KR20200104106A - Recurrence-specific markers for determining treatment strategies and diagnosing prognosis of patient of clear cell renal cell carcinoma - Google Patents

Abstract

The present invention relates to a marker for diagnosing recurrence or prognosis of renal cancer patients. Since the mutation of a gene of the present invention and the recurrence of renal cancer are correlated, and the mutation of a gene of the present invention and the total survival rate or the disease-free survival rate of recurrent renal cancer patients are respectively correlated, a mutated gene of the present invention can be used as a marker for diagnosing recurrence of renal cancer, predicting a difference in the therapeutic effect of renal cancer, or prognosis of renal cancer patients based on recurrence.

Description

Recurrence-specific markers for determining treatment strategies and diagnosing prognosis of patient of clear cell renal cell carcinoma

The present invention relates to a recurrence-specific marker for determining a treatment strategy and diagnosing prognosis for patients with kidney cancer.

The kidney is an important urinary system that has the role of excreting waste products from the body by filtering blood to produce urine. It is also an important endocrine organ that produces hormones such as angiotensin that regulates blood pressure and erythropoietin, which is a hematopoietic factor of red blood cells.

Tumors occurring in the kidney include renal cell carcinoma (RCC) in adults, Wilms' tumor in children, and sarcomas as rare tumors. Kidney cancer refers to renal cell carcinoma that occurs mostly in the parenchyma of the kidney (the part where the cells that make urine in the kidney are gathered and consists of the medulla and cortex). Genetic factors are also known as risk factors for kidney cancer, but in general, smoking and excessive fat intake are included. In addition, it is known that the incidence of tumors is high in patients undergoing long-term dialysis.

Renal cell carcinoma is clear cell type renal cell carcinoma (clear cell RCC), papillary type renal cell carcinoma (papillary RCC), chromophobe RCC, medullary type renal cell carcinoma (medullary RCC), and unclassifiable renal cell carcinoma. (unclassified RCC), etc., of which clear cell type renal cell carcinoma accounts for 66-75% of all renal cell carcinomas, papillary type renal cell carcinoma accounts for about 15%, and anaerobic renal cell carcinoma is about 5 Accounts for %.

Kidney cancer has almost no symptoms when the tumor is small, and symptoms appear only when the tumor grows to some extent and pushes the organs out. Therefore, since diagnosis is often delayed, about 30% of patients appear to have already metastasized when first diagnosed. The most common symptom is hematuria, but it also appears in only 60% of patients. Rather, depending on the metastasized site, symptoms such as shortness of breath, cough, and headache appear, and renal cancer is diagnosed due to these metastases, reaching 30% of all patients. Because kidney cancer can cause high blood pressure, hypercalcemia, and liver dysfunction due to certain hormones produced by cancer cells, tumors may be found during testing for these other symptoms. Recently, while undergoing a medical examination without any symptoms, there are many cases where it is accidentally detected on an imaging examination, and in this case, since it is mainly detected early, the treatment result is relatively good.

Renal cancer has a high survival rate due to tumor removal after onset, but it is difficult to diagnose at an early stage because there are no clear symptoms. For this reason, there is a need for early diagnosis of kidney cancer and the development of markers that can check the remaining lifespan after the onset of cancer.

Patent Document 1 discloses transglutaminase 2 as a marker used for detection or diagnosis of human kidney cancer. Markers for diagnosing cancer, including renal cancer, have been developed, but the relationship between the recurrence or survival rate of recurrent renal cancer patients and specific gene mutations has not been studied.

The present inventors need to develop a marker capable of diagnosing recurrence of renal cancer, or a marker capable of diagnosing the prognosis of recurrent renal cancer patients in order to determine a treatment strategy by discovering a therapeutic agent for recurrent kidney cancer patients. With the focus of this study, the relationship between the genetic mutation found in renal cancer patients and the recurrence of renal cancer, or the relationship between the genetic mutation found in recurrent renal cancer patients and the survival period was studied.

Korean Patent Publication No. 1267580

In order to apply a therapeutic strategy suitable for renal cancer patients, it is necessary to develop a marker that can provide information for predicting the prognosis of renal cancer patients and determining treatment strategies. An object of the present invention is to provide a marker that helps in determining a treatment strategy and prognosing a recurrent renal cancer patient based on the recurrence of the renal cancer patient.

In order to solve the above problem, one aspect of the present invention is ALAS2, ARHGEF5, BAZ2B, C20orf26, CLCN2, FAM59A, KIAA1614, MCPH1, NLRP2, NOS1AP, PRSS38, RGPD5, USP29, XPO1, ZFAND2B, ZNF33A, ANKRD50, CNGB1 , DMRT2, ENO1, FMR1, KDM5A, LUM, OLFML2B, OR10AG1, OR10G7, PCSK9, RGS9, RTN3, SUPV3L1, TINAGL1, TRIT1, UNC5D and USP40 Check whether the mutation of the gene encoding at least one selected from the group consisting of It provides a composition for predicting recurrence or prognosis of renal cancer, comprising the following formulations.

Another aspect of the present invention provides a kit for predicting recurrence or prognosis of renal cancer, comprising a composition for predicting recurrence or prognosis of renal cancer.

Another aspect of the present invention comprises the steps of preparing sample DNA from a sample of a patient with recurrent kidney cancer; Amplifying the sample DNA using a kit for predicting recurrence or prognosis of kidney cancer; Confirming the presence or absence of a recurrence-specific marker from the amplification result; Treating a renal cancer patient whose recurrence-specific marker has been identified with any candidate for renal cancer treatment or by any method; And adopting any of the renal cancer treatment candidate substances or any treatment method as a treatment candidate suitable for patients with recurrent renal cancer, or treatment methods for improving renal cancer, or for patients with relapse-specific markers for which recurrence specific markers have been identified. It provides a method of providing information necessary to determine the difference in the renal cancer treatment effect according to the recurrence of a renal cancer patient.

Another aspect of the present invention comprises the steps of preparing sample DNA from a sample of a patient with recurrent kidney cancer; Amplifying the sample DNA using a kit for predicting recurrence or prognosis of kidney cancer; And determining the presence or absence of a recurrence-specific marker from the amplification result; providing a method of providing information necessary for prognostic diagnosis of a kidney cancer patient comprising.

At least one gene selected from the group consisting of ALAS2, ARHGEF5, BAZ2B, C20orf26, CLCN2, FAM59A, KIAA1614, MCPH1, NLRP2, NOS1AP, PRSS38, RGPD5, USP29, XPO1, ZFAND2B and ZNF33A, which are mutant genes discovered in the present invention Since the mutation of is associated with the recurrence of renal cancer patients, it is possible to predict the difference in the effect of renal cancer treatment according to the recurrence of renal cancer patients by checking whether the gene mutation.

In addition, the mutant genes ALAS2, ANKRD50, ARHGEF5, BAZ2B, C20orf26, CCBL2, CLCN2, CNGB1, DMRT2, ENO1, FAM59A, FMR1, KDM5A, KIAA1614, LUM, MCPH1, NLRP2, NOS1AP, OLFML OR10G7, PCSK9, PRSS38, RGS9, RTN3, SUPV3L1, TINAGL1, TRIT1, UNC5D, USP29, USP40, XPO1, ZFAND2B and ZNF33A mutation of at least one gene selected from the group consisting of, and the survival rate of recurrent kidney cancer patients, or Since the mutation of the gene and the disease-free survival rate of recurrent renal cancer patients are respectively correlated, mutations of the genes of the present invention can be used as markers to predict the prognosis of renal cancer patients.

1 to 34 are ALAS2, ANKRD50, ARHGEF5, BAZ2B, C20orf26, CCBL2, CLCN2, CNGB1, DMRT2, ENO1, FAM59A, FMR1, KDM5A, KIAA1614, LUM, MCPH1, NLRP2, NOS1AP, OLFML2B, OR10AG9, OR10B, For each gene of PRSS38, RGS9, RTN3, SUPV3L1, TINAGL1, TRIT1, UNC5D, USP29, USP40, XPO1, ZFAND2B and ZNF33A, kidney cancer patients with mutations in the gene (red) and kidney cancer without mutations in the gene It is a graph of the total survival or disease-free survival of the patient (blue).

In this specification, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. In general, the nomenclature used herein and the experimental methods described below are well known and commonly used in the art.

Hereinafter, the present invention will be described in detail.

1. Mutant genes in patients with recurrent kidney cancer

One aspect of the present invention is ALAS2 (Gene bank accession number: NM_000032.4.), ARHGEF5 (Gene bank accession number: NM_005435.3.), BAZ2B (Gene bank accession number: NM_013450.3.), C20orf26 (Gene bank accession) number: NM_001167816.1.), CLCN2 (Gene bank accession number: NM_001171087.2.), FAM59A (Gene bank accession number: NM_001242409.1.), KIAA1614 (Gene bank accession number: NM_020950.1.), MCPH1 (Gene bank accession number: NM_001172574.1.), NLRP2 (Gene bank accession number: NM_001174081.2.), NOS1AP (Gene bank accession number: NM_001126060.1.), PRSS38 (Gene bank accession number: NM_183062.2.), RGPD5 (Gene bank accession number: NM_005054.3), USP29 (Gene bank accession number: NM_020903.2.), XPO1 (Gene bank accession number: NM_003400.3.), ZFAND2B (Gene bank accession number: NM_001270998.1.), ZNF33A (Gene bank accession number: NM_006954.1.), ANKRD50 (Gene bank accession number: NM_001167882.1.), CCBL2 (Gene bank accession number: NM_001008661.2.), CNGB1 (Gene bank accession number: NM_001135639.1. ), DMRT2(Gene ba nk accession number: NM_001130865.2.), ENO1 (Gene bank accession number: NM_001201483.1.), FMR1 (Gene bank accession number: NM_001185075.1.), KDM5A (Gene bank accession number: NM_001042603.2.), LUM (Gene bank accession number: NM_002345.3.), OLFML2B (Gene bank accession number: NM_015441.2.), OR10AG1 (Gene bank accession number: NM_001005491.1.), OR10G7 (Gene bank accession number: NM_001004463.1.) , PCSK9 (Gene bank accession number: NM_174936.3.), RGS9 (Gene bank accession number: NM_001081955.2.), RTN3 (Gene bank accession number: NM_001265589.1.), SUPV3L1 (Gene bank accession number: NM_003171.4 .), TINAGL1 (Gene bank accession number: NM_001204414.1.), TRIT1 (Gene bank accession number: NM_017646.5.), UNC5D (Gene bank accession number: NM_080872.3.), and USP40 (Gene bank accession number: NM_018218.2.) is a mutation of at least one gene selected from the gene group consisting of a mutant gene that appears in patients with recurrent kidney cancer.

The full names of the abbreviations of the genes are ALAS2 (5'-aminolevulinate synthase 2), ARHGEF5 (Rho guanine nucleotide exchange factor 5), BAZ2B (bromodomain adjacent to zinc finger domain 2B), C20orf26 (cilia and flagella associated protein 61), respectively, Chloride voltage-gated channel 2 (CLCN2), FAM59A (family with sequence similarity 59, member A), KIAA1614, MCPH1 (microcephalin 1), NLRP2 (NLR family pyrin domain containing 2), NOS1AP (nitric oxide synthase 1 adapter protein), PRSS38 (serine protease 38), RGPD5 (RANBP2-like and GRIP domain containing 5), USP29 (ubiquitin specific peptidase 29), XPO1 (exportin 1), ZFAND2B (zinc finger AN1-type containing 2B), ZNF33A (zinc finger protein 33A) ), ANKRD50 (ankyrin repeat domain 50), CCBL2 (cysteine-S-conjugate beta-lyase 2), CNGB1 (cyclic nucleotide gated channel beta 1), DMRT2 (doublesex and mab-3 related transcription factor 2), ENO1 (enolase 1) ), FMR1(fragile X mental retardation 1), KDM5A(lysine demethylase 5A), LUM(lumican), OLFML2B(olfactomedin like 2B), OR10AG1(olfactory receptor family 10 subfamily AG member 1), OR10G7 (olfactory receptor family 10 subfamily G member 7), PCSK9 (proprotein convertase subtilisin/kexin type 9), RGS9 (regulator of G protein signaling 9), RTN3 (reticulon 3), SUPV3L1 (Suv3 like RNA helicase), TINAGL1 (tubulointerstitial nephritis antigen like 1), TRIT1 (tRNA isopentenyltransferase 1), UNC5D (unc-5 netrin receptor D), USP40 (ubiquitin specific peptidase 40).

2. Composition for predicting recurrence or prognosis of kidney cancer

One aspect of the present invention provides a composition for predicting recurrence or prognosis of renal cancer, and includes the following agents: ALAS2, ARHGEF5, BAZ2B, C20orf26, CLCN2, FAM59A, KIAA1614, MCPH1, NLRP2, NOS1AP, PRSS38, RGPD5, USP29 , XPO1, ZFAND2B, ZNF33A, ANKRD50, CCBL2, CNGB1, DMRT2, ENO1, FMR1, KDM5A, LUM, OLFML2B, OR10AG1, OR10G7, PCSK9, RGS9, RTN3, SUPV3L1, TINAGL1, TRIT1, UNC5D selected from the group consisting of SUPV3L1, TINAGL1 and USP40 A formulation for confirming the presence or absence of mutations in at least one gene encoding.

In the present invention, the term'diagnosis' is to confirm the presence or characteristics of a pathology, and for the purposes of the present invention, not only to confirm the difference in the effect of cancer treatment depending on the recurrence of a cancer patient, but also to the individual after treatment of cancer It means to determine whether or not recurrence, drug reactivity, resistance, etc. Preferably, by using the mutation of the gene of the present invention, it is possible to know the difference in the therapeutic effect of kidney cancer according to the recurrence of the kidney cancer patient by confirming the mutation from the sample of the kidney cancer patient.

In the present invention, the term'cancer' includes any member of the class of diseases characterized by the uncontrolled growth of abnormal cells. The term includes all known cancers and neoplastic states, whether characterized as malignant, benign, soft tissue or solid, and cancers of all stages and grades, including pre/post metastasis.

In the present invention, the term'gene' and its modifications include DNA fragments involved in the production of a polypeptide chain; It includes sites before and after the coding site, such as promoters and 3′-untranslated sites, respectively, as well as intervening sequences (introns) between individual coding fragments (exons).

The mutation of the gene may include any one or more mutations, for example, a truncating mutation, a missense mutation (or a mistake mutation), a nonsense mutation, a frame shift ) Mutation, in-frame mutation (or in-frame mutation), splice mutation, and splice site (splice_region) mutation may have at least one mutation selected from the group consisting of. The frame shift mutation may be at least one of a frame shift insert (FS ins) mutation and a frame shift deletion mutation (frame shift delete, FS del). The in-frame mutation may be at least one of an in-frame insertion (IF ins) mutation and an in-frame deletion (IF del) mutation.

The term "X#Y" with respect to a mutation in a polypeptide sequence is clearly recognized in the art, where "#" represents the position of the mutation with respect to the amino acid number of the polypeptide, and "X" is the wild-type amino acid sequence. Represents the amino acid found at that position, and “Y” represents the mutant amino acid at that position. For example, the designation “G1717V” with respect to the BAZ2B polypeptide indicates that glycine is present at amino acid number 1717 of the wild-type BAZ2B sequence and that glycine has been replaced by valine in the mutant BAZ2B sequence. The mutations of these genes are as follows:

The mutation of the gene encoding ALAS2 is a missense mutation that is at least one of K100R and K97N, or a nonsense mutation that is E530* in the amino acid sequence of SEQ ID NO: 1; The mutation of the gene encoding ARHGEF5 is a missense mutation that is at least one of E487G and V1574F in the amino acid sequence of SEQ ID NO: 2; The mutation of the gene encoding BAZ2B is at least one missense mutation selected from the group consisting of E1064Q, G1717V, E616D, I1153K and H295Q in the amino acid sequence of SEQ ID NO: 3, or E1830* nonsense mutation; The mutation of the gene encoding C20orf26 is at least one missense mutation selected from the group consisting of D195N, P341R, Q799L, R800W, and A68D in the amino acid sequence of SEQ ID NO: 4; The mutation of the gene encoding CLCN2 is an in-frame insert (IF ins) mutation of R646dup, a missense mutation of R881H, or a frame shift deletion of E871Gfs*35 in the amino acid sequence of SEQ ID NO: 5 ( frame shift delete, FS del) mutation; The mutation of the gene encoding FAM59A is at least one missense mutation selected from the group consisting of E853D, F297I, K180Q, Q228E and T380I in the amino acid sequence of SEQ ID NO: 6, or frame shift insertion of D412Rfs*8 insert, FS ins) mutant; The mutation of the gene encoding KIAA1614 is at least one missense mutation selected from the group consisting of E592A, G1014S and P1037S in the amino acid sequence of SEQ ID NO: 7; The mutation of the gene encoding MCPH1 is at least one missense mutation selected from the group consisting of R613G, N523S, and C510G in the amino acid sequence of SEQ ID NO: 8, or a FS del mutation of S293Kfs*16; The mutation of the gene encoding NLRP2 is a nonsense mutation of R115* in the amino acid sequence of SEQ ID NO: 9, or at least one missense mutation selected from the group consisting of V120M, R103M, and L932V; The mutation of the gene encoding NOS1AP is a missense mutation of at least one of A25T and G199V, or an FS ins mutation of R207Gfs*32 in the amino acid sequence of SEQ ID NO: 10; The mutation of the gene encoding PRSS38 is in the amino acid sequence of SEQ ID NO: 11, a FS ins mutation of S314Qfs*21, a missense mutation of V315I, or a splice mutation of X104_splice (G is substituted for T at chromosome 228004909) ; The mutation of the gene encoding RGPD5 is at least one missense mutation selected from the group consisting of F946L, E1674K and E798G in the amino acid sequence of SEQ ID NO: 12; The mutation of the gene encoding USP29 is a nonsense mutation of E259* in the amino acid sequence of SEQ ID NO: 13, or a missense mutation of at least one of R899L and G833E; The mutation of the gene encoding XPO1 is at least one missense mutation selected from the group consisting of R1043P, H1050R, S984P and Q81H in the amino acid sequence of SEQ ID NO: 14; The mutation of the gene encoding ZFAND2B is a missense mutation of at least one of I149T and S159G in the amino acid sequence of SEQ ID NO: 15; The mutation of the gene encoding ZNF33A is a missense mutation of at least one of K165M and D271E, or an FS del mutation of Y161* in the amino acid sequence of SEQ ID NO: 16; The mutation of the gene encoding ANKRD50 is a FS ins mutation of K1272Efs*19 in the amino acid sequence of SEQ ID NO: 17, or at least one missense mutation selected from the group consisting of R1193G, D1145A, S46T and L1376H; The mutation of the gene encoding CCBL2 is a missense mutation of Q5H in the amino acid sequence of SEQ ID NO: 18; The mutation of the gene encoding CNGB1 is a missense mutation of at least one of I688N and S283T, or an FS ins mutation of L849Afs*3 in the amino acid sequence of SEQ ID NO: 19; The mutation of the gene encoding DMRT2 is a missense mutation of Q368E in the amino acid sequence of SEQ ID NO: 20; The mutation of the gene encoding ENO1 is at least one missense mutation selected from the group consisting of M165I, V240A and V84I in the amino acid sequence of SEQ ID NO: 21; The mutation of the gene encoding FMR1 is a missense mutation of P618T or an FS ins mutation of H481Afs*13 in the amino acid sequence of SEQ ID NO: 22; The mutation of the gene encoding KDM5A is a FS ins mutation of E499Gfs*29 in the amino acid sequence of SEQ ID NO: 23, or at least one missense mutation selected from the group consisting of V537I, D1339V and R1217W; The mutation of the gene encoding LUM is a nonsense mutation of Y20* in the amino acid sequence of SEQ ID NO: 24; The mutation of the gene encoding OLFML2B is a missense mutation of at least one of V8D and E644D in the amino acid sequence of SEQ ID NO: 25; The mutation of the gene encoding OR10AG1 is a missense mutation of at least one of L156F and L204F in the amino acid sequence of SEQ ID NO: 26; The mutation of the gene encoding OR10G7 is at least one missense mutation selected from the group consisting of F163Y, T159A, F26Y and V273I in the amino acid sequence of SEQ ID NO: 27, or a FS ins mutation of L25Pfs*44; The mutation of the gene encoding PCSK9 is a missense mutation of at least one of R167G and S666N in the amino acid sequence of SEQ ID NO: 28; The mutation of the gene encoding RGS9 is a missense mutation of at least one of N38K and V60F in the amino acid sequence of SEQ ID NO: 29; The mutation of the gene encoding RTN3 is a missense mutation of at least one of E260D and S312N in the amino acid sequence of SEQ ID NO: 30; The mutation of the gene encoding SUPV3L1 is a missense mutation of at least one of K495Q and M295I in the amino acid sequence of SEQ ID NO: 31; The mutation of the gene encoding TINAGL1 is a missense mutation of at least one of G45D and C226F in the amino acid sequence of SEQ ID NO: 32; The mutation of the gene encoding TRIT1 is a missense mutation of V70G in the amino acid sequence of SEQ ID NO: 33; The mutation of the gene encoding UNC5D is a missense mutation of at least one of D866N and E924D in the amino acid sequence of SEQ ID NO: 34; The mutation of the gene encoding USP40 may be a nonsense mutation of R91*, an IF ins mutation of K740dup, or a missense mutation of at least one of A681T and I748S in the amino acid sequence of SEQ ID NO: 35.

Next generation sequencing (NGS), RT-PCR, direct nucleic acid sequencing, and microarrays may be used as analysis methods for diagnosing recurrence of renal cancer using mutations in the gene. Any method that can confirm the existence of a mutation using a mutation in a gene can be applied without limitation. In one embodiment, the presence of a mutation is determined using an anti-(mutation of each gene) antibody or nucleic acid probe that hybridizes to the polynucleotide of the mutation of each gene under stringent conditions. In another embodiment, the antibody or nucleic acid probe is detectably labeled. In another embodiment, the label is selected from the group consisting of an immunofluorescent label, a chemiluminescent label, a phosphorescent label, an enzyme label, a radioactive label, avidin/biotin, colloidal gold particles, colored particles and magnetic particles. In another embodiment, the presence of the mutation is radioimmunoassay, western blot assay, immunofluorescence assay, enzyme immunoassay, immunoprecipitation assay, chemiluminescence assay, immunohistochemistry assay, dot blot assay, slot blot assay or flow cytometry. Determined by testing. In another embodiment, the presence of the mutation is determined by RT-PCR. In another embodiment, the presence of the mutation is determined by nucleic acid sequencing.

In the present invention, the term'polynucleotide' generally refers to any polyribonucleotide or polydeoxyribonucleotide that may be unmodified RNA or DNA or modified RNA or DNA. Thus, for example, polynucleotides as defined herein include, but are not limited to, single- and double-stranded DNA, DNA comprising single- and double-stranded regions, single- and double-stranded RNA, and single- and double-stranded RNA. RNA comprising -stranded regions, hybrid molecules comprising DNA and RNA, which may be single-stranded or more typically double-stranded or may include single- and double-stranded regions. Thus, DNA or RNA having a modified backbone for stability or other reasons is a'polynucleotide' as the term intended herein. In addition, DNA or RNA comprising an unconventional base such as inosine or a modified base such as a tritiumized base is included in the term'polynucleotide' as defined herein. In general, the term'polynucleotide' includes all chemically, enzymatically and/or metabolically modified forms of an unmodified polynucleotide. Polynucleotides can be prepared by a variety of methods, including in vitro recombinant DNA-mediated techniques, and by expression of DNA in cells and organisms.

The agent for confirming the occurrence of the mutation may include a primer or a probe for detection of the mutation. Primers or probes can be produced using known techniques, and primers or probes capable of detecting mutations in the genes of the present invention are included in the scope of the present invention.

In the present invention, the term'primer' is a nucleic acid sequence having a short free 3'hydroxyl group, which can form a complementary template and a base pair, and is the starting point for template strand copying. It refers to a short nucleic acid sequence that functions as. Primers are capable of initiating DNA synthesis in the presence of reagents for the polymerization reaction (ie, DNA polymerase or reverse transcriptase) and four different nucleoside triphosphates in an appropriate buffer solution and temperature. In the present invention, PCR amplification is performed using the forward and reverse primers of the mutant gene, and recurrence of renal cancer can be diagnosed through the production of a desired product. For example, in the case of a forward primer, a primer corresponding to a mutant in which deletion, substitution or insertion has occurred is designed, and a primer corresponding to a position where mutation does not occur is designed and PCR is performed for the reverse primer. In the case of chain, an amplification product will be generated by PCR, but if it is not a mutant of the gene of the present invention, an amplification product will not be generated. PCR conditions, the length of the forward and reverse primers can be modified based on those known in the art.

In the present invention, the term'probe' refers to a nucleic acid fragment such as RNA or DNA capable of specific binding to DNA, and consists of a few bases to a long, hundreds of bases. The probe is labeled so that the presence or absence of a specific DNA can be confirmed. The probe may be manufactured in the form of an oligonucleotide probe, a single stranded DNA probe, a double stranded DNA probe, or an RNA probe. In the present invention, hybridization is performed using a probe complementary to a mutation of a gene, and recurrence of renal cancer can be diagnosed through hybridization. For example, when a probe corresponding to a mutant in which deletion, substitution or insertion has occurred is synthesized and hybridized with the genomic DNA of a kidney cancer patient, hybridization will occur in the case of a mutant of the gene of the present invention. If it is not a mutant of the gene of, hybridization will not occur. Selection of suitable probes and conditions for hybridization can be modified based on those known in the art.

