcc gtattcttcc ttgaagaaac tgttatcttt actcaatggc 60ttcgtggctg tgtctggcat catcctagtt ggcctgggca ttggtggtaa atgtggaggg 120gcctctctga cgaatgtcct cgggctgtcc tccgcatacc tccttcacgt tggcaacctg 180tgcctggtga tgggatgcat cacggtactg cttggctgtg ccgggtggta tggagcgact 240aaagagagca gaggcacgct cttgttttgc atcctgtcaa tggttattgt cctcatcatg 300gaagttacag ctgccacagt ggtccttctt ttctttccaa ttgttggaga tgtggccttg 360gaacacacct tcgtgaccct gaggaagaat tacagaggtt acaacgagcc agacgactat 420tctacacagt ggaacttggt catggagaag ctaaagtgct gtggggtgaa taactacaca 480gatttttctg gctcttcctt cgaaatgaca acgggccaca cctaccccag gagttgctgt 540aaatccatcg gaagtgtgtc ctgtgacgga cgcgatgtgt ctccaaacgt catccaccag 600aagggctgtt tccataaact cctaaaaatc accaagactc agagcttcac cctgagtggg 660agctctctgg gagctgcagt gatacagagg tgggggtctc gctatgttgc gcaggctggt 720cttgaactgc tggcctaaag c 74141288DNAHomo sapiens 4ggcgtccctc tgcctgccca ctcagtggca acacccggga gctgttttgt cctttgtgga 60gcctcagcag ttccctcttt cagaactcac tgccaagagc cctgaacagg agccaccatg 120cagtgcttca gcttcattaa gaccatgatg atcctcttca atttgctcat ctttctgtgt 180ggtgcagccc tgttggcagt gggcatctgg gtgtcaatcg atggggcatc ctttctgaag 240atcttcgggc cactgtcgtc cagtgccatg cagtttgtca acgtgggcta cttcctcatc 300gcagccggcg ttgtggtctt tgctcttggt ttcctgggct gctatggtgc taagactgag 360agcaagtgtg ccctcgtgac gttcttcttc atcctcctcc tcatcttcat tgctgaggtt 420gcagctgctg tggtcgcctt ggtgtacacc acaatggctg agcacttcct gacgttgctg 480gtagtgcctg ccatcaagaa agattatggt tcccaggaag acttcactca agtgtggaac 540accaccatga aagggctcaa gtgctgtggc ttcaccaact atacggattt tgaggactca 600ccctacttca aagagaacag tgcctttccc ccattctgtt gcaatgacaa cgtcaccaac 660acagccaatg aaacctgcac caagcaaaag gctcacgacc aaaaagtaga gggttgcttc 720aatcagcttt tgtatgacat ccgaactaat gcagtcaccg tgggtggtgt ggcagctgga 780attgggggcc tcgagctggc tgccatgaat tgtgtccatg tatctgtact gcaatctaca 840ataagtccac ttctgcctct gccactactg ctgccacatg ggaactgtga agaggcaccc 900tggcaagcag cagtgattgg gggaggggac aggatctaac aatgtcactt gggccagaat 960ggacctgccc tttctgctcc agacttgggg ctagataggg accactcctt ttaggcgatg 1020cctgactttc cttccattgg tgggtggatg ggtggggggc attccagagc ctctaaggta 1080gccagttctg ttgcccattc ccccagtcta ttaaaccctt gatatgcccc ctaggcctag 1140tggtgatccc agtgctctac tgggggatga gagaaaggca ttttatagcc tgggcataag 1200tgaaatcagc agagcctctg ggtggatgtg tagaaggcac ttcaaaatgc ataaacctgt 1260tacaatgtta aaaaaaaaaa aaaaaaaa 128851236DNAHomo sapiens 5aaaaaaaaca aggtccccac agcaaagaaa aggaatagga tcaagagata cgtggctgct 60ggcagagcaa gcatgaattc gatgacttca gcagttccgg tggccaattc tgtgttggtg 120gtggcacccc acaatggtta tcctgtgacc ccaggaatta tgtctcacgt gcccctgtat 180ccaaacagcc agccgcaagt ccacctagtt cctgggaacc cacctagttt ggtgtcgaat 240gtgaatgggc agcctgtgca gaaagctctg aaagaaggca aaaccttggg ggccatccag 300atcatcattg gcctggctca catcggcctc ggctccatca tggcgacggt tctcgtaggg 360gaatacctgt ctatttcatt ctacggaggc tttcccttct ggggaggctt gtggtttatc 420atttcaggat ctctctccgt ggcagcagaa aatcagccat attcttattg cctgctgtct 480ggcagtttgg gcttgaacat cgtcagtgca atctgctctg cagttggagt catactcttc 540atcacagatc taagtattcc ccacccatat gcctaccccg actattatcc ttacgcctgg 600ggtgtgaacc ctggaatggc gatttctggc gtgctgctgg tcttctgcct cctggagttt 660ggcatcgcat gcgcatcttc ccactttggc tgccagttgg tctgctgtca atcaagcaat 720gtgagtgtca tctatccaaa catctatgca gcaaacccag tgatcacccc agaaccggtg 780acctcaccac caagttattc cagtgagatc caagcaaata agtaaggcta cagattctgg 840aagcatcttt cactgggacc aaaagaagtc ctcctccctt tctgggcttc cataacccag 900gtcgttcctg ttctgacagc tgaggaaacg tctctcccac tgtttgtact ctcaccttca 960ttcttcaatt cagtctagga aaccatgctg tttctctatc aagaagaaga cagagatttt 1020aaacagatgt taaccaagag ggactcccta gggcacatgc atcagcacat atgtgggcat 1080ccagcctctg gggccttggc acacccattc gtgtgctctg ctgcatgtga gcttgtgggt 1140tagaggaaca aatatctaga cattcaatct tcactctttc aattgtgcat tcatttaata 1200aatagatact gagcattcaa aaaaaaaaaa aaaaaa 123661115DNAHomo sapiens 6cacgagcagg gtctcgggct agtcatggcg tccccgtctc ggagactgca gactaaacca 60gtcattactt gtttcaagag cgttctgcta atctacactt ttattttctg gatcactggc 120gttatccttc ttgcagttgg catttggggc aaggtgagcc tggagaatta cttttctctt 180ttaaatgaga aggccaccaa tgtccccttc gtgctcattg ctactggtac cgtcattatt 240cttttgggca cctttggttg ttttgctacc tgccgagctt ctgcatggat gctaaaactg 300tatgcaatgt ttctgactct cgtttttttg gtcgaactgg tcgctgccat cgtaggattt 360gttttcagac atgagattaa gaacagcttt aagaataatt atgagaaggc tttgaagcag 420tataactcta caggagatta tagaagccat gcagtagaca agatccaaaa tacgttgcat 480tgttgtggtg tcaccgatta tagagattgg acagatacta attattactc agaaaaagga 540tttcctaaga gttgctgtaa acttgaagat tgtactccac agagagatgc agacaaagta 600aacaatgaag gttgttttat aaaggtgatg accattatag agtcagaaat gggagtcgtt 660gcaggaattt cctttggagt tgcttgcttc caactgattg gaatctttct cgcctactgc 720ctctctcgtg ccataacaaa taaccagtat gagatagtgt aacccaatgt atctgtgggc 780ctattcctct ctacctttaa ggacatttag ggtcccccct gtgaattaga aagttgcttg 840gctggagaac tgacaacact acttactgat agaccaaaaa actacaccag taggttgatt 900caatcaagat gtatgtagac ctaaaactac accaataggc tgattcaatc aagatccgtg 960ctcgcagtgg gctgattcaa tcaagatgta tgtttgctat gttctaagtc caccttctat 1020cccattcatg ttagatcgtt gaaaccctgt atccctctga aacactggaa gagctagtaa 1080attgtaaatg aagtaaaaaa aaaaaaaaaa aaaaa 111571662DNAHomo sapiens 7cacgagcatt gccgctctct cggtgagcgc agccccgctc tccgggccgg gccttcgcgg 60gccaccggcg ccatgggcca gtgcggcatc acctcctcca agaccgtgct ggtctttctc 120aacctcatct tctggggggc agctggcatt ttatgctatg tgggagccta tgtcttcatc 180acttatgatg actatgacca cttctttgaa gatgtgtaca cgctcatccc tgctgtagtg 240atcatagctg taggagccct gcttttcatc attgggctaa ttggctgctg tgccacaatc 300cgggaaagtc gctgtggact tgccacgttt gtcatcatcc tgctcttggt ttttgtcaca 360gaagttgttg tagtggtttt gggatatgtt tacagagcaa aggtggaaaa tgaggttgat 420cgcagcattc agaaagtgta taagacctac aatggaacca accctgatgc tgctagccgg 480gctattgatt atgtacagag acagctgcat tgttgtggaa ttcacaacta ctcagactgg 540gaaaatacag attggttcaa agaaaccaaa aaccagagtg tccctcttag ctgctgcaga 600gagactgcca gcaattgtaa tggcagcctg gcccaccctt ccgacctcta tgctgagggg 660tgtgaggctc tagttgtgaa gaagctacaa gaaatcatga tgcatgtgat ctgggccgca 720ctggcatttg cagctattca gctgctgggc atgctgtgtg cttgcatcgt gttgtgcaga 780aggagtagag atcctgctta cgagctcttc atcactggcg gaacctatgc atagttgaca 840atctcaagcc tgagcttttt ggtcttgttc tgatttggaa ggtgaattga gcaggtctgc 900tgctgttggc ctctggagtt catttagtta aagcacatgt acactggtgt tggacagagc 960agcttggctt ttcatgtgcc cacctactta cctactacct gcgactttct ttttccttgt 1020tctagctgac tcttcatgcc cctaagattt taagtacgat ggtgaacgtt ctaatttcag 1080aaccaattgc gagtcatgta gtgtggtaga attaaaggag gacacgagcc tgcttctgtt 1140acctccaagt ggtaacagga ctgatgccga aatgtcacca ggtcctttca gtcttcacag 1200tggagaactc ttggccaaag gtttttgggg ggaggaggag gaaaccagct ttctggttaa 1260ggttaacacc agatggtgcc cctcattggt gtccttttaa aaaatattta ctgtagtcca 1320ataagatagc agctgtacaa aatgactaaa atagattgta ggatcatatg gcgtatatct 1380tggttcatct tcaaaatcag agactgagct ttgaaactag tggtttttaa tcaaagttgg 1440ctttatagga ggagtataat gtatgcacta ctgttttaaa agaattagtg tgagtgtgtt 1500tttgtatgaa tgagcccatt catggtaagt cttaagcttg ttggaaataa tgtacccatg 1560tagactagca aaatagtatg tagatgtgat ctcagttgta aatagaaaaa tctaattcaa 1620taaactctgt atcagccccc aacaaaaaaa aaaaaaaaaa aa 166281345DNAHomo sapiens 8cacgagcgca gagcttgggg cttccttggt cgcacccacc acctgcctgc ccactggtca 60gccttcaggg accctgagca ccgcctggtc tctttcctgt ggccagccca gaactgaagc 120gctgcggcat ggcgcgcgcc tgcctccagg ccgtcaagta cctcatgttc gccttcaacc 180tgttcttctg gctgggaggc tgtggcgtgc tgggtgtcgg catctggctg gccgccacac 240aggggagctt cgccacgctg tcttcttcct tcccgtccct gtcggctgcc aacctgctca 300tcatcaccgg cgcctttgtc atggccatcg gcttcgtggg ctgcctgggt gccatcaagg 360agaacaagtg cctcctgctc actttcttcc tgctgctgct gctggtgttc ctgctggagg 420ccaccatcgc catcctcttc ttcgcctaca cggacaagat tgacaggtat gcccagcaag 480acctgaagaa aggcttgcac ctgtacggca cgcagggcaa cgtgggcctc accaacgcct 540ggagcatcat ccagaccgac ttccgctgct gtggcgtctc caactacact gactggttcg 600aggtgtacaa cgccacgcgg gtacctgact cctgctgctt ggagttcagt gagagctgtg 660ggctgcacgc ccccggcacc tggtggaagg cgccgtgcta cgagacggtg aaggtgtggc 720ttcaggagaa cctgctggct gtgggcatct ttgggctgtg cacggcgctg gtgcagatcc 780tgggcctgac cttcgccatg accatgtact gccaagtggt caaggcagac acctactgcg 840cgtaggccgc ccaccgccgg cttctctgcc aaaaggacgc ccacggggag atggccgcac 900ccacagctgc ttttcccacc accagcttcg gtgttctgcc ccatgctggg aggagggagg 960gagggacagg tgcctggagc ccccggaacc ctgtttctgg aaggccctag ctcaggtggc 1020ttcagggcct ccggaccccc cctgggaggg gtggccacgt gctggctgcg gaacccaggg 1080caggggtggg aggggcctcc agcacttttt atatttacgt attctccaaa gcagtgttca 1140cacgggagcc agcctgtggc ccccagcttc ctggaaaaca ggttggcgct ggaggagccg 1200ggtcttggca tcctggaggt ggccccactg gtcctggtgc tccaggcggg gccgtggacc 1260cctcacctac attccatagt gggcccgtgg ggctcctggt gcatcttaat aaagtgtgag 1320cagcaaaaaa aaaaaaaaaa aaaaa 13459734DNAHomo sapiens 9gcgccgccgg gccgcagcat ggggcgcttc cgcgggggcc tgcggtgcat caagtacctg 60ctgcttggct tcaacctgct cttctggctg gctggatcgg ccgtcattgc ttttggacta 120tggtttcggt tcggaggtgc cataaaggag ttatcatcag aggacaagtc cccagagtat 180ttctatgtgg ggctgtatgt tctggttgga gccggggccc tgatgatggc cgtggggttc 240ttcggatgct gcggagccat gcgggagtcg caatgtgtgc ttggatcatt ttttacctgc 300ctcctggtga tatttgctgc tgaagtaacc actggagtat ttgcttttat aggcaagggg 360gtagctatcc gacatgttca gaccatgtat gaagaggctt acaatgatta ccttaaagac 420aggggaaaag gcaatgggac actcatcacc ttccactcaa catttcagtg ctgtggaaaa 480gaaagctccg aacaggtcca acctacatgc ccaaaggagc ttctaggaca caagaattgc 540atcgatgaaa ttgagaccat aatcagtgtt aagctccagc tcattggaat tgtcggtatt 600ggaattgcag gtctgacgat ctttggcatg atattcagca tggtcctctg ctgtgcgata 660cgaaactcac gagatgtgat atgaagctac ttctacatga aaattgcaat ctaaagcttt 720cataccaaat gttc 73410577DNAHomo sapiens 10agtgtttatg ggactaaaaa acttttaaca cctttttagg ggaaatattt tggtcctata 60caaaacatgt aaatatgctt tattactttc attttctgac cctgctgtaa actactgcaa 120ccctcacatc cctcaaaggg acttttatgt caaactcttc tgtttctcca aatataagga 180aaaaagacta aagcaagaga tctggcagtt gaaaattgtg ggaaagagaa tttgtatggg 240cactgtatct atgaaatacc tcatacttac gtttacatgt tttcctaact ttttgtattt 300ttcttgtata gccacctaga gaattcttca tagattaaga actacagttt tcaccactta 360acataagtaa aacaaagtcc ttcataattt aaccattagc atctttggcc aaaccaaaat 420aaagaaaagc atcttctcct agttgtgtgt gggcaacaga aacaagttaa ggaaacaaaa 480atacttatat atacacagaa caaaaataat gttcttttta tgcaaatccc ctgtgaaaat 540aaaattttca atgtttaaaa aaaaaaaaaa aaaaaaa 57711936DNAHomo sapiens 11ttcggcacga gctgcgggcg gtgggcggct gggcggcccc gggagccgcg ctctcagtct 60ctctaggcgc agtcccttcg ccgcttccgg agcccctggc agggcccaga agccatggcc 120cactataaga ctgagcagga cgactggctg atcatctact tgaagtattt actctttgtc 180ttcaacttct tcttctgggt cgggggagca gccgtcctgg ctgtgggcat ctggaccctg 240gtggagaaga gtggctacct cagcgtcctg gcctccagca cctttgccgc ctccgcctac 300atcctcatct ttgcgggcgt acttgtcatg gtgaccggct tcctgggctt cggtgccatc 360ctctgggagc ggaagggctg cctctccacg tatttctgcc tgttgctcgt catcttcctg 420gttgagctgg tggcgggagt cctggcccat gtgtattacc agaggctgag tgatgaactg 480aagcagcact tgaaccggac tctggctgag aactacgggc agccggagca cgcagatcac 540gcctcagtgg accgactcca gcaggatttc aagtgctgcg gaagcaacag ctcagccgac 600tggcagcaca gcacgtacat cctgttgcgg gaggccgagg gccgccaggt gcccgacagc 660tgctgcaaga cagtggtggc gcgctgcggc cagcgggccc acccctccaa catctataag 720gtggagggag gctgcctcac caagctggag cagttcctgg ccgaccacct gctgcttatg 780ggggcagtgg gcatcggggt ggcctgcctg cagatctgcg ggatggttct cacctgctgc 840ttgcaccaga ggctccagcg gcatttttac taatggcaac cacctcctct tccaactgcc 900cctcaagaca acatgtggca catgccatct gcaagg 93612738DNAHomo sapiens 12agcttacttt cactcaccgc ctgtccttcc tgacacctca ccatgtgtac gggaaaatgt 60gcccgctgtg tggggctctc cctcattacc ctctgcctcg tctgcattgt ggccaacgcc 120ctcctgctgg tacctaatgg ggagacctcc tggaccaaca ccaaccatct cagcttgcaa 180gtctggctca tgggcggctt cattggcggg ggcctaatgg tactgtgtcc agggattgca 240gccgttcggg cagggggcaa gggctgctgt ggtgctgggt gctgtggaaa ccgctgcagg 300atgctgcgct cggtcttctc ctcggcgttc ggggtgcttg gtgccatcta ctgcctctcg 360gtgtctggag ctgggctccg aaatggaccc agatgcttaa tgaacggcga gtggggctac 420cacttcgaag acaccgcggg agcttacttg ctcaaccgca ctctatggga tcggtgcgag 480gcgccccctc gcgtggtccc ctggaatgtg acgctcttct cgctgctggt ggccgcctcc 540tgcctggaga tagtactgtg tgggatccag ctggtgaacg cgaccattgg tgtcttctgc 600ggcgattgca ggaaaaaaca ggacacacct cactgaggct ccactgaccg ccgggttaca 660cctgctcctt cctggacgct cactcccttg ctcgctagaa taaactgctt tgcgctctca 720aaaaaaaaaa aaaaaaac 738131071DNAHomo sapiens 13ggcacgagag attgtcggct gcgggtatat tccaattccc cgtctcctca tgaatatgaa 60gtgaagggct ctgaccctgg aagtggttct aagcagggca aaatggggtc tcggaagtgt 120ggaggctgcc taagttgttt gctgattccg cttgcacttt ggagtataat cgtgaacata 180ttattgtatt tcccgaatgg gcaaacttcc tatgcatcca gcaataaact caccaactac 240gtgtggtatt ttgaaggaat ctgtttctca ggcatcatga tgcttatagt aacaacagtt 300cttctggtac tggagaataa taacaactat aaatgttgcc agagtgaaaa ctgcagcaaa 360aaatatgtga cactgctgtc aattatcttt tcttccctcg gaattgcttt ttctggatac 420tgcctggtca tctctgcctt gggtcttgtc caagggccat attgccgcac ccttgatggc 480tgggagtatg cttttgaagg cactgctgga cgtttcctta cagattctag catatggatt 540cagtgcctgg aacctgcaca tgttgtggag tggaacatca ttttattttc cattctcata 600accctcagtg ggcttcaagt gatcatctgc ctcatcagag tagtcatgca actatccaag 660atactgtgtg gaagctattc agtgatcttc cagcctggaa tcatttgaat aaggacaaaa 720tgttttccat tatcaagaca tggccatcta tctaaatatt