Another aspect of the present invention provides a kit for predicting recurrence or prognosis of renal cancer, comprising a composition for predicting recurrence or prognosis of renal cancer.

The kit of the present invention produced as described above is very economical because it saves time and cost compared to the conventional method for searching for mutations in genes. To test all of a gene using conventional gene mutation detection methods such as SSCP (Single Strand Conformational Polymorphism), PTT (Protein Truncation Test), cloning, direct sequencing, etc. It takes several months. In addition, through next generation sequencing (NGS), gene mutations can be quickly and simply examined precisely. When the mutation is tested by conventional analysis methods such as SSCP, cloning, direct sequencing, and Restriction Fragment Length Polymorphism (RFLP), it takes about a month to complete the test, whereas sample DNA is prepared using the kit of the present invention. If so, results can be obtained within about 10 to 11 hours, and since a set of primers capable of detecting mutations is integrated on one chip, it is possible to save not only time but also cost compared to conventional methods. Compared to the existing method, less than half of the reagent cost per experiment is consumed on average, so when considering the labor cost of the researcher, further cost savings can be expected.

3. A method of providing necessary information to determine the difference in the effect of renal cancer treatment according to the recurrence of kidney cancer patients

Another aspect of the present invention provides a method of providing information necessary to determine the difference in the effect of renal cancer treatment according to the recurrence of a renal cancer patient comprising the following steps: Sample DNA from a sample of a recurrent renal cancer patient Preparing; Amplifying the sample DNA using a kit for predicting recurrence or prognosis of kidney cancer; Determining the presence or absence of a recurrence-specific marker from the amplification result; Treating a renal cancer patient whose recurrence-specific marker has been identified with any candidate for renal cancer treatment or by any method; And adopting any candidate for renal cancer treatment or any treatment method to improve renal cancer, or as a treatment candidate suitable for patients with relapsed renal cancer whose relapse-specific markers have been identified when the treatment is treated.

The method may be to select any candidate for renal cancer treatment or any treatment method for each recurrence-specific marker, but is not limited thereto.

The description of the'kit for predicting recurrence or prognosis of renal cancer ' is the same as described in 2. Composition for predicting recurrence or prognosis of renal cancer, so a detailed description will be omitted.

The optional therapeutic agent may be a therapeutic agent commonly used for the treatment of kidney cancer, or a novel substance whose therapeutic effect on kidney cancer is unknown, but is not limited thereto. By treating the renal cancer patient with a specific recurrence-specific marker with any of the above candidates for treatment and then confirming the therapeutic effect, it is possible to know whether the therapeutic candidate is effective for a specific patient group. If any candidate for treatment has a renal cancer treatment effect for a renal cancer patient group having a specific recurrence-specific marker, it can be predicted that the therapeutic effect is high when applied to a patient group with the same recurrence-specific marker, so it is useful in determining a treatment strategy. You can provide information. In addition, if the treatment effect does not appear when using any of the candidates for treatment, treatment strategies can be efficiently designed because unnecessary treatment is not required by not proceeding any further treatment to the patient group having the same recurrence-specific marker. have.

Any renal cancer treatment method is also applicable instead of any of the treatment candidates, and whether to apply to a patient group having the same recurrence-specific marker can be determined by confirming the therapeutic effect in a patient group having a specific recurrence-specific marker. When confirming the therapeutic effect in the patient group having a recurrence-specific marker, any therapeutic candidate material and any renal cancer treatment method may be combined.

In the present invention, the term'sample' includes any biological specimen obtained from a patient. Samples include whole blood, plasma, serum, red blood cells, white blood cells (e.g., peripheral blood mononuclear cells), milk ducts, ascites, pleural efflux, nipple aspirate, lymph fluid (e.g. disseminated tumors of lymph nodes). Cells), bone marrow aspirate, saliva, urine, feces (i.e. feces), sputum, bronchial lavage fluid, tears, microneedle aspirate (e.g. harvested by random mammary gland microneedle aspiration), any other body fluid, tissue Sample (e.g. tumor tissue), such as a tumor biopsy (e.g., a puncture biopsy) or lymph node (e.g., a sentinel lymph node biopsy), a tissue sample (e.g., tumor tissue), e.g. surgical resection of a tumor , And cell extracts thereof. In some embodiments, the sample is whole blood or some component thereof, such as plasma, serum or cell pellets. In another embodiment, a sample is obtained by isolating circulating cells of a solid tumor from whole blood or a cell fraction thereof using any technique known in the art. In another embodiment, the sample is a formalin fixed paraffin embedded (FFPE) tumor tissue sample from a solid tumor such as, for example, colorectal cancer.

In one embodiment, the sample is a tumor lysate or extract prepared from frozen tissue obtained from a subject with kidney cancer.

The term'patient' usually includes not only humans, but may also include other animals, such as other primates, rodents, dogs, cats, horses, sheep, pigs, and the like.

The term'subject' includes subjects other than humans that are judged or suspected of renal cancer.

4. How to provide necessary information to diagnose the prognosis of kidney cancer

Another aspect of the present invention provides a method of providing information necessary for a prognosis diagnosis of renal cancer comprising the following steps: preparing sample DNA from a sample of a patient with recurrent renal cancer; Amplifying the sample DNA using a kit for predicting recurrence or prognosis of kidney cancer; And confirming the presence or absence of a recurrence-specific marker from the amplification result.

The recurrence specific markers are ALAS2, ANKRD50, ARHGEF5, BAZ2B, C20orf26, CCBL2, CLCN2, CNGB1, DMRT2, ENO1, FAM59A, FMR1, KDM5A, KIAA1614, LUM, MCPH1, NLRP2, NOS1AP, OLFML2B, OR10AG9, OR10B, PRSS38, RGS9, RTN3, SUPV3L1, TINAGL1, TRIT1, UNC5D, USP29, USP40, XPO1, ZFAND2B and ZNF33A may be a mutation of a gene encoding one selected from the group consisting of.

Since the'kit for predicting recurrence or prognosis of kidney cancer' is the same as described in ' 2. Composition for predicting recurrence or prognosis of kidney cancer ', detailed descriptions are omitted.

In the present invention, the term'prognosis' refers to the course of and cure of a neoplastic disease such as cancer, for example, recurrence, metastatic spread, and the likelihood of cancer-caused death or progression, including drug resistance. For the purpose of the present invention, it may be to predict the prognosis of renal cancer, and preferably, to predict disease-free survival or survival of renal cancer patients.

The method can predict the total survival rate or disease-free survival rate of kidney cancer patients.

In the present invention, the term'overall survival (OS)' includes a clinical endpoint describing a patient who survives for a limited period of time after being diagnosed with or treated for a disease, such as cancer, regardless of recurrence of cancer. It means the possibility of survival.

In the present invention, the term'disease-free survival (DFS)' includes a period in which a patient survives without recurrence of cancer after treatment for a specific disease (eg, cancer).

In the present invention, by analyzing the presence of a mutation of the gene of the present invention in a sample of a kidney cancer patient, it is possible to determine what prognosis for cancer is an individual having a target sample. In addition, such a method can be achieved by comparing the total survival rate or disease-free survival rate of individuals of a control group without mutations known to have a good prognosis. In the present invention, an individual known to have a good prognosis means an individual who has no history of metastasis, recurrence, or death after the onset of cancer.

The sample of an individual suspected of cancer is a sample of an individual or tissue in which cancer or tumor has already occurred or is expected to occur, and means a target sample for which the prognosis is to be diagnosed.

The method of providing the necessary information for the prognosis diagnosis of kidney cancer is that patients with renal cancer are recurrent, BAZ2B, CCBL2, CLCN2, CNGB1, DMRT2, FAM59A, KIAA1614, LUM, NLRP2, OR10AG1, RGS9, RTN3, SUPV3L1, TINAGL1, In the case of a kidney cancer patient whose mutation in the gene encoding at least one selected from the group consisting of TRIT1, UNC5D, ZFAND2B and ZNF33A is confirmed, the total survival rate of the kidney cancer patient is low, or the disease-free survival rate of the kidney cancer patient is low. It may further include determining;

The method of providing necessary information for the prognosis diagnosis of kidney cancer is the total survival rate of the kidney cancer patient when the kidney cancer patient is relapsed and the mutation in the gene encoding at least one of FMR1 and KDM5A is confirmed. It may further include a step of determining that this is low.

The method of providing necessary information for the prognosis diagnosis of kidney cancer is that recurrent patients with renal cancer, ALAS2, ANKRD50, ARHGEF5, C20orf26, ENO1, MCPH1, NOS1AP, OLFML2B, OR10G7, PCSK9, PRSS38, USP29, USP40 and XPO1. In the case of a kidney cancer patient whose mutation is confirmed in a gene encoding one selected from the group consisting of, determining that the disease-free survival rate of the kidney cancer patient is low; may further include.

As described above, one selected from the group consisting of ALAS2, ARHGEF5, BAZ2B, C20orf26, CLCN2, FAM59A, KIAA1614, MCPH1, NLRP2, NOS1AP, PRSS38, RGPD5, USP29, XPO1, ZFAND2B and ZNF33A, which are mutations of the genes of the present invention, are used as described above. Thus, the content of determining whether or not cancer, particularly renal cancer, recurs has not yet been revealed. In addition, ALAS2, ANKRD50, ARHGEF5, BAZ2B, C20orf26, CCBL2, CLCN2, CNGB1, DMRT2, ENO1, FAM59A, FMR1, KDM5A, KIAA1614, LUM, MCPH1, NLRP2, NOS1AP, OLFML2B, OR10AG1, OR10AG1, RTN3, SUPV3L1, TINAGL1, TRIT1, UNC5D, USP29, USP40, XPO1, ZFAND2B and at least one selected from the group consisting of ZNF33A can be used to diagnose the prognosis of recurrent kidney cancer patients has not yet been revealed. In addition, it has not been reported that the total survival rate or disease-free survival rate may be different in each gene. The present inventors were the first to find out that mutations of the genes can be used as diagnostic markers capable of predicting the difference in the therapeutic effect of kidney cancer according to recurrence of kidney cancer patients or diagnosing the prognosis of kidney cancer patients.

The method of providing the information necessary to predict the difference in the effect of renal cancer treatment according to the recurrence of renal cancer patients of the present invention is used to diagnose recurrence due to genetic mutation, or to increase the total survival rate or disease-free survival rate of renal cancer patients. I can. Through the method for prognosis diagnosis of renal cancer of the present invention, the therapeutic effect of renal cancer can be predicted using information on the occurrence of mutations in genes according to recurrence of renal cancer, or the total survival rate or disease-free survival rate of renal cancer patients can be predicted. In addition, it is possible to efficiently design a therapeutic strategy for kidney cancer, as it can provide information on the selection of treatment, as well as discovering suitable treatments for each patient.

Hereinafter, the present invention will be described in detail by examples and experimental examples.

However, the following examples and experimental examples are for illustrative purposes only, and the contents of the present invention are not limited by the following examples and experimental examples.

Securing genetic and clinical information

Genes of the present invention (ALAS2, ARHGEF5, BAZ2B, C20orf26, CLCN2, FAM59A, KIAA1614, MCPH1, NLRP2, NOS1AP, PRSS38, RGPD5, USP29, XPO1, ZFAND2B, ZNF33A, ANKRD50, CCBL2, CNGB1, CCBL2, CNGB1 KDM5A, LUM, OLFML2B, OR10AG1, OR10G7, PCSK9, RGS9, RTN3, SUPV3L1, TINAGL1, TRIT1, UNC5D, USP40 (also referred to as'candidate genes' below) mutations in recurrent or recurrent kidney cancer patients It was confirmed whether it can be used as a marker that can predict the survival rate. The above candidate genes are genes whose mutations occurred in recurrent renal cancer patients, so they were specified as specific for recurrent renal cancer patients. Among them, mutation genes significant for recurrence, or survival of recurrent renal cancer patients. Each of the mutant genes significant for prediction was identified. Among 538 clear cell kidney cancer patients with both genetic and clinical information from TCGA (The Cancer Genome Atlas), 338 patients with recurrence can be identified, depending on the presence or absence of recurrence (R0), relapse or The advanced group (R1) was divided into 2 groups, and data on recurrence, death, and observation time of clear cell kidney cancer patients were obtained and used for analysis. Table 1 below shows data on recurrence and death of clear cell kidney cancer patients.

Recurrence Number of patients (%) Group without recurrence (R0) 229 (67.8%) Relapsed or advanced group (R1) 109 (32.2%) survival 270 (79.9%) Dead 68 (20.1%) Total number of patients 338 (100%)

Confirmation of utility as a recurrence-specific marker

According to the presence or absence of recurrence, 338 patients were classified into two groups: 229 patients who did not recur and 109 patients who relapsed, and the correlation between mutation of the candidate genes of Example 1 and recurrence was evaluated by three Feature Selection (Information Gain, Chi-Square, MR). The mutated positions of the genes are shown in Tables 2 to 9 below.

Gene Accession No. AA change Type Copy# COSMIC Chr Start Pos End Pos Ref Var ABLIM3 NM_014945.4. D575A Missense Gain One 5 148629402 148629402 A C K192N Missense Diploid One 5 148590289 148590289 G T ALAS2 NM_000032.4. K100R Missense Diploid One X 55051156 55051156 T C E530* Nonsense Diploid One X 55039931 55039931 C A K97N Missense Gain One X 55051164 55051164 C G ANKRD50 NM_001167882.1. K1272Efs*19 FS ins Diploid 4 125590618 125590619 - C K1272Efs*19 FS ins Diploid 4 125590618 125590619 - C K1272Efs*19 FS ins ShallowDel 4 125590618 125590619 - C K1272Efs*19 FS ins Diploid 4 125590618 125590619 - C R1193G Missense Diploid One 4 125590855 125590855 T C D1145A Missense Diploid One 4 125590998 125590998 T G S46T Missense ShallowDel One 4 125631530 125631530 C G L1376H Missense Diploid One 4 125590305 125590305 A T

Gene Accession No. AA change Type Copy# COSMIC Chr Start Pos End Pos Ref Var ARHGEF5 NM_005435.3. E487G Missense Diploid 7 7 144061222 144061222 A G E487G Missense Gain 7 7 144061222 144061222 A G V1574F Missense Diploid One 7 144077075 144077075 G T BAZ2B NM_013450.3. E1064Q Missense Gain One 2 160245882 160245882 C G E1830* Nonsense Gain One 2 160194250 160194250 C A G1717V Missense Diploid One 2 160205332 160205332 C A E616D Missense Diploid One 2 160289320 160289320 T G I1153K Missense Diploid One 2 160242877 160242877 A T H295Q Missense Diploid One 2 160295535 160295535 A T C20orf26 NM_001167816.1. D195N Missense Diploid 20 20071504 20071504 G A P341R Missense Diploid 20 20140084 20140084 C G Q799L Missense Diploid 20 20243667 20243667 A T R800W Missense Diploid 20 20243669 20243669 C T A68D Missense Diploid 20 20051557 20051557 C A

Gene Accession No. AA change Type Copy# COSMIC Chr Start Pos End Pos Ref Var CACNA1B NM_000718.3. G2185S Missense Diploid 3 9 141015984 141015984 G A N702I Missense Diploid One 9 140904474 140904474 A T V1298I Missense Diploid One 9 140948382 140948382 G A CCBL2 NM_001008661.2. Q5H Missense Diploid One 89454019 89454019 C A CLCN2 NM_001171087.2. R646dup IF ins Gain 3 184071131 184071132 - CGG R881H Missense Gain One 3 184064449 184064449 C T E871Gfs*35 FS del Diploid 3 184064478 184064479 CT - CNGB1 NM_001135639.1. I688N Missense Diploid One 16 57951275 57951275 A T S283T Missense Gain One 16 57991272 57991272 A T L849Afs*3 FS ins Diploid 16 57938727 57938728 - C L849Afs*3 FS ins Diploid 16 57938727 57938728 - C L849Afs*3 FS ins Gain 16 57938727 57938728 - C L849Afs*3 FS ins Diploid 16 57938727 57938728 - C CPED1 NM_001105533.1. S908N Missense Diploid 7 120911339 120911339 G A E531A Missense Gain 7 120773891 120773891 A C P670S Missense Diploid 7 120782148 120782148 C T H873P Missense Diploid 7 120906847 120906847 A C

Gene Accession No. AA change Type Copy# COSMIC Chr Start Pos End Pos Ref Var DMRT2 NM_001130865.2. Q368E Missense Gain 9 1056689 1056689 C G ENO1 NM_001201483.1. M165I Missense Diploid One 8926510 8926510 C A V240A Missense Diploid 2 One 8925490 8925490 A G V84I Missense Diploid One One 8928107 8928107 C T FAM59A NM_001242409.1. E853D Missense ShallowDel 18 29847906 29847906 C A F297I Missense ShallowDel 18 29867671 29867671 A T K180Q Missense Diploid 18 29868022 29868022 T G Q228E Missense Diploid 18 29867878 29867878 G C T380I Missense Diploid 18 29867421 29867421 G A D412Rfs*8 FS ins Gain 18 29867327 29867328 - C FMR1 NM_001185075.1. P618T Missense Diploid One X 147030317 147030317 C A H481Afs*13 FS ins Diploid X 147024810 147024811 - G FREM1 NM_001177704.1. M737Hfs*19 FS ins Diploid 9 14823286 14823287 - G M737Hfs*19 FS ins Diploid 9 14823286 14823287 - G M737Hfs*19 FS ins Diploid 9 14823286 14823287 - G M737Hfs*19 FS ins Diploid 9 14823286 14823287 - G M737Hfs*19 FS ins Diploid 9 14823286 14823287 - G I1302V Missense Diploid One 9 14792818 14792818 T C H1866N Missense Gain One 9 14748599 14748599 G T P1857Lfs*47 FS del ShallowDel 9 14748627 14748627 A - C765S Missense Gain One 9 14823201 14823201 C G R415Pfs*12 FS ins ShallowDel 9 14848680 14848681 - G R415Pfs*12 FS ins Diploid 9 14848680 14848681 - G K467Efs*9 FS ins Diploid 9 14842653 14842654 - C

Gene Accession No. AA change Type Copy# COSMIC Chr Start Pos End Pos Ref Var KDM5A NM_001042603.2. E499Gfs*29 FS ins Diploid 12 442810 442811 - C V537I Missense Gain One 12 442697 442697 C T D1339V Missense Gain One 12 416170 416170 T A R1217W Missense Diploid One 12 416901 416901 G A KIAA1614 NM_020950.1. E592A Missense Diploid One One 180904820 180904820 A C G1014S Missense Diploid One One 180910302 180910302 G A P1037S Missense Diploid One One 180910371 180910371 C T LUM NM_002345.3. Y20* Nonsense Gain One 12 91502697 91502697 G C MCPH1 NM_001172574.1. R613G Missense ShallowDel 8 6312675 6312675 A G N523S Missense Diploid 8 6302811 6302811 A G S293Kfs*16 FS del ShallowDel 8 6302121 6302122 GT - C510G Missense Diploid 8 6302771 6302771 T G NLRP2 NM_001174081.2. R115* Nonsense Diploid 19 55489137 55489137 C T V120M Missense Diploid 19 55489152 55489152 G A R103M Missense Diploid 19 55485895 55485895 G T L932V Missense Diploid 19 55505722 55505722 C G

Gene Accession No. AA change Type Copy# COSMIC Chr Start Pos End Pos Ref Var NOS1AP NM_001126060.1. A25T Missense Diploid One One 162040040 162040040 G A G199V Missense Diploid One One 162324977 162324977 G T R207Gfs*32 FS ins Diploid One 162324998 162324999 - GG OLFML2B NM_015441.2. V8D Missense Diploid One One 161993198 161993198 A T E644D Missense Gain One One 161953786 161953786 C G OR10AG1 NM_001005491.1. L156F Missense Diploid 2 11 55735474 55735474 G A L204F Missense Diploid 2 11 55735328 55735328 C A OR10G7 NM_001004463.1. F163Y Missense Diploid One 11 123909221 123909221 A T T159A Missense Diploid 5 11 123909234 123909234 T C F26Y Missense Diploid One 11 123909632 123909632 A T V273I Missense Diploid One 11 123908892 123908892 C T L25Pfs*44 FS ins Diploid 11 123909635 123909636 - G PCSK9 NM_174936.3. R167G Missense Gain 2 One 55512295 55512295 C G S666N Missense Diploid One One 55529175 55529175 G A PRSS38 NM_183062.2. S314Qfs*21 FS ins Diploid One 228033865 228033866 - T V315I Missense Diploid One One 228033871 228033871 G A X104_splice Splice Diploid One 228004909 228004909 G T RBM11 NM_144770.4. R273* Nonsense Diploid One 21 15599585 15599585 C T Q83L Missense Diploid One 21 15592035 15592035 A T

Gene Accession No. AA change Type Copy# COSMIC Chr Start Pos End Pos Ref Var RGPD5 NM_005054.3 F946L Missense Diploid 2 2 110593536 110593536 C A F946L Missense Gain 2 2 110593536 110593536 C A E1674K Missense Diploid One 2 110602778 110602778 G A E798G Missense Gain One 2 110585652 110585652 A G RGS9 NM_001081955.2. N38K Missense Diploid One 17 63149596 63149596 C A V60F Missense Diploid One 17 63154436 63154436 G T RTN3 NM_001265589.1. E260D Missense Diploid 11 63486754 63486754 A C S312N Missense Diploid 11 63486909 63486909 G A SUPV3L1 NM_003171.4. K495Q Missense Diploid One 10 70960220 70960220 A C M295I Missense Diploid One 10 70954975 70954975 G A TINAGL1 NM_001204414.1. G45D Missense Diploid One One 32042883 32042883 G A C226F Missense ShallowDel One One 32050373 32050373 G T TRIT1 NM_017646.5. V70G Missense Diploid One One 40323055 40323055 A C UNC5D NM_080872.3. D866N Missense Diploid 8 35631934 35631934 G A E924D Missense Diploid 8 35647991 35647991 G T USP29 NM_020903.2. E259* Nonsense Diploid One 19 57640818 57640818 G T R899L Missense Diploid One 19 57642739 57642739 G T G833E Missense Gain One 19 57642541 57642541 G A

Gene Accession No. AA change Type Copy# COSMIC Chr Start Pos End Pos Ref Var USP40 NM_018218.2. R91* Nonsense Gain 2 234468567 234468567 G A K740dup IF ins Diploid 2 234429739 234429740 - TTC A681T Missense Gain 2 234431973 234431973 C T I748S Missense Diploid 2 234429716 234429716 A C XPO1 NM_003400.3. R1043P Missense Gain One 2 61706043 61706043 C G H1050R Missense Diploid One 2 61706022 61706022 T C S984P Missense Diploid 2 2 61709537 61709537 A G Q81H Missense Diploid One 2 61749804 61749804 T A ZFAND2B NM_001270998.1. I149T Missense Diploid 2 2 220072989 220072989 T C I149T Missense Diploid 2 2 220072989 220072989 T C S159G Missense Diploid One 2 220073018 220073018 A G ZNF33A NM_006954.1. K165M Missense Diploid One 10 38343549 38343549 A T D271E Missense Diploid One 10 38343868 38343868 C A Y161* FS del Diploid 10 38343536 38343539 TATT -

Based on the number of patients having a gene with a mutation included in the relapsed group or the non-relapsed group, respectively (see “Mutation number” in Tables 10 to 11 below), mutation of candidate genes and recurrence of kidney cancer patients Confirmed the association of. P-values less than 0.05 were considered statistically significant. Information of candidate genes related to Tables 10 to 11 is shown below (R0: no recurrence, R1: recurrence).