atatcaactg tgttagactt 780gagggcaata ttgaaaatga tggtgctttc tgcatttggt gtttatttgt aaaaaatttg 840cagtcctcac tgcacatgca agtataccac ccttccattt agtatgtttt ttaagtaata 900tgcatcagaa acttcagaaa tacttctgcc ctttgatcaa acaaatccat ttccaagaat 960ctgtactagg gaagtaaata agaatatgag agaaaccttt atgcaatatg tatattgcaa 1020cattatttaa tattctggaa aattggaaac accccaaaat tctaactcaa a 107114865DNAHomo sapiens 14tttgtggagg gcagcagaga gtacccagct ggacatcctt tcctgctgat gagccccagg 60ctggaggtgc cctgctcaca tgctcttccc cagggtctct cgcctgggca ggtcatcata 120gtacggggac tggtcttgca agagccgaag cattttactg tgagcctgag ggaccaggct 180gcccatgctc ctgtgacact cagggcctcc ttcgcagaca gaactctggc ctggatctcc 240cgctgggggc agaagaaact gatctcagcc cccttcctct tttaccccca gagattcttt 300gaggtgctgc tcctgttcca ggagggaggg ctgaagctgg cgctcaatgg gcaggggctg 360ggggccacca gcatgaacca gcaggccctg gagcagctgc gggagctccg gatcagtgga 420agtgtccagc tctactgtgt ccactcctga aggatggttc caggaaatac cgcagaaaac 480aagagtcagc cactccccag ggccccactc tcctcccctc attaaaccat ccacctgaac 540accagcacat cagggcctgg ttcacctctg gggtcacgag actgagtcta caggagcttt 600gggcctgagg gaaggcacaa gagtgcaaag gttcctcgaa ctctgcacct tcctccacca 660ggagcctggg atatggctcc atctgccttc agggcctgga ctgcactcac agaggcaagt 720gttgtagact aacaaagata ctccaaaata caatggctta aagaatgtgg tcatttattc 780tttattattt atttatttgt ggtcaaataa ataaataagg ttatttattt aaaaaaaaaa 840aaaaaaaaaa aaaaaaaaaa aaaaa 86515441DNAHomo sapiens 15gcacgagaga cgacatcaga gatgaggaca gcattgctgc tccttgcagc cctggctgtg 60gctacagggc cagcccttac cctgcgctgc cacgtgtgca ccagctccag caactgcaag 120cattctgtgg tctgcccggc cagctctcgc ttctgcaaga ccacgaacac agtggagcct 180ctgagggctt ccccgaaagt ctgggaccag gtccaggtgg gcatggaatg ctgatgactt 240ggagcaggcc ccacagaccc cacagaggat gaagccaccc cacagaggat gcagccccca 300gctgcatgga aggtggagga cagaagccct gtggatcccc ggatttcaca ctccttctgt 360tttgttgccg tttatttttg tactcaaatc tctacatgga gataaatgat ttaaaccagt 420aaaaaaaaaa aaaaaaaaaa a 441161066DNAHomo sapiens 16agcgggcccg aaccctcgtg tgaagggtgc agtacctaag ccggagcggg gtagaggcgg 60gccggcaccc ccttctgacc tccagtgccg ccggcctcaa gatcagacat ggcccagaac 120ttgaaggact tggcgggacg gctgcccgcc gggccccggg gcatgggcac ggccctgaag 180ctgttgctgg gggccggcgc cgtggcctac ggtgtgcgcg aatctgtgtt caccgtggaa 240ggcgggcaca gagccatctt cttcaatcgg atcggtggag tgcagcagga cactatcctg 300gccgagggcc ttcacttcag gatcccttgg ttccagtacc ccattatcta tgacattcgg 360gccagacctc gaaaaatctc ctcccctaca ggctccaaag acctacagat ggtgaatatc 420tccctgcgag tgttgtctcg acccaatgct caggagcttc ctagcatgta ccagcgccta 480gggctggact acgaggaacg agtgttgccg tccattgtca acgaggtgct caagagtgtg 540gtggccaagt tcaatgcctc acagctgatc acccagcggg cccaggtatc cctgttgatc 600cgccgggagc tgacagagag ggccaaggac ttcagcctca tcctggatga tgtggccatc 660acagagctga gctttagccg agagtacaca gctgctgtag aagccaaaca agtggcccag 720caggaggccc agcgggccca attcttggta gaaaaagcaa agcaggaaca gcggcagaaa 780attgtgcagg ccgagggtga ggccgaggct gccaagatgc ttggagaagc actgagcaag 840aaccctggct acatcaaact tcgcaagatt cgagcagccc agaatatctc caagacgatc 900gccacatcac agaatcgtat ctatctcaca gctgacaacc ttgtgctgaa cctacaggat 960gaaagtttca ccaggggaag tgacagcctc atcaagggta agaaatgagc ctagtcacca 1020agaactccac ccccacaaga agtggatctg cttctccagt ttttga 106617704DNAHomo sapiens 17ggcacgagat gacatcacta agtggccgat ctgcacagag caggccagga gcaaccacac 60aggcttcctg cacatggact gcgagatcaa gggccgcccc tgctgcatcg gcaccaaggg 120cagctgtgag atcaccaccc gggaatactg tgagttcatg cacggctatt tccatgagga 180agcaacactc tgctcccagg tgaggcgagg caggcctgga gtagtggagg agaggacgct 240gggcatggca gcctgctggg gccggggctc acgcactccc tcccatgtcg gagcctcaga 300ctcaggctgc ttctggggcg ctgagcacca tatgcccatt cccaggtgca ctgttttgga 360caaggtgtgt tgggctgctg ccttcctcaa ccctgaggtc ccagatcagt tttacaggtc 420tggctgtctc ttttcctaca tgttgggtaa gaggtcctca atgcccccga acccgacccc 480tgtgatggac acccaggcgg acccctgggg aaaggttcct gggccagggt atggtcggtc 540caacctgccg aagactactg ctcctgaagt gtctggatga aggccgctgc ctggtgtgtc 600cctcccccag tgtgggtgca ctgccctcgg tgtcttgtgg gtcttttcaa atgacatccc 660tgaaggggac ctggaggaag gtggtccggc tggcacccta tcgc 70418315PRTHomo sapiens 18Met Leu Leu Leu Leu Leu Leu Pro Leu Leu Trp Gly Arg Glu Arg Val1 5 10 15Glu Gly Gln Lys Ser Asn Arg Lys Asp Tyr Ser Leu Thr Met Gln Ser 20 25 30Ser Val Thr Val Gln Glu Gly Met Cys Val His Val Arg Cys Ser Phe 35 40 45Ser Tyr Pro Val Asp Ser Gln Thr Asp Ser Asp Pro Val His Gly Tyr 50 55 60Trp Phe Arg Ala Gly Asn Asp Ile Ser Trp Lys Ala Pro Val Ala Thr65 70 75 80Asn Asn Pro Ala Trp Ala Val Gln Glu Glu Thr Arg Asp Arg Phe His 85 90 95Leu Leu Gly Asp Pro Gln Thr Lys Asn Cys Thr Leu Ser Ile Arg Asp 100 105 110Ala Arg Met Ser Asp Ala Gly Arg Tyr Phe Phe Arg Met Glu Lys Gly 115 120 125Asn Ile Lys Trp Asn Tyr Lys Tyr Asp Gln Leu Ser Val Asn Val Thr 130 135 140Tyr Pro Pro Gln Asn Leu Thr Val Thr Val Phe Gln Gly Glu Gly Thr145 150 155 160Ala Ser Thr Ala Leu Gly Asn Ser Ser Ser Leu Ser Val Leu Glu Gly 165 170 175Gln Ser Leu Arg Leu Val Cys Ala Val Asp Ser Asn Pro Pro Ala Arg 180 185 190Leu Ser Trp Thr Trp Arg Ser Leu Thr Leu Tyr Pro Ser Gln Pro Ser 195 200 205Asn Pro Leu Val Leu Glu Leu Gln Val His Leu Gly Asp Glu Gly Glu 210 215 220Phe Thr Cys Arg Ala Gln Asn Ser Leu Gly Ser Gln His Val Ser Leu225 230 235 240Asn Leu Ser Leu Gln Gln Glu Tyr Thr Gly Lys Met Lys Pro Val Ser 245 250 255Gly Val Leu Leu Gly Ala Val Gly Gly Thr Gly Ala Thr Ala Leu Val 260 265 270Phe Leu Ser Phe Cys Val Ile Phe Ile Val Val Arg Ser Cys Arg Lys 275 280 285Lys Ser Ala Arg Pro Ala Ala Asp Val Gly Asp Ile Gly Met Lys Asp 290 295 300Ala Asn Thr Ile Gln Gly Leu Ser Leu Ser Gly305 310 31519245PRTHomo sapiens 19Met Ala Glu Ile His Thr Pro Tyr Ser Ser Leu Lys Lys Leu Leu Ser1 5 10 15Leu Leu Asn Gly Phe Val Ala Val Ser Gly Ile Ile Leu Val Gly Leu 20 25 30Gly Ile Gly Gly Lys Cys Gly Gly Ala Ser Leu Thr Asn Val Leu Gly 35 40 45Leu Ser Ser Ala Tyr Leu Leu His Val Gly Asn Leu Cys Leu Val Met 50 55 60Gly Cys Ile Thr Val Leu Leu Gly Cys Ala Gly Trp Tyr Gly Ala Thr65 70 75 80Lys Glu Ser Arg Gly Thr Leu Leu Phe Cys Ile Leu Ser Met Val Ile 85 90 95Val Leu Ile Met Glu Val Thr Ala Ala Thr Val Val Leu Leu Phe Phe 100 105 110Pro Ile Val Gly Asp Val Ala Leu Glu His Thr Phe Val Thr Leu Arg 115 120 125Lys Asn Tyr Arg Gly Tyr Asn Glu Pro Asp Asp Tyr Ser Thr Gln Trp 130 135 140Asn Leu Val Met Glu Lys Leu Lys Cys Cys Gly Val Asn Asn Tyr Thr145 150 155 160Asp Phe Ser Gly Ser Ser Phe Glu Met Thr Thr Gly His Thr Tyr Pro 165 170 175Arg Ser Cys Cys Lys Ser Ile Gly Ser Val Ser Cys Asp Gly Arg Asp 180 185 190Val Ser Pro Asn Val Ile His Gln Lys Gly Cys Phe His Lys Leu Leu 195 200 205Lys Ile Thr Lys Thr Gln Ser Phe Thr Leu Ser Gly Ser Ser Leu Gly 210 215 220Ala Ala Val Ile Gln Arg Trp Gly Ser Arg Tyr Val Ala Gln Ala Gly225 230 235 240Leu Glu Leu Leu Ala 24520273PRTHomo sapiens 20Met Gln Cys Phe Ser Phe Ile Lys Thr Met Met Ile Leu Phe Asn Leu1 5 10 15Leu Ile Phe Leu Cys Gly Ala Ala Leu Leu Ala Val Gly Ile Trp Val 20 25 30Ser Ile Asp Gly Ala Ser Phe Leu Lys Ile Phe Gly Pro Leu Ser Ser 35 40 45Ser Ala Met Gln Phe Val Asn Val Gly Tyr Phe Leu Ile Ala Ala Gly 50 55 60Val Val Val Phe Ala Leu Gly Phe Leu Gly Cys Tyr Gly Ala Lys Thr65 70 75 80Glu Ser Lys Cys Ala Leu Val Thr Phe Phe Phe Ile Leu Leu Leu Ile 85 90 95Phe Ile Ala Glu Val Ala Ala Ala Val Val Ala Leu Val Tyr Thr Thr 100 105 110Met Ala Glu His Phe Leu Thr Leu Leu Val Val Pro Ala Ile Lys Lys 115 120 125Asp Tyr Gly Ser Gln Glu Asp Phe Thr Gln Val Trp Asn Thr Thr Met 130 135 140Lys Gly Leu Lys Cys Cys Gly Phe Thr Asn Tyr Thr Asp Phe Glu Asp145 150 155 160Ser Pro Tyr Phe Lys Glu Asn Ser Ala Phe Pro Pro Phe Cys Cys Asn 165 170 175Asp Asn Val Thr Asn Thr Ala Asn Glu Thr Cys Thr Lys Gln Lys Ala 180 185 190His Asp Gln Lys Val Glu Gly Cys Phe Asn Gln Leu Leu Tyr Asp Ile 195 200 205Arg Thr Asn Ala Val Thr Val Gly Gly Val Ala Ala Gly Ile Gly Gly 210 215 220Leu Glu Leu Ala Ala Met Asn Cys Val His Val Ser Val Leu Gln Ser225 230 235 240Thr Ile Ser Pro Leu Leu Pro Leu Pro Leu Leu Leu Pro His Gly Asn 245 250 255Cys Glu Glu Ala Pro Trp Gln Ala Ala Val Ile Gly Gly Gly Asp Arg 260 265 270Ile21250PRTHomo sapiens 21Met Asn Ser Met Thr Ser Ala Val Pro Val Ala Asn Ser Val Leu Val1 5 10 15Val Ala Pro His Asn Gly Tyr Pro Val Thr Pro Gly Ile Met Ser His 20 25 30Val Pro Leu Tyr Pro Asn Ser Gln Pro Gln Val His Leu Val Pro Gly 35 40 45Asn Pro Pro Ser Leu Val Ser Asn Val Asn Gly Gln Pro Val Gln Lys 50 55 60Ala Leu Lys Glu Gly Lys Thr Leu Gly Ala Ile Gln Ile Ile Ile Gly65 70 75 80Leu Ala His Ile Gly Leu Gly Ser Ile Met Ala Thr Val Leu Val Gly 85 90 95Glu Tyr Leu Ser Ile Ser Phe Tyr Gly Gly Phe Pro Phe Trp Gly Gly 100 105 110Leu Trp Phe Ile Ile Ser Gly Ser Leu Ser Val Ala Ala Glu Asn Gln 115 120 125Pro Tyr Ser Tyr Cys Leu Leu Ser Gly Ser Leu Gly Leu Asn Ile Val 130 135 140Ser Ala Ile Cys Ser Ala Val Gly Val Ile Leu Phe Ile Thr Asp Leu145 150 155 160Ser Ile Pro His Pro Tyr Ala Tyr Pro Asp Tyr Tyr Pro Tyr Ala Trp 165 170 175Gly Val Asn Pro Gly Met Ala Ile Ser Gly Val Leu Leu Val Phe Cys 180 185 190Leu Leu Glu Phe Gly Ile Ala Cys Ala Ser Ser His Phe Gly Cys Gln 195 200 205Leu Val Cys Cys Gln Ser Ser Asn Val Ser Val Ile Tyr Pro Asn Ile 210 215 220Tyr Ala Ala Asn Pro Val Ile Thr Pro Glu Pro Val Thr Ser Pro Pro225 230 235 240Ser Tyr Ser Ser Glu Ile Gln Ala Asn Lys 245 25022245PRTHomo sapiens 22Met Ala Ser Pro Ser Arg Arg Leu Gln Thr Lys Pro Val Ile Thr Cys1 5 10 15Phe Lys Ser Val Leu Leu Ile Tyr Thr Phe Ile Phe Trp Ile Thr Gly 20 25 30Val Ile Leu Leu Ala Val Gly Ile Trp Gly Lys Val Ser Leu Glu Asn 35 40 45Tyr Phe Ser Leu Leu Asn Glu Lys Ala Thr Asn Val Pro Phe Val Leu 50 55 60Ile Ala Thr Gly Thr Val Ile Ile Leu Leu Gly Thr Phe Gly Cys Phe65 70 75 80Ala Thr Cys Arg Ala Ser Ala Trp Met Leu Lys Leu Tyr Ala Met Phe 85 90 95Leu Thr Leu Val Phe Leu Val Glu Leu Val Ala Ala Ile Val Gly Phe 100 105 110Val Phe Arg His Glu Ile Lys Asn Ser Phe Lys Asn Asn Tyr Glu Lys 115 120 125Ala Leu Lys Gln Tyr Asn Ser Thr Gly Asp Tyr Arg Ser His Ala Val 130 135 140Asp Lys Ile Gln Asn Thr Leu His Cys Cys Gly Val Thr Asp Tyr Arg145 150 155 160Asp Trp Thr Asp Thr Asn Tyr Tyr Ser Glu Lys Gly Phe Pro Lys Ser 165 170 175Cys Cys Lys Leu Glu Asp Cys Thr Pro Gln Arg Asp Ala Asp Lys Val 180 185 190Asn Asn Glu Gly Cys Phe Ile Lys Val Met Thr Ile Ile Glu Ser Glu 195 200 205Met Gly Val Val Ala Gly Ile Ser Phe Gly Val Ala Cys Phe Gln Leu 210 215 220Ile Gly Ile Phe Leu Ala Tyr Cys Leu Ser Arg Ala Ile Thr Asn Asn225 230 235 240Gln Tyr Glu Ile Val 24523253PRTHomo sapiens 23Met Gly Gln Cys Gly Ile Thr Ser Ser Lys Thr Val Leu Val Phe Leu1 5 10 15Asn Leu Ile Phe Trp Gly Ala Ala Gly Ile Leu Cys Tyr Val Gly Ala 20 25 30Tyr Val Phe Ile Thr Tyr Asp Asp Tyr Asp His Phe Phe Glu Asp Val 35 40 45Tyr Thr Leu Ile Pro Ala Val Val Ile Ile Ala Val Gly Ala Leu Leu 50 55 60Phe Ile Ile Gly Leu Ile Gly Cys Cys Ala Thr Ile Arg Glu Ser Arg65 70 75 80Cys Gly Leu Ala Thr Phe Val Ile Ile Leu Leu Leu Val Phe Val Thr 85 90 95Glu Val Val Val Val Val Leu Gly Tyr Val Tyr Arg Ala Lys Val Glu 100 105 110Asn Glu Val Asp Arg Ser Ile Gln Lys Val Tyr Lys Thr Tyr Asn Gly 115 120 125Thr Asn Pro Asp Ala Ala Ser Arg Ala Ile Asp Tyr Val Gln Arg Gln 130 135 140Leu His Cys Cys Gly Ile His Asn Tyr Ser Asp Trp Glu Asn Thr Asp145 150 155 160Trp Phe Lys Glu Thr Lys Asn Gln Ser Val Pro Leu Ser Cys Cys Arg 165 170 175Glu Thr Ala Ser Asn Cys Asn Gly Ser Leu Ala His Pro Ser Asp Leu 180 185 190Tyr Ala Glu Gly Cys Glu Ala Leu Val Val Lys Lys Leu Gln Glu Ile 195 200 205Met Met His Val Ile Trp Ala Ala Leu Ala Phe Ala Ala Ile Gln Leu 210 215 220Leu Gly Met Leu Cys Ala Cys Ile Val Leu Cys Arg Arg Ser Arg Asp225 230 235 240Pro Ala Tyr Glu Leu Phe Ile Thr Gly Gly Thr Tyr Ala 245 25024238PRTHomo sapiens 24Met Ala Arg Ala Cys Leu Gln Ala Val Lys Tyr Leu Met Phe Ala Phe1 5 10 15Asn Leu Phe Phe Trp Leu Gly Gly Cys Gly Val Leu Gly Val Gly Ile 20 25 30Trp Leu Ala Ala Thr Gln Gly Ser Phe Ala Thr Leu Ser Ser Ser Phe 35 40 45Pro Ser Leu Ser Ala Ala Asn Leu Leu Ile Ile Thr Gly Ala Phe Val 50 55 60Met Ala Ile Gly Phe Val Gly Cys Leu Gly Ala Ile Lys Glu Asn Lys65 70 75 80Cys Leu Leu Leu Thr Phe Phe Leu Leu Leu Leu Leu Val Phe Leu Leu 85 90 95Glu Ala Thr Ile Ala Ile Leu Phe Phe Ala Tyr Thr Asp Lys Ile Asp 100 105 110Arg Tyr Ala Gln Gln Asp Leu Lys Lys Gly Leu His Leu Tyr Gly Thr 115 120 125Gln Gly Asn Val Gly Leu Thr Asn Ala Trp Ser Ile Ile Gln Thr Asp 130 135 140Phe Arg Cys Cys Gly Val Ser Asn Tyr Thr Asp Trp Phe Glu Val Tyr145 150 155 160Asn Ala Thr Arg Val Pro Asp Ser Cys Cys Leu Glu Phe Ser Glu Ser 165 170 175Cys Gly Leu His Ala Pro Gly Thr Trp Trp Lys Ala Pro Cys Tyr Glu 180 185 190Thr Val Lys Val Trp Leu Gln Glu Asn Leu Leu Ala Val Gly Ile Phe 195 200 205Gly Leu Cys Thr Ala Leu Val Gln Ile Leu Gly Leu Thr Phe Ala Met 210 215 220Thr Met Tyr Cys Gln Val Val Lys Ala Asp Thr Tyr Cys Ala225 230 23525221PRTHomo sapiens 25Met Gly Arg Phe Arg Gly Gly Leu Arg Cys Ile Lys Tyr Leu Leu Leu1 5 10 15Gly Phe Asn Leu Leu Phe Trp Leu Ala Gly Ser Ala Val Ile Ala Phe 20 25 30Gly Leu Trp Phe Arg Phe Gly Gly Ala Ile Lys Glu Leu Ser Ser Glu 35 40 45Asp Lys Ser

Pro Glu Tyr Phe Tyr Val Gly Leu Tyr Val Leu Val Gly 50 55 60Ala Gly Ala Leu Met Met Ala Val Gly Phe Phe Gly Cys Cys Gly Ala65 70 75 80Met Arg Glu Ser Gln Cys Val Leu Gly Ser Phe Phe Thr Cys Leu Leu 85 90 95Val Ile Phe Ala Ala Glu Val Thr Thr Gly Val Phe Ala Phe Ile Gly 100 105 110Lys Gly Val Ala Ile Arg His Val Gln Thr Met Tyr Glu Glu Ala Tyr 115 120 125Asn Asp Tyr Leu Lys Asp Arg Gly Lys Gly Asn Gly Thr Leu Ile Thr 130 135 140Phe His Ser Thr Phe Gln Cys Cys Gly Lys Glu Ser Ser Glu Gln Val145 150 155 160Gln Pro Thr Cys Pro Lys Glu Leu Leu Gly His Lys Asn Cys Ile Asp 165 170 175Glu Ile Glu Thr Ile Ile Ser Val Lys Leu Gln Leu Ile Gly Ile Val 180 185 190Gly Ile Gly Ile Ala Gly Leu Thr Ile Phe Gly Met Ile Phe Ser Met 195 200 205Val Leu Cys Cys Ala Ile Arg Asn Ser Arg Asp Val Ile 210 215 22026252PRTHomo sapiens 26Met Ala His Tyr Lys Thr Glu Gln Asp Asp Trp Leu Ile Ile Tyr Leu1 5 10 15Lys Tyr Leu Leu Phe Val Phe Asn Phe Phe Phe Trp Val Gly Gly Ala 20 25 30Ala Val Leu Ala Val Gly Ile Trp Thr Leu Val Glu Lys Ser Gly Tyr 35 40 45Leu Ser Val Leu Ala Ser Ser Thr Phe Ala Ala Ser Ala Tyr Ile Leu 50 55 60Ile Phe Ala Gly Val Leu Val Met Val Thr Gly Phe Leu Gly Phe Gly65 70 75 80Ala Ile Leu Trp Glu Arg Lys Gly Cys Leu Ser Thr Tyr Phe Cys Leu 85 90 95Leu Leu Val Ile Phe Leu Val Glu Leu Val Ala Gly Val Leu Ala His 100 105 110Val Tyr Tyr Gln Arg Leu Ser Asp Glu Leu Lys Gln His Leu Asn Arg 115 120 125Thr Leu Ala Glu Asn Tyr Gly Gln Pro Glu His Ala Asp His Ala Ser 130 135 140Val Asp Arg Leu Gln Gln Asp Phe Lys Cys Cys Gly Ser Asn Ser Ser145 150 155 160Ala Asp Trp Gln His Ser Thr Tyr Ile Leu Leu Arg Glu Ala Glu Gly 165 170 175Arg Gln Val Pro Asp Ser Cys Cys Lys Thr Val Val Ala Arg Cys Gly 180 185 190Gln Arg Ala His Pro Ser Asn Ile Tyr Lys Val Glu Gly Gly Cys Leu 195 200 205Thr Lys Leu Glu Gln Phe Leu Ala Asp His Leu Leu Leu Met Gly Ala 210 215 220Val Gly Ile Gly Val Ala Cys Leu Gln Ile Cys Gly Met Val Leu Thr225 230 235 240Cys Cys Leu His Gln Arg Leu Gln Arg His Phe Tyr 245 25027197PRTHomo sapiens 27Met Cys Thr Gly Lys Cys Ala Arg Cys Val Gly Leu Ser Leu Ile Thr1 5 10 15Leu Cys Leu Val Cys Ile Val Ala Asn Ala Leu Leu Leu Val Pro Asn 20 25 30Gly Glu Thr Ser Trp Thr Asn Thr Asn His Leu Ser Leu Gln Val Trp 35 40 45Leu Met Gly Gly Phe Ile Gly Gly Gly Leu Met Val Leu Cys Pro Gly 50 55 60Ile Ala Ala Val Arg Ala Gly Gly Lys Gly Cys Cys Gly Ala Gly Cys65 70 75 80Cys Gly Asn Arg Cys Arg Met Leu Arg Ser Val Phe Ser Ser Ala Phe 85 90 95Gly Val Leu Gly Ala Ile Tyr Cys Leu Ser Val Ser Gly Ala Gly Leu 100 105 110Arg Asn Gly Pro Arg Cys Leu Met Asn Gly Glu Trp Gly Tyr His Phe 115 120 125Glu Asp Thr Ala Gly Ala Tyr Leu Leu Asn Arg Thr Leu Trp Asp Arg 130 135 140Cys Glu Ala Pro Pro Arg Val Val Pro Trp Asn Val Thr Leu Phe Ser145 150 155 160Leu Leu Val Ala Ala Ser Cys Leu Glu Ile Val Leu Cys Gly Ile Gln 165 170 175Leu Val Asn Ala Thr Ile Gly Val Phe Cys Gly Asp Cys Arg Lys Lys 180 185 190Gln Asp Thr Pro His 19528201PRTHomo sapiens 28Met Gly Ser Arg Lys Cys Gly Gly Cys Leu Ser Cys Leu Leu Ile Pro1 5 10 15Leu Ala Leu Trp Ser Ile Ile Val Asn Ile Leu Leu Tyr Phe Pro Asn 20 25 30Gly Gln Thr Ser Tyr Ala Ser Ser Asn Lys Leu Thr Asn Tyr Val Trp 35 40 45Tyr Phe Glu Gly Ile Cys Phe Ser Gly Ile Met Met Leu Ile Val Thr 50 55 60Thr Val Leu Leu Val Leu Glu Asn Asn Asn Asn Tyr Lys Cys Cys Gln65 70 75 80Ser Glu Asn Cys Ser Lys Lys Tyr Val Thr Leu Leu Ser Ile Ile Phe 85 90 95Ser Ser Leu Gly Ile Ala Phe Ser Gly Tyr Cys Leu Val Ile Ser Ala 100 105 110Leu Gly Leu Val Gln Gly Pro Tyr Cys Arg Thr Leu Asp Gly Trp Glu 115 120 125Tyr Ala Phe Glu Gly Thr Ala Gly Arg Phe Leu Thr Asp Ser Ser Ile 130 135 140Trp Ile Gln Cys Leu Glu Pro Ala His Val Val Glu Trp Asn Ile Ile145 150 155 160Leu Phe Ser Ile Leu Ile Thr Leu Ser Gly Leu Gln Val Ile Ile Cys 165 170 175Leu Ile Arg Val Val Met Gln Leu Ser Lys Ile Leu Cys Gly Ser Tyr 180 185 190Ser Val Ile Phe Gln Pro Gly Ile Ile 195 20029133PRTHomo sapiens 29Met Ser Pro Arg Leu Glu Val Pro Cys Ser His Ala Leu Pro Gln Gly1 5 10 15Leu Ser Pro Gly Gln Val Ile Ile Val Arg Gly Leu Val Leu Gln Glu 20 25 30Pro Lys His Phe Thr Val Ser Leu Arg Asp Gln Ala Ala His Ala Pro 35 40 45Val Thr Leu Arg Ala Ser Phe Ala Asp Arg Thr Leu Ala Trp Ile Ser 50 55 60Arg Trp Gly Gln Lys Lys Leu Ile Ser Ala Pro Phe Leu Phe Tyr Pro65 70 75 80Gln Arg Phe Phe Glu Val Leu Leu Leu Phe Gln Glu Gly Gly Leu Lys 85 90 95Leu Ala Leu Asn Gly Gln Gly Leu Gly Ala Thr Ser Met Asn Gln Gln 100 105 110Ala Leu Glu Gln Leu Arg Glu Leu Arg Ile Ser Gly Ser Val Gln Leu 115 120 125Tyr Cys Val His Ser 1303070PRTHomo sapiens 30Met Arg Thr Ala Leu Leu Leu Leu Ala Ala Leu Ala Val Ala Thr Gly1 5 10 15Pro Ala Leu Thr Leu Arg Cys His Val Cys Thr Ser Ser Ser Asn Cys 20 25 30Lys His Ser Val Val Cys Pro Ala Ser Ser Arg Phe Cys Lys Thr Thr 35 40 45Asn Thr Val Glu Pro Leu Arg Ala Ser Pro Lys Val Trp Asp Gln Val 50 55 60Gln Val Gly Met Glu Cys65 7031299PRTHomo sapiens 31Met Ala Gln Asn Leu Lys Asp Leu Ala Gly Arg Leu Pro Ala Gly Pro1 5 10 15Arg Gly Met Gly Thr Ala Leu Lys Leu Leu Leu Gly Ala Gly Ala Val 20 25 30Ala Tyr Gly Val Arg Glu Ser Val Phe Thr Val Glu Gly Gly His Arg 35 40 45Ala Ile Phe Phe Asn Arg Ile Gly Gly Val Gln Gln Asp Thr Ile Leu 50 55 60Ala Glu Gly Leu His Phe Arg Ile Pro Trp Phe Gln Tyr Pro Ile Ile65 70 75 80Tyr Asp Ile Arg Ala Arg Pro Arg Lys Ile Ser Ser Pro Thr Gly Ser 85 90 95Lys Asp Leu Gln Met Val Asn Ile Ser Leu Arg Val Leu Ser Arg Pro 100 105 110Asn Ala Gln Glu Leu Pro Ser Met Tyr Gln Arg Leu Gly Leu Asp Tyr 115 120 125Glu Glu Arg Val Leu Pro Ser Ile Val Asn Glu Val Leu Lys Ser Val 130 135 140Val Ala Lys Phe Asn Ala Ser Gln Leu Ile Thr Gln Arg Ala Gln Val145 150 155 160Ser Leu Leu Ile Arg Arg Glu Leu Thr Glu Arg Ala Lys Asp Phe Ser 165 170 175Leu Ile Leu Asp Asp Val Ala Ile Thr Glu Leu Ser Phe Ser Arg Glu 180 185 190Tyr Thr Ala Ala Val Glu Ala Lys Gln Val Ala Gln Gln Glu Ala Gln 195 200 205Arg Ala Gln Phe Leu Val Glu Lys Ala Lys Gln Glu Gln Arg Gln Lys 210 215 220Ile Val Gln Ala Glu Gly Glu Ala Glu Ala Ala Lys Met Leu Gly Glu225 230 235 240Ala Leu Ser Lys Asn Pro Gly Tyr Ile Lys Leu Arg Lys Ile Arg Ala 245 250 255Ala Gln Asn Ile Ser Lys Thr Ile Ala Thr Ser Gln Asn Arg Ile Tyr 260 265 270Leu Thr Ala Asp Asn Leu Val Leu Asn Leu Gln Asp Glu Ser Phe Thr 275 280 285Arg Gly Ser Asp Ser Leu Ile Lys Gly Lys Lys 290 29532168PRTHomo sapiens 32Met Asp Cys Glu Ile Lys Gly Arg Pro Cys Cys Ile Gly Thr Lys Gly1 5 10 15Ser Cys Glu Ile Thr Thr Arg Glu Tyr Cys Glu Phe Met His Gly Tyr 20 25 30Phe His Glu Glu Ala Thr Leu Cys Ser Gln Val Arg Arg Gly Arg Pro 35 40 45Gly Val Val Glu Glu Arg Thr Leu Gly Met Ala Ala Cys Trp Gly Arg 50 55 60Gly Ser Arg Thr Pro Ser His Val Gly Ala Ser Asp Ser Gly Cys Phe65 70 75 80Trp Gly Ala Glu His His Met Pro Ile Pro Arg Cys Thr Val Leu Asp 85 90 95Lys Val Cys Trp Ala Ala Ala Phe Leu Asn Pro Glu Val Pro Asp Gln 100 105 110Phe Tyr Arg Ser Gly Cys Leu Phe Ser Tyr Met Leu Gly Lys Arg Ser 115 120 125Ser Met Pro Pro Asn Pro Thr Pro Val Met Asp Thr Gln Ala Asp Pro 130 135 140Trp Gly Lys Val Pro Gly Pro Gly Tyr Gly Arg Ser Asn Leu Pro Lys145 150 155 160Thr Thr Ala Pro Glu Val Ser Gly 16533551PRTHomo sapiens 33Met Leu Pro Leu Leu Leu Leu Pro Leu Leu Trp Gly Gly Ser Leu Gln1 5 10 15Glu Lys Pro Val Tyr Glu Leu Gln Val Gln Lys Ser Val Thr Val Gln 20 25 30Glu Gly Leu Cys Val Leu Val Pro Cys Ser Phe Ser Tyr Pro Trp Arg 35 40 45Ser Trp Tyr Ser Ser Pro Pro Leu Tyr Val Tyr Trp Phe Arg Asp Gly 50 55 60Glu Ile Pro Tyr Tyr Ala Glu Val Val Ala Thr Asn Asn Pro Asp Arg65 70 75 80Arg Val Lys Pro Glu Thr Gln Gly Arg Phe Arg Leu Leu Gly Asp Val 85 90 95Gln Lys Lys Asn Cys Ser Leu Ser Ile Gly Asp Ala Arg Met Glu Asp 100 105 110Thr Gly Ser Tyr Phe Phe Arg Val Glu Arg Gly Arg Asp Val Lys Tyr 115 120 125Ser Tyr Gln Gln Asn Lys Leu Asn Leu Glu Val Thr Ala Leu Ile Glu 130 135 140Lys Pro Asp Ile His Phe Leu Glu Pro Leu Glu Ser Gly Arg Pro Thr145 150 155 160Arg Leu Ser Cys Ser Leu Pro Gly Ser Cys Glu Ala Gly Pro Pro Leu 165 170 175Thr Phe Ser Trp Thr Gly Asn Ala Leu Ser Pro Leu Asp Pro Glu Thr 180 185 190Thr Arg Ser Ser Glu Leu Thr Leu Thr Pro Arg Pro Glu Asp His Gly 195 200 205Thr Asn Leu Thr Cys Gln Met Lys Arg Gln Gly Ala Gln Val Thr Thr 210 215 220Glu Arg Thr Val Gln Leu Asn Val Ser Tyr Ala Pro Gln Thr Ile Thr225 230 235 240Ile Phe Arg Asn Gly Ile Ala Leu Glu Ile Leu Gln Asn Thr Ser Tyr 245 250 255Leu Pro Val Leu Glu Gly Gln Ala Leu Arg Leu Leu Cys Asp Ala Pro 260 265 270Ser Asn Pro Pro Ala His Leu Ser Trp Phe Gln Gly Ser Pro Ala Leu 275 280 285Asn Ala Thr Pro Ile Ser Asn Thr Gly Ile Leu Glu Leu Arg Arg Val 290 295 300Arg Ser Ala Glu Glu Gly Gly Phe Thr Cys Arg Ala Gln His Pro Leu305 310 315 320Gly Phe Leu Gln Ile Phe Leu Asn Leu Ser Val Tyr Ser Leu Pro Gln 325 330 335Leu Leu Gly Pro Ser Cys Ser Trp Glu Ala Glu Gly Leu His Cys Arg 340 345 350Cys Ser Phe Arg Ala Arg Pro Ala Pro Ser Leu Cys Trp Arg Leu Glu 355 360 365Glu Lys Pro Leu Glu Gly Asn Ser Ser Gln Gly Ser Phe Lys Val Asn 370 375 380Ser Ser Ser Ala Gly Pro Trp Ala Asn Ser Ser Leu Ile Leu His Gly385 390 395 400Gly Leu Ser Ser Asp Leu Lys Val Ser Cys Lys Ala Trp Asn Ile Tyr 405 410 415Gly Ser Gln Ser Gly Ser Val Leu Leu Leu Gln Gly Arg Ser Asn Leu 420 425 430Gly Thr Gly Val Val Pro Ala Ala Leu Gly Gly Ala Gly Val Met Ala 435 440 445Leu Leu Cys Ile Cys Leu Cys Leu Ile Phe Phe Leu Ile Val Lys Ala 450 455 460Arg Arg Lys Gln Ala Ala Gly Arg Pro Glu Lys Met Asp Asp Glu Asp465 470 475 480Pro Ile Met Gly Thr Ile Thr Ser Gly Ser Arg Lys Lys Pro Trp Pro 485 490 495Asp Ser Pro Gly Asp Gln Ala Ser Pro Pro Gly Asp Ala Pro Pro Leu 500 505 510Glu Glu Gln Lys Glu Leu His Tyr Ala Ser Leu Ser Phe Ser Glu Met 515 520 525Lys Ser Arg Glu Pro Lys Asp Gln Glu Ala Pro Ser Thr Thr Glu Tyr 530 535 540Ser Glu Ile Lys Thr Ser Lys545 55034219PRTRattus sp. 34Met Gly Met Ser Ser Leu Lys Leu Leu Lys Tyr Val Leu Phe Phe Phe1 5 10 15Asn Phe Leu Phe Trp Val Cys Gly Cys Cys Ile Leu Gly Phe Gly Ile 20 25 30His Leu Leu Val Gln Asn Thr Tyr Gly Ile Leu Phe Arg Asn Leu Pro 35 40 45Phe Leu Thr Leu Gly Asn Val Leu Val Ile Val Gly Ser Ile Ile Met 50 55 60Val Val Ala Phe Leu Gly Cys Met Gly Ser Ile Lys Glu Asn Lys Cys65 70 75 80Leu Leu Met Ser Phe Phe Val Leu Leu Leu Leu Ile Leu Leu Ala Glu 85 90 95Val Thr Leu Ala Ile Leu Leu Phe Val Tyr Glu Lys Lys Ile Asn Thr 100 105 110Leu Val Ala Glu Gly Leu Asn Asp Ser Ile Gln His Tyr His Ser Asp 115 120 125Asn Ser Thr Arg Met Ala Trp Asp Phe Ile Gln Ser Gln Leu Gln Cys 130 135 140Cys Gly Val Asn Gly Ser Ser Asp Trp Ile Ser Gly Pro Pro Ser Ser145 150 155 160Cys Pro Ser Gly Ala Asp Val Gln Gly Cys Tyr Lys Lys Gly Gln Ala 165 170 175Trp Phe His Ser Asn Phe Leu Tyr Ile Gly Ile Val Thr Ile Cys Val 180 185 190Cys Val Ile Gln Val Leu Gly Met Ser Phe Ala Leu Thr Leu Asn Cys 195 200 205Gln Ile Asp Lys Thr Ser Gln Ala Leu Gly Leu 210 21535253PRTHomo sapiens 35Met Gly Glu Phe Asn Glu Lys Lys Thr Thr Cys Gly Thr Val Cys Leu1 5 10 15Lys Tyr Leu Leu Phe Thr Tyr Asn Cys Cys Phe Trp Leu Ala Gly Leu 20 25 30Ala Val Met Ala Val Gly Ile Trp Thr Leu Ala Leu Lys Ser Asp Tyr 35 40 45Ile Ser Leu Leu Ala Ser Gly Thr Tyr Leu Ala Thr Ala Tyr Ile Leu 50 55 60Val Val Ala Gly Thr Val Val Met Val Thr Gly Val Leu Gly Cys Cys65 70 75 80Ala Thr Phe Lys Glu Arg Arg Asn Leu Leu Arg Leu Tyr Phe Ile Leu 85 90 95Leu Leu Ile Ile Phe Leu Leu Glu Ile Ile Ala Gly Ile Leu Ala Tyr 100 105 110Ala Tyr Tyr Gln Gln Leu Asn Thr Glu Leu Lys Glu Asn Leu Lys Asp 115 120 125Thr Met Thr Lys Arg Tyr His Gln Pro Gly His Glu Ala Val Thr Ser 130 135 140Ala Val Asp Gln Leu Gln Gln Glu Phe His Cys Cys Gly Ser Asn Asn145 150 155 160Ser Gln Asp Trp Arg Asp Ser Glu Trp Ile Arg Ser Gln Glu Ala Gly 165 170 175Gly Arg Val Val Pro Asp Ser Cys Cys Lys Thr Val Val Ala Leu Cys 180 185 190Gly Gln Arg Asp His Ala