Type Recurrence group Recurrence percent (%) Mutation Number Mutation (%) Mutation Type Fisher's exact (p-value) cytoband R0 R1 Trunca
ting Missense Infram
e ABLIM3 0 2 100.00% 2 0.59% 0 2 0 0.103 5q32 ALAS2 0 3 100.00% 3 0.89% One 2 0 0.033 Xp11.21 ANKRD50 3 5 62.50% 8 2.37% 4 4 0 0.107 4q28.1 ARHGEF5 0 3 100.00% 3 0.89% 0 3 0 0.033 7q35 BAZ2B One 5 83.33% 6 1.78% One 5 0 0.015 2q24.2 C20orf26 One 4 80.00% 5 1.48% 0 5 0 0.039 20p11.23 CACNA1B One 2 66.67% 3 0.89% 0 3 0 0.244 9q34.3 CCBL2 0 One 100.00% One 0.30% 0 One 0 0.322 1p22.2 CLCN2 0 3 100.00% 3 0.89% One One One 0.033 3q27.1 CNGB1 3 3 50.00% 6 1.78% 4 2 0 0.392 16q21 CPED1 One 3 75.00% 4 1.18% 0 4 0 0.1 7q31.31 DMRT2 0 One 100.00% One 0.30% 0 One 0 0.322 9p24.3 ENO1 One 2 66.67% 3 0.89% 0 3 0 0.244 1p36.23 FAM59A 0 6 100.00% 6 1.78% One 5 0 0.001 18q12.1 FMR1 One One 50.00% 2 0.59% One One 0 0.244 Xq27.3 FREM1 5 5 50.00% 10 2.96% 7 3 0 0.302 9p22.3 KDM5A 2 2 50.00% 4 1.18% One 3 0 0.597 12p13.33 KIAA1614 0 3 100.00% 3 0.89% 0 3 0 0.033 1q25.3 LUM 0 One 100.00% One 0.30% One 0 0 0.322 12q21.33 MCPH1 0 4 100.00% 4 1.18% One 3 0 0.01 8p23.1

Type Recurrence group Recurrence percent (%) Mutation Number Mutation (%) Mutation Type Fisher's exact (p-value) cytoband R0 R1 Truncating Missense Infram
e NLRP2 0 4 100.00% 4 1.18% One 3 0 0.01 19q13.42 NOS1AP 0 3 100.00% 3 0.89% One 2 0 0.033 1q23.3 OLFML2B 0 2 100.00% 2 0.59% 0 2 0 0.103 1q23.3 OR10AG1 0 2 100.00% 2 0.59% 0 2 0 0.103 11q12.1 OR10G7 2 3 60.00% 5 1.48% One 4 0 0.333 11q24.2 PCSK9 0 2 100.00% 2 0.59% 0 2 0 0.103 1p32.3 PRSS38 0 3 100.00% 3 0.89% 2 One 0 0.033 1q42.13 RBM11 0 2 100.00% 2 0.59% One One 0 0.103 21q11.2 RGPD5 0 3 100.00% 3 0.89% 0 3 0 0.033 2q13 RGS9 0 2 100.00% 2 0.59% 0 2 0 0.103 17q24.1 RTN3 0 2 100.00% 2 0.59% 0 2 0 0.103 11q13.1 SUPV3L1 0 2 100.00% 2 0.59% 0 2 0 0.103 10q22.1 TINAGL1 0 2 100.00% 2 0.59% 0 2 0 0.103 1p35.2 TRIT1 0 One 100.00% One 0.30% 0 One 0 0.322 1p34.2 UNC5D 0 2 100.00% 2 0.59% 0 2 0 0.103 8p12 USP29 0 3 100.00% 3 0.89% One 2 0 0.033 19q13.43 USP40 One 3 75.00% 4 1.18% One 2 One 0.1 2q37.1 XPO1 0 4 100.00% 4 1.18% 0 4 0 0.01 2p15 ZFAND2B 0 3 100.00% 3 0.89% 0 3 0 0.033 2q35 ZNF33A 0 3 100.00% 3 0.89% One 2 0 0.033 10p11.1

As a result of the analysis, when there is a mutation in the gene, when comparing the recurring group and the non-recurring group, there are genes with a P-value of less than 0.05, while genes with a P-value of 0.05 or more even if a mutation occurs in the gene. Was confirmed. Mutated genes with a P-value less than 0.05 were selected as recurrence-specific genes because they were correlated with the recurrence group compared to the non-recurrent group. Compared between groups, ALAS2, ARHGEF5, BAZ2B, C20orf26, CLCN2, FAM59A, KIAA1614, MCPH1, NLRP2, NOS1AP, PRSS38, RGPD5, USP29, XPO1, ZFAND2B, and ZNF33A had P-values of less than 0.05, and these genes mutated. Recurrence was found to be correlated. On the other hand, ANKRD50 had a large number of mutated total patients, but the P-value was as high as 0.05 or higher, indicating that there was no correlation between mutation and recurrence of this gene.

From the above results, mutations of ALAS2, ARHGEF5, BAZ2B, C20orf26, CLCN2, FAM59A, KIAA1614, MCPH1, NLRP2, NOS1AP, PRSS38, RGPD5, USP29, XPO1, ZFAND2B, ZNF33A can be used as specific markers for recurrence diagnosis of kidney cancer. I can see that there is.

Confirmation of the possibility of using relapse-related genes as survival-specific markers

Among the candidate genes of Example 1, it was confirmed whether there was a survival-specific mutant gene. The 338 target patients obtained in Example 1 were classified into surviving patients (270) and deceased patients (68), and based on the clinical information (whether event (death or recurrence), observation time) obtained in Example 1 The overall survival kaplan-meier estimate and disease free survival kaplan-meier estimate were calculated using the Kaplan Meyer survival assay (Spss 21). Death was defined as an event in the total survival period, and recurrence of kidney cancer was defined as an event in the disease-free survival period. In order to determine whether the occurrence of mutations in each of the above genes is correlated with death due to renal cancer or recurrence of renal cancer in recurrent renal cancer patients, the event time of each group obtained by the Kaplan Meyer survival assay (event time), the association between the occurrence of mutations and the total survival period, and the association between the occurrence of mutations and the disease-free survival period were confirmed by a log rank test. P-values less than 0.05 were considered statistically significant. The experimental group was defined as a case with alterations in query gene of the present invention, and as a control group, a case without alterations in query gene of the present invention. The median months survival is a value that is located in the middle when the survival periods of patients in the group are listed. The median months desease free means a value located in the center when the survival periods of patients in the group are listed. The slope in the survival curve by Kaplan Meyer survival assay is determined by the survival time.

In order to confirm whether the occurrence of mutations in each of the candidate genes is associated with the survival rate of recurrent kidney cancer patients (the null hypothesis), the prognosis of 338 kidney cancer patients obtained in Example 1 was analyzed.

As a result of the analysis, as shown in FIGS. 1 to 34, when comparing between groups, ALAS2, ANKRD50, ARHGEF5, BAZ2B, C20orf26, CCBL2, CLCN2, CNGB1, DMRT2, ENO1, FAM59A, FMR1, KDM5A, KIAA1614, LUM, Mutation incidence and recurrent renal cancer survival rates of MCPH1, NLRP2, NOS1AP, OLFML2B, OR10AG1, OR10G7, PCSK9, PRSS38, RGS9, RTN3, SUPV3L1, TINAGL1, TRIT1, UNC5D, USP29, USP40, XPO1, ZFAND2B, ZNF33A genes Since the probability that the null hypothesis that there is a connection is correct is 99.5% or more, that is, the probability that the null hypothesis is incorrect is less than 0.5%, it can be seen that the occurrence of mutations in the above genes is related to the survival rate of patients with recurrent kidney cancer ( For information on patients with recurrent kidney cancer, refer to the information on the presence or absence of recurrence (R0, R1) according to the gene types in Tables 10 to 11 and the information on the total number of patients with confirmed gene mutations (Mutation Number)).

In Example 1, when only the association between mutation occurrence and recurrence was confirmed, P-value was 0.05 or more, and thus some mutant genes determined to be insignificant were P when the association between mutation occurrence and the survival time of recurrent kidney cancer patients was confirmed. The -value was found to be significant as less than 0.05. For example, in the case of ANKRD50, it was found that there was no significance when only confirming the association between mutation occurrence and recurrence in Example 1, but in this example, significance when the association between the mutation of ANKRD50 and the survival period of recurrent kidney cancer patients was confirmed. (The information on patients with recurrent kidney cancer includes information on recurrence (R0, R1) according to gene types in Tables 10 to 11, and information on the total number of patients with a mutation in the gene (Mutation Number), See P-value).

The results of survival analysis of recurrent kidney cancer patients having the mutant gene are shown in FIGS. 1 to 34.

As a result of the analysis, according to FIG. 1, ALAS2 showed no recurrence for more than 100 months in 50% or more of kidney cancer patients who did not have a mutation in the ALAS2 gene (blue), but if there is a mutation in the ALAS2 gene, kidney cancer was less than 20 months. Renal cancer recurred in more than 50% of patients (red). Therefore, it can be seen that the mutation of the ALAS2 gene is significant as a marker for predicting recurrence of renal cancer because the renal cancer patients have a high probability of recurrence of renal cancer.

According to FIG. 2, 50% or more of kidney cancer patients who did not have a mutation in the ANKRD50 gene had no recurrence for more than 100 months (blue), but if there is a mutation in the ANKRD50 gene, 50 of the kidney cancer patients were less than 40 months. Renal cancer recurred in more than% (red). Therefore, it can be seen that the mutation of the ANKRD50 gene is significant as a predictive marker for recurrence of kidney cancer, since the renal cancer patients have a high probability of recurrence of kidney cancer.

According to FIG. 3, ARHGEF5 showed no recurrence for more than 100 months in 50% or more of kidney cancer patients who did not have a mutation in the ARHGEF5 gene (blue), but if there is a mutation in the ARHGEF5 gene, 50 of the kidney cancer patients were less than 20 months. Renal cancer recurred in more than% (red). Therefore, it can be seen that the mutation of the ARHGEF5 gene is significant as a marker for predicting recurrence of renal cancer because the renal cancer patients have a higher probability of recurrence of renal cancer.

BAZ2B, as can be seen in (A) of Figure 4, in the case of kidney cancer patients who do not have a mutation in the BAZ2B gene, more than 50% survived for more than 100 months (blue), whereas a mutation occurred in the BAZ2B gene. Since more than 50% of kidney cancer patients died before 20 months, the survival rate was lower than that of kidney cancer patients without mutation (red). According to (B) of FIG. 4, in the case of kidney cancer patients who did not have a mutation in the BAZ2B gene, more than 50% had no recurrence for more than 100 months (blue), but if there was a mutation in the BAZ2B gene, the kidney cancer patient was less than 20 months old. Renal cancer recurred in more than 50% of patients (red). Therefore, it can be seen that the mutation of the BAZ2B gene is significant as a predictor of survival or recurrence of renal cancer in kidney cancer patients with a mutation in the BAZ2B gene, since the probability of death or recurrence is increased due to renal cancer.

According to FIG. 5, C20orf26 showed no recurrence for more than 100 months in 50% or more of kidney cancer patients who did not have a mutation in the C20orf26 gene (blue), but if there is a mutation in the C20orf26 gene, it is less than 40 months. Renal cancer recurred in more than% (red). Therefore, it can be seen that the mutation of the C20orf26 gene is significant as a marker for predicting recurrence of renal cancer because the renal cancer patient has a high probability of recurrence of renal cancer.

As can be seen in (A) of FIG. 6, in the case of kidney cancer patients who do not have a mutation in the CCBL2 gene, more than 50% survived for more than 80 months (blue), whereas a mutation occurred in the CCBL2 gene. Since more than 50% of kidney cancer patients died before 20 months, the survival rate was lower than that of kidney cancer patients without mutation (red). According to (B) of Figure 6, in the case of renal cancer patients who did not have a mutation in the CCBL2 gene, 50% or more had no recurrence for more than 100 months (blue), but if there was a mutation in the CCBL2 gene, kidney cancer patients were less than 20 months old. Renal cancer recurred in more than 50% of patients (red). Therefore, it can be seen that the mutation of the CCBL2 gene is significant as a predictor of survival or recurrence of renal cancer in renal cancer patients with a mutation in the CCBL2 gene because the probability of death or recurrence is high due to renal cancer.

CLCN2, as can be seen in Figure 7 (A), in the case of kidney cancer patients that do not have a mutation in the CLCN2 gene, more than 50% survived for more than 80 months (blue), whereas a mutation occurred in the CLCN2 gene. Since more than 50% of kidney cancer patients died before 20 months, the survival rate was lower than that of kidney cancer patients without mutation (red). According to Figure 7 (B), in the case of kidney cancer patients who did not have mutations in the CLCN2 gene, 50% or more had no recurrence for more than 100 months (blue), but if there was a mutation in the CLCN2 gene, kidney cancer patients were less than 20 months old. Renal cancer recurred in more than 50% of patients (red). Therefore, since the CLCN2 gene mutation has a high probability of death or recurrence due to kidney cancer in kidney cancer patients, it can be seen that the mutation in the CLCN2 gene is significant as a marker for predicting the survival rate of kidney cancer patients or recurrence of kidney cancer.

CNGB1, as can be seen in Figure 8 (A), in the case of kidney cancer patients who do not have a mutation in the CNGB1 gene, 50% or more survived for more than 80 months (blue), whereas the CNGB1 gene mutation occurred. In renal cancer patients, more than 50% of renal cancer patients died before 40 months, so it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of FIG. 8, in the case of kidney cancer patients who did not have a mutation in the CNGB1 gene, 50% or more had no recurrence for more than 100 months (blue), but if there was a mutation in the CNGB1 gene, kidney cancer patients were less than 20 months old. Renal cancer recurred in more than 50% of patients (red). Therefore, since the CNGB1 gene mutation has a high probability of death or recurrence due to kidney cancer in kidney cancer patients, it can be seen that the mutation in the CNGB1 gene is significant as a marker for predicting the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen in (A) of FIG. 9, in the case of kidney cancer patients who do not have mutations in the DMRT2 gene, more than 50% survive for more than 80 months (blue), whereas a mutation in the DMRT2 gene occurs. Since more than 50% of kidney cancer patients died before 20 months, the survival rate was lower than that of kidney cancer patients without mutation (red). According to (B) of FIG. 9, in the case of kidney cancer patients who did not have a mutation in the DMRT2 gene, more than 50% had no recurrence for more than 100 months (blue), but if there was a mutation in the DMRT2 gene, kidney cancer patients were less than 20 months old. Renal cancer recurred in more than 50% of patients (red). Therefore, it can be seen that the mutation of the DMRT2 gene is significant as a marker for predicting the survival rate or recurrence of kidney cancer in kidney cancer patients with a mutation in the DMRT2 gene because the probability of death or recurrence due to kidney cancer is increased.

According to FIG. 10, ENO1 showed no recurrence for more than 100 months in more than 50% of renal cancer patients who did not have a mutation in the ENO1 gene (blue), but if there is a mutation in the ENO1 gene, it was less than 20 months. Renal cancer recurred in more than% (red). Therefore, it can be seen that the mutation of the ENO1 gene is significant as a predictor of recurrence of kidney cancer because the renal cancer patient has a high probability of recurrence of kidney cancer.

FAM59A, as can be seen in (A) of Figure 11, in the case of kidney cancer patients who do not have a mutation in the FAM59A gene survived for more than 80 months (blue), whereas a mutation occurred in the FAM59A gene Since more than 50% of kidney cancer patients died before 20 months, the survival rate was lower than that of kidney cancer patients without mutation (red). According to (B) of FIG. 11, in the case of kidney cancer patients who did not have a mutation in the gene, 50% or more had no recurrence for more than 100 months (blue), but if there is a mutation in the FAM59A gene, it is less than 20 months. Renal cancer recurred in more than 50% (red). Accordingly, it can be seen that the mutation of the FAM59A gene is significant as a predictor of survival or recurrence of renal cancer in patients with renal cancer, since the mutation in the FAM59A gene has a higher probability of death or recurrence due to renal cancer.

FMR1, as can be seen in Figure 12, in the case of kidney cancer patients who do not have a mutation in the FMR1 gene, 50% or more survived for 80 months or more (blue), whereas a kidney cancer patient with a mutation in the FMR1 gene Since more than 50% of kidney cancer patients died before 30 months, it was confirmed that the survival rate was lower than that of kidney cancer patients without mutation (red). Therefore, it can be seen that the mutation of the FMR1 gene is significant as a predictive marker of the survival rate of the kidney cancer patient because the probability of death of the kidney cancer patient is increased.

KDM5A, as can be seen in Figure 13, in the case of kidney cancer patients who do not have mutations in the KDM5A gene survive for more than 80 months (blue), whereas the kidney cancer patients with mutations in the KDM5A gene Since more than 50% of renal cancer patients died before 20 months, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). Therefore, it can be seen that the mutation of the KDM5A gene is significant as a marker for predicting the survival rate of the kidney cancer patient because the mutation in the KDM5A gene increases the probability of death of kidney cancer patients.

KIAA1614, as can be seen in (A) of Fig. 14, in the case of kidney cancer patients who do not have a mutation in the KIAA1614 gene, more than 50% survived for more than 80 months (blue), whereas a mutation occurred in the KIAA1614 gene. Since more than 50% of kidney cancer patients died before 20 months, the survival rate was lower than that of kidney cancer patients without mutation (red). According to (B) of Figure 14, in the case of kidney cancer patients who did not have mutations in the KIAA1614 gene, 50% or more had no recurrence for more than 100 months (blue), but if there was a mutation in the KIAA1614 gene, kidney cancer patients were less than 20 months old. Renal cancer recurred in more than 50% of patients (red). Therefore, since the KIAA1614 gene mutation has a high probability of death or recurrence due to kidney cancer in kidney cancer patients, the mutation in the KIAA1614 gene can be seen to be significant as a marker for predicting the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen in (A) of FIG. 15, in the case of kidney cancer patients who do not have a mutation in the LUM gene, 50% or more survived for more than 80 months (blue), whereas a mutation occurred in the LUM gene. Since more than 50% of kidney cancer patients died before 20 months, the survival rate was lower than that of kidney cancer patients without mutation (red). According to (B) of FIG. 15, in the case of kidney cancer patients who did not have a mutation in the LUM gene, more than 50% had no recurrence for more than 100 months (blue), but if there was a mutation in the LUM gene, kidney cancer patients were less than 20 months old. Renal cancer recurred in more than 50% of patients (red). Accordingly, it can be seen that the mutation of the LUM gene is significant as a marker for predicting the survival rate or recurrence of kidney cancer in kidney cancer patients with a mutation in the LUM gene because the probability of death or recurrence is high due to kidney cancer.

According to FIG. 16, in the case of kidney cancer patients who did not have a mutation in the MCPH1 gene, MCPH1 had no recurrence for more than 100 months in 50% or more (blue), but if there was a mutation in the MCPH1 gene, it was less than 20 months. Renal cancer recurred in more than% (red). Therefore, it can be seen that the mutation of the MCPH1 gene is significant as a marker for predicting recurrence of renal cancer because the renal cancer patients have a high probability of recurrence of renal cancer.

NLRP2, as can be seen in (A) of FIG. 17, in the case of kidney cancer patients who do not have a mutation in the NLRP2 gene, more than 50% survived for more than 80 months (blue), whereas a mutation occurred in the NLRP2 gene. Since more than 50% of kidney cancer patients died before 20 months, the survival rate was lower than that of kidney cancer patients without mutation (red). According to (B) of FIG. 17, in the case of kidney cancer patients who did not have a mutation in the NLRP2 gene, 50% or more had no recurrence for more than 100 months (blue), but if there was a mutation in the NLRP2 gene, kidney cancer patients were less than 20 months old. Renal cancer recurred in more than 50% of patients (red). Therefore, since the NLRP2 gene mutation, kidney cancer patients have a high probability of death or recurrence due to kidney cancer, the mutation of the NLRP2 gene can be seen to be significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

According to FIG. 18, NOS1AP showed that 50% or more of kidney cancer patients who did not have mutations in the NOS1AP gene had no recurrence for more than 100 months (blue), but if there was a mutation in the NOS1AP gene, 50 of the kidney cancer patients were less than 20 months old. Renal cancer recurred in more than% (red). Therefore, it can be seen that the mutation of the NOS1AP gene is significant as a predictive marker for recurrence of kidney cancer, since the renal cancer patient has a high probability of recurrence of kidney cancer.

OLFML2B according to FIG. 19 shows that 50% or more of kidney cancer patients who did not have mutations in the OLFML2B gene had no recurrence for more than 100 months (blue), but if there was a mutation in the OLFML2B gene, 50 of kidney cancer patients were less than 20 months old. Renal cancer recurred in more than% (red). Therefore, it can be seen that the mutation of the OLFML2B gene is significant as a marker for predicting recurrence of renal cancer because the renal cancer patient has a high probability of recurrence of kidney cancer.

OR10AG1, as can be seen in (A) of Figure 20, in the case of kidney cancer patients that do not have a mutation in the OR10AG1 gene, 50% or more survived for 80 months or more (blue), whereas a mutation occurred in the OR10AG1 gene. Since more than 50% of kidney cancer patients died before 20 months, the survival rate was lower than that of kidney cancer patients without mutation (red). According to (B) of FIG. 20, in the case of kidney cancer patients who did not have a mutation in the OR10AG1 gene, 50% or more had no recurrence for more than 100 months (blue), but if there is a mutation in the OR10AG1 gene, the kidney cancer patient was less than 20 months old. Renal cancer recurred in more than 50% of patients (red). Therefore, it can be seen that the mutation of the OR10AG1 gene is significant as a predictive marker for survival or recurrence of kidney cancer, since the OR10AG1 gene mutation has a high probability of death or recurrence due to kidney cancer.

According to FIG. 21, in the case of kidney cancer patients who did not have a mutation in the OR10G7 gene, 50% or more did not have recurrence for more than 100 months (blue), but if there is a mutation in the OR10G7 gene, 50 of the kidney cancer patients were less than 20 months. Renal cancer recurred in more than% (red). Therefore, it can be seen that the mutation of the OR10G7 gene is significant as a predictor of recurrence of renal cancer because the renal cancer patients with a mutation in the OR10G7 gene have a higher probability of recurrence of renal cancer.

According to Fig. 22, in the case of kidney cancer patients who did not have a mutation in the PCSK9 gene, 50% or more had no recurrence for more than 100 months (blue), but if there is a mutation in the PCSK9 gene, it is less than 20 months. Renal cancer recurred in more than% (red). Therefore, since the renal cancer patients having a mutation in the PCSK9 gene have a high probability of recurrence of renal cancer, it can be seen that the mutation of the PCSK9 gene is significant as a predictor of recurrence of renal cancer.

According to Fig. 23, in the case of kidney cancer patients who did not have a mutation in the PRSS38 gene, 50% or more had no recurrence for more than 100 months (blue), but if there is a mutation in the PRSS38 gene, it was less than 40 months. Renal cancer recurred in more than% (red). Therefore, it can be seen that the mutation of the PRSS38 gene is significant as a predictive marker for recurrence of renal cancer, since a renal cancer patient having a mutation in the PRSS38 gene has a higher probability of recurrence of renal cancer.

RGS9, as can be seen in Figure 24 (A), in the case of renal cancer patients who do not have a mutation in the RGS9 gene, 50% or more survived for more than 80 months (blue), whereas a mutation occurred in the RGS9 gene. Since more than 50% of kidney cancer patients died before 20 months, the survival rate was lower than that of kidney cancer patients without mutation (red). According to (B) of FIG. 24, in the case of kidney cancer patients who did not have a mutation in the RGS9 gene, 50% or more had no recurrence for more than 100 months (blue), but if there was a mutation in the RGS9 gene, kidney cancer patients were less than 20 months old. Renal cancer recurred in more than 50% of patients (red). Therefore, since the RGS9 gene mutation has a high probability of death or recurrence due to kidney cancer in kidney cancer patients, the mutation of the RGS9 gene can be seen to be significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen in (A) of FIG. 25, in the case of kidney cancer patients who do not have mutations in the RTN3 gene, more than 50% survive for more than 80 months (blue), whereas mutations in the RTN3 gene occur. Since more than 50% of kidney cancer patients died before 20 months, the survival rate was lower than that of kidney cancer patients without mutation (red). According to (B) of FIG. 25, in the case of kidney cancer patients who did not have a mutation in the RTN3 gene, more than 50% had no recurrence for more than 100 months (blue), but if there was a mutation in the RTN3 gene, kidney cancer patients were less than 20 months old. Renal cancer recurred in more than 50% of patients (red). Therefore, it can be seen that the mutation of the RTN3 gene is significant as a survival rate or a predictor of recurrence of kidney cancer, since a kidney cancer patient having a mutation in the RTN3 gene has a high probability of death or recurrence due to kidney cancer.

SUPV3L1, as can be seen in (A) of FIG. 26, in the case of kidney cancer patients who do not have a mutation in the SUPV3L1 gene, more than 50% survived for more than 80 months (blue), whereas a mutation in the SUPV3L1 gene occurred. In renal cancer patients, more than 50% of renal cancer patients died before 40 months, so it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of FIG. 26, in the case of kidney cancer patients who did not have a mutation in the SUPV3L1 gene, 50% or more had no recurrence for more than 100 months (blue), but if there is a mutation in the SUPV3L1 gene, the kidney cancer patient was less than 20 months old. Renal cancer recurred in more than 50% of patients (red). Therefore, since the SUPV3L1 gene mutation has a high probability of death or recurrence in kidney cancer patients, it can be seen that the mutation in the gene is significant as a marker for predicting the survival rate of kidney cancer patients or recurrence of kidney cancer.

TINAGL1, as can be seen in (A) of Figure 27, in the case of kidney cancer patients who do not have a mutation in the TINAGL1 gene, more than 50% survived for more than 80 months (blue), whereas a mutation occurred in the TINAGL1 gene. Since more than 50% of kidney cancer patients died before 30 months, the survival rate was lower than that of kidney cancer patients without mutation (red). According to (B) of FIG. 27, in the case of kidney cancer patients who did not have a mutation in the TINAGL1 gene, 50% or more had no recurrence for more than 100 months (blue), but if there is a mutation in the TINAGL1 gene, kidney cancer patients were less than 20 months old. Renal cancer recurred in more than 50% of patients (red). Therefore, since the TINAGL1 gene mutation has a high probability of death or recurrence due to kidney cancer in kidney cancer patients, it can be seen that the mutation in the TINAGL1 gene is significant as a marker for predicting the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen in (A) of FIG. 28, in the case of kidney cancer patients who do not have a mutation in the TRIT1 gene, more than 50% survived for more than 80 months (blue), whereas a mutation in the TRIT1 gene occurred. Since more than 50% of kidney cancer patients died before 30 months, the survival rate was lower than that of kidney cancer patients without mutation (red). According to (B) of FIG. 28, in the case of kidney cancer patients who did not have a mutation in the TRIT1 gene, more than 50% had no recurrence for more than 100 months (blue), but if there was a mutation in the TRIT1 gene, kidney cancer patients were less than 20 months old. Renal cancer recurred in more than 50% of patients (red). Therefore, it can be seen that the mutation of the TRIT1 gene is significant as a survival rate of the kidney cancer patient or a predictive marker of recurrence of kidney cancer, since a kidney cancer patient having a mutation in the TRIT1 gene has a high probability of death or recurrence due to kidney cancer.

As can be seen in (A) of FIG. 29, in the case of kidney cancer patients who do not have mutations in the UNC5D gene, 50% or more survived for more than 80 months (blue), whereas mutations occurred in the UNC5D gene. Since more than 50% of kidney cancer patients died before 30 months, the survival rate was lower than that of kidney cancer patients without mutation (red). According to (B) of FIG. 29, in the case of kidney cancer patients who did not have a mutation in the UNC5D gene, more than 50% had no recurrence for more than 100 months (blue), but if there was a mutation in the UNC5D gene, the kidney cancer patient was less than 20 months old. Renal cancer recurred in more than 50% of patients (red). Therefore, since the UNC5D gene mutation has a high probability of death or recurrence due to kidney cancer in kidney cancer patients, it can be seen that the mutation in the UNC5D gene is significant as a marker for predicting the survival rate of kidney cancer patients or recurrence of kidney cancer.

According to Figure 30, USP29 shows that 50% or more of kidney cancer patients without mutation in the USP29 gene had no recurrence for more than 100 months (blue), but if there is a mutation in the USP29 gene within 20 months, 50 Renal cancer recurred in more than% (red). Therefore, it can be seen that the mutation of the USP29 gene is significant as a predictive marker for recurrence of renal cancer because the renal cancer patient has a high probability of recurrence of renal cancer.

According to Fig. 31, in the case of renal cancer patients who did not have a mutation in the USP40 gene, 50% or more had no recurrence for more than 100 months (blue), but if there was a mutation in the USP40 gene, 50 of the kidney cancer patients were not. Renal cancer recurred in more than% (red). Therefore, it can be seen that the mutation of the USP40 gene is significant as a marker for predicting recurrence of renal cancer because the renal cancer patient has a high probability of recurrence of renal cancer.

According to FIG. 32, in the case of kidney cancer patients who did not have a mutation in the XPO1 gene, XPO1 showed no recurrence for more than 100 months in 50% or more (blue), but if there was a mutation in the XPO1 gene, it was less than 20 months. Renal cancer recurred in more than% (red). Therefore, it can be seen that the mutation of the XPO1 gene is significant as a predictor of recurrence of renal cancer because the renal cancer patient has a high probability of recurrence of renal cancer.

ZFAND2B, as can be seen in (A) of Figure 33, in the case of kidney cancer patients who do not have a mutation in the ZFAND2B gene survived for more than 80 months (blue), whereas a mutation occurred in the ZFAND2B gene In renal cancer patients, more than 50% of renal cancer patients died before 40 months, so it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of FIG. 33, in the case of kidney cancer patients who did not have a mutation in the ZFAND2B gene, 50% or more had no recurrence for more than 100 months (blue), but if there was a mutation in the ZFAND2B gene, kidney cancer patients were less than 40 months old. Renal cancer recurred in more than 50% of patients (red). Therefore, since the ZFAND2B gene mutation has a high probability of death or recurrence due to kidney cancer in kidney cancer patients, it can be seen that the mutation in the ZFAND2B gene is significant as a marker for predicting the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen in (A) of FIG. 34, in the case of kidney cancer patients who do not have a mutation in the ZNF33A gene, more than 50% survived for more than 80 months (blue), whereas a mutation occurred in the ZNF33A gene. In renal cancer patients, more than 50% of renal cancer patients died before 40 months, so it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of Figure 34, in the case of kidney cancer patients who did not have a mutation in the ZNF33A gene, 50% or more had no recurrence for more than 100 months (blue), but if there was a mutation in the ZNF33A gene, kidney cancer patients were less than 20 months old. Renal cancer recurred in more than 50% of patients (red). Therefore, it can be seen that the mutation of the ZNF33A gene is significant as a predictor of survival or recurrence of renal cancer in patients with kidney cancer, since the probability of death or recurrence is high in kidney cancer patients with a mutation in the ZNF33A gene.

In the above, the preferred embodiments of the present invention have been exemplarily described, but the scope of the present invention is not limited to the specific embodiments as described above, and those of ordinary skill in the relevant field have the scope described in the claims of the present invention. It will be possible to change appropriately within.