Ser Asn Ile Tyr Lys Val Glu Gly Gly Cys 195 200 205Ile Thr Lys Leu Glu Thr Phe Ile Gln Glu His Leu Arg Val Ile Gly 210 215 220Ala Val Gly Ile Gly Ile Ala Cys Val Gln Val Phe Gly Met Ile Phe225 230 235 240Thr Cys Cys Leu Tyr Arg Ser Leu Lys Leu Glu His Tyr 245 25036238PRTHomo sapiens 36Met Ala Arg Ala Cys Leu Gln Ala Val Lys Tyr Leu Met Phe Ala Phe1 5 10 15Asn Leu Leu Phe Trp Leu Gly Gly Cys Gly Val Leu Gly Val Gly Ile 20 25 30Trp Leu Ala Ala Thr Gln Gly Ser Phe Ala Thr Leu Ser Ser Ser Phe 35 40 45Pro Ser Leu Ser Ala Ala Asn Leu Leu Ile Ile Thr Gly Ala Phe Val 50 55 60Met Ala Ile Gly Phe Val Gly Cys Leu Gly Ala Ile Lys Glu Asn Lys65 70 75 80Cys Leu Leu Leu Thr Phe Phe Leu Leu Leu Leu Leu Val Phe Leu Leu 85 90 95Glu Ala Thr Ile Ala Ile Leu Phe Phe Ala Tyr Thr Asp Lys Ile Asp 100 105 110Arg Tyr Ala Gln Gln Asp Leu Lys Lys Gly Leu His Leu Tyr Gly Thr 115 120 125Gln Gly Asn Val Gly Leu Thr Asn Ala Trp Ser Ile Ile Gln Thr Asp 130 135 140Phe Arg Cys Cys Gly Val Ser Asn Tyr Thr Asp Trp Phe Glu Val Tyr145 150 155 160Asn Ala Thr Arg Val Pro Asp Ser Cys Cys Leu Glu Phe Ser Glu Ser 165 170 175Cys Gly Leu His Ala Pro Gly Thr Trp Trp Lys Ala Pro Cys Tyr Glu 180 185 190Thr Val Lys Val Trp Leu Gln Glu Asn Leu Leu Ala Val Gly Ile Phe 195 200 205Gly Leu Cys Thr Ala Leu Val Gln Ile Leu Gly Leu Thr Phe Ala Met 210 215 220Thr Met Tyr Cys Gln Val Val Lys Ala Asp Thr Tyr Cys Ala225 230 23537244PRTHomo sapiens 37Met Glu Thr Lys Pro Val Ile Thr Cys Leu Lys Thr Leu Leu Ile Ile1 5 10 15Tyr Ser Phe Val Phe Trp Ile Thr Gly Val Ile Leu Leu Ala Val Gly 20 25 30Val Trp Gly Lys Leu Thr Leu Gly Thr Tyr Ile Ser Leu Ile Ala Glu 35 40 45Asn Ser Thr Asn Ala Pro Tyr Val Leu Ile Gly Thr Gly Thr Thr Ile 50 55 60Val Val Phe Gly Leu Phe Gly Cys Phe Ala Thr Cys Arg Gly Ser Pro65 70 75 80Trp Met Leu Lys Leu Tyr Ala Met Phe Leu Ser Leu Val Phe Leu Ala 85 90 95Glu Leu Val Ala Gly Ile Ser Gly Phe Val Phe Arg His Glu Ile Lys 100 105 110Asp Thr Phe Leu Arg Thr Tyr Thr Asp Ala Met Gln Thr Tyr Asn Gly 115 120 125Asn Asp Glu Arg Ser Arg Ala Val Asp His Val Gln Arg Ser Leu Ser 130 135 140Cys Cys Gly Val Gln Asn Tyr Thr Asn Trp Ser Thr Ser Pro Tyr Phe145 150 155 160Leu Glu His Gly Ile Pro Pro Ser Cys Cys Met Asn Glu Thr Asp Cys 165 170 175Asn Pro Gln Asp Leu His Asn Leu Thr Val Ala Ala Thr Lys Val Asn 180 185 190Gln Lys Gly Cys Tyr Asp Leu Val Thr Ser Phe Met Glu Thr Asn Met 195 200 205Gly Ile Ile Ala Gly Val Ala Phe Gly Ile Ala Phe Ser Gln Leu Ile 210 215 220Gly Met Leu Leu Ala Cys Cys Leu Ser Arg Phe Ile Thr Ala Asn Gln225 230 235 240Tyr Glu Met Val38297PRTHomo sapiens 38Met Thr Thr Pro Arg Asn Ser Val Asn Gly Thr Phe Pro Ala Glu Pro1 5 10 15Met Lys Gly Pro Ile Ala Met Gln Ser Gly Pro Lys Pro Leu Phe Arg 20 25 30Arg Met Ser Ser Leu Val Gly Pro Thr Gln Ser Phe Phe Met Arg Glu 35 40 45Ser Lys Thr Leu Gly Ala Val Gln Ile Met Asn Gly Leu Phe His Ile 50 55 60Ala Leu Gly Gly Leu Leu Met Ile Pro Ala Gly Ile Tyr Ala Pro Ile65 70 75 80Cys Val Thr Val Trp Tyr Pro Leu Trp Gly Gly Ile Met Tyr Ile Ile 85 90 95Ser Gly Ser Leu Leu Ala Ala Thr Glu Lys Asn Ser Arg Lys Cys Leu 100 105 110Val Lys Gly Lys Met Ile Met Asn Ser Leu Ser Leu Phe Ala Ala Ile 115 120 125Ser Gly Met Ile Leu Ser Ile Met Asp Ile Leu Asn Ile Lys Ile Ser 130 135 140His Phe Leu Lys Met Glu Ser Leu Asn Phe Ile Arg Ala His Thr Pro145 150 155 160Tyr Ile Asn Ile Tyr Asn Cys Glu Pro Ala Asn Pro Ser Glu Lys Asn 165 170 175Ser Pro Ser Thr Gln Tyr Cys Tyr Ser Ile Gln Ser Leu Phe Leu Gly 180 185 190Ile Leu Ser Val Met Leu Ile Phe Ala Phe Phe Gln Glu Leu Val Ile 195 200 205Ala Gly Ile Val Glu Asn Glu Trp Lys Arg Thr Cys Ser Arg Pro Lys 210 215 220Ser Asn Ile Val Leu Leu Ser Ala Glu Glu Lys Lys Glu Gln Thr Ile225 230 235 240Glu Ile Lys Glu Glu Val Val Gly Leu Thr Glu Thr Ser Ser Gln Pro 245 250 255Lys Asn Glu Glu Asp Ile Glu Ile Ile Pro Ile Gln Glu Glu Glu Glu 260 265 270Glu Glu Thr Glu Thr Asn Phe Pro Glu Pro Pro Gln Asp Gln Glu Ser 275 280 285Ser Pro Ile Glu Asn Asp Ser Ser Pro 290 29539228PRTHomo sapiens 39Met Pro Val Lys Gly Gly Thr Lys Cys Ile Lys Tyr Leu Leu Phe Gly1 5 10 15Phe Asn Phe Ile Phe Trp Leu Ala Gly Ile Ala Val Leu Ala Ile Gly 20 25 30Leu Trp Leu Arg Phe Asp Ser Gln Thr Lys Ser Ile Phe Glu Gln Glu 35 40 45Thr Asn Asn Asn Asn Ser Ser Phe Tyr Thr Gly Val Tyr Ile Leu Ile 50 55 60Gly Ala Gly Ala Leu Met Met Leu Val Gly Phe Leu Gly Cys Cys Gly65 70 75 80Ala Val Gln Glu Ser Gln Cys Met Leu Gly Leu Phe Phe Gly Phe Leu 85 90 95Leu Val Ile Phe Ala Ile Glu Ile Ala Ala Ala Ile Trp Gly Tyr Ser 100 105 110His Lys Asp Glu Val Ile Lys Glu Val Gln Glu Phe Tyr Lys Asp Thr 115 120 125Tyr Asn Lys Leu Lys Thr Lys Asp Glu Pro Gln Arg Glu Thr Leu Lys 130 135 140Ala Ile His Tyr Ala Leu Asn Cys Cys Gly Leu Ala Gly Gly Val Glu145 150 155 160Gln Phe Ile Ser Asp Ile Cys Pro Lys Lys Asp Val Leu Glu Thr Phe 165 170 175Thr Val Lys Ser Cys Pro Asp Ala Ile Lys Glu Val Phe Asp Asn Lys 180 185 190Phe His Ile Ile Gly Ala Val Gly Ile Gly Ile Ala Val Val Met Ile 195 200 205Phe Gly Met Ile Phe Ser Met Ile Leu Cys Cys Ala Ile Arg Arg Asn 210 215 220Arg Glu Met Val22540197PRTHomo sapiens 40Met Cys Thr Gly Lys Cys Ala Arg Cys Val Gly Leu Ser Leu Ile Thr1 5 10 15Leu Cys Phe Val Cys Ile Val Ala Asn Ala Leu Leu Leu Val Pro Asn 20 25 30Gly Glu Thr Ser Trp Thr Asn Thr Asn His Leu Ser Leu Gln Val Trp 35 40 45Leu Met Gly Gly Phe Ile Gly Gly Gly Leu Met Val Leu Cys Pro Gly 50 55 60Ile Ala Ala Val Arg Ala Gly Gly Lys Gly Cys Cys Gly Ala Gly Cys65 70 75 80Cys Gly Asn Arg Cys Arg Met Leu Arg Ser Val Phe Ser Ser Ala Phe 85 90 95Gly Val Leu Gly Ala Ile Tyr Cys Leu Ser Val Ser Gly Ala Gly Leu 100 105 110Arg Asn Gly Pro Arg Cys Leu Met Asn Gly Glu Trp Gly Tyr His Phe 115 120 125Glu Asp Thr Ala Gly Ala Tyr Leu Leu Asn Arg Thr Leu Trp Asp Arg 130 135 140Cys Glu Ala Pro Pro Arg Val Val Pro Trp Asn Val Thr Leu Phe Ser145 150 155 160Leu Leu Val Ala Ala Ser Cys Leu Glu Ile Val Leu Cys Gly Ile Gln 165 170 175Leu Val Asn Ala Thr Ile Gly Val Phe Cys Gly Asp Cys Arg Lys Lys 180 185 190Gln Asp Thr Pro His 19541202PRTHomo sapiens 41Met Cys Tyr Gly Lys Cys Ala Arg Cys Ile Gly His Ser Leu Val Gly1 5 10 15Leu Ala Leu Leu Cys Ile Ala Ala Asn Ile Leu Leu Tyr Phe Pro Asn 20 25 30Gly Glu Thr Lys Tyr Ala Ser Glu Asn His Leu Ser Arg Phe Val Trp 35 40 45Phe Phe Ser Gly Ile Val Gly Gly Gly Leu Leu Met Leu Leu Pro Ala 50 55 60Phe Val Phe Ile Gly Leu Glu Gln Asp Asp Cys Cys Gly Cys Cys Gly65 70 75 80His Glu Asn Cys Gly Lys Arg Cys Ala Met Leu Ser Ser Val Leu Ala 85 90 95Ala Leu Ile Gly Ile Ala Gly Ser Gly Tyr Cys Val Ile Val Ala Ala 100 105 110Leu Gly Leu Ala Glu Gly Pro Leu Cys Leu Asp Ser Leu Gly Gln Trp 115 120 125Asn Tyr Thr Phe Ala Ser Thr Glu Gly Gln Tyr Leu Leu Asp Thr Ser 130 135 140Thr Trp Ser Glu Cys Thr Glu Pro Lys His Ile Val Glu Trp Asn Val145 150 155 160Ser Leu Phe Ser Ile Leu Leu Ala Leu Gly Gly Ile Glu Phe Ile Leu 165 170 175Cys Leu Ile Gln Val Ile Asn Gly Val Leu Gly Gly Ile Cys Gly Phe 180 185 190Cys Cys Ser His Gln Gln Gln Tyr Asp Cys 195 20042145PRTRattus sp. 42Met Ser Ser Phe Ser Thr Gln Thr Pro Tyr Pro Asn Leu Ala Val Pro1 5 10 15Phe Phe Thr Ser Ile Pro Asn Gly Leu Tyr Pro Ser Lys Ser Ile Val 20 25 30Ile Ser Gly Val Val Leu Ser Asp Ala Lys Arg Phe Gln Ile Asn Leu 35 40 45Arg Cys Gly Gly Asp Ile Ala Phe His Leu Asn Pro Arg Phe Asp Glu 50 55 60Asn Ala Val Val Arg Asn Thr Gln Ile Asn Asn Ser Trp Gly Pro Glu65 70 75 80Glu Arg Ser Leu Pro Gly Ser Met Pro Phe Ser Arg Gly Gln Arg Phe 85 90 95Ser Val Trp Ile Leu Cys Glu Gly His Cys Phe Lys Val Ala Val Asp 100 105 110Gly Gln His Ile Cys Glu Tyr Ser His Arg Leu Met Asn Leu Pro Asp 115 120 125Ile Asn Thr Leu Glu Val Ala Gly Asp Ile Gln Leu Thr His Val Glu 130 135 140Thr14543318PRTHomo sapiens 43Met Met Leu Ser Leu Asn Asn Leu Gln Asn Ile Ile Tyr Asn Pro Val1 5 10 15Ile Pro Phe Val Gly Thr Ile Pro Asp Gln Leu Asp Pro Gly Thr Leu 20 25 30Ile Val Ile Arg Gly His Val Pro Ser Asp Ala Asp Arg Phe Gln Val 35 40 45Asp Leu Gln Asn Gly Ser Ser Met Lys Pro Arg Ala Asp Val Ala Phe 50 55 60His Phe Asn Pro Arg Phe Lys Arg Ala Gly Cys Ile Val Cys Asn Thr65 70 75 80Leu Ile Asn Glu Lys Trp Gly Arg Glu Glu Ile Thr Tyr Asp Thr Pro 85 90 95Phe Gln Lys Glu Lys Lys Ser Phe Glu Ile Val Ile Met Val Leu Lys 100 105 110Ala Lys Phe Gln Val Ala Val Asn Gly Lys His Thr Leu Leu Tyr Gly 115 120 125His Arg Ile Gly Pro Glu Lys Ile Asp Thr Leu Gly Ile Tyr Gly Lys 130 135 140Val Asn Ile His Ser Ile Gly Phe Ser Phe Ser Ser Asp Leu Gln Ser145 150 155 160Thr Gln Ala Ser Ser Leu Glu Leu Thr Glu Ile Ser Arg Glu Asn Val 165 170 175Pro Lys Ser Gly Thr Pro Gln Leu Arg Leu Pro Phe Ala Ala Arg Leu 180 185 190Asn Thr Pro Met Gly Pro Gly Arg Thr Val Val Val Lys Gly Glu Val 195 200 205Asn Ala Asn Ala Lys Ser Phe Asn Val Asp Leu Leu Ala Gly Lys Ser 210 215 220Lys Asp Ile Ala Leu His Leu Asn Pro Arg Leu Asn Ile Lys Ala Phe225 230 235 240Val Arg Asn Ser Phe Leu Gln Glu Ser Trp Gly Glu Glu Glu Arg Asn 245 250 255Ile Thr Ser Phe Pro Phe Ser Pro Gly Met Tyr Phe Glu Met Ile Ile 260 265 270Tyr Cys Asp Val Arg Glu Phe Lys Val Ala Val Asn Gly Val His Ser 275 280 285Leu Glu Tyr Lys His Arg Phe Lys Glu Leu Ser Ser Ile Asp Thr Leu 290 295 300Glu Ile Asn Gly Asp Ile His Leu Leu Glu Val Arg Ser Trp305 310 31544128PRTHomo sapiens 44Met Arg Thr Ala Leu Leu Leu Leu Ala Ala Leu Ala Val Ala Thr Gly1 5 10 15Pro Ala Leu Thr Leu Arg Cys His Val Cys Thr Ser Ser Ser Asn Cys 20 25 30Lys His Ser Val Val Cys Pro Ala Ser Ser Arg Phe Cys Lys Thr Thr 35 40 45Asn Thr Val Glu Pro Leu Arg Gly Asn Leu Val Lys Lys Asp Cys Ala 50 55 60Glu Ser Cys Thr Pro Ser Tyr Thr Leu Gln Gly Gln Val Ser Ser Gly65 70 75 80Thr Ser Ser Thr Gln Cys Cys Gln Glu Asp Leu Cys Asn Glu Lys Leu 85 90 95His Asn Ala Ala Pro Thr Arg Thr Ala Leu Ala His Ser Ala Leu Ser 100 105 110Leu Gly Leu Ala Leu Ser Leu Leu Ala Val Ile Leu Ala Pro Ser Leu 115 120 12545299PRTMus sp. 45Met Ala Gln Asn Leu Lys Asp Leu Ala Gly Arg Leu Pro Ala Gly Pro1 5 10 15Arg Gly Met Gly Thr Ala Leu Lys Leu Leu Leu Gly Ala Gly Ala Val 20 25 30Ala Tyr Gly Val Arg Glu Ser Val Phe Thr Val Glu Gly Gly His Arg 35 40 45Ala Ile Phe Phe Asn Arg Ile Gly Gly Val Gln Gln Asp Thr Ile Leu 50 55 60Ala Glu Gly Leu His Phe Arg Ile Pro Trp Phe Gln Tyr Pro Ile Ile65 70 75 80Tyr Asp Ile Arg Ala Arg Pro Arg Lys Ile Ser Ser Pro Thr Gly Ser 85 90 95Lys Asp Leu Gln Met Val Asn Ile Ser Leu Arg Val Leu Ser Arg Pro 100 105 110Asn Ala Gln Glu Leu Pro Ser Met Tyr Gln Arg Leu Gly Leu Asp Tyr 115 120 125Glu Glu Arg Val Leu Pro Ser Ile Val Asn Glu Val Leu Lys Ser Val 130 135 140Val Ala Lys Phe Asn Ala Ser Gln Leu Ile Thr Gln Arg Ala Gln Val145 150 155 160Ser Leu Leu Ile Arg Arg Glu Leu Thr Glu Arg Ala Lys Asp Phe Ser 165 170 175Leu Ile Leu Asp Asp Val Ala Ile Thr Glu Leu Ser Phe Ser Arg Glu 180 185 190Tyr Thr Ala Ala Val Glu Ala Lys Gln Val Ala Gln Gln Glu Ala Gln 195 200 205Arg Ala Gln Phe Leu Val Glu Lys Ala Lys Gln Glu Gln Arg Gln Lys 210 215 220Ile Val Gln Ala Glu Gly Glu Ala Glu Ala Ala Lys Met Leu Gly Glu225 230 235 240Ala Leu Ser Lys Asn Pro Gly Tyr Ile Lys Leu Arg Lys Ile Arg Ala 245 250 255Ala Gln Asn Ile Ser Lys Thr Ile Ala Thr Ser Gln Asn Arg Ile Tyr 260 265 270Leu Thr Ala Asp Asn Leu Val Leu Asn Leu Gln Asp Glu Ser Phe Thr 275 280 285Arg Gly Ser Asp Ser Leu Ile Lys Gly Lys Lys 290 2954680PRTHomo sapiens 46Met Asp Cys Val Ile Thr Gly Arg Pro Cys Cys Ile Gly Thr Lys Gly1 5 10 15Arg Cys Glu Ile Thr Ser Arg Glu Tyr Cys Asp Phe Met Arg Gly Tyr 20 25 30Phe His Glu Glu Ala Thr Leu Cys Ser Gln Val His Cys Met Asp Asp 35 40 45Val Cys Gly Leu Leu Pro Phe Leu Asn Pro Glu Val Pro Asp Gln Phe 50 55 60Tyr Arg Leu Trp Leu Ser Leu Phe Leu His Ala Gly Ile Leu His Cys65 70 75 80471497DNAHomo sapiens 47tttttttttt tttttttttt cacgttacaa tctcactata ttcggaatct aaagtagtca 60tccttagaga agtacagagg agaatggtgg gtacagaggc cagggcgggg agtgtggacc 120gattggatgg ggaaagggag agtttggtca tcaggcatgc

attttcagtt agacaagagg 180aataagttct gatgtcttgt tgcacagcat tgagggctgc taattctact ggaatcagcc 240tcagactcct ttgctggagg ggtcgtgaac cctcaaacaa gcccgagcct ctgcattttc 300ttacttgggg atcttgatct ctgagtactc attgttggtg gcttcttgac ctggataggt 360cctgaggctc ccccttatga aagctgaggg gtgcatactg ggatctctct ttcctcccct 420gagggagtgg gcagccaggc catggtgtcg ggggttatca tctgcccagg actcatccag 480ttaccctgag aggctgagcc cctgaatggt gtttgcatcc ttcatgccta tgtctcccac 540gtccgctgct ggtcttgccg atttcttcct gcaggacctc actacaatga agatgacaca 600gaaggagagg aagaccaggg ctgtggctcc agttcccccg accgccccca gcaacactcc 660tgatacaggc ttcattttgc ctgtgtactc ctgttgcagg gagaggttca gggaaacgtg 720ctgggaaccc agagagttct gagctcgaca ggtgaattcc ccttcatccc ccaggtgcac 780ttgcagctcc agtaccagag ggtttgaggg ctgtgagggg tacagggtca gactcctcca 840ggtccagctc agcctggcag ggggattgct gtcaacagca cagaccaagc gcagagactg 900gccctctagg actgaaagag atgagctgtt ccccagagct gtggatgctg tgccttctcc 960ttggaagaca gtcacagtca agttctgagg agggtatgtc acgttcacag agagctggtc 1020atatttataa ttccatttta tatttccttt ctccatacga aagaagtatc tccccgcatc 1080actcattctg gcatctctga tgctcagggt gcaatttttg gtctgtgggt ccccaaggag 1140gtggaatcgg tcccgagttt cctcctgcac tgcccaagct gggttgtttg tggccactgg 1200agccttccag cttatatcat tccctgcccg gaaccagtag ccatgaactg ggtcagagtc 1260agtctggctg tccactgggt aggagaagga gcagcgcaca tggacacaca tgccctcttg 1320cacggtcacg gaactctgca tcgtcagcga gtaatccttc cggttactct tctgtccttc 1380caccctctcc ctcccccaga gcaggggcag cagcagcagc agcagcatat ctggggttgg 1440aggtgccagg gccgcgaggg aacgtctgtt cctcagggtt cttctctcag gaactgc 1497481849DNAHomo sapiens 48ttttttttta caatcaaaat gcacatttat taaactgtac tgtgtgaggg aatgtctgac 60caaagagcat tcccacaggc actcggggca ctggctggaa agcgctctca ggtgttcttc 120tcagaaccgg agaagctgca catcacttgt atttgtaaaa tccttctcca gtcttcttgc 180cgaacttgtt ctctgctacc agcttattta aggatgggct gggctgatgt aatgggttct 240ctgcatccat ttcatgccac ccatccacga tgaacttcgt agtatccagt ccgacataat 300ctagaagctc aaatgggccc atggggtaac cggctcctaa tttcatagca gtgtcaatgt 360cttctttgga tgcgtcacct tttaatcaaa agcagagatc caggatatca atctgggccg 420gccatgcaat tgctctggct gggactgtag tgggggtggt gggagttcca gaaacctttc 480tcagaagccc acagggaaag ccaggaggcc ctcgttcata cagcctgatt gcttccatga 540ggtatggaac caggaggcgg ttcacaataa acccaggagt gtccttgcaa gaaacaggat 600gctttcctag ggttttgcta aagtctacca aagattcaaa tgtcttctgg ctggtcattg 660gtgttttaat gacctccaca agtttcatga caggcactgg gttgaagaaa tggaggccag 720cgaatcggtc ttgtctggtg gtggcattag ctatgcttgt aatctgcaag gaggaagtgt 780tgctggcaaa gattgtatgt cttggtgatg tggcaggtgg ggctgcatgg agattcaggg 840acagctcctc tcaggcagac cctcaggaac cttaaaagga tgcaggaagc ccagcgtggt 900ggctcacgct ggtaaaccca gcactttggg aggcctaggc ggggggatcg ctttaggcca 960gcagttcaag accagcctgc gcaacatagc gagaccccca cctctgtatc actgcagctc 1020ccagagagct cccactcagg gtgaagctct gagtcttggt gatttttagg agtttatgga 1080aacagccctt ctggtggatg acgtttggag acacatcgcg tccgtcacag gacacacttc 1140cgatggattt acagcaactc ctggggtagg tgtggcccgt tgtcatttcg aaggaagagc 1200cagaaaaatc tgtgtagtta ttcaccccac agcactttag cttctccatg accaagttcc 1260actgtgtaga atagtcgtct ggctcgttgt aacctctgta attcttcctc agggtcacga 1320aggtgtgttc caaggccaca tctccaacaa ttggaaagaa aagaaggacc actgtggcag 1380ctgtaacttc catgatgagg acaataacca ttgacaggat gcaaaacaag agcgtgcctc 1440tgctctcttt agtcgctcca taccacccgg cacagccaag cagtaccgtg atgcatccca 1500tcaccaggca caggttgcca acgtgaagga ggtatgcgga ggacagcccg aggacattcg 1560tcagagaggc ccctccacat ttaccaccaa tgcccaggcc aactaggatg atgccagaca 1620cagccacgaa gccattgagt aaagataaca gtttcttcaa ggaagaatac ggagtgtgga 1680tttcagccat gctgaacaga ctggggcacc ccgaacattt aagttaacat cttcctgaac 1740ctctgggcta ctgtttccca agatgatagg gatctgagga aggggcgcca atgctgactt 1800gctctgcccc tctgtgtcct ggctccctga tggttgtcca ctcgtgccg 184949741DNAHomo sapiens 49gctttaggcc agcagttcaa gaccagcctg cgcaacatag cgagaccccc acctctgtat 60cactgcagct cccagagagc tcccactcag ggtgaagctc tgagtcttgg tgatttttag 120gagtttatgg aaacagccct tctggtggat gacgtttgga gacacatcgc gtccgtcaca 180ggacacactt ccgatggatt tacagcaact cctggggtag gtgtggcccg ttgtcatttc 240gaaggaagag ccagaaaaat ctgtgtagtt attcacccca cagcacttta gcttctccat 300gaccaagttc cactgtgtag aatagtcgtc tggctcgttg taacctctgt aattcttcct 360cagggtcacg aaggtgtgtt ccaaggccac atctccaaca attggaaaga aaagaaggac 420cactgtggca gctgtaactt ccatgatgag gacaataacc attgacagga tgcaaaacaa 480gagcgtgcct ctgctctctt tagtcgctcc ataccacccg gcacagccaa gcagtaccgt 540gatgcatccc atcaccaggc acaggttgcc aacgtgaagg aggtatgcgg aggacagccc 600gaggacattc gtcagagagg cccctccaca tttaccacca atgcccaggc caactaggat 660gatgccagac acagccacga agccattgag taaagataac agtttcttca aggaagaata 720cggagtgtgg atttcagcca t 741501288DNAHomo sapiens 50tttttttttt ttttttttta acattgtaac aggtttatgc attttgaagt gccttctaca 60catccaccca gaggctctgc tgatttcact tatgcccagg ctataaaatg cctttctctc 120atcccccagt agagcactgg gatcaccact aggcctaggg ggcatatcaa gggtttaata 180gactggggga atgggcaaca gaactggcta ccttagaggc tctggaatgc cccccaccca 240tccacccacc aatggaagga aagtcaggca tcgcctaaaa ggagtggtcc ctatctagcc 300ccaagtctgg agcagaaagg gcaggtccat tctggcccaa gtgacattgt tagatcctgt 360cccctccccc aatcactgct gcttgccagg gtgcctcttc acagttccca tgtggcagca 420gtagtggcag aggcagaagt ggacttattg tagattgcag tacagataca tggacacaat 480tcatggcagc cagctcgagg cccccaattc cagctgccac accacccacg gtgactgcat 540tagttcggat gtcatacaaa agctgattga agcaaccctc tactttttgg tcgtgagcct 600tttgcttggt gcaggtttca ttggctgtgt tggtgacgtt gtcattgcaa cagaatgggg 660gaaaggcact gttctctttg aagtagggtg agtcctcaaa atccgtatag ttggtgaagc 720cacagcactt gagccctttc atggtggtgt tccacacttg agtgaagtct tcctgggaac 780cataatcttt cttgatggca ggcactacca gcaacgtcag gaagtgctca gccattgtgg 840tgtacaccaa ggcgaccaca gcagctgcaa cctcagcaat gaagatgagg aggaggatga 900agaagaacgt cacgagggca cacttgctct cagtcttagc accatagcag cccaggaaac 960caagagcaaa gaccacaacg ccggctgcga tgaggaagta gcccacgttg acaaactgca 1020tggcactgga cgacagtggc ccgaagatct tcagaaagga tgccccatcg attgacaccc 1080agatgcccac tgccaacagg gctgcaccac acagaaagat gagcaaattg aagaggatca 1140tcatggtctt aatgaagctg aagcactgca tggtggctcc tgttcagggc tcttggcagt 1200gagttctgaa agagggaact gctgaggctc cacaaaggac aaaacagctc ccgggtgttg 1260ccactgagtg ggcaggcaga gggacgcc 1288511236DNAHomo sapiens 51tttttttttt ttttttttga atgctcagta tctatttatt aaatgaatgc acaattgaaa 60gagtgaagat tgaatgtcta gatatttgtt cctctaaccc acaagctcac atgcagcaga 120gcacacgaat gggtgtgcca aggccccaga ggctggatgc ccacatatgt gctgatgcat 180gtgccctagg gagtccctct tggttaacat ctgtttaaaa tctctgtctt cttcttgata 240gagaaacagc atggtttcct agactgaatt gaagaatgaa ggtgagagta caaacagtgg 300gagagacgtt tcctcagctg tcagaacagg aacgacctgg gttatggaag cccagaaagg 360gaggaggact tcttttggtc ccagtgaaag atgcttccag aatctgtagc cttacttatt 420tgcttggatc tcactggaat aacttggtgg tgaggtcacc ggttctgggg tgatcactgg 480gtttgctgca tagatgtttg gatagatgac actcacattg cttgattgac agcagaccaa 540ctggcagcca aagtgggaag atgcgcatgc gatgccaaac tccaggaggc agaagaccag 600cagcacgcca gaaatcgcca ttccagggtt cacaccccag gcgtaaggat aatagtcggg 660gtaggcatat gggtggggaa tacttagatc tgtgatgaag agtatgactc caactgcaga 720gcagattgca ctgacgatgt tcaagcccaa actgccagac agcaggcaat aagaatatgg 780ctgattttct gctgccacgg agagagatcc tgaaatgata aaccacaagc ctccccagaa 840gggaaagcct ccgtagaatg aaatagacag gtattcccct acgagaaccg tcgccatgat 900ggagccgagg ccgatgtgag ccaggccaat gatgatctgg atggccccca aggttttgcc 960ttctttcaga gctttctgca caggctgccc attcacattc gacaccaaac taggtgggtt 1020cccaggaact aggtggactt gcggctggct gtttggatac aggggcacgt gagacataat 1080tcctggggtc acaggataac cattgtgggg tgccaccacc aacacagaat tggccaccgg 1140aactgctgaa gtcatcgaat tcatgcttgc tctgccagca gccacgtatc tcttgatcct 1200attccttttc tttgctgtgg ggaccttgtt tttttt 1236521115DNAHomo sapiens 52tttttttttt tttttttttt tacttcattt acaatttact agctcttcca gtgtttcaga 60gggatacagg gtttcaacga tctaacatga atgggataga aggtggactt agaacatagc 120aaacatacat cttgattgaa tcagcccact gcgagcacgg atcttgattg aatcagccta 180ttggtgtagt tttaggtcta catacatctt gattgaatca acctactggt gtagtttttt 240ggtctatcag taagtagtgt tgtcagttct ccagccaagc aactttctaa ttcacagggg 300ggaccctaaa tgtccttaaa ggtagagagg aataggccca cagatacatt gggttacact 360atctcatact ggttatttgt tatggcacga gagaggcagt aggcgagaaa gattccaatc 420agttggaagc aagcaactcc aaaggaaatt cctgcaacga ctcccatttc tgactctata 480atggtcatca cctttataaa acaaccttca ttgtttactt tgtctgcatc tctctgtgga 540gtacaatctt caagtttaca gcaactctta ggaaatcctt tttctgagta ataattagta 600tctgtccaat ctctataatc ggtgacacca caacaatgca acgtattttg gatcttgtct 660actgcatggc ttctataatc tcctgtagag ttatactgct tcaaagcctt ctcataatta 720ttcttaaagc tgttcttaat ctcatgtctg aaaacaaatc ctacgatggc agcgaccagt 780tcgaccaaaa aaacgagagt cagaaacatt