<110> THE CATHOLIC UNIVERSITY OF KOREA INDUSTRY-ACADEMIC COOPERATION FOUNDATION <120> Recurrence-specific markers for determining treatment strategies and diagnosing prognosis of patient of clear cell renal cell carcinoma <130> 2018-DPA-2697 <160> 35 <170> KoPatentIn 3.0 <210> 1 <211> 587 <212> PRT <213> Homo sapiens <400> 1 Met Val Thr Ala Ala Met Leu Leu Gln Cys Cys Pro Val Leu Ala Arg 1 5 10 15 Gly Pro Thr Ser Leu Leu Gly Lys Val Val Lys Thr His Gln Phe Leu 20 25 30 Phe Gly Ile Gly Arg Cys Pro Ile Leu Ala Thr Gln Gly Pro Asn Cys 35 40 45 Ser Gln Ile His Leu Lys Ala Thr Lys Ala Gly Gly Asp Ser Pro Ser 50 55 60 Trp Ala Lys Gly His Cys Pro Phe Met Leu Ser Glu Leu Gln Asp Gly 65 70 75 80 Lys Ser Lys Ile Val Gln Lys Ala Ala Pro Glu Val Gln Glu Asp Val 85 90 95 Lys Ala Phe Lys Thr Asp Leu Pro Ser Ser Leu Val Ser Val Ser Leu 100 105 110 Arg Lys Pro Phe Ser Gly Pro Gln Glu Gln Glu Gln Ile Ser Gly Lys 115 120 125 Val Thr His Leu Ile Gln Asn Asn Met Pro Gly Asn Tyr Val Phe Ser 130 135 140 Tyr Asp Gln Phe Phe Arg Asp Lys Ile Met Glu Lys Lys Gln Asp His 145 150 155 160 Thr Tyr Arg Val Phe Lys Thr Val Asn Arg Trp Ala Asp Ala Tyr Pro 165 170 175 Phe Ala Gln His Phe Ser Glu Ala Ser Val Ala Ser Lys Asp Val Ser 180 185 190 Val Trp Cys Ser Asn Asp Tyr Leu Gly Met Ser Arg His Pro Gln Val 195 200 205 Leu Gln Ala Thr Gln Glu Thr Leu Gln Arg His Gly Ala Gly Ala Gly 210 215 220 Gly Thr Arg Asn Ile Ser Gly Thr Ser Lys Phe His Val Glu Leu Glu 225 230 235 240 Gln Glu Leu Ala Glu Leu His Gln Lys Asp Ser Ala Leu Leu Phe Ser 245 250 255 Ser Cys Phe Val Ala Asn Asp Ser Thr Leu Phe Thr Leu Ala Lys Ile 260 265 270 Leu Pro Gly Cys Glu Ile Tyr Ser Asp Ala Gly Asn His Ala Ser Met 275 280 285 Ile Gln Gly Ile Arg Asn Ser Gly Ala Ala Lys Phe Val Phe Arg His 290 295 300 Asn Asp Pro Asp His Leu Lys Lys Leu Leu Glu Lys Ser Asn Pro Lys 305 310 315 320 Ile Pro Lys Ile Val Ala Phe Glu Thr Val His Ser Met Asp Gly Ala 325 330 335 Ile Cys Pro Leu Glu Glu Leu Cys Asp Val Ser His Gln Tyr Gly Ala 340 345 350 Leu Thr Phe Val Asp Glu Val His Ala Val Gly Leu Tyr Gly Ser Arg 355 360 365 Gly Ala Gly Ile Gly Glu Arg Asp Gly Ile Met His Lys Ile Asp Ile 370 375 380 Ile Ser Gly Thr Leu Gly Lys Ala Phe Gly Cys Val Gly Gly Tyr Ile 385 390 395 400 Ala Ser Thr Arg Asp Leu Val Asp Met Val Arg Ser Tyr Ala Ala Gly 405 410 415 Phe Ile Phe Thr Thr Ser Leu Pro Met Val Leu Ser Gly Ala Leu 420 425 430 Glu Ser Val Arg Leu Leu Lys Gly Glu Glu Gly Gln Ala Leu Arg Arg 435 440 445 Ala His Gln Arg Asn Val Lys His Met Arg Gln Leu Leu Met Asp Arg 450 455 460 Gly Leu Pro Val Ile Pro Cys Pro Ser His Ile Ile Pro Ile Arg Val 465 470 475 480 Gly Asn Ala Ala Leu Asn Ser Lys Leu Cys Asp Leu Leu Leu Ser Lys 485 490 495 His Gly Ile Tyr Val Gln Ala Ile Asn Tyr Pro Thr Val Pro Arg Gly 500 505 510 Glu Glu Leu Leu Arg Leu Ala Pro Ser Pro His His Ser Pro Gln Met 515 520 525 Met Glu Asp Phe Val Glu Lys Leu Leu Leu Ala Trp Thr Ala Val Gly 530 535 540 Leu Pro Leu Gln Asp Val Ser Val Ala Ala Cys Asn Phe Cys Arg Arg 545 550 555 560 Pro Val His Phe Glu Leu Met Ser Glu Trp Glu Arg Ser Tyr Phe Gly 565 570 575 Asn Met Gly Pro Gln Tyr Val Thr Thr Tyr Ala 580 585 <210> 2 <211> 1597 <212> PRT <213> Homo sapiens <400> 2 Met Glu Ala Glu Glu Ala Gln Arg Gly Ala Ser Pro Pro Ile Ser Ala 1 5 10 15 Ile Glu Glu Phe Ser Ile Ile Pro Glu Ala Pro Met Arg Ser Ser Gln 20 25 30 Val Ser Ala Leu Gly Leu Glu Ala Gln Glu Asp Glu Asp Pro Ser Tyr 35 40 45 Lys Trp Arg Glu Glu His Arg Leu Ser Ala Thr Gln Gln Ser Glu Leu 50 55 60 Arg Asp Val Cys Asp Tyr Ala Ile Glu Thr Met Pro Ser Phe Pro Lys 65 70 75 80 Glu Gly Ser Ala Asp Val Glu Pro Asn Gln Glu Ser Leu Val Ala Glu 85 90 95 Ala Cys Asp Thr Pro Glu His Trp Glu Ala Val Pro Gln Ser Leu Ala 100 105 110 Gly Arg Gln Ala Arg Thr Leu Ala Pro Pro Glu Leu Trp Ala Cys Pro 115 120 125 Ile Gln Ser Glu His Leu Asp Met Ala Pro Phe Ser Ser Asp Leu Gly 130 135 140 Ser Glu Glu Glu Glu Val Glu Phe Trp Pro Gly Leu Thr Ser Leu Thr 145 150 155 160 Leu Gly Ser Gly Gln Ala Glu Glu Glu Glu Glu Glu Thr Ser Ser Asp Asn 165 170 175 Ser Gly Gln Thr Arg Tyr Tyr Ser Pro Cys Glu Glu His Pro Ala Glu 180 185 190 Thr Asn Gln Asn Glu Gly Ser Glu Ser Gly Thr Ile Arg Gln Gly Glu 195 200 205 Glu Leu Pro Pro Glu Glu Leu Gln Glu Ser Gln Gly Leu Leu His Pro 210 215 220 Gln Glu Val Gln Val Leu Glu Glu Gln Gly Gln Gln Glu Ala Gly Phe 225 230 235 240 Arg Gly Glu Gly Thr Leu Arg Glu Asp Val Cys Ala Asp Gly Leu Leu 245 250 255 Gly Glu Glu Gln Met Ile Glu Gln Val Asn Asp Glu Lys Gly Glu Gln 260 265 270 Lys Gln Lys Gln Glu Gln Val Gln Asp Val Met Leu Gly Arg Gln Gly 275 280 285 Glu Arg Met Gly Leu Thr Gly Glu Pro Glu Gly Leu Asn Asp Gly Glu 290 295 300 Trp Glu Gln Glu Asp Met Glu Arg Lys Ala Gln Gly Gln Gly Gly Pro 305 310 315 320 Glu Gln Gly Glu Glu Arg Lys Arg Glu Leu Gln Val Pro Glu Glu Asn 325 330 335 Arg Ala Asp Ser Gln Asp Glu Lys Ser Gln Thr Phe Leu Gly Lys Ser 340 345 350 Glu Glu Val Thr Gly Lys Gln Glu Asp His Gly Ile Lys Glu Lys Gly 355 360 365 Val Pro Val Ser Gly Gln Glu Ala Lys Glu Pro Glu Ser Trp Asp Gly 370 375 380 Gly Arg Leu Gly Ala Val Gly Arg Ala Arg Ser Arg Glu Glu Glu Asn 385 390 395 400 Glu His His Gly Pro Ser Met Pro Ala Leu Ile Ala Pro Glu Asp Ser 405 410 415 Pro His Cys Asp Leu Phe Pro Gly Ala Ser Tyr Leu Met Thr Gln Ile 420 425 430 Pro Gly Thr Gln Thr Glu Ser Arg Ala Glu Glu Leu Ser Pro Ala Ala 435 440 445 Leu Ser Pro Ser Leu Glu Pro Ile Arg Cys Ser His Gln Pro Ile Ser 450 455 460 Leu Leu Gly Ser Phe Leu Thr Glu Glu Ser Pro Asp Lys Glu Ile Asp 465 470 475 480 Gln Asn Ser Gln Gln Glu Glu Ser Arg Leu Arg Lys Gly Thr Val Ser 485 490 495 Ser Gln Gly Thr Glu Val Val Phe Ala Ser Ala Ser Val Thr Pro Pro 500 505 510 Arg Thr Pro Asp Ser Ala Pro Pro Ser Pro Ala Glu Ala Tyr Pro Ile 515 520 525 Thr Pro Ala Ser Val Ser Ala Arg Pro Pro Val Ala Phe Pro Arg Arg 530 535 540 Glu Thr Ser Cys Ala Ala Arg Ala Pro Glu Thr Ala Ser Ala Pro Leu 545 550 555 560 Ser Met Asp Asp Pro Ser Pro Cys Gly Thr Ser Glu Met Cys Pro Ala 565 570 575 Ala Leu Tyr Gly Phe Pro Ser Thr Gly Thr Ser Pro Pro Arg Pro Pro 580 585 590 Ala Asn Ser Thr Gly Thr Val Gln His Leu Arg Ser Asp Ser Phe Pro 595 600 605 Gly Ser His Arg Thr Glu Gln Thr Pro Asp Leu Val Gly Met Leu Leu 610 615 620 Ser Tyr Ser His Ser Glu Leu Pro Gln Arg Pro Pro Lys Pro Ala Ile 625 630 635 640 Tyr Ser Ser Val Thr Pro Arg Arg Asp Arg Arg Ser Gly Arg Asp Tyr 645 650 655 Ser Thr Val Ser Ala Ser Pro Thr Ala Leu Ser Thr Leu Lys Gln Asp 660 665 670 Ser Gln Glu Ser Ile Ser Asn Leu Glu Arg Pro Ser Ser Pro Pro Ser 675 680 685 Ile Gln Pro Trp Val Ser Pro His Asn Pro Ala Phe Ala Thr Glu Ser 690 695 700 Pro Ala Tyr Gly Ser Ser Pro Ser Phe Val Ser Met Glu Asp Val Arg 705 710 715 720 Ile His Glu Pro Leu Pro Pro Pro Pro Pro Gln Arg Arg Asp Thr His 725 730 735 Pro Ser Val Val Glu Thr Asp Gly His Ala Arg Val Val Val Pro Thr 740 745 750 Leu Lys Gln His Ser His Pro Pro Pro Leu Ala Leu Gly Ser Gly Leu 755 760 765 His Ala Pro His Lys Gly Pro Leu Pro Gln Ala Ser Asp Pro Ala Val 770 775 780 Ala Arg Gln His Arg Pro Leu Pro Ser Thr Pro Asp Ser Ser His His 785 790 795 800 Ala Gln Ala Thr Pro Arg Trp Arg Tyr Asn Lys Pro Leu Pro Pro Thr 805 810 815 Pro Asp Leu Pro Gln Pro His Leu Pro Pro Ile Ser Ala Pro Gly Ser 820 825 830 Ser Arg Ile Tyr Arg Pro Leu Pro Pro Leu Pro Ile Ile Asp Pro Pro 835 840 845 Thr Glu Pro Pro Pro Leu Pro Pro Lys Ser Arg Gly Arg Ser Arg Ser 850 855 860 Thr Arg Gly Gly His Met Asn Ser Gly Gly His Ala Lys Thr Arg Pro 865 870 875 880 Ala Cys Gln Asp Trp Thr Val Pro Leu Pro Ala Ser Ala Gly Arg Thr 885 890 895 Ser Trp Pro Pro Ala Thr Ala Arg Ser Thr Glu Ser Phe Thr Ser Thr 900 905 910 Ser Arg Ser Lys Ser Glu Val Ser Pro Gly Met Ala Phe Ser Asn Met 915 920 925 Thr Asn Phe Leu Cys Pro Ser Ser Pro Thr Thr Pro Trp Thr Pro Glu 930 935 940 Leu Gln Gly Pro Thr Ser Lys Asp Glu Ala Gly Val Ser Glu His Pro 945 950 955 960 Glu Ala Pro Ala Arg Glu Pro Leu Arg Arg Thr Thr Pro Gln Gln Gly 965 970 975 Ala Ser Gly Pro Gly Arg Ser Pro Val Gly Gln Ala Arg Gln Pro Glu 980 985 990 Lys Pro Ser His Leu His Leu Glu Lys Ala Ser Ser Trp Pro His Arg 995 1000 1005 Arg Asp Ser Gly Arg Pro Pro Gly Asp Ser Ser Gly Gln Ala Val Ala 1010 1015 1020 Pro Ser Glu Gly Ala Asn Lys His Lys Gly Trp Ser Arg Gln Gly Leu 1025 1030 1035 1040 Arg Arg Pro Ser Ile Leu Pro Glu Gly Ser Ser Asp Ser Arg Gly Pro 1045 1050 1055 Ala Val Glu Lys His Pro Gly Pro Ser Asp Thr Val Val Phe Arg Glu 1060 1065 1070 Lys Lys Pro Lys Glu Val Met Gly Gly Phe Ser Arg Arg Cys Ser Lys 1075 1080 1085 Leu Ile Asn Ser Ser Gln Leu Leu Tyr Gln Glu Tyr Ser Asp Val Val 1090 1095 1100 Leu Asn Lys Glu Ile Gln Ser Gln Gln Arg Leu Glu Ser Leu Ser Glu 1105 1110 1115 1120 Thr Pro Gly Pro Ser Ser Pro Arg Gln Pro Arg Lys Ala Leu Val Ser 1125 1130 1135 Ser Glu Ser Tyr Leu Gln Arg Leu Ser Met Ala Ser Ser Gly Ser Leu 1140 1145 1150 Trp Gln Glu Ile Pro Val Val Arg Asn Ser Thr Val Leu Leu Ser Met 1155 1160 1165 Thr His Glu Asp Gln Lys Leu Gln Glu Val Lys Phe Glu Leu Ile Val 1170 1175 1180 Ser Glu Ala Ser Tyr Leu Arg Ser Leu Asn Ile Ala Val Asp His Phe 1185 1190 1195 1200 Gln Leu Ser Thr Ser Leu Arg Ala Thr Leu Ser Asn Gln Glu His Gln 1205 1210 1215 Trp Leu Phe Ser Arg Leu Gln Asp Val Arg Asp Val Ser Ala Thr Phe 1220 1225 1230 Leu Ser Asp Leu Glu Glu Asn Phe Glu Asn Asn Ile Phe Ser Phe Gln 1235 1240 1245 Val Cys Asp Val Val Leu Asn His Ala Pro Asp Phe Arg Arg Val Tyr 1250 1255 1260 Leu Pro Tyr Val Thr Asn Gln Thr Tyr Gln Glu Arg Thr Phe Gln Ser 1265 1270 1275 1280 Leu Met Asn Ser Asn Ser Asn Phe Arg Glu Val Leu Glu Lys Leu Glu 1285 1290 1295 Ser Asp Pro Val Cys Gln Arg Leu Ser Leu Lys Ser Phe Leu Ile Leu 1300 1305 1310 Pro Phe Gln Arg Ile Thr Arg Leu Lys Leu Leu Leu Gln Asn Ile Leu 1315 1320 1325 Lys Arg Thr Gln Pro Gly Ser Ser Glu Glu Ala Glu Ala Thr Lys Ala 1330 1335 1340 His His Ala Leu Glu Gln Leu Ile Arg Asp Cys Asn Asn Asn Val Gln 1345 1350 1355 1360 Ser Met Arg Arg Thr Glu Glu Leu Ile Tyr Leu Ser Gln Lys Ile Glu 1365 1370 1375 Phe Glu Cys Lys Ile Phe Pro Leu Ile Ser Gln Ser Arg Trp Leu Val 1380 1385 1390 Lys Ser Gly Glu Leu Thr Ala Leu Glu Phe Ser Ala Ser Pro Gly Leu 1395 1400 1405 Arg Arg Lys Leu Asn Thr Arg Pro Val His Leu His Leu Phe Asn Asp 1410 1415 1420 Cys Leu Leu Leu Ser Arg Pro Arg Glu Gly Ser Arg Phe Leu Val Phe 1425 1430 1435 1440 Asp His Ala Pro Phe Ser Ser Ile Arg Gly Glu Lys Cys Glu Met Lys 1445 1450 1455 Leu His Gly Pro His Lys Asn Leu Phe Arg Leu Phe Leu Arg Gln Asn 1460 1465 1470 Thr Gln Gly Ala Gln Ala Glu Phe Leu Phe Arg Thr Glu Thr Gln Ser 1475 1480 1485 Glu Lys Leu Arg Trp Ile Ser Ala Leu Ala Met Pro Arg Glu Glu Leu 1490 1495 1500 Asp Leu Leu Glu Cys Tyr Asn Ser Pro Gln Val Gln Cys Leu Arg Ala 1505 1510 1515 1520 Tyr Lys Pro Arg Glu Asn Asp Glu Leu Ala Leu Glu Lys Ala Asp Val 1525 1530 1535 Val Met Val Thr Gln Gln Ser Ser Asp Gly Trp Leu Glu Gly Val Arg 1540 1545 1550 Leu Ser Asp Gly Glu Arg Gly Trp Phe Pro Val Gln Gln Val Glu Phe 1555 1560 1565 Ile Ser Asn Pro Glu Val Arg Ala Gln Asn Leu Lys Glu Ala His Arg 1570 1575 1580 Val Lys Thr Ala Lys Leu Gln Leu Val Glu Gln Gln Ala 1585 1590 1595 <210> 3 <211> 2168 <212> PRT <213> Homo sapiens <400> 3 Met Glu Ser Gly Glu Arg Leu Pro Ser Ser Ala Ala Ser Ser Thr Thr 1 5 10 15 Pro Thr Ser Ser Ser Thr Pro Ser Val Ala Ser Val Val Ser Lys Gly 20 25 30 Gly Leu Ser Thr Gly Val Ala Ser Leu Ser Ser Thr Ile Asn Pro Cys 35 40 45 Gly His Leu Phe Arg Thr Ala Gly Asp Gln Pro Phe Asn Leu Ser Thr 50 55 60 Val Ser Ser Ala Phe Pro Met Val Ser His Pro Val Phe Gly Leu His 65 70 75 80 Ser Ala Ser Ser Gly His Ser Glu Phe Gly Gly Leu Gly Thr Leu Gly 85 90 95 Thr Pro Thr Ala Leu Ala Ala His Pro Gln Leu Ala Ser Phe Pro Gly 100 105 110 Ala Glu Trp Trp Arg Thr Thr Asp Ala His Thr Arg Thr Gly Ala Thr 115 120 125 Phe Phe Pro Pro Leu Leu Gly Ile Pro Pro Leu Phe Ala Pro Pro Ala 130 135 140 Gln Asn His Asp Ser Ser Ser Phe His Ser Arg Thr Ser Gly Lys Ser 145 150 155 160 Asn Arg Asn Gly Pro Glu Lys Gly Val Asn Gly Ser Ile Asn Gly Ser 165 170 175 Asn Thr Ser Ser Val Ile Gly Ile Asn Thr Ser Val Leu Ser Thr Thr 180 185 190 Ala Ser Ser Ser Met Gly Gln Thr Lys Ser Thr Ser Ser Gly Gly Gly 195 200 205 Asn Arg Lys Cys Asn Gln Glu Gln Ser Lys Asn Gln Pro Leu Asp Ala 210 215 220 Arg Val Asp Lys Ile Lys Asp Lys Lys Pro Arg Lys Lys Ala Met Glu 225 230 235 240 Ser Ser Ser Asn Ser Asp Ser Asp Ser Gly Thr Ser Ser Asp Thr Ser 245 250 255 Ser Glu Gly Ile Ser Ser Ser Asp Ser Asp Asp Leu Glu Glu Asp Glu 260 265 270 Glu Glu Glu Asp Gln Ser Ile Glu Glu Ser Glu Asp Asp Asp Ser Asp 275 280 285 Ser Glu Ser Glu Ala Gln His Lys Ser Asn Asn Gln Val Leu Leu His 290 295 300 Gly Ile Ser Asp Pro Lys Ala Asp Gly Gln Lys Ala Thr Glu Lys Ala 305 310 315 320 Gln Glu Lys Arg Ile His Gln Pro Leu Pro Leu Ala Ser Glu Ser Gln 325 330 335 Thr His Ser Phe Gln Ser Gln Gln Lys Gln Pro Gln Val Leu Ser Gln 340 345 350 Gln Leu Pro Phe Ile Phe Gln Ser Ser Gln Ala Lys Glu Glu Ser Val 355 360 365 Asn Lys His Thr Ser Val Ile Gln Ser Thr Gly Leu Val Ser Asn Val 370 375 380 Lys Pro Leu Ser Leu Val Asn Gln Ala Lys Lys Glu Thr Tyr Met Lys 385 390 395 400 Leu Ile Val Pro Ser Pro Asp Val Leu Lys Ala Gly Asn Lys Asn Thr 405 410 415 Ser Glu Glu Ser Ser Leu Leu Thr Ser Glu Leu Arg Ser Lys Arg Glu 420 425 430 Gln Tyr Lys Gln Ala Phe Pro Ser Gln Leu Lys Lys Gln Glu Ser Ser 435 440 445 Lys Ser Leu Lys Lys Val Ile Ala Ala Leu Ser Asn Pro Lys Ala Thr 450 455 460 Ser Ser Ser Pro Ala His Pro Lys Gln Thr Leu Glu Asn Asn His Pro 465 470 475 480 Asn Pro Phe Leu Thr Asn Ala Leu Leu Gly Asn His Gln Pro Asn Gly 485 490 495 Val Ile Gln Ser Val Ile Gln Glu Ala Pro Leu Ala Leu Thr Thr Lys 500 505 510 Thr Lys Met Gln Ser Lys Ile Asn Glu Asn Ile Ala Ala Ala Ser Ser 515 520 525 Thr Pro Phe Ser Ser Pro Val Asn Leu Ser Thr Ser Gly Arg Arg Thr 530 535 540 Pro Gly Asn Gln Thr Pro Val Met Pro Ser Ala Ser Pro Ile Leu His 545 550 555 560 Ser Gln Gly Lys Glu Lys Ala Val Ser Asn Asn Val Asn Pro Val Lys 565 570 575 Thr Gln His His Ser His Pro Ala Lys Ser Leu Val Glu Gln Phe Arg 580 585 590 Gly Thr Asp Ser Asp Ile Pro Ser Ser Lys Asp Ser Glu Asp Ser Asn 595 600 605 Glu Asp Glu Glu Glu Asp Asp Glu Glu Glu Asp Glu Glu Asp Asp Glu 610 615 620 Asp Asp Glu Ser Asp Asp Ser Gln Ser Glu Ser Asp Ser Asn Ser Glu 625 630 635 640 Ser Asp Thr Glu Gly Ser Glu Glu Glu Asp Asp Asp Asp Lys Asp Gln 645 650 655 Asp Glu Ser Asp Ser Asp Thr Glu Gly Glu Lys Thr Ser Met Lys Leu 660 665 670 Asn Lys Thr Thr Ser Ser Val Lys Ser Pro Ser Met Ser Leu Thr Gly 675 680 685 His Ser Thr Pro Arg Asn Leu His Ile Ala Lys Ala Pro Gly Ser Ala 690 695 700 Pro Ala Ala Leu Cys Ser Glu Ser Gln Ser Pro Ala Phe Leu Gly Thr 705 710 715 720 Ser Ser Ser Thr Leu Thr Ser Ser Pro His Ser Gly Thr Ser Lys Arg 725 730 735 Arg Arg Val Thr Asp Glu Arg Glu Leu Arg Ile Pro Leu Glu Tyr Gly 740 745 750 Trp Gln Arg Glu Thr Arg Ile Arg Asn Phe Gly Gly Arg Leu Gln Gly 755 760 765 Glu Val Ala Tyr Tyr Ala Pro Cys Gly Lys Lys Leu Arg Gln Tyr Pro 770 775 780 Glu Val Ile Lys Tyr Leu Ser Arg Asn Gly Ile Met Asp Ile Ser Arg 785 790 795 800 Asp Asn Phe Ser Phe Ser Ala Lys Ile Arg Val Gly Asp Phe Tyr Glu 805 810 815 Ala Arg Asp Gly Pro Gln Gly Met Gln Trp Cys Leu Leu Lys Glu Glu 820 825 830 Asp Val Ile Pro Arg Ile Arg Ala Met Glu Gly Arg Arg Gly Arg Pro 835 840 845 Pro Asn Pro Asp Arg Gln Arg Ala Arg Glu Glu Ser Arg Met Arg Arg 850 855 860 Arg Lys Gly Arg Pro Pro Asn Val Gly Asn Ala Glu Phe Leu Asp Asn 865 870 875 880 Ala Asp Ala Lys Leu Leu Arg Lys Leu Gln Ala Gln Glu Ile Ala Arg 885 890 895 Gln Ala Ala Gln Ile Lys Leu Leu Arg Lys Leu Gln Lys Gln Glu Gln 900 905 910 Ala Arg Val Ala Lys Glu Ala Lys Lys Gln Gln Ala Ile Met Ala Ala 915 920 925 Glu Glu Lys Arg Lys Gln Lys Glu Gln Ile Lys Ile Met Lys Gln Gln 930 935 940 Glu Lys Ile Lys Arg Ile Gln Gln Ile Arg Met Glu Lys Glu Leu Arg 945 950 955 960 Ala Gln Gln Ile Leu Glu Ala Lys Lys Lys Lys Lys Glu Glu Ala Ala 965 970 975 Asn Ala Lys Leu Leu Glu Ala Glu Lys Arg Ile Lys Glu Lys Glu Met 980 985 990 Arg Arg Gln Gln Ala Val Leu Leu Lys His Gln Glu Arg Glu Arg Arg 995 1000 1005 Arg Gln His Met Met Leu Met Lys Ala Met Glu Ala Arg Lys Lys Ala 1010 1015 1020 Glu Glu Lys Glu Arg Leu Lys Gln Glu Lys Arg Asp Glu Lys Arg Leu 1025 1030 1035 1040 Asn Lys Glu Arg Lys Leu Glu Gln Arg Arg Leu Glu Leu Glu Met Ala 1045 1050 1055 Lys Glu Leu Lys Lys Pro Asn Glu Asp Met Cys Leu Ala Asp Gln Lys 1060 1065 1070 Pro Leu Pro Glu Leu Pro Arg Ile Pro Gly Leu Val Leu Ser Gly Ser 1075 1080 1085 Thr Phe Ser Asp Cys Leu Met Val Val Gln Phe Leu Arg Asn Phe Gly 1090 1095 1100 Lys Val Leu Gly Phe Asp Val Asn Ile Asp Val Pro Asn Leu Ser Val 1105 1110 1115 1120 Leu Gln Glu Gly Leu Leu Asn Ile Gly Asp Ser Met Gly Glu Val Gln 1125 1130 1135 Asp Leu Leu Val Arg Leu Leu Ser Ala Ala Val Cys Asp Pro Gly Leu 1140 1145 1150 Ile Thr Gly Tyr Lys Ala Lys Thr Ala Leu Gly Glu His Leu Leu Asn 1155 1160 1165 Val Gly Val Asn Arg Asp Asn Val Ser Glu Ile Leu Gln Ile Phe Met 1170 1175 1180 Glu Ala His Cys Gly Gln Thr Glu Leu Thr Glu Ser Leu Lys Thr Lys 1185 1190 1195 1200 Ala Phe Gln Ala His Thr Pro Ala Gln Lys Ala Ser Val Leu Ala Phe 1205 1210 1215 Leu Ile Asn Glu Leu Ala Cys Ser Lys Ser Val Val Ser Glu Ile Asp 1220 1225 1230 Lys Asn Ile Asp Tyr Met Ser Asn Leu Arg Arg Asp Lys Trp Val Val 1235 1240 1245 Glu Gly Lys Leu Arg Lys Leu Arg Ile Ile His Ala Lys Lys Thr Gly 1250 1255 1260 Lys Arg Asp Thr Ser Gly Gly Ile Asp Leu Gly Glu Glu Gln His Pro 1265 1270 1275 1280 Leu Gly Thr Pro Thr Pro Gly Arg Lys Arg Arg Arg Lys Gly Gly Asp 1285 1290 1295 Ser Asp Tyr Asp Asp Asp Asp Asp Asp Asp Ser Asp Asp Gln Gly Asp 1300 1305 1310 Glu Asp Asp Glu Asp Glu Glu Asp Lys Glu Asp Lys Lys Gly Lys Lys 1315 1320 1325 Thr Asp Ile Cys Glu Asp Glu Asp Glu Gly Asp Gln Ala Ala Ser Val 1330 1335 1340 Glu Glu Leu Glu Lys Gln Ile Glu Lys Leu Ser Lys Gln Gln Ser Gln 1345 1350 1355 1360 Tyr Arg Arg Lys Leu Phe Asp Ala Ser His Ser Leu Arg Ser Val Met 1365 1370 1375 Phe Gly Gln Asp Arg Tyr Arg Arg Arg Tyr Trp Ile Leu Pro Gln Cys 1380 1385 1390 Gly Gly Ile Phe Val Glu Gly Met Glu Ser Gly Glu Gly Leu Glu Glu 1395 1400 1405 Ile Ala Lys Glu Arg Glu Lys Leu Lys Lys Ala Glu Ser Val Gln Ile 1410 1415 1420 Lys Glu Glu Met Phe Glu Thr Ser Gly Asp Ser Leu Asn Cys Ser Asn 1425 1430 1435 1440 Thr Asp His Cys Glu Gln Lys Glu Asp Leu Lys Glu Lys Asp Asn Thr 1445 1450 1455 Asn Leu Phe Leu Gln