gcatacagtt ttagcatcca tgcagaagct 840cggcaggtag caaaacaacc aaaggtgccc aaaagaataa tgacggtacc agtagcaatg 900agcacgaagg ggacattggt ggccttctca tttaaaagag aaaagtaatt ctccaggctc 960accttgcccc aaatgccaac tgcaagaagg ataacgccag tgatccagaa aataaaagtg 1020tagattagca gaacgctctt gaaacaagta atgactggtt tagtctgcag tctccgagac 1080ggggacgcca tgactagccc gagaccctgc tcgtg 1115531662DNAHomo sapiens 53tttttttttt tttttttttg ttgggggctg atacagagtt tattgaatta gatttttcta 60tttacaactg agatcacatc tacatactat tttgctagtc tacatgggta cattatttcc 120aacaagctta agacttacca tgaatgggct cattcataca aaaacacact cacactaatt 180cttttaaaac agtagtgcat acattatact cctcctataa agccaacttt gattaaaaac 240cactagtttc aaagctcagt ctctgatttt gaagatgaac caagatatac gccatatgat 300cctacaatct attttagtca ttttgtacag ctgctatctt attggactac agtaaatatt 360ttttaaaagg acaccaatga ggggcaccat ctggtgttaa ccttaaccag aaagctggtt 420tcctcctcct ccccccaaaa acctttggcc aagagttctc cactgtgaag actgaaagga 480cctggtgaca tttcggcatc agtcctgtta ccacttggag gtaacagaag caggctcgtg 540tcctccttta attctaccac actacatgac tcgcaattgg ttctgaaatt agaacgttca 600ccatcgtact taaaatctta ggggcatgaa gagtcagcta gaacaaggaa aaagaaagtc 660gcaggtagta ggtaagtagg tgggcacatg aaaagccaag ctgctctgtc caacaccagt 720gtacatgtgc tttaactaaa tgaactccag aggccaacag cagcagacct gctcaattca 780ccttccaaat cagaacaaga ccaaaaagct caggcttgag attgtcaact atgcataggt 840tccgccagtg atgaagagct cgtaagcagg atctctactc cttctgcaca acacgatgca 900agcacacagc atgcccagca gctgaatagc tgcaaatgcc agtgcggccc agatcacatg 960catcatgatt tcttgtagct tcttcacaac tagagcctca cacccctcag catagaggtc 1020ggaagggtgg gccaggctgc cattacaatt gctggcagtc tctctgcagc agctaagagg 1080gacactctgg tttttggttt ctttgaacca atctgtattt tcccagtctg agtagttgtg 1140aattccacaa caatgcagct gtctctgtac ataatcaata gcccggctag cagcatcagg 1200gttggttcca ttgtaggtct tatacacttt ctgaatgctg cgatcaacct cattttccac 1260ctttgctctg taaacatatc ccaaaaccac tacaacaact tctgtgacaa aaaccaagag 1320caggatgatg acaaacgtgg caagtccaca gcgactttcc cggattgtgg cacagcagcc 1380aattagccca atgatgaaaa gcagggctcc tacagctatg atcactacag cagggatgag 1440cgtgtacaca tcttcaaaga agtggtcata gtcatcataa gtgatgaaga cataggctcc 1500cacatagcat aaaatgccag ctgcccccca gaagatgagg ttgagaaaga ccagcacggt 1560cttggaggag gtgatgccgc actggcccat ggcgccggtg gcccgcgaag gcccggcccg 1620gagagcgggg ctgcgctcac cgagagagcg gcaatgctcg tg 1662541345DNAHomo sapiens 54tttttttttt tttttttttt tgctgctcac actttattaa gatgcaccag gagccccacg 60ggcccactat ggaatgtagg tgaggggtcc acggccccgc ctggagcacc aggaccagtg 120gggccacctc caggatgcca agacccggct cctccagcgc caacctgttt tccaggaagc 180tgggggccac aggctggctc ccgtgtgaac actgctttgg agaatacgta aatataaaaa 240gtgctggagg cccctcccac ccctgccctg ggttccgcag ccagcacgtg gccacccctc 300ccaggggggg tccggaggcc ctgaagccac ctgagctagg gccttccaga aacagggttc 360cgggggctcc aggcacctgt ccctccctcc ctcctcccag catggggcag aacaccgaag 420ctggtggtgg gaaaagcagc tgtgggtgcg gccatctccc cgtgggcgtc cttttggcag 480agaagccggc ggtgggcggc ctacgcgcag taggtgtctg ccttgaccac ttggcagtac 540atggtcatgg cgaaggtcag gcccaggatc tgcaccagcg ccgtgcacag cccaaagatg 600cccacagcca gcaggttctc ctgaagccac accttcaccg tctcgtagca cggcgccttc 660caccaggtgc cgggggcgtg cagcccacag ctctcactga actccaagca gcaggagtca 720ggtacccgcg tggcgttgta cacctcgaac cagtcagtgt agttggagac gccacagcag 780cggaagtcgg tctggatgat gctccaggcg ttggtgaggc ccacgttgcc ctgcgtgccg 840tacaggtgca agcctttctt caggtcttgc tgggcatacc tgtcaatctt gtccgtgtag 900gcgaagaaga ggatggcgat ggtggcctcc agcaggaaca ccagcagcag cagcaggaag 960aaagtgagca ggaggcactt gttctccttg atggcaccca ggcagcccac gaagccgatg 1020gccatgacaa aggcgccggt gatgatgagc aggttggcag ccgacaggga cgggaaggaa 1080gaagacagcg tggcgaagct cccctgtgtg gcggccagcc agatgccgac acccagcacg 1140ccacagcctc ccagccagaa gaacaggttg aaggcgaaca tgaggtactt gacggcctgg 1200aggcaggcgc gcgccatgcc gcagcgcttc agttctgggc tggccacagg aaagagacca 1260ggcggtgctc agggtccctg aaggctgacc agtgggcagg caggtggtgg gtgcgaccaa 1320ggaagcccca agctctgcgc tcgtg 134555734DNAHomo sapiens 55gaacatttgg tatgaaagct ttagattgca attttcatgt agaagtagct tcatatcaca 60tctcgtgagt ttcgtatcgc acagcagagg accatgctga atatcatgcc aaagatcgtc 120agacctgcaa ttccaatacc gacaattcca atgagctgga gcttaacact gattatggtc 180tcaatttcat cgatgcaatt cttgtgtcct agaagctcct ttgggcatgt aggttggacc 240tgttcggagc tttcttttcc acagcactga aatgttgagt ggaaggtgat gagtgtccca 300ttgccttttc ccctgtcttt aaggtaatca ttgtaagcct cttcatacat ggtctgaaca 360tgtcggatag ctaccccctt gcctataaaa gcaaatactc cagtggttac ttcagcagca 420aatatcacca ggaggcaggt aaaaaatgat ccaagcacac attgcgactc ccgcatggct 480ccgcagcatc cgaagaaccc cacggccatc atcagggccc cggctccaac cagaacatac 540agccccacat agaaatactc tggggacttg tcctctgatg ataactcctt tatggcacct 600ccgaaccgaa accatagtcc aaaagcaatg acggccgatc cagccagcca gaagagcagg 660ttgaagccaa gcagcaggta cttgatgcac cgcaggcccc cgcggaagcg ccccatgctg 720cggcccggcg gcgc 73456577DNAHomo sapiens 56tttttttttt tttttttttt taaacattga aaattttatt ttcacagggg atttgcataa 60aaagaacatt atttttgttc tgtgtatata taagtatttt tgtttcctta acttgtttct 120gttgcccaca cacaactagg agaagatgct tttctttatt ttggtttggc caaagatgct 180aatggttaaa ttatgaagga ctttgtttta cttatgttaa gtggtgaaaa ctgtagttct 240taatctatga agaattctct aggtggctat acaagaaaaa tacaaaaagt taggaaaaca 300tgtaaacgta agtatgaggt atttcataga tacagtgccc atacaaattc tctttcccac 360aattttcaac tgccagatct cttgctttag tcttttttcc ttatatttgg agaaacagaa 420gagtttgaca taaaagtccc tttgagggat gtgagggttg cagtagttta cagcagggtc 480agaaaatgaa agtaataaag catatttaca tgttttgtat aggaccaaaa tatttcccct 540aaaaaggtgt taaaagtttt ttagtcccat aaacact 57757936DNAHomo sapiens 57ccttgcagat ggcatgtgcc acatgttgtc ttgaggggca gttggaagag gaggtggttg 60ccattagtaa aaatgccgct ggagcctctg gtgcaagcag caggtgagaa ccatcccgca 120gatctgcagg caggccaccc cgatgcccac tgcccccata agcagcaggt ggtcggccag 180gaactgctcc agcttggtga ggcagcctcc ctccacctta tagatgttgg aggggtgggc 240ccgctggccg cagcgcgcca ccactgtctt gcagcagctg tcgggcacct ggcggccctc 300ggcctcccgc aacaggatgt acgtgctgtg ctgccagtcg gctgagctgt tgcttccgca 360gcacttgaaa tcctgctgga gtcggtccac tgaggcgtga tctgcgtgct ccggctgccc 420gtagttctca gccagagtcc ggttcaagtg ctgcttcagt tcatcactca gcctctggta 480atacacatgg gccaggactc ccgccaccag ctcaaccagg aagatgacga gcaacaggca 540gaaatacgtg gagaggcagc ccttccgctc ccagaggatg gcaccgaagc ccaggaagcc 600ggtcaccatg acaagtacgc ccgcaaagat gaggatgtag gcggaggcgg caaaggtgct 660ggaggccagg acgctgaggt agccactctt ctccaccagg gtccagatgc ccacagccag 720gacggctgct cccccgaccc agaagaagaa gttgaagaca aagagtaaat acttcaagta 780gatgatcagc cagtcgtcct gctcagtctt atagtgggcc atggcttctg ggccctgcca 840ggggctccgg aagcggcgaa gggactgcgc ctagagagac tgagagcgcg gctcccgggg 900ccgcccagcc gcccaccgcc cgcagctcgt gccgaa 93658738DNAHomo sapiens 58gttttttttt tttttttttg agagcgcaaa gcagtttatt ctagcgagca agggagtgag 60cgtccaggaa ggagcaggtg taacccggcg gtcagtggag cctcagtgag gtgtgtcctg 120ttttttcctg caatcgccgc agaagacacc aatggtcgcg ttcaccagct ggatcccaca 180cagtactatc tccaggcagg aggcggccac cagcagcgag aagagcgtca cattccaggg 240gaccacgcga gggggcgcct cgcaccgatc ccatagagtg cggttgagca agtaagctcc 300cgcggtgtct tcgaagtggt agccccactc gccgttcatt aagcatctgg gtccatttcg 360gagcccagct ccagacaccg agaggcagta gatggcacca agcaccccga acgccgagga 420gaagaccgag cgcagcatcc tgcagcggtt tccacagcac ccagcaccac agcagccctt 480gccccctgcc cgaacggctg caatccctgg acacagtacc attaggcccc cgccaatgaa 540gccgcccatg agccagactt gcaagctgag atggttggtg ttggtccagg aggtctcccc 600attaggtacc agcaggaggg cgttggccac aatgcagacg aggcagaggg taatgaggga 660gagccccaca cagcgggcac attttcccgt acacatggtg aggtgtcagg aaggacaggc 720ggtgagtgaa agtaagct 738591071DNAHomo sapiens 59tttgagttag aattttgggg tgtttccaat tttccagaat attaaataat gttgcaatat 60acatattgca taaaggtttc tctcatattc ttatttactt ccctagtaca gattcttgga 120aatggatttg tttgatcaaa gggcagaagt atttctgaag tttctgatgc atattactta 180aaaaacatac taaatggaag ggtggtatac ttgcatgtgc agtgaggact gcaaattttt 240tacaaataaa caccaaatgc agaaagcacc atcattttca atattgccct caagtctaac 300acagttgata taatatttag atagatggcc atgtcttgat aatggaaaac attttgtcct 360tattcaaatg attccaggct ggaagatcac tgaatagctt ccacacagta tcttggatag 420ttgcatgact actctgatga ggcagatgat cacttgaagc ccactgaggg ttatgagaat 480ggaaaataaa atgatgttcc actccacaac atgtgcaggt tccaggcact gaatccatat 540gctagaatct gtaaggaaac gtccagcagt gccttcaaaa gcatactccc agccatcaag 600ggtgcggcaa tatggccctt ggacaagacc caaggcagag atgaccaggc agtatccaga 660aaaagcaatt ccgagggaag aaaagataat tgacagcagt gtcacatatt ttttgctgca 720gttttcactc tggcaacatt tatagttgtt attattctcc agtaccagaa gaactgttgt 780tactataagc atcatgatgc ctgagaaaca gattccttca aaataccaca cgtagttggt 840gagtttattg ctggatgcat aggaagtttg cccattcggg aaatacaata atatgttcac 900gattatactc caaagtgcaa gcggaatcag caaacaactt