Lys Pro Gly Ser Phe Ser Lys Leu Ser Lys Leu 1460 1465 1470 Leu Glu Val Ala Lys Met Pro Pro Glu Ser Glu Val Met Thr Pro Lys 1475 1480 1485 Pro Asn Ala Gly Ala Asn Gly Cys Thr Leu Ser Tyr Gln Asn Ser Gly 1490 1495 1500 Lys His Ser Leu Gly Ser Val Gln Ser Thr Ala Thr Gln Ser Asn Val 1505 1510 1515 1520 Glu Lys Ala Asp Ser Asn Asn Leu Phe Asn Thr Gly Ser Ser Gly Pro 1525 1530 1535 Gly Lys Phe Tyr Ser Pro Leu Pro Asn Asp Gln Leu Leu Lys Thr Leu 1540 1545 1550 Thr Glu Lys Asn Arg Gln Trp Phe Ser Leu Leu Pro Arg Thr Pro Cys 1555 1560 1565 Asp Asp Thr Ser Leu Thr His Ala Asp Met Ser Thr Ala Ser Leu Val 1570 1575 1580 Thr Pro Gln Ser Gln Pro Pro Ser Lys Ser Pro Ser Pro Thr Pro Ala 1585 1590 1595 1600 Pro Leu Gly Ser Ser Ala Gln Asn Pro Val Gly Leu Asn Pro Phe Ala 1605 1610 1615 Leu Ser Pro Leu Gln Val Lys Gly Gly Val Ser Met Met Gly Leu Gln 1620 1625 1630 Phe Cys Gly Trp Pro Thr Gly Val Val Thr Ser Asn Ile Pro Phe Thr 1635 1640 1645 Ser Ser Val Pro Ser Leu Gly Ser Gly Leu Gly Leu Ser Glu Gly Asn 1650 1655 1660 Gly Asn Ser Phe Leu Thr Ser Asn Val Ala Ser Ser Lys Ser Glu Ser 1665 1670 1675 1680 Pro Val Pro Gln Asn Glu Lys Ala Thr Ser Ala Gln Pro Ala Ala Val 1685 1690 1695 Glu Val Ala Lys Pro Val Asp Phe Pro Ser Pro Lys Pro Ile Pro Glu 1700 1705 1710 Glu Met Gln Phe Gly Trp Trp Arg Ile Ile Asp Pro Glu Asp Leu Lys 1715 1720 1725 Ala Leu Leu Lys Val Leu His Leu Arg Gly Ile Arg Glu Lys Ala Leu 1730 1735 1740 Gln Lys Gln Ile Gln Lys His Leu Asp Tyr Ile Thr Gln Ala Cys Leu 1745 1750 1755 1760 Lys Asn Lys Asp Val Ala Ile Ile Glu Leu Asn Glu Asn Glu Glu Asn 1765 1770 1775 Gln Val Thr Arg Asp Ile Val Glu Asn Trp Ser Val Glu Glu Gln Ala 1780 1785 1790 Met Glu Met Asp Leu Ser Val Leu Gln Gln Val Glu Asp Leu Glu Arg 1795 1800 1805 Arg Val Ala Ser Ala Ser Leu Gln Val Lys Gly Trp Met Cys Pro Glu 1810 1815 1820 Pro Ala Ser Glu Arg Glu Asp Leu Val Tyr Phe Glu His Lys Ser Phe 1825 1830 1835 1840 Thr Lys Leu Cys Lys Glu His Asp Gly Glu Phe Thr Gly Glu Asp Glu 1845 1850 1855 Ser Ser Ala His Ala Leu Glu Arg Lys Ser Asp Asn Pro Leu Asp Ile 1860 1865 1870 Ala Val Thr Arg Leu Ala Asp Leu Glu Arg Asn Ile Glu Arg Arg Ile 1875 1880 1885 Glu Glu Asp Ile Ala Pro Gly Leu Arg Val Trp Arg Arg Ala Leu Ser 1890 1895 1900 Glu Ala Arg Ser Ala Ala Gln Val Ala Leu Cys Ile Gln Gln Leu Gln 1905 1910 1915 1920 Lys Ser Ile Ala Trp Glu Lys Ser Ile Met Lys Val Tyr Cys Gln Ile 1925 1930 1935 Cys Arg Lys Gly Asp Asn Glu Glu Leu Leu Leu Leu Cys Asp Gly Cys 1940 1945 1950 Asp Lys Gly Cys His Thr Tyr Cys His Arg Pro Lys Ile Thr Thr Ile 1955 1960 1965 Pro Asp Gly Asp Trp Phe Cys Pro Ala Cys Ile Ala Lys Ala Ser Gly 1970 1975 1980 Gln Thr Leu Lys Ile Lys Lys Leu His Val Lys Gly Lys Lys Thr Asn 1985 1990 1995 2000 Glu Ser Lys Lys Gly Lys Lys Val Thr Leu Thr Gly Asp Thr Glu Asp 2005 2010 2015 Glu Asp Ser Ala Ser Thr Ser Ser Ser Leu Lys Arg Gly Asn Lys Asp 2020 2025 2030 Leu Lys Lys Arg Lys Met Glu Glu Asn Thr Ser Ile Asn Leu Ser Lys 2035 2040 2045 Gln Glu Ser Phe Thr Ser Val Lys Lys Pro Lys Arg Asp Asp Ser Lys 2050 2055 2060 Asp Leu Ala Leu Cys Ser Met Ile Leu Thr Glu Met Glu Thr His Glu 2065 2070 2075 2080 Asp Ala Trp Pro Phe Leu Leu Pro Val Asn Leu Lys Leu Val Pro Gly 2085 2090 2095 Tyr Lys Lys Val Ile Lys Lys Pro Met Asp Phe Ser Thr Ile Arg Glu 2100 2105 2110 Lys Leu Ser Ser Gly Gln Tyr Pro Asn Leu Glu Thr Phe Ala Leu Asp 2115 2120 2125 Val Arg Leu Val Phe Asp Asn Cys Glu Thr Phe Asn Glu Asp Asp Ser 2130 2135 2140 Asp Ile Gly Arg Ala Gly His Asn Met Arg Lys Tyr Phe Glu Lys Lys 2145 2150 2155 2160 Trp Thr Asp Thr Phe Lys Val Ser 2165 <210> 4 <211> 470 <212> PRT <213> Homo sapiens <400> 4 Met Ser Val Leu Thr Ser Pro Arg Gly Lys Val Glu Val Val His Cys 1 5 10 15 Arg Arg Thr Glu Ser Gln Asp Val Tyr Cys Ile Lys Ser Leu Ile Arg 20 25 30 Lys Phe Thr Cys Lys Leu Phe Gly Lys Leu Asn Ile Ile Tyr Leu Leu 35 40 45 Glu Lys Ala Asn Leu Ala Val Thr Leu Cys Asn Asp Lys Glu Glu Ile 50 55 60 Met Ala Gln Ala Thr Phe Leu Asp Tyr Pro Asn Trp Asn Val Ala Lys 65 70 75 80 Gln Asp Asp Trp Val Ser Val Phe Arg Glu Leu Asp Ser Asp Ile Pro 85 90 95 Cys Thr Pro Leu Asn Thr Leu Phe Met His Leu Phe Val Ala Val Asp 100 105 110 Glu Tyr Ser Val Gly Cys Cys Lys Glu Ile Leu Arg Thr Val Tyr Lys 115 120 125 Ala Val Pro Glu Leu His Phe Ile Phe Leu Ile Val Pro Ser Tyr Met 130 135 140 Ser Leu Gly Ser Thr Leu Ile Thr Val Phe Asp Gln Val Gly Asn Ile 145 150 155 160 Pro Cys Leu Thr Tyr Glu Glu Asp Phe Ala Val His Ile Cys His Arg 165 170 175 His Ser His Tyr Pro Gln Leu His Val Arg Lys Ala Arg Val Glu Asp 180 185 190 His Asp Asp Leu Met Pro Ile Phe Met Arg Tyr Asp Thr Ile Leu Lys 195 200 205 Glu Thr Tyr Gly Glu Tyr Phe Leu Ala Glu Leu Ile Glu Ala Gln Asp 210 215 220 Glu Glu Asn His Ala Val Val Cys Glu Val Glu Gly Thr Ala Val Gly 225 230 235 240 Phe Met Ser Val Cys Ser Arg Val Asn Met Gln Leu Leu His Glu Cys 245 250 255 Phe Asp Leu Gly Pro Phe His Gly Leu Cys Phe Pro His Pro Asp Asp 260 265 270 Val Leu Glu Ser Pro Gln Asp Leu Ser Val Arg Arg Ser Gln Asp Ala 275 280 285 Glu Leu Arg Ser Ser Gln Gly Ser Gln Lys Ile Val Glu Glu Leu 290 295 300 Gln Glu Pro Val Ser Pro Asp Thr Met Glu Asn Ile Gln Gly Asn Ile 305 310 315 320 Ala Arg Glu Ala Ala Ser Glu Glu Ala Leu Thr Ala Val Gln Ser Gly 325 330 335 Asn Val Ser Glu Pro Glu Asp Ile Glu Lys Leu Ser Asp Ile Ser Thr 340 345 350 Gly Tyr Ala Gln Tyr His His Val Ser Ser Arg Ser Leu Ala Ser Leu 355 360 365 Val Leu Pro Glu Glu Pro Val His Phe Arg Pro Ile Tyr Arg Gly Ala 370 375 380 Ser Ala Ala Phe Cys Ile Gln Leu Phe Cys Ile Asp Glu Lys Tyr Glu 385 390 395 400 Ala Arg Ser Leu Asp Phe Met Asn Phe Val Phe Ser Leu Phe Ser Asp 405 410 415 Lys Asn Phe Cys Val Ile Ser Leu Pro His Leu Thr Pro Glu Phe Phe 420 425 430 Leu Ile Gln Asn Phe Val Lys Met Val Pro Phe Asn Thr Cys Thr Leu 435 440 445 Glu Gln Asp Leu Tyr Val Phe His Arg Ala Gly Leu Leu Lys Asn Ile 450 455 460 Cys Leu Gly Arg Ser Ser 465 470 <210> 5 <211> 881 <212> PRT <213> Homo sapiens <400> 5 Met Ala Ala Ala Ala Ala Glu Glu Gly Met Glu Pro Arg Ala Leu Gln 1 5 10 15 Tyr Glu Gln Thr Leu Met Tyr Gly Arg Tyr Thr Gln Asp Leu Gly Ala 20 25 30 Phe Ala Lys Glu Glu Ala Ala Arg Ile Arg Leu Gly Gly Pro Glu Pro 35 40 45 Trp Lys Gly Pro Pro Ser Ser Arg Ala Ala Pro Glu Leu Leu Glu Tyr 50 55 60 Gly Arg Ser Arg Cys Ala Arg Cys Arg Val Cys Ser Val Arg Cys His 65 70 75 80 Lys Phe Leu Val Ser Arg Val Gly Glu Asp Trp Ile Phe Leu Val Leu 85 90 95 Leu Gly Leu Leu Met Ala Leu Val Ser Trp Val Met Asp Tyr Ala Ile 100 105 110 Ala Ala Cys Leu Gln Ala Gln Gln Trp Met Ser Arg Gly Leu Asn Thr 115 120 125 Ser Ile Leu Leu Gln Tyr Leu Ala Trp Val Thr Tyr Pro Val Val Leu 130 135 140 Ile Thr Phe Ser Ala Gly Phe Thr Gln Ile Leu Ala Pro Gln Ala Val 145 150 155 160 Gly Ser Gly Ile Pro Glu Met Lys Thr Ile Leu Arg Gly Val Val Leu 165 170 175 Lys Glu Tyr Leu Thr Leu Lys Thr Phe Ile Ala Lys Val Ile Gly Leu 180 185 190 Thr Cys Ala Leu Gly Ser Gly Met Pro Leu Gly Lys Glu Gly Pro Phe 195 200 205 Val His Ile Ala Ser Met Cys Ala Ala Leu Leu Ser Lys Phe Leu Ser 210 215 220 Leu Phe Gly Gly Ile Tyr Glu Asn Glu Ser Arg Asn Thr Glu Met Leu 225 230 235 240 Ala Ala Ala Cys Ala Val Gly Val Gly Cys Cys Phe Ala Ala Pro Ile 245 250 255 Gly Gly Val Leu Phe Ser Ile Glu Val Thr Ser Thr Phe Phe Ala Val 260 265 270 Arg Asn Tyr Trp Arg Gly Phe Phe Ala Ala Thr Phe Ser Ala Phe Ile 275 280 285 Phe Arg Val Leu Ala Val Trp Asn Arg Asp Glu Glu Thr Ile Thr Ala 290 295 300 Leu Phe Lys Thr Arg Phe Arg Leu Asp Phe Pro Phe Asp Leu Gln Glu 305 310 315 320 Leu Pro Ala Phe Ala Val Ile Gly Ile Ala Ser Gly Phe Gly Gly Ala 325 330 335 Leu Phe Val Tyr Leu Asn Arg Lys Ile Val Gln Val Met Arg Lys Gln 340 345 350 Lys Thr Ile Asn Arg Phe Leu Met Arg Lys Arg Leu Leu Phe Pro Ala 355 360 365 Leu Val Thr Leu Leu Ile Ser Thr Leu Thr Phe Pro Pro Gly Phe Gly 370 375 380 Gln Phe Met Ala Gly Gln Leu Ser Gln Lys Glu Thr Leu Val Thr Leu 385 390 395 400 Phe Asp Asn Arg Thr Trp Val Arg Gln Gly Leu Val Glu Glu Leu Glu 405 410 415 Pro Pro Ser Thr Ser Gln Ala Trp Asn Pro Pro Arg Ala Asn Val Phe 420 425 430 Leu Thr Leu Val Ile Phe Ile Leu Met Lys Phe Trp Met Ser Ala Leu 435 440 445 Ala Thr Thr Ile Pro Val Pro Cys Gly Ala Phe Met Pro Val Phe Val 450 455 460 Ile Asp Gly Ile His Thr Asp Ser Ser Thr Tyr Arg Ile Val Pro Gly 465 470 475 480 Gly Tyr Ala Val Val Gly Ala Ala Ala Leu Ala Gly Ala Val Thr His 485 490 495 Thr Val Ser Thr Ala Val Ile Val Phe Glu Leu Thr Gly Gln Ile Ala 500 505 510 His Ile Leu Pro Val Met Ile Ala Val Ile Leu Ala Asn Ala Val Ala 515 520 525 Gln Ser Leu Gln Pro Ser Leu Tyr Asp Ser Ile Ile Arg Ile Lys Lys 530 535 540 Leu Pro Tyr Leu Pro Glu Leu Gly Trp Gly Arg His Gln Gln Tyr Arg 545 550 555 560 Val Arg Val Glu Asp Ile Met Val Arg Asp Val Pro His Val Ala Leu 565 570 575 Ser Cys Thr Phe Arg Asp Leu Arg Leu Ala Leu His Arg Thr Lys Gly 580 585 590 Arg Met Leu Ala Leu Val Glu Ser Pro Glu Ser Met Ile Leu Leu Gly 595 600 605 Ser Ile Glu Arg Ser Gln Val Val Ala Leu Leu Gly Ala Gln Leu Ser 610 615 620 Pro Ala Arg Arg Arg Gln His Met Gln Glu Arg Arg Ala Thr Gln Thr 625 630 635 640 Ser Pro Leu Ser Asp Gln Glu Gly Pro Pro Thr Pro Glu Ala Ser Val 645 650 655 Cys Phe Gln Val Asn Thr Glu Asp Ser Ala Phe Pro Ala Ala Arg Gly 660 665 670 Glu Thr His Lys Pro Leu Lys Pro Ala Leu Lys Arg Gly Pro Ser Val 675 680 685 Thr Arg Asn Leu Gly Glu Ser Pro Thr Gly Ser Ala Glu Ser Ala Gly 690 695 700 Ile Ala Leu Arg Ser Leu Phe Cys Gly Ser Pro Pro Pro Glu Ala Ala 705 710 715 720 Ser Glu Lys Leu Glu Ser Cys Glu Lys Arg Lys Leu Lys Arg Val Arg 725 730 735 Ile Ser Leu Ala Ser Asp Ala Asp Leu Glu Gly Glu Met Ser Pro Glu 740 745 750 Glu Ile Leu Glu Trp Glu Glu Gln Gln Leu Asp Glu Pro Val Asn Phe 755 760 765 Ser Asp Cys Lys Ile Asp Pro Ala Pro Phe Gln Leu Val Glu Arg Thr 770 775 780 Ser Leu His Lys Thr His Thr Ile Phe Ser Leu Leu Gly Val Asp His 785 790 795 800 Ala Tyr Val Thr Ser Ile Gly Arg Leu Ile Gly Ile Val Thr Leu Lys 805 810 815 Glu Leu Arg Lys Ala Ile Glu Gly Ser Val Thr Ala Gln Gly Val Lys 820 825 830 Val Arg Pro Pro Leu Ala Ser Phe Arg Asp Ser Ala Thr Ser Ser Ser 835 840 845 Asp Thr Glu Thr Thr Glu Val His Ala Leu Trp Gly Pro His Ser Arg 850 855 860 His Gly Leu Pro Arg Glu Gly Ser Pro Ser Asp Ser Asp Asp Lys Cys 865 870 875 880 Gln <210> 6 <211> 876 <212> PRT <213> Homo sapiens <400> 6 Met Asp Pro Ala Pro Ser Leu Gly Cys Ser Leu Lys Asp Val Lys Trp 1 5 10 15 Ser Ser Val Ala Val Pro Leu Asp Leu Leu Val Ser Thr Tyr Arg Leu 20 25 30 Pro Gln Ile Ala Arg Leu Asp Asn Gly Glu Cys Val Glu Gly Leu Arg 35 40 45 Glu Asn Asp Tyr Leu Leu Ile His Ser Cys Arg Gln Trp Thr Thr Ile 50 55 60 Thr Ala His Ser Leu Glu Glu Gly His Tyr Val Ile Gly Pro Lys Ile 65 70 75 80 Glu Ile Pro Val His Tyr Ala Gly Gln Phe Lys Leu Leu Glu Gln Asp 85 90 95 Arg Asp Ile Lys Glu Pro Val Gln Tyr Phe Asn Ser Val Glu Glu Val 100 105 110 Ala Lys Ala Phe Pro Glu Arg Val Tyr Val Met Glu Asp Ile Thr Phe 115 120 125 Asn Val Lys Val Ala Ser Gly Glu Cys Asn Glu Asp Thr Glu Val Tyr 130 135 140 Asn Ile Thr Leu Cys Thr Gly Asp Glu Leu Thr Leu Met Gly Gln Ala 145 150 155 160 Glu Ile Leu Tyr Ala Lys Thr Phe Lys Glu Lys Ser Arg Leu Asn Thr 165 170 175 Ile Phe Lys Lys Ile Gly Lys Leu Asn Ser Ile Ser Lys Leu Gly Lys 180 185 190 Gly Lys Met Pro Cys Leu Ile Cys Met Asn His Arg Thr Asn Glu Ser 195 200 205 Ile Ser Leu Pro Phe Gln Cys Lys Gly Arg Phe Ser Thr Arg Ser Pro 210 215 220 Leu Glu Leu Gln Met Gln Glu Gly Glu His Thr Ile Arg Asn Ile Val 225 230 235 240 Glu Lys Thr Arg Leu Pro Val Asn Val Thr Val Pro Ser Pro Pro Pro 245 250 255 Arg Asn Pro Tyr Asp Leu His Phe Ile Arg Glu Gly His Arg Tyr Lys 260 265 270 Phe Val Asn Ile Gln Thr Lys Thr Val Val Val Cys Cys Val Leu Arg 275 280 285 Asn Asn Lys Ile Leu Pro Met His Phe Pro Leu His Leu Thr Val Pro 290 295 300 Lys Phe Ser Leu Pro Glu His Leu Val Lys Gly Glu Ser Trp Pro Glu 305 310 315 320 Thr Leu Val His His Trp Leu Gly Ile Cys Gln Glu Gln Phe Asp Ile 325 330 335 Asp Glu Tyr Ser Arg Ala Val Arg Asp Val Lys Thr Asp Trp Asn Glu 340 345 350 Glu Cys Lys Ser Pro Lys Lys Gly Arg Cys Ser Gly His Asn His Val 355 360 365 Pro Asn Ser Leu Ser Tyr Ala Arg Asp Glu Leu Thr Gln Ser Phe His 370 375 380 Arg Leu Ser Val Cys Val Tyr Gly Asn Asn Leu His Gly Asn Ser Glu 385 390 395 400 Val Asn Leu His Gly Cys Arg Asp Leu Gly Gly Asp Trp Ala Pro Phe 405 410 415 Pro His Asp Ile Leu Pro Tyr Gln Asp Ser Gly Asp Ser Gly Ser Asp 420 425 430 Tyr Leu Phe Pro Glu Ala Ser Glu Glu Ser Ala Gly Ile Pro Gly Lys 435 440 445 Ser Glu Leu Pro Tyr Glu Glu Leu Trp Leu Glu Glu Gly Lys Pro Ser 450 455 460 His Gln Pro Leu Thr Arg Ser Leu Ser Glu Lys Asn Arg Cys Asp Gln 465 470 475 480 Phe Arg Gly Ser Val Arg Ser Lys Cys Ala Thr Ser Pro Leu Pro Ile 485 490 495 Pro Gly Thr Leu Gly Ala Ala Val Lys Ser Ser Asp Thr Ala Leu Pro 500 505 510 Pro Pro Pro Val Pro Pro Lys Ser Glu Ala Val Arg Glu Glu Cys Arg 515 520 525 Leu Leu Asn Ala Pro Pro Val Pro Pro Arg Ser Ala Lys Pro Leu Ser 530 535 540 Thr Ser Pro Ser Ile Pro Pro Arg Thr Val Lys Pro Ala Arg Gln Gln 545 550 555 560 Thr Arg Ser Pro Ser Pro Thr Leu Ser Tyr Tyr Ser Ser Gly Leu His 565 570 575 Asn Ile Ser Val Thr Lys Thr Asp Thr Asn Pro Ser Glu Ser Thr Pro 580 585 590 Val Ser Cys Tyr Pro Cys Asn Arg Val Lys Thr Asp Ser Val Asp Leu 595 600 605 Lys Ser Pro Phe Gly Ser Pro Ser Ala Glu Ala Val Ser Ser Arg Leu 610 615 620 Ser Trp Pro Asn His Tyr Ser Gly Ala Ser Glu Ser Gln Thr Arg Ser 625 630 635 640 Asp Phe Leu Leu Asp Pro Ser Arg Ser Tyr Ser Tyr Pro Arg Gln Lys 645 650 655 Thr Pro Gly Thr Pro Lys Arg Asn Cys Pro Ala Pro Phe Asp Phe Asp 660 665 670 Gly Cys Glu Leu Leu Ala Ser Pro Thr Ser Pro Val Thr Ala Glu Phe 675 680 685 Ser Ser Ser Val Ser Gly Cys Pro Lys Ser Ala Ser Tyr Ser Leu Glu 690 695 700 Ser Thr Asp Val Lys Ser Leu Ala Ala Gly Val Thr Lys Gln Ser Thr 705 710 715 720 Ser Cys Pro Ala Leu Pro Pro Arg Ala Pro Lys Leu Val Glu Glu Lys 725 730 735 Val Ala Ser Glu Thr Ser Pro Leu Pro Leu Lys Ile Asp Gly Ala Glu 740 745 750 Glu Asp Pro Lys Ser Gly Ser Pro Asp Leu Ser Glu Asp Gln Tyr Phe 755 760 765 Val Lys Lys Gly Met Gln Asp Ile Phe Ser Ala Ser Tyr Pro Phe Ser 770 775 780 Ser Pro Leu His Leu Gln Leu Ala Pro Arg Ser Cys Gly Asp Gly Ser 785 790 795 800 Pro Trp Gln Pro Pro Ala Asp Leu Ser Gly Leu Ser Ile Glu Glu Val 805 810 815 Ser Lys Ser Leu Arg Phe Ile Gly Leu Ser Glu Asp Val Ile Ser Phe 820 825 830 Phe Val Thr Glu Lys Ile Asp Gly Asn Leu Leu Val Gln Leu Thr Glu 835 840 845 Glu Ile Leu Ser Glu Asp Phe Lys Leu Ser Lys Leu Gln Val Lys Lys 850 855 860 Ile Met Gln Phe Ile Asn Gly Trp Arg Pro Lys Ile 865 870 875 <210> 7 <211> 1190 <212> PRT <213> Homo sapiens <400> 7 Met Glu Gly Thr Glu Ala Ala Ala Ala Lys Pro Ala Gly Gly Ser Pro 1 5 10 15 Gln Gly Pro Lys Thr Gly Ser Gly Thr Ala Ser Pro Val Glu Gly Thr 20 25 30 Ser Ala Val Glu Trp Ser Gly Pro Glu Pro Gln Leu Asp Asn Gly His 35 40 45 Pro Pro Arg Pro Trp Pro Cys Pro Gln Glu Asn Arg Thr Ser Ser Leu 50 55 60 Met Ala Pro Gln Pro Pro Arg Val Trp Gly Val Gln Leu Gln Gly Pro 65 70 75 80 Ser Val Leu Glu Ser Lys Val Arg Ala Leu Lys Glu Lys Met Thr Val 85 90 95 Ala Lys Gln Gly Val Ser Pro Cys Ser Ala Ser Gln Glu Trp Ser Ser 100 105 110 Pro Lys Lys Pro Gln Cys Arg Arg Gly Lys Ala Gly Arg Ala Gly Thr 115 120 125 Pro Ser Glu Gly Ser Phe Leu Pro Gly Ala Val Val Ala Pro Arg Thr 130 135 140 Gln Asn Leu Pro Asp Gly Gln Leu Asp Gly Ser Ile Asn Glu Glu Gln 145 150 155 160 Pro Ala Arg Asp Gly Gly Pro Arg Leu Pro Arg Pro Pro Ala Pro Gly 165 170 175 Arg Glu Tyr Cys Asn Arg Gly Ser Pro Trp Pro Pro Glu Ala Glu Trp 180 185 190 Thr Leu Pro Asp His Asp Arg Gly Pro Leu Leu Gly Pro Ser Ser Leu 195 200 205 Gln Gln Ser Pro Ile His Gly Val Thr Pro Gly Arg Pro Gly Gly Pro 210 215 220 Gly His Cys Asn Lys Ile Ile His Ile Pro Ser Pro Arg Thr Gly Arg 225 230 235 240 Ser Tyr Pro Phe Pro Asp Gly Val Val Thr Glu Ala Asp Leu Asp Ser 245 250 255 Thr Ser Leu Thr Ser Glu Glu Val Phe Val Pro Arg Thr Ala Leu Leu 260 265 270 Gly Glu Arg Trp Arg Ala Gly Asp Leu Glu Ala Leu Gly Ala Gly Ser 275 280 285 Ser Val Leu Ser Leu Ser Asp Arg Val Glu Arg Asn Arg Leu Leu Leu 290 295 300 Gln Glu Met Leu Asn Val Ser Gly Gln Ser Pro Arg Lys Val Gly Thr 305 310 315 320 Pro Ala Trp Thr Pro Ser Trp Asp Thr Ala Ala Pro Glu Arg Pro Val 325 330 335 Gly Asp Val Asp Trp Ala Ser Gly Thr Ser Leu Gln Asp Ser Gly Gln 340 345 350 Asn Arg Thr Val Gly Pro Asn Pro Glu Pro Val Leu Ser Pro Arg His 355 360 365 Glu Glu Ala Thr His Leu Leu Gln Arg Ala Arg Met Lys Ala Arg Thr 370 375 380 Arg Pro Leu Arg Ala Ser His Asp Ile Val Pro Thr Ile Thr Gln Gly 385 390 395 400 Ser Arg Asp Gly His Arg Ser Pro Ala Arg Asp Pro Arg Thr Thr Pro 405 410 415 Ala Cys Arg Asp Ser Leu Gln Asn Gly His Thr Ser Asp Ser Ser Ser 420 425 430 Gly Glu Ser Ser Gly Gly His Arg Pro Arg Arg Gly Pro Ser Pro Ser 435 440 445 His Val Arg Phe Glu Asp Glu Ser Ala Arg Glu Ala Glu Phe Arg His 450 455 460 Leu Glu Arg Leu Gln Gln Arg Gln Arg Gln Val Leu Ser Thr Val Leu 465 470 475 480 Gln Ala Ala Asp Gln Gly Pro Leu Arg Ser Lys Pro Asp Leu Ala Asp 485 490 495 Tyr Ile Asn Gly Ala Pro Arg Leu Arg Asp Ala Gly Gln Gly Thr Phe 500 505 510 His Arg Leu Val Gly Ser Leu Asp Arg Arg Gly His Pro Ala Pro Pro 515 520 525 Ala Pro Gly Ser Glu Arg Arg Cys Gln Ala Cys Gly Ser Cys Ile Asp 530 535 540 Asp Pro Arg Pro Ala Gln Gly Lys Ala Pro Pro Val Pro Arg Thr Leu 545 550 555 560 Gln Glu Leu Gln Ala Ala Cys Gly Met Glu Arg Val Leu Gly Gly Leu 565 570 575 Ser Ser Pro Leu Arg Leu Leu Pro Ala Glu Pro Arg Leu His Met Glu 580 585 590 Trp Ile Arg Glu Thr His Ile Gly Asp Thr Val Cys Pro Ala Glu Val 595 600 605 Asp Ser Ala Leu Asp Ser Thr Asp Asn Ser Asp Asn Cys Arg Thr Asp 610 615 620 Ser Glu Glu Ala Gly Thr Ser Gln Ala Gly Trp Ala Cys Gly Arg Thr 625 630 635 640 Gln Gly Ser Ser Pro Arg Leu Arg Leu Arg Gly Ser Arg Pro Arg Gly 645 650 655 His Arg Trp Ser Lys Lys Ala Glu Ala Glu Leu Pro Trp Gly Leu Gln 660 665 670 Ala Gln Gln His Leu Pro Arg Ala Asp Asp Val Glu Val Glu Asn Glu 675 680 685 Val Lys Glu Gly Arg Gly His Thr Pro Glu Gly Thr Leu Phe Leu Arg 690 695 700 Glu Asp Ala Lys Pro Pro Asp Leu Glu Leu Lys Arg Val Ser Leu Gly 705 710 715 720 Pro Gln Trp Gln Pro Gly Pro Gly Leu Gly Ser His Gln Pro His Pro 725 730 735 Leu Asp Ser Arg Thr Pro Cys Arg Thr Ala Tyr Ala Thr Thr Ala Pro 740 745 750 Met Thr Pro Glu Ser Ser Gly Pro Gly Gly Gln Ala Gln Val Thr Glu 755 760 765 Ser His Glu Ser Leu Glu Ile Val