aggcagcctc cacacttccg 960agaccccatt ttgccctgct tagaaccact tccagggtca gagcccttca cttcatattc 1020atgaggagac ggggaattgg aatatacccg cagccgacaa tctctcgtgc c 107160865DNAHomo sapiens 60tttttttttt tttttttttt tttttttttt tttttaaata aataacctta tttatttatt 60tgaccacaaa taaataaata ataaagaata aatgaccaca ttctttaagc cattgtattt 120tggagtatct ttgttagtct acaacacttg cctctgtgag tgcagtccag gccctgaagg 180cagatggagc catatcccag gctcctggtg gaggaaggtg cagagttcga ggaacctttg 240cactcttgtg ccttccctca ggcccaaagc tcctgtagac tcagtctcgt gaccccagag 300gtgaaccagg ccctgatgtg ctggtgttca ggtggatggt ttaatgaggg gaggagagtg 360gggccctggg gagtggctga ctcttgtttt ctgcggtatt tcctggaacc atccttcagg 420agtggacaca gtagagctgg acacttccac tgatccggag ctcccgcagc tgctccaggg 480cctgctggtt catgctggtg gcccccagcc cctgcccatt gagcgccagc ttcagccctc 540cctcctggaa caggagcagc acctcaaaga atctctgggg gtaaaagagg aagggggctg 600agatcagttt cttctgcccc cagcgggaga tccaggccag agttctgtct gcgaaggagg 660ccctgagtgt cacaggagca tgggcagcct ggtccctcag gctcacagta aaatgcttcg 720gctcttgcaa gaccagtccc cgtactatga tgacctgccc aggcgagaga ccctggggaa 780gagcatgtga gcagggcacc tccagcctgg ggctcatcag caggaaagga tgtccagctg 840ggtactctct gctgccctcc acaaa 86561441DNAHomo sapiens 61tttttttttt tttttttttt tactggttta aatcatttat ctccatgtag agatttgagt 60acaaaaataa acggcaacaa aacagaagga gtgtgaaatc cggggatcca cagggcttct 120gtcctccacc ttccatgcag ctgggggctg catcctctgt ggggtggctt catcctctgt 180ggggtctgtg gggcctgctc caagtcatca gcattccatg cccacctgga cctggtccca 240gactttcggg gaagccctca gaggctccac tgtgttcgtg gtcttgcaga agcgagagct 300ggccgggcag accacagaat gcttgcagtt gctggagctg gtgcacacgt ggcagcgcag 360ggtaagggct ggccctgtag ccacagccag ggctgcaagg agcagcaatg ctgtcctcat 420ctctgatgtc gtctctcgtg c 441621066DNAHomo sapiens 62tcaaaaactg gagaagcaga tccacttctt gtgggggtgg agttcttggt gactaggctc 60atttcttacc cttgatgagg ctgtcacttc ccctggtgaa actttcatcc tgtaggttca 120gcacaaggtt gtcagctgtg agatagatac gattctgtga tgtggcgatc gtcttggaga 180tattctgggc tgctcgaatc ttgcgaagtt tgatgtagcc agggttcttg ctcagtgctt 240ctccaagcat cttggcagcc tcggcctcac cctcggcctg cacaattttc tgccgctgtt 300cctgctttgc tttttctacc aagaattggg cccgctgggc ctcctgctgg gccacttgtt 360tggcttctac agcagctgtg tactctcggc taaagctcag ctctgtgatg gccacatcat 420ccaggatgag gctgaagtcc ttggccctct ctgtcagctc ccggcggatc aacagggata 480cctgggcccg ctgggtgatc agctgtgagg cattgaactt ggccaccaca ctcttgagca 540cctcgttgac aatggacggc aacactcgtt cctcgtagtc cagccctagg cgctggtaca 600tgctaggaag ctcctgagca ttgggtcgag acaacactcg cagggagata ttcaccatct 660gtaggtcttt ggagcctgta ggggaggaga tttttcgagg tctggcccga atgtcataga 720taatggggta ctggaaccaa gggatcctga agtgaaggcc ctcggccagg atagtgtcct 780gctgcactcc accgatccga ttgaagaaga tggctctgtg cccgccttcc acggtgaaca 840cagattcgcg cacaccgtag gccacggcgc cggcccccag caacagcttc agggccgtgc 900ccatgccccg gggcccggcg ggcagccgtc ccgccaagtc cttcaagttc tgggccatgt 960ctgatcttga ggccggcggc actggaggtc agaagggggt gccggcccgc ctctaccccg 1020ctccggctta ggtactgcac ccttcacacg agggttcggg cccgct 106663704DNAHomo sapiens 63gcgatagggt gccagccgga ccaccttcct ccaggtcccc ttcagggatg tcatttgaaa 60agacccacaa gacaccgagg gcagtgcacc cacactgggg gagggacaca ccaggcagcg 120gccttcatcc agacacttca ggagcagtag tcttcggcag gttggaccga ccataccctg 180gcccaggaac ctttccccag gggtccgcct gggtgtccat cacaggggtc gggttcgggg 240gcattgagga cctcttaccc aacatgtagg aaaagagaca gccagacctg taaaactgat 300ctgggacctc agggttgagg aaggcagcag cccaacacac cttgtccaaa acagtgcacc 360tgggaatggg catatggtgc tcagcgcccc agaagcagcc tgagtctgag gctccgacat 420gggagggagt gcgtgagccc cggccccagc aggctgccat gcccagcgtc ctctcctcca 480ctactccagg cctgcctcgc ctcacctggg agcagagtgt tgcttcctca tggaaatagc 540cgtgcatgaa ctcacagtat tcccgggtgg tgatctcaca gctgcccttg gtgccgatgc 600agcaggggcg gcccttgatc tcgcagtcca tgtgcaggaa gcctgtgtgg ttgctcctgg 660cctgctctgt gcagatcggc cacttagtga tgtcatctcg tgcc 704

Claims

1. An isolated polynucleotide comprising a nucleotide sequence that has at least 80% identity over its entire length to a nucleotide sequence selected from the group consisting of: (a) a nucleotide sequence encoding the polypeptide of SEQ ID NO:Y; (b) a nucleotide sequence having at least 80% identity to a nucleotide sequence encoding the polypeptide expressed by the cDNA insert deposited at the ATCC; or (c) a nucleotide sequence complementary to said isolated polynucleotide.

2. The polynucleotide of claim 1, wherein said polynucleotide is (a).

3. The polynucleotide of claim 1, wherein said polynucleotide is (b).

4. The polynucleotide of claim 1, wherein said polynucleotide is (c).

5. A method of diagnosing a disease or a susceptibility to a disease in a subject that is related to the presence of mutations in, or the production of, a nucleotide sequence, comprising collecting a sample from a subject and: (a) determining the presence or absence of a mutation in a nucleotide sequence encoding the polypeptide of SEQ ID NO:Y in the genome of said subject; and/or (b) analyzing for the presence or amount of the nucleotide in said sample derived from said subject.

6. The method of claim 5, wherein the polynucleotide is a fragment of the nucleotide sequence encoding the polypeptide of SEQ ID NO:Y.

7. The method of claim 6, wherein the polynucleotide fragment comprises at least 30 consecutive nucleotides of the nucleotide sequence encoding the polypeptide of SEQ ID NO:Y

8. The method of claim 6, wherein the polynucleotide fragment comprises at least 50 consecutive nucleotides of the nucleotide sequence encoding the polypeptide of SEQ ID NO:Y.

9. An isolated polypeptide comprising an amino acid sequence that has at least 80% identity over its entire length to an amino acid sequence encoding the polypeptide of SEQ ID NO:Y.

10. The polypeptide of claim 9, wherein the polypeptide comprises at least 30 consecutive amino acids of SEQ ID NO:Y.

11. The polypeptide of claim 9, wherein the polypeptide comprises at least 50 consecutive amino acids of SEQ ID NO:Y.