Ser Pro Ser Ser Leu Gln Gln Ser 770 775 780 His Ala Glu Pro Ser Ala Pro His Gln Ala Trp Gln Pro Thr Ala Ser 785 790 795 800 Leu Cys Pro Glu Gly Trp Ala Pro Thr Pro Pro Pro Ser Arg Lys Thr 805 810 815 Thr Ser Pro Val Ser His Arg Lys Ala Ala Leu Ala Gly Leu Leu Arg 820 825 830 Leu Gly Asp Gln Thr Glu Pro Val Gly Ile Pro Arg Pro Pro Ser Arg 835 840 845 Ser Ala Val Leu Arg Thr Cys Glu Leu Pro Pro Ser Gln Thr Gln Pro 850 855 860 Ser Arg Pro Gln Val Arg His Pro Leu Leu Ala Leu Ser Thr Asn Asn 865 870 875 880 Cys Asn Asn Ser Ala Pro Arg Gly Leu Gln Glu Pro Tyr Gly Gly Ala 885 890 895 Val His Glu Gly Arg Val Glu Arg Gly Pro Cys Ser Arg Glu Pro Glu 900 905 910 Pro Pro Leu Glu Asn Ser Arg Asp Gly Gly Pro Gln Gly Phe Leu Gly 915 920 925 Ser Ala Asp Val Ala Thr Ile Asn Ser Thr Gly Ile Thr Leu Ser Leu 930 935 940 Ser Ser Glu Glu Ser Glu Ser Ser Lys Glu Ser Glu Gly Ser Leu Gln 945 950 955 960 Arg Thr Gly Ser Gly Ser Gly Gly His Val Leu Ser Arg Ala Ser Ala 965 970 975 Gly Ala Gly Thr Gly Pro Gly Ser Pro Ser Ala Ala Pro Leu Asp Gln 980 985 990 Asn Lys Lys Arg Ser Ser Ser Ile Ala Ser Thr Leu Gly Leu Lys Lys 995 1000 1005 Leu Phe Ser Ala Leu Gly Gln Ser Ser Arg Pro Lys Leu Gly Lys Ser 1010 1015 1020 Arg Ser Tyr Ser Val Glu Gln Leu Gln Pro Ala Pro Pro Gly Leu Thr 1025 1030 1035 1040 Ser Gln Ser Arg Ala Pro Ser Leu Gln Ser Leu His Pro Val Ser Pro 1045 1050 1055 Ser His Gln Arg Arg Lys Ala Ala Ser Phe Gln Asn Leu His Ser Leu 1060 1065 1070 Leu Ser Ser Lys Gly Asn Arg Ser Ser Leu Tyr Leu Val Ala Gly Pro 1075 1080 1085 Gly Asp His Ser Ala Ala Gly Arg Pro Ala Lys Thr Ser Pro Arg Arg 1090 1095 1100 Ala Leu Ser Val Glu Asp Val Gly Ala Pro Ser Leu Ala Arg Thr Val 1105 1110 1115 1120 Gly Arg Leu Val Glu Val Phe Pro Asp Gly Thr Ser Gln Leu Gln Leu 1125 1130 1135 Gln Arg Ser Pro Gly Gly Thr Phe Gly Phe Cys Val Ala Ser Gly Asn 1140 1145 1150 Gly Arg Pro Asp Ser Gly Met Pro Ser Pro Leu Pro Gln Pro His Gly 1155 1160 1165 Trp Gly Gly Leu Ser Lys Gln Gly Arg Ala Phe Trp Leu Trp Ser Glu 1170 1175 1180 Ala Phe Leu Val Phe Gly 1185 1190 <210> 8 <211> 610 <212> PRT <213> Homo sapiens <400> 8 Met Ala Ala Pro Ile Leu Lys Asp Val Val Ala Tyr Val Glu Val Trp 1 5 10 15 Ser Ser Asn Gly Thr Glu Asn Tyr Ser Lys Thr Phe Thr Thr Gln Leu 20 25 30 Val Asp Met Gly Ala Lys Val Ser Lys Thr Phe Asn Lys Gln Val Thr 35 40 45 His Val Ile Phe Lys Asp Gly Tyr Gln Ser Thr Trp Asp Lys Ala Gln 50 55 60 Lys Arg Gly Val Lys Leu Val Ser Val Leu Trp Val Glu Lys Cys Arg 65 70 75 80 Thr Ala Gly Ala His Ile Asp Glu Ser Leu Phe Pro Ala Ala Asn Met 85 90 95 Asn Glu His Leu Ser Ser Leu Ile Lys Lys Lys Arg Lys Cys Met Gln 100 105 110 Pro Lys Asp Phe Asn Phe Lys Thr Pro Glu Asn Asp Lys Arg Phe Gln 115 120 125 Lys Lys Phe Glu Lys Met Ala Lys Glu Leu Gln Arg Gln Lys Thr Asn 130 135 140 Leu Asp Asp Asp Val Pro Ile Leu Leu Phe Glu Ser Asn Gly Ser Leu 145 150 155 160 Ile Tyr Thr Pro Thr Ile Glu Ile Asn Ser Ser His His Ser Ala Met 165 170 175 Glu Lys Arg Leu Gln Glu Met Lys Glu Lys Arg Glu Asn Leu Ser Pro 180 185 190 Thr Ser Ser Gln Met Ile Gln Gln Ser His Asp Asn Pro Ser Asn Ser 195 200 205 Leu Cys Glu Ala Pro Leu Asn Ile Ser Arg Asp Thr Leu Cys Ser Asp 210 215 220 Glu Tyr Phe Ala Gly Gly Leu His Ser Ser Phe Asp Asp Leu Cys Gly 225 230 235 240 Asn Ser Gly Cys Gly Asn Gln Glu Arg Lys Leu Glu Gly Ser Ile Asn 245 250 255 Asp Ile Lys Ser Asp Val Cys Ile Ser Ser Leu Val Leu Lys Ala Asn 260 265 270 Asn Ile His Ser Ser Pro Ser Phe Thr His Leu Asp Lys Ser Ser Pro 275 280 285 Gln Lys Phe Leu Ser Asn Leu Ser Lys Glu Glu Ile Asn Leu Gln Arg 290 295 300 Asn Ile Ala Gly Lys Val Val Thr Pro Asp Gln Lys Gln Ala Ala Gly 305 310 315 320 Met Ser Gln Glu Thr Phe Glu Glu Lys Tyr Arg Leu Ser Pro Thr Leu 325 330 335 Ser Ser Thr Lys Gly His Leu Leu Ile His Ser Arg Pro Arg Ser Ser 340 345 350 Ser Val Lys Arg Lys Arg Val Ser His Gly Ser His Ser Pro Pro Lys 355 360 365 Glu Lys Cys Lys Arg Lys Arg Ser Thr Arg Arg Ser Ile Met Pro Arg 370 375 380 Leu Gln Leu Cys Arg Ser Glu Asp Arg Leu Gln His Val Ala Gly Pro 385 390 395 400 Ala Leu Glu Ala Leu Ser Cys Gly Glu Ser Ser Tyr Asp Asp Tyr Phe 405 410 415 Ser Pro Asp Asn Leu Lys Glu Arg Tyr Ser Glu Asn Leu Pro Pro Glu 420 425 430 Ser Gln Leu Pro Ser Ser Pro Ala Gln Leu Ser Cys Arg Ser Leu Ser 435 440 445 Lys Lys Glu Arg Thr Ser Ile Phe Glu Met Ser Asp Phe Ser Cys Val 450 455 460 Gly Lys Lys Thr Arg Thr Val Asp Ile Thr Asn Phe Thr Ala Lys Thr 465 470 475 480 Ile Ser Ser Pro Arg Lys Thr Gly Asn Gly Glu Gly Arg Ala Thr Ser 485 490 495 Ser Cys Val Thr Ser Ala Pro Glu Glu Ala Leu Arg Cys Cys Arg Gln 500 505 510 Ala Gly Lys Glu Asp Ala Cys Pro Glu Gly Asn Gly Phe Ser Tyr Thr 515 520 525 Ile Glu Asp Pro Ala Leu Pro Lys Gly His Asp Asp Asp Leu Thr Pro 530 535 540 Leu Glu Gly Ser Leu Glu Glu Met Lys Glu Ala Val Gly Leu Lys Ser 545 550 555 560 Thr Gln Asn Lys Gly Thr Thr Ser Lys Ile Ser Asn Ser Ser Glu Gly 565 570 575 Glu Ala Gln Ser Glu His Glu Pro Cys Phe Ile Val Asp Cys Asn Met 580 585 590 Glu Thr Ser Thr Glu Glu Lys Glu Asn Leu Pro Gly Gly Tyr Ser Gly 595 600 605 Ser Met 610 <210> 9 <211> 1062 <212> PRT <213> Homo sapiens <400> 9 Met Val Ser Ser Ala Gln Met Gly Phe Asn Leu Gln Ala Leu Leu Glu 1 5 10 15 Gln Leu Ser Gln Asp Glu Leu Ser Lys Phe Lys Tyr Leu Ile Thr Thr 20 25 30 Phe Ser Leu Ala His Glu Leu Gln Lys Ile Pro His Lys Glu Val Asp 35 40 45 Lys Ala Asp Gly Lys Gln Leu Val Glu Ile Leu Thr Thr His Cys Asp 50 55 60 Ser Tyr Trp Val Glu Met Ala Ser Leu Gln Val Phe Glu Lys Met His 65 70 75 80 Arg Met Asp Leu Ser Glu Arg Ala Lys Asp Glu Val Arg Glu Ala Ala 85 90 95 Leu Lys Ser Phe Asn Lys Arg Lys Pro Leu Ser Leu Gly Ile Thr Arg 100 105 110 Lys Glu Arg Pro Pro Leu Asp Val Asp Glu Met Leu Glu Arg Phe Lys 115 120 125 Thr Glu Ala Gln Ala Phe Thr Glu Thr Lys Gly Asn Val Ile Cys Leu 130 135 140 Gly Lys Glu Val Phe Lys Gly Lys Lys Pro Asp Lys Asp Asn Arg Cys 145 150 155 160 Arg Tyr Ile Leu Lys Thr Lys Phe Arg Glu Met Trp Lys Ser Trp Pro 165 170 175 Gly Asp Ser Lys Glu Val Gln Val Met Ala Glu Arg Tyr Lys Met Leu 180 185 190 Ile Pro Phe Ser Asn Pro Arg Val Leu Pro Gly Pro Phe Ser Tyr Thr 195 200 205 Val Val Leu Tyr Gly Pro Ala Gly Leu Gly Lys Thr Thr Leu Ala Gln 210 215 220 Lys Leu Met Leu Asp Trp Ala Glu Asp Asn Leu Ile His Lys Phe Lys 225 230 235 240 Tyr Ala Phe Tyr Leu Ser Cys Arg Glu Leu Ser Arg Leu Gly Pro Cys 245 250 255 Ser Phe Ala Glu Leu Val Phe Arg Asp Trp Pro Glu Leu Gln Asp Asp 260 265 270 Ile Pro His Ile Leu Ala Gln Ala Arg Lys Ile Leu Phe Val Ile Asp 275 280 285 Gly Phe Asp Glu Leu Gly Ala Ala Pro Gly Ala Leu Ile Glu Asp Ile 290 295 300 Cys Gly Asp Trp Glu Lys Lys Lys Pro Val Pro Val Leu Leu Gly Ser 305 310 315 320 Leu Leu Asn Arg Val Met Leu Pro Lys Ala Ala Leu Leu Val Thr Thr 325 330 335 Arg Pro Arg Ala Leu Arg Asp Leu Arg Ile Leu Ala Glu Glu Pro Ile 340 345 350 Tyr Ile Arg Val Glu Gly Phe Leu Glu Glu Asp Arg Arg Ala Tyr Phe 355 360 365 Leu Arg His Phe Gly Asp Glu Asp Gln Ala Met Arg Ala Phe Glu Leu 370 375 380 Met Arg Ser Asn Ala Ala Leu Phe Gln Leu Gly Ser Ala Pro Ala Val 385 390 395 400 Cys Trp Ile Val Cys Thr Thr Leu Lys Leu Gln Met Glu Lys Gly Glu 405 410 415 Asp Pro Val Pro Thr Cys Leu Thr Arg Thr Gly Leu Phe Leu Arg Phe 420 425 430 Leu Cys Ser Arg Phe Pro Gln Gly Ala Gln Leu Arg Gly Ala Leu Arg 435 440 445 Thr Leu Ser Leu Leu Ala Ala Gln Gly Leu Trp Ala Gln Thr Ser Val 450 455 460 Leu His Arg Glu Asp Leu Glu Arg Leu Gly Val Gln Glu Ser Asp Leu 465 470 475 480 Arg Leu Phe Leu Asp Gly Asp Ile Leu Arg Gln Asp Arg Val Ser Lys 485 490 495 Gly Cys Tyr Ser Phe Ile His Leu Ser Phe Gln Gln Phe Leu Thr Ala 500 505 510 Leu Phe Tyr Thr Leu Glu Lys Glu Glu Glu Glu Asp Arg Asp Gly His 515 520 525 Thr Trp Asp Ile Gly Asp Val Gln Lys Leu Leu Ser Gly Val Glu Arg 530 535 540 Leu Arg Asn Pro Asp Leu Ile Gln Ala Gly Tyr Tyr Ser Phe Gly Leu 545 550 555 560 Ala Asn Glu Lys Arg Ala Lys Glu Leu Glu Ala Thr Phe Gly Cys Arg 565 570 575 Met Ser Pro Asp Ile Lys Gln Glu Leu Leu Arg Cys Asp Ile Ser Cys 580 585 590 Lys Gly Gly His Ser Thr Val Thr Asp Leu Gln Glu Leu Leu Gly Cys 595 600 605 Leu Tyr Glu Ser Gln Glu Glu Glu Leu Val Lys Glu Val Met Ala Gln 610 615 620 Phe Lys Glu Ile Ser Leu His Leu Asn Ala Val Asp Val Val Pro Ser 625 630 635 640 Ser Phe Cys Val Lys His Cys Arg Asn Leu Gln Lys Met Ser Leu Gln 645 650 655 Val Ile Lys Glu Asn Leu Pro Glu Asn Val Thr Ala Ser Glu Ser Asp 660 665 670 Ala Glu Val Glu Arg Ser Gln Asp Asp Gln His Met Leu Pro Phe Trp 675 680 685 Thr Asp Leu Cys Ser Ile Phe Gly Ser Asn Lys Asp Leu Met Gly Leu 690 695 700 Ala Ile Asn Asp Ser Phe Leu Ser Ala Ser Leu Val Arg Ile Leu Cys 705 710 715 720 Glu Gln Ile Ala Ser Asp Thr Cys His Leu Gln Arg Val Val Phe Lys 725 730 735 Asn Ile Ser Pro Ala Asp Ala His Arg Asn Leu Cys Leu Ala Leu Arg 740 745 750 Gly His Lys Thr Val Thr Tyr Leu Thr Leu Gln Gly Asn Asp Gln Asp 755 760 765 Asp Met Phe Pro Ala Leu Cys Glu Val Leu Arg His Pro Glu Cys Asn 770 775 780 Leu Arg Tyr Leu Gly Leu Val Ser Cys Ser Ala Thr Thr Gln Gln Trp 785 790 795 800 Ala Asp Leu Ser Leu Ala Leu Glu Val Asn Gln Ser Leu Thr Cys Val 805 810 815 Asn Leu Ser Asp Asn Glu Leu Leu Asp Glu Gly Ala Lys Leu Leu Tyr 820 825 830 Thr Thr Leu Arg His Pro Lys Cys Phe Leu Gln Arg Leu Ser Leu Glu 835 840 845 Asn Cys His Leu Thr Glu Ala Asn Cys Lys Asp Leu Ala Ala Val Leu 850 855 860 Val Val Ser Arg Glu Leu Thr His Leu Cys Leu Ala Lys Asn Pro Ile 865 870 875 880 Gly Asn Thr Gly Val Lys Phe Leu Cys Glu Gly Leu Arg Tyr Pro Glu 885 890 895 Cys Lys Leu Gln Thr Leu Val Leu Trp Asn Cys Asp Ile Thr Ser Asp 900 905 910 Gly Cys Cys Asp Leu Thr Lys Leu Leu Gln Glu Lys Ser Ser Leu Leu 915 920 925 Cys Leu Asp Leu Gly Leu Asn His Ile Gly Val Lys Gly Met Lys Phe 930 935 940 Leu Cys Glu Ala Leu Arg Lys Pro Leu Cys Asn Leu Arg Cys Leu Trp 945 950 955 960 Leu Trp Gly Cys Ser Ile Pro Pro Phe Ser Cys Glu Asp Leu Cys Ser 965 970 975 Ala Leu Ser Cys Asn Gln Ser Leu Val Thr Leu Asp Leu Gly Gln Asn 980 985 990 Pro Leu Gly Ser Ser Gly Val Lys Met Leu Phe Glu Thr Leu Thr Cys 995 1000 1005 Ser Ser Gly Thr Leu Arg Thr Leu Arg Leu Lys Ile Asp Asp Phe Asn 1010 1015 1020 Asp Glu Leu Asn Lys Leu Leu Glu Glu Ile Glu Glu Lys Asn Pro Gln 1025 1030 1035 1040 Leu Ile Ile Asp Thr Glu Lys His His Pro Trp Ala Glu Arg Pro Ser 1045 1050 1055 Ser His Asp Phe Met Ile 1060 <210> 10 <211> 211 <212> PRT <213> Homo sapiens <400> 10 Met Ser Leu Ser Ser Leu Cys Pro Val Phe Ser Ala Ala Ala Ser Ser 1 5 10 15 Leu Gln Val His Leu Leu Lys Asp Gln Leu Ala Ala Glu Ala Ala Ala 20 25 30 Arg Leu Glu Ala Gln Ala Arg Val His Gln Leu Leu Leu Gln Asn Lys 35 40 45 Asp Met Leu Gln His Ile Ser Leu Leu Val Lys Gln Val Gln Glu Leu 50 55 60 Glu Leu Lys Leu Ser Gly Gln Asn Ala Met Gly Ser Gln Asp Ser Leu 65 70 75 80 Leu Glu Ile Thr Phe Arg Ser Gly Ala Leu Pro Val Leu Cys Asp Pro 85 90 95 Thr Thr Pro Lys Pro Glu Asp Leu His Ser Pro Pro Leu Gly Ala Gly 100 105 110 Leu Ala Asp Phe Ala His Pro Ala Gly Ser Pro Leu Gly Arg Arg Asp 115 120 125 Cys Leu Val Lys Leu Glu Cys Phe Arg Phe Leu Pro Glu Asp Thr 130 135 140 Pro Pro Pro Ala Gln Gly Glu Ala Leu Leu Gly Gly Leu Glu Leu Ile 145 150 155 160 Lys Phe Arg Glu Ser Gly Ile Ala Ser Glu Tyr Glu Ser Asn Thr Asp 165 170 175 Glu Ser Glu Glu Arg Asp Ser Trp Ser Gln Glu Glu Leu Pro Arg Leu 180 185 190 Leu Asn Val Leu Gln Arg Gln Glu Leu Gly Asp Gly Leu Asp Asp Glu 195 200 205 Ile Ala Val 210 <210> 11 <211> 326 <212> PRT <213> Homo sapiens <400> 11 Met Ala Ala Pro Ala Ser Val Met Gly Pro Leu Gly Pro Ser Ala Leu 1 5 10 15 Gly Leu Leu Leu Leu Leu Leu Val Val Ala Pro Pro Arg Val Ala Ala 20 25 30 Leu Val His Arg Gln Pro Glu Asn Gln Gly Ile Ser Leu Thr Gly Ser 35 40 45 Val Ala Cys Gly Arg Pro Ser Met Glu Gly Lys Ile Leu Gly Gly Val 50 55 60 Pro Ala Pro Glu Arg Lys Trp Pro Trp Gln Val Ser Val His Tyr Ala 65 70 75 80 Gly Leu His Val Cys Gly Gly Ser Ile Leu Asn Glu Tyr Trp Val Leu 85 90 95 Ser Ala Ala His Cys Phe His Arg Asp Lys Asn Ile Lys Ile Tyr Asp 100 105 110 Met Tyr Val Gly Leu Val Asn Leu Arg Val Ala Gly Asn His Thr Gln 115 120 125 Trp Tyr Glu Val Asn Arg Val Ile Leu His Pro Thr Tyr Glu Met Tyr 130 135 140 His Pro Ile Gly Gly Asp Val Ala Leu Val Gln Leu Lys Thr Arg Ile 145 150 155 160 Val Phe Ser Glu Ser Val Leu Pro Val Cys Leu Ala Thr Pro Glu Val 165 170 175 Asn Leu Thr Ser Ala Asn Cys Trp Ala Thr Gly Trp Gly Leu Val Ser 180 185 190 Lys Gln Gly Glu Thr Ser Asp Glu Leu Gln Glu Met Gln Leu Pro Leu 195 200 205 Ile Leu Glu Pro Trp Cys His Leu Leu Tyr Gly His Met Ser Tyr Ile 210 215 220 Met Pro Asp Met Leu Cys Ala Gly Asp Ile Leu Asn Ala Lys Thr Val 225 230 235 240 Cys Glu Gly Asp Ser Gly Gly Pro Leu Val Cys Glu Phe Asn Arg Ser 245 250 255 Trp Leu Gln Ile Gly Ile Val Ser Trp Gly Arg Gly Cys Ser Asn Pro 260 265 270 Leu Tyr Pro Gly Val Tyr Ala Ser Val Ser Tyr Phe Ser Lys Trp Ile 275 280 285 Cys Asp Asn Ile Glu Ile Thr Pro Thr Pro Ala Gln Pro Ala Pro Ala 290 295 300 Leu Ser Pro Ala Leu Gly Pro Thr Leu Ser Val Leu Met Ala Met Leu 305 310 315 320 Ala Gly Trp Ser Val Leu 325 <210> 12 <211> 1765 <212> PRT <213> Homo sapiens <400> 12 Met Arg Arg Ser Lys Ala Asp Val Glu Arg Tyr Val Ala Ser Val Leu 1 5 10 15 Gly Leu Thr Pro Ser Pro Arg Gln Lys Ser Met Lys Gly Phe Tyr Phe 20 25 30 Ala Lys Leu Tyr Tyr Glu Ala Lys Glu Tyr Asp Leu Ala Lys Lys Tyr 35 40 45 Ile Cys Thr Tyr Ile Asn Val Gln Glu Arg Asp Pro Lys Ala His Arg 50 55 60 Phe Leu Gly Leu Leu Tyr Glu Leu Glu Glu Asn Thr Glu Lys Ala Val 65 70 75 80 Glu Cys Tyr Arg Arg Ser Val Glu Leu Asn Pro Thr Gln Lys Asp Leu 85 90 95 Val Leu Lys Ile Ala Glu Leu Leu Cys Lys Asn Asp Val Thr Asp Gly 100 105 110 Arg Ala Lys Tyr Trp Val Glu Arg Ala Ala Lys Leu Phe Pro Gly Ser 115 120 125 Pro Ala Ile Tyr Lys Leu Lys Glu Gln Leu Leu Asp Cys Glu Gly Glu 130 135 140 Asp Gly Trp Asn Lys Leu Phe Asp Leu Ile Gln Ser Glu Leu Tyr Val 145 150 155 160 Arg Pro Asp Asp Val His Val Asn Ile Arg Leu Val Glu Leu Tyr Arg 165 170 175 Ser Thr Lys Arg Leu Lys Asp Ala Val Ala His Cys His Glu Ala Glu 180 185 190 Arg Asn Ile Ala Leu Arg Ser Ser Leu Glu Trp Asn Ser Cys Val Val 195 200 205 Gln Thr Leu Lys Glu Tyr Leu Glu Ser Leu Gln Cys Leu Glu Ser Asp 210 215 220 Lys Ser Asp Trp Gln Ala Thr Asn Thr Asp Leu Leu Leu Ala Tyr Ala 225 230 235 240 Asn Leu Met Leu Leu Thr Leu Ser Thr Arg Asp Val Gln Glu Asn Arg 245 250 255 Glu Leu Leu Glu Ser Phe Asp Ser Ala Leu Gln Ser Ala Lys Ser Ser 260 265 270 Leu Gly Gly Asn Asp Glu Leu Ser Ala Thr Phe Leu Glu Met Lys Gly 275 280 285 His Phe Tyr Met Tyr Ala Gly Ser Leu Leu Leu Lys Met Gly Gln His 290 295 300 Gly Asn Asn Val Gln Trp Arg Ala Leu Ser Glu Leu Ala Ala Leu Cys 305 310 315 320 Tyr Leu Ile Ala Phe Gln Val Pro Arg Pro Lys Ile Lys Leu Arg Glu 325 330 335 Gly Lys Ala Gly Gln Asn Leu Leu Glu Met Met Ala Cys Asp Arg Leu 340 345 350 Ser Gln Ser Gly His Met Leu Leu Ser Leu Ser Arg Gly Lys Gln Asp 355 360 365 Phe Leu Lys Glu Val Val Glu Thr Phe Ala Asn Lys Ile Gly Gln Ser 370 375 380 Ala Leu Tyr Asp Ala Leu Phe Ser Ser Gln Ser Pro Lys Asp Thr Ser 385 390 395 400 Phe Leu Gly Ser Asp Asp Ile Gly Lys Ile Asp Val Gln Glu Pro Glu 405 410 415 Leu Glu Asp Leu Ala Arg Tyr Asp Val Gly Ala Ile Arg Ala His Asn 420 425 430 Gly Ser Leu Gln His Leu Thr Trp Leu Gly Leu Gln Trp Asn Ser Leu 435 440 445 Pro Ala Leu Pro Gly Ile Arg Lys Trp Leu Lys Gln Leu Phe His Arg 450 455 460 Leu Pro His Glu Thr Ser Arg Leu Glu Thr Asn Ala Pro Glu Ser Ile 465 470 475 480 Cys Ile Leu Asp Leu Glu Val Phe Leu Leu Gly Val Val Tyr Thr Ser 485 490 495 His Leu Gln Leu Lys Glu Lys Cys Asn Ser His His Ser Ser Tyr Gln 500 505 510 Pro Leu Cys Leu Pro Phe Pro Val Cys Lys Gln Leu Cys Thr Glu Arg 515 520 525 Gln Lys Ser Trp Trp Asp Ala Val Cys Thr Leu Ile His Arg Lys Ala 530 535 540 Val Pro Gly Asn Leu Ala Lys Leu Arg Leu Leu Val Gln His Glu Ile 545 550 555 560 Asn Thr Leu Arg Ala Gln Glu Lys His Gly Leu Gln Pro Ala Leu Leu 565 570 575 Val His Trp Ala Lys Tyr Leu Gln Lys Thr Gly Ser Gly Leu Asn Ser 580 585 590 Phe Tyr Gly Gln Leu Glu Tyr Ile Gly Arg Ser Val His Tyr Trp Lys 595 600 605 Lys Val Leu Pro Leu Leu Lys Ile Ile Lys Lys Asn Ser Ile Pro Glu 610 615 620 Pro Ile Asp Pro Leu Phe Lys His Phe His Ser Val Asp Ile Gln Ala 625 630 635 640 Ser Glu Ile Val Glu Tyr Glu Glu Asp Ala His Ile Thr Phe Ala Met 645 650 655 Leu Asp Ala Val Asn Gly Asn Ile Glu Asp Ala Val Thr Ala Phe Glu 660 665 670 Ser Ile Lys Ser Val Val Ser Tyr Trp Asn Leu Ala Leu Ile Phe His 675 680 685 Arg Lys Ala Glu Asp Ile Glu Asn Asp Ala Leu Ser Pro Glu Glu Gln 690 695 700 Glu Glu Cys Arg Asn Tyr Leu Thr Lys Thr Arg Asp Tyr Leu Ile Lys 705 710 715 720 Ile Ile Asp Asp Gly Asp Ser Asn Leu Ser Val Val Lys Lys Leu Pro 725 730 735 Val Pro Leu Glu Ser Val Lys Gln Met Leu Asn Ser Val Met Gln Glu 740 745 750 Leu Glu Asp Tyr Ser Glu Gly Gly Pro Leu Tyr Lys Asn Gly Ser Leu 755 760 765 Arg Asn Ala Asp Ser Glu Ile Lys His Ser Thr Pro Ser Pro Thr Lys 770 775 780 Tyr Ser Leu Ser Pro Ser Lys Ser Tyr Lys Tyr Ser Pro Glu Thr Pro 785 790 795 800 Pro Arg Trp Thr Glu Asp Arg Asn Ser Leu Leu Asn Met Ile Cys Gln 805 810 815 Gln Val Glu Ala Ile Lys Lys Glu Met Gln Glu Leu Lys Leu Asn Ser 820 825 830 Ser Lys Ser Ala Ser Arg His Arg Trp Pro Thr Glu Asn Tyr Gly Pro 835 840 845 Asp Ser Val Pro Asp Gly Tyr Gln Gly Ser Gln Thr Phe His Gly Ala 850 855 860 Pro Leu Thr Val Ala Thr Thr Gly Pro Ser Val Tyr Tyr Ser Gln Ser 865 870 875 880 Pro Ala Tyr Asn Ser Gln Tyr Leu Leu Arg Pro Ala Ala Asn Val Thr 885 890 895 Pro Thr Lys Gly Ser Ser Asn Thr Glu Phe Lys Ser Thr Lys Glu Gly 900 905 910 Phe Ser Ile Pro Val Ser Ala Asp Gly Phe Lys Phe Gly Ile Ser Glu 915 920 925 Pro Gly Asn Gln Glu Lys Lys Arg Glu Lys Pro Leu Glu Asn Asp Thr 930 935 940 Gly Phe Gln Ala Gln Asp Ile Ser Gly Arg Lys Lys Gly Arg Gly Val 945 950 955 960 Ile Phe Gly Gln Thr Ser Ser Thr Phe Thr Phe Ala Asp Val Ala Lys 965 970 975 Ser Thr Ser Gly Glu Gly Phe Gln Phe Gly Lys Lys Asp Leu Asn Phe 980 985 990 Lys Gly Phe Ser Gly Ala Gly Glu Lys Leu Phe Ser Ser Arg Tyr Gly 995 1000 1005 Lys Met Ala Asn Lys Ala Asn Thr Ser Gly Asp Phe Glu Lys Asp Asp 1010 1015 1020 Asp Ala Tyr Lys Thr Glu Asp Ser Asp Asp Ile His Phe Glu Pro Val 1025 1030 1035 1040 Val Gln Met Pro Glu Lys Val Glu Leu Val Thr Gly Glu Glu Gly Glu 1045 1050 1055 Lys Val Leu Tyr Ser Gln Gly Val Lys Leu Phe Arg Phe Asp Ala Glu 1060 1065 1070 Val Arg Gln Trp Lys Glu Arg Gly Leu Gly Asn Leu Lys Ile Leu Lys 1075 1080 1085 Asn Glu Val Asn Gly Lys Leu Arg Met Leu Met Arg Arg Glu Gln Val 1090 1095 1100 Leu Lys Val Cys Ala Asn His Trp Ile Thr Thr Thr Met Asn Leu Lys 1105 1110 1115 1120 Pro Leu Ser Gly Ser Asp Arg Ala Trp Met Trp Ser Ala Ser Asp Phe 1125 1130 1135 Ser Asp Gly Asp Ala Lys Leu Glu Arg Leu Ala Ala Lys Phe Lys Thr 1140 1145 1150 Pro Glu Leu Ala Glu Glu Phe Lys Gln Lys Phe Glu Glu Cys Gln Arg 1155 1160 1165 Leu Leu Leu Asp Ile Pro Leu Gln Thr Pro His Lys Leu Val Asp Thr 1170 1175 1180 Gly Arg Ala Ala Lys Leu Ile Gln Arg Ala Glu Glu Met Lys Ser Gly 1185 1190 1195 1200 Leu Lys Asp Phe Lys Thr Phe Leu Thr Asn Asp Gln Thr Lys Val Thr 1205 1210 1215 Glu Glu Glu Asn Lys Gly Ser Gly Thr Gly Ala Ala Gly Ala Ser Asp 1220 1225 1230 Thr Thr Ile Lys Pro Asn Ala Glu Asn Thr Gly Pro Thr Leu Glu Trp 1235 1240 1245 Asp Asn Tyr Asp Leu Arg Glu Asp Ala Leu Asp Asp Ser Val Ser Ser 1250 1255 1260 Ser Ser Val His Ala Ser Pro Leu Ala Ser Ser Pro Val Arg Lys Asn 1265 1270 1275 1280 Leu Phe Arg Phe Asp Glu Ser Thr Thr Gly Ser Asn Phe Ser Phe Lys 1285 1290 1295 Ser Ala Leu Ser Leu Ser Lys Ser Pro Ala Lys Leu Asn Gln Ser Gly 1300 1305 1310 Thr Ser Val Gly Thr Asp Glu Glu Ser Val Val Thr Gln Glu Glu Glu 1315 1320 1325 Arg Asp Gly Gln Tyr Phe Glu Pro Val Val Pro Leu Pro Asp Leu Val 1330 1335 1340 Glu Val Ser Ser Gly Glu Glu Asn Glu Gln Val Val Phe Ser His Arg 1345 1350 1355 1360 Ala Glu Ile Tyr Arg Tyr Asp Lys Asp Val Gly Gln Trp Lys Glu Arg 1365 1370 1375 Gly Ile Gly Asp Ile Lys Ile Leu Gln Asn Tyr Asp Asn Lys Gln Val 1380 1385 1390 Arg Ile Val Met Arg Arg Asp Gln Val Leu Lys Leu Cys Ala Asn His 1395 1400 1405 Arg Ile Thr Pro Asp Met Ser Leu Gln Asn Met Lys Gly Thr Glu Arg 1410 1415 1420 Val Trp Val Trp Thr Ala Cys Asp Phe Ala Asp Gly Glu Arg Lys Val 1425 1430 1435 1440 Glu His Leu Ala Val Arg Phe Lys Leu Gln Asp Val Ala Asp Ser Phe 1445 1450 1455 Lys Lys Ile Phe Asp Glu Ala Lys Thr Ala Gln Glu Lys Asp Ser Leu 1460 1465 1470 Ile Thr Pro His Val Ser Arg Ser Ser Thr Pro Arg Glu Ser Pro Cys 1475 1480 1485 Gly Lys Ile Ala Val Ala Ile Leu Glu Glu Thr Thr Arg Glu Arg Thr 1490 1495 1500 Asp Val Ile Gln Gly Asp Asp Val Ala Asp Ala Ala Ser Glu Val Glu 1505 1510 1515 1520 Val Ser Ser Thr Ser Glu Thr Thr Thr Lys Ala Val Val Ser Pro Pro 1525 1530 1535 Lys Phe Val Phe Val Ser Glu Ser Val Lys Arg Ile Phe Ser Ser Glu 1540 1545 1550 Lys Ser Lys Pro Phe Val Phe Gly Asn Ser Ser Ala Thr Gly Ser Leu 1555 1560 1565 Phe Gly Phe Ser Phe Asn Ala Pro Leu Lys Ser Asn Asn Ser Glu Thr 1570 1575 1580 Ser Ser Val Ala Gln Ser Gly Ser Glu Ser Lys Val Glu Pro Lys Lys 1585 1590 1595 1600 Cys Glu Leu Ser Lys Asn Ser Asp Ile Glu Gln Ser Ser Asp Ser Lys 1605 1610 1615 Val Lys Asn Leu Ser Ala Ser Phe Pro Thr Glu Glu Ser Ser Ile Asn 1620 1625 1630 Tyr Thr Phe Lys Thr Pro Glu Lys Glu Pro Pro Leu Trp His Ala Glu 1635 1640 1645 Phe Thr Lys Glu Glu Leu Val Gln Lys Leu Arg Ser Thr Thr Lys Ser 1650 1655 1660 Ala Asp His Leu Asn Gly Leu Leu Arg Glu Ile Glu Ala Thr Asn Ala 1665 1670 1675 1680 Val Leu Met Glu Gln Ile Lys Leu Leu Lys Ser Glu Ile Arg Arg Leu 1685 1690 1695 Glu Arg Asn Gln Glu Arg Glu Lys Ser Ala Ala Asn Leu Glu Tyr Leu 1700 1705 1710 Lys Asn Val Leu Leu Gln Phe Ile Phe Leu Lys Pro Gly Ser Glu Arg 1715 1720 1725 Glu Arg Leu Leu Pro Val Ile Asn Thr Met Leu Gln Leu Ser Pro Glu 1730 1735 1740 Glu Lys Gly Lys Leu Ala Ala Val Ala Gln Asp Glu Glu Glu Asn Ala 1745 1750 1755 1760 Ser Arg Ser Ser Gly 1765 <210> 13 <211> 922 <212> PRT <213> Homo sapiens <400> 13 Met Ile Ser Leu Lys Val Cys Gly Phe Ile Gln Ile Trp Ser Gln Lys 1 5 10 15 Thr Gly Met Thr Lys Leu Lys Glu Ala Leu Ile Glu Thr Val Gln Arg 20 25 30 Gln Lys Glu Ile Lys Leu Val Val Thr Phe Lys Ser Gly Lys Phe Ile 35 40 45 Arg Ile Phe Gln Leu Ser Asn Asn Ile Arg Ser Val Val Leu Arg His 50 55 60 Cys Lys Lys Arg Gln Ser His Leu Arg Leu Thr Leu Lys Asn Asn Val 65 70 75 80 Phe Leu Phe Ile Asp Lys Leu Ser Tyr Arg Asp Ala Lys Gln Leu Asn 85 90 95 Met Phe Leu Asp Ile Ile His Gln Asn Lys Ser Gln Gln Pro Met Lys 100 105 110 Ser Asp Asp Asp Trp Ser Val Phe Glu Ser Arg Asn Met Leu Lys Glu 115 120 125 Ile Asp Lys Thr Ser Phe Tyr Ser Ile Cys Asn Lys Pro Ser Tyr Gln 130 135 140 Lys Met Pro Leu Phe Met Ser Lys Ser Pro Thr His Val Lys Lys Gly 145 150 155 160 Ile Leu Glu Asn Gln Gly Gly Lys Gly Gln Asn Thr Leu Ser Ser Asp 165 170 175 Val Gln Thr Asn Glu Asp Ile Leu Lys Glu Asp Asn Pro Val Pro Asn 180 185 190 Lys Lys Tyr Lys Thr Asp Ser Leu Lys Tyr Ile Gln Ser Asn Arg Lys 195 200 205 Asn Pro Ser Ser Leu Glu Asp Leu Glu Lys Asp Arg Asp Leu Lys Leu 210 215 220 Gly Pro Ser Phe Asn Thr Asn Cys Asn Gly Asn Pro Asn Leu Asp Glu 225 230 235 240 Thr Val Leu Ala Thr Gln Thr Leu Asn Ala Lys Asn Gly Leu Thr Ser 245 250 255 Pro Leu Glu Pro Glu His Ser Gln Gly Asp Pro Arg Cys Asn Lys Ala 260 265 270 Gln Val Pro Leu Asp Ser His Ser Gln Gln Leu Gln Gln Gly Phe Pro 275 280 285 Asn Leu Gly Asn Thr Cys Tyr Met Asn Ala Val Leu Gln Ser Leu Phe 290 295 300 Ala Ile Pro Ser Phe Ala Asp Asp Leu Leu Thr Gln Gly Val Pro Trp 305 310 315 320 Glu Tyr Ile Pro Phe Glu Ala Leu Ile Met Thr Leu Thr Gln Leu Leu 325 330 335 Ala Leu Lys Asp Phe Cys Ser Thr Lys Ile Lys Arg Glu Leu Leu Gly 340 345 350 Asn Val Lys Lys Val Ile Ser Ala Val Ala Glu Ile Phe Ser Gly Asn 355 360 365 Met Gln Asn Asp Ala His Glu Phe Leu Gly Gln Cys Leu Asp Gln Leu 370 375 380 Lys Glu Asp Met Glu Lys Leu Asn Ala Thr Leu Asn Thr Gly Lys Glu 385 390 395 400 Cys Gly Asp Glu Asn Ser Ser Pro Gln Met His Val Gly Ser Ala Ala 405 410 415 Thr Lys Val Phe Val Cys Pro Val Val Ala Asn Phe Glu Phe Glu Leu 420 425 430 Gln Leu Ser Leu Ile Cys Lys Ala Cys Gly His Ala Val Leu Lys Val 435 440 445 Glu Pro Asn Asn Tyr Leu Ser Ile Asn Leu His Gln Glu Thr Lys Pro 450 455 460 Leu Pro Leu Ser Ile Gln Asn Ser Leu Asp Leu Phe Phe Lys Glu Glu 465 470 475 480 Glu Leu Glu Tyr Asn Cys Gln Met Cys Lys Gln Lys Ser Cys Val Ala 485 490 495 Arg His Thr Phe Ser Arg Leu Ser Arg Val Leu Ile Ile His Leu Lys 500 505 510 Arg Tyr Ser Phe Asn Asn Ala Trp Leu Leu Val Lys Asn Asn Glu Gln 515 520 525 Val Tyr Ile Pro Lys Ser Leu Ser Leu Ser Ser Tyr Cys Asn Glu Ser 530 535 540 Thr Lys Pro Pro Leu Pro Leu Ser Ser Ser Ala Pro Val Gly Lys Cys 545 550 555 560 Glu Val Leu Glu Val Ser Gln Glu Met Ile Ser Glu Ile Asn Ser Pro 565 570 575 Leu Thr Pro Ser Met Lys Leu Thr Ser Glu Ser Ser Asp Ser Leu Val 580 585 590 Leu Pro Val Glu Pro Asp Lys Asn Ala Asp Leu Gln Arg Phe Gln Arg 595 600 605 Asp Cys Gly Asp Ala Ser Gln Glu Gln His Gln Arg Asp Leu Glu Asn 610 615 620 Gly Ser Ala Leu Glu Ser Glu Leu Val His Phe Arg Asp Arg Ala Ile 625 630 635 640 Gly Glu Lys Glu Leu Pro Val Ala Asp Ser Leu Met Asp Gln Gly Asp 645 650 655 Ile Ser Leu Pro Val Met Tyr Glu Asp Gly Gly Lys Leu Ile Ser Ser 660 665 670 Pro Asp Thr Arg Leu Val Glu Val His Leu Gln Glu Val Pro Gln His 675 680 685 Pro Glu Leu Gln Lys Tyr Glu Lys Thr Asn Thr Phe Val Glu Phe Asn 690 695 700 Phe Asp Ser Val Thr Glu Ser Thr Asn Gly Phe Tyr Asp Cys Lys Glu 705 710 715 720 Asn Arg Ile Pro Glu Gly Ser Gln Gly Met Ala Glu Gln Leu Gln Gln 725 730 735 Cys Ile Glu Glu Ser Ile Ile Asp Glu Phe Leu Gln Gln Ala Pro Pro 740 745 750 Pro Gly Val Arg Lys Leu Asp Ala Gln Glu His Thr Glu Glu Thr Leu 755 760 765 Asn Gln Ser Thr Glu Leu Arg Leu Gln Lys Ala Asp Leu Asn His Leu 770 775 780 Gly Ala Leu Gly Ser Asp Asn Pro Gly Asn Lys Asn Ile Leu Asp Ala 785 790 795 800 Glu Asn Thr Arg Gly Glu Ala Lys Glu Leu Thr Arg Asn Val Lys Met 805 810 815 Gly Asp Pro Leu Gln Ala Tyr Arg Leu Ile Ser Val Val Ser His Ile 820 825 830 Gly Ser Ser Pro Asn Ser Gly His Tyr Ile Ser Asp Val Tyr Asp Phe 835 840 845 Gln Lys Gln Ala Trp Phe Thr Tyr Asn Asp Leu Cys Val Ser Glu Ile 850 855 860 Ser Glu Thr Lys Met Gln Glu Ala Arg Leu His Ser Gly Tyr Ile Phe 865 870 875 880 Phe Tyr Met His Asn Gly Ile Phe Glu Glu Leu Leu Arg Lys Ala Glu 885 890 895 Asn Ser Arg Leu Pro Ser Thr Gln Ala Gly Val Ile Pro Gln Gly Glu 900 905 910 Tyr Glu Gly Asp Ser Leu Tyr Arg Pro Ala 915 920 <210> 14 <211> 1071 <212> PRT <213> Homo sapiens <400> 14 Met Pro Ala Ile Met Thr Met Leu Ala Asp His Ala Ala Arg Gln Leu 1 5 10 15 Leu Asp Phe Ser Gln Lys Leu Asp Ile Asn Leu Leu Asp Asn Val Val 20 25 30 Asn Cys Leu Tyr His Gly Glu Gly Ala Gln Gln Arg Met Ala Gln Glu 35 40 45 Val Leu Thr His Leu Lys Glu His Pro Asp Ala Trp Thr Arg Val Asp 50 55 60 Thr Ile Leu Glu Phe Ser Gln Asn Met Asn Thr Lys Tyr Tyr Gly Leu 65 70 75 80 Gln Ile Leu Glu Asn Val Ile Lys Thr Arg Trp Lys Ile Leu Pro Arg 85 90 95 Asn Gln Cys Glu Gly Ile Lys Lys Tyr Val Val Gly Leu Ile Ile Lys 100 105 110 Thr Ser Ser Asp Pro Thr Cys Val Glu Lys Glu Lys Val Tyr Ile Gly 115 120 125 Lys Leu Asn Met Ile Leu Val Gln Ile Leu Lys Gln Glu Trp Pro Lys 130 135 140 His Trp Pro Thr Phe Ile Ser Asp Ile Val Gly Ala Ser Arg Thr Ser 145 150 155 160 Glu Ser Leu Cys Gln Asn Asn Met Val Ile Leu Lys Leu Leu Ser Glu 165 170 175 Glu Val Phe Asp Phe Ser Ser Gly Gln Ile Thr Gln Val Lys Ser Lys 180 185 190 His Leu Lys Asp Ser Met Cys Asn Glu Phe Ser Gln Ile Phe Gln Leu 195 200 205 Cys Gln Phe Val Met Glu Asn Ser Gln Asn Ala Pro Leu Val His Ala 210 215 220 Thr Leu Glu Thr Leu Leu Arg Phe Leu Asn Trp Ile Pro Leu Gly Tyr 225 230 235 240 Ile Phe Glu Thr Lys Leu Ile Ser Thr Leu Ile Tyr Lys Phe Leu Asn 245 250 255 Val Pro Met Phe Arg Asn Val Ser Leu Lys Cys Leu Thr Glu Ile Ala 260 265 270 Gly Val Ser Val Ser Gln Tyr Glu Glu Gln Phe Val Thr Leu Phe Thr 275 280 285 Leu Thr Met Met Gln Leu Lys Gln Met Leu Pro Leu Asn Thr Asn Ile 290 295 300 Arg Leu Ala Tyr Ser Asn Gly Lys Asp Asp Glu Gln Asn Phe Ile Gln 305 310 315 320 Asn Leu Ser Leu Phe Leu Cys Thr Phe Leu Lys Glu His Asp Gln Leu 325 330 335 Ile Glu Lys Arg Leu Asn Leu Arg Glu Thr Leu Met Glu Ala Leu His 340 345 350 Tyr Met Leu Leu Val Ser Glu Val Glu Glu Thr Glu Ile Phe Lys Ile 355 360 365 Cys Leu Glu Tyr Trp Asn His Leu Ala Ala Glu Leu Tyr Arg Glu Ser 370 375 380 Pro Phe Ser Thr Ser Ala Ser Pro Leu Leu Ser Gly Ser Gln His Phe 385 390 395 400 Asp Val Pro Pro Arg Arg Gln Leu Tyr Leu Pro Met Leu Phe Lys Val 405 410 415 Arg Leu Leu Met Val Ser Arg Met Ala Lys Pro Glu Glu Val Leu Val 420 425 430 Val Glu Asn Asp Gln Gly Glu Val Val Arg Glu Phe Met Lys Asp Thr 435 440 445 Asp Ser Ile Asn Leu Tyr Lys Asn Met Arg Glu Thr Leu Val Tyr Leu 450 455 460 Thr His Leu Asp Tyr Val Asp Thr Glu Arg Ile Met Thr Glu Lys Leu 465 470 475 480 His Asn Gln Val Asn Gly Thr Glu Trp Ser Trp Lys Asn Leu Asn Thr 485 490 495 Leu Cys Trp Ala Ile Gly Ser Ile Ser Gly Ala Met His Glu Glu Asp 500 505 510 Glu Lys Arg Phe Leu Val Thr Val Ile Lys Asp Leu Leu Gly Leu Cys 515 520 525 Glu Gln Lys Arg Gly Lys Asp Asn Lys Ala Ile Ile Ala Ser Asn Ile 530 535 540 Met Tyr Ile Val Gly Gln Tyr Pro Arg Phe Leu Arg Ala His Trp Lys 545 550 555 560 Phe Leu Lys Thr Val Val Asn Lys Leu Phe Glu Phe Met His Glu Thr 565 570 575 His Asp Gly Val Gln Asp Met Ala Cys Asp Thr Phe Ile Lys Ile Ala 580 585 590 Gln Lys Cys Arg Arg His Phe Val Gln Val Gln Val Gly Glu Val Met 595 600 605 Pro Phe Ile Asp Glu Ile Leu Asn Asn Ile Asn Thr Ile Ile Cys Asp 610 615 620 Leu Gln Pro Gln Gln Val His Thr Phe Tyr Glu Ala Val Gly Tyr Met 625 630 635 640 Ile Gly Ala Gln Thr Asp Gln Thr Val Gln Glu His Leu Ile Glu Lys 645 650 655 Tyr Met Leu Leu Pro Asn Gln Val Trp Asp Ser Ile Ile Gln Gln Ala 660 665 670 Thr Lys Asn Val Asp Ile Leu Lys Asp Pro Glu Thr Val Lys Gln Leu 675 680 685 Gly Ser Ile Leu Lys Thr Asn Val Arg Ala Cys Lys Ala Val Gly His 690 695 700 Pro Phe Val Ile Gln Leu Gly Arg Ile Tyr Leu Asp Met Leu Asn Val 705 710 715 720 Tyr Lys Cys Leu Ser Glu Asn Ile Ser Ala Ala Ile Gln Ala Asn Gly 725 730 735 Glu Met Val Thr Lys Gln Pro Leu Ile Arg Ser Met Arg Thr Val Lys 740 745 750 Arg Glu Thr Leu Lys Leu Ile Ser Gly Trp Val Ser Arg Ser Asn Asp 755 760 765 Pro Gln Met Val Ala Glu Asn Phe Val Pro Pro Leu Leu Asp Ala Val 770 775 780 Leu Ile Asp Tyr Gln Arg Asn Val Pro Ala Ala Arg Glu Pro Glu Val 785 790 795 800 Leu Ser Thr Met Ala Ile Ile Val Asn Lys Leu Gly Gly His Ile Thr 805 810 815 Ala Glu Ile Pro Gln Ile Phe Asp Ala Val Phe Glu Cys Thr Leu Asn 820 825 830 Met Ile Asn Lys Asp Phe Glu Glu Tyr Pro Glu His Arg Thr Asn Phe 835 840 845 Phe Leu Leu Leu Gln Ala Val Asn Ser His Cys Phe Pro Ala Phe Leu 850 855 860 Ala Ile Pro Pro Thr Gln Phe Lys Leu Val Leu Asp Ser Ile Ile Trp 865 870 875 880 Ala Phe Lys His Thr Met Arg Asn Val Ala Asp Thr Gly Leu Gln Ile 885 890 895 Leu Phe Thr Leu Leu Gln Asn Val Ala Gln Glu Glu Ala Ala Ala Gln 900 905 910 Ser Phe Tyr Gln Thr Tyr Phe Cys Asp Ile Leu Gln His Ile Phe Ser 915 920 925 Val Val Thr Asp Thr Ser His Thr Ala Gly Leu Thr Met His Ala Ser 930 935 940 Ile Leu Ala Tyr Met Phe Asn Leu Val Glu Glu Glu Gly Lys Ile Ser Thr 945 950 955 960 Ser Leu Asn Pro Gly Asn Pro Val Asn Asn Gln Ile Phe Leu Gln Glu 965 970 975 Tyr Val Ala Asn Leu Leu Lys Ser Ala Phe Pro His Leu Gln Asp Ala 980 985 990 Gln Val Lys Leu Phe Val Thr Gly Leu Phe Ser Leu Asn Gln Asp Ile 995 1000 1005 Pro Ala Phe Lys Glu His Leu Arg Asp Phe Leu Val Gln Ile Lys Glu 1010 1015 1020 Phe Ala Gly Glu Asp Thr Ser Asp Leu Phe Leu Glu Glu Arg Glu Ile 1025 1030 1035 1040 Ala Leu Arg Gln Ala Asp Glu Glu Lys His Lys Arg Gln Met Ser Val 1045 1050 1055 Pro Gly Ile Phe Asn Pro His Glu Ile Pro Glu Glu Met Cys Asp 1060 1065 1070 <210> 15 <211> 257 <212> PRT <213> Homo sapiens <400> 15 Met Glu Phe Pro Asp Leu Gly Ala His Cys Ser Glu Pro Ser Cys Gln 1 5 10 15 Arg Leu Asp Phe Leu Pro Leu Lys Cys Asp Ala Cys Ser Gly Ile Phe 20 25 30 Cys Ala Asp His Val Ala Tyr Ala Gln His His Cys Gly Ser Ala Tyr 35 40 45 Gln Lys Asp Ile Gln Val Pro Val Cys Pro Leu Cys Asn Val Pro Val 50 55 60 Pro Val Ala Arg Gly Glu Pro Pro Asp Arg Ala Val Gly Glu His Ile 65 70 75 80 Asp Arg Asp Cys Arg Ser Asp Pro Ala Gln Gln Lys Arg Lys Ile Phe 85 90 95 Thr Asn Lys Cys Glu Arg Ala Gly Cys Arg Gln Arg Glu Met Met Lys 100 105 110 Leu Thr Cys Glu Arg Cys Ser Arg Asn Phe Cys Ile Lys His Arg His 115 120 125 Pro Leu Asp His Asp Cys Ser Gly Glu Gly His Pro Thr Ser Arg Ala 130 135 140 Gly Leu Ala Ala Ile Ser Arg Ala Gln Ala Val Ala Ser Thr Ser Thr 145 150 155 160 Val Pro Ser Pro Ser Gln Thr Met Pro Ser Cys Thr Ser Pro Ser Arg 165 170 175 Ala Thr Thr Arg Ser Pro Ser Trp Thr Ala Pro Pro Val Ile Ala Leu 180 185 190 Gln Asn Gly Leu Ser Glu Asp Glu Ala Leu Gln Arg Ala Leu Glu Met 195 200 205 Ser Leu Ala Glu Thr Lys Pro Gln Val Pro Ser Cys Gln Glu Glu Glu 210 215 220 Asp Leu Ala Leu Ala Gln Ala Leu Ser Ala Ser Glu Ala Glu Tyr Gln 225 230 235 240 Arg Gln Gln Ala Gln Ser Arg Ser Ser Lys Pro Ser Asn Cys Ser Leu 245 250 255 Cys <210> 16 <211> 811 <212> PRT <213> Homo sapiens <400> 16 Met Asn Lys Val Glu Gln Lys Ser Gln Glu Ser Val Ser Phe Lys Asp 1 5 10 15 Val Thr Val Gly Phe Thr Gln Glu Glu Trp Gln His Leu Asp Pro Ser 20 25 30 Gln Arg Ala Leu Tyr Arg Asp Val Met Leu Glu Asn Tyr Ser Asn Leu 35 40 45 Val Ser Val Gly Tyr Cys Val His Lys Pro Glu Val Ile Phe Arg Leu 50 55 60 Gln Gln Gly Glu Glu Pro Trp Lys Gln Glu Glu Glu Phe Pro Ser Gln 65 70 75 80 Ser Phe Pro Glu Val Trp Thr Ala Asp His Leu Lys Glu Arg Ser Gln 85 90 95 Glu Asn Gln Ser Lys His Leu Trp Glu Val Val Phe Ile Asn Asn Glu 100 105 110 Met Leu Thr Lys Glu Gln Gly Asp Val Ile Gly Ile Pro Phe Asn Val 115 120 125 Asp Val Ser Ser Phe Pro Ser Arg Lys Met Phe Cys Gln Cys Asp Ser 130 135 140 Cys Gly Met Ser Phe Asn Thr Val Ser Glu Leu Val Ile Ser Lys Ile 145 150 155 160 Asn Tyr Leu Gly Lys Lys Ser Asp Glu Phe Asn Ala Cys Gly Lys Leu 165 170 175 Leu Leu Asn Ile Lys His Asp Glu Thr His Thr Gln Glu Lys Asn Glu 180 185 190 Val Leu Lys Asn Arg Asn Thr Leu Ser His His Glu Glu Thr Leu Gln 195 200 205 His Glu Lys Ile Gln Thr Leu Glu His Asn Phe Glu Tyr Ser Ile Cys 210 215 220 Gln Glu Thr Leu Leu Glu Lys Ala Val Phe Asn Thr Gln Lys Arg Glu 225 230 235 240 Asn Ala Glu Glu Asn Asn Cys Asp Tyr Asn Glu Phe Gly Arg Thr Leu 245 250 255 Cys Asp Ser Ser Ser Leu Leu Phe His Gln Ile Ser Pro Ser Arg Asp 260 265 270 Asn His Tyr Glu Phe Ser Asp Cys Glu Lys Phe Leu Cys Val Lys Ser 275 280 285 Thr Leu Ser Lys Pro His Gly Val Ser Met Lys His Tyr Asp Cys Gly 290 295 300 Glu Ser Gly Asn Asn Phe Arg Arg Lys Leu Cys Leu Ser His Leu Gln 305 310 315 320 Lys Gly Asp Lys Gly Glu Lys His Phe Glu Cys Asn Glu Cys Gly Lys 325 330 335 Ala Phe Trp Glu Lys Ser His Leu Thr Arg His Gln Arg Val His Thr 340 345 350 Gly Gln Lys Pro Phe Gln Cys Asn Glu Cys Glu Lys Ala Phe Trp Asp 355 360 365 Lys Ser Asn Leu Thr Lys His Gln Arg Ser His Thr Gly Glu Lys Pro 370 375 380 Phe Glu Cys Asn Glu Cys Gly Lys Ala Phe Ser His Lys Ser Ala Leu 385 390 395 400 Thr Leu His Gln Arg Thr His Thr Gly Glu Lys Pro Tyr Gln Cys Asn 405 410 415 Ala Cys Gly Lys Thr Phe Cys Gln Lys Ser Asp Leu Thr Lys His Gln 420 425 430 Arg Thr His Thr Gly Leu Lys Pro Tyr Glu Cys Tyr Glu Cys Gly Lys 435 440 445 Ser Phe Arg Val Thr Ser His Leu Lys Val His Gln Arg Thr His Thr 450 455 460 Gly Glu Lys Pro Phe Glu Cys Leu Glu Cys Gly Lys Ser Phe Ser Glu 465 470 475 480 Lys Ser Asn Leu Thr Gln His Gln Arg Ile His Ile Gly Asp Lys Ser 485 490 495 Tyr Glu Cys Asn Ala Cys Gly Lys Thr Phe Tyr His Lys Ser Leu Leu 500 505 510 Thr Arg His Gln Ile Ile His Thr Gly Trp Lys Pro Tyr Glu Cys Tyr 515 520 525 Glu Cys Gly Lys Thr Phe Cys Leu Lys Ser Asp Leu Thr Val His Gln 530 535 540 Arg Thr His Thr Gly Gln Lys Pro Phe Ala Cys Pro Glu Cys Gly Lys 545 550 555 560 Phe Phe Ser His Lys Ser Thr Leu Ser Gln His Tyr Arg Thr His Thr 565 570 575 Gly Glu Lys Pro Tyr Glu Cys His Glu Cys Gly Lys Ile Phe Tyr Asn 580 585 590 Lys Ser Tyr Leu Thr Lys His Asn Arg Thr His Thr Gly Glu Lys Pro 595 600 605 Tyr Glu Cys Asn Glu Cys Gly Lys Ala Phe Tyr Gln Lys Ser Gln Leu 610 615 620 Thr Gln His Gln Arg Ile His Ile Gly Glu Lys Pro Tyr Lys Cys Asn 625 630 635 640 Glu Cys Gly Lys Ala Phe Cys His Lys Ser Ala Leu Ile Val His Gln 645 650 655 Arg Thr His Thr Gln Glu Lys Pro Tyr Lys Cys Asn Glu Cys Gly Lys 660 665 670 Ser Phe Cys Val Lys Ser Gly Leu Ile Phe His Glu Arg Lys His Thr 675 680 685 Gly Glu Lys Pro Tyr Glu Cys Asn Glu Cys Gly Lys Phe Phe Arg His 690 695 700 Lys Ser Ser Leu Thr Val His His Arg Ala His Thr Gly Glu Lys Ser 705 710 715 720 Cys Gln Cys Asn Glu Cys Gly Lys Ile Phe Tyr Arg Lys Ser Glu Leu 725 730 735 Ala Gln His Gln Arg Ser His Thr Gly Glu Lys Pro Tyr Glu Cys Asn 740 745 750 Thr Cys Arg Lys Thr Phe Ser Gln Lys Ser Asn Leu Ile Val His Gln 755 760 765 Arg Arg His Ile Gly Glu Asn Leu Met Asn Glu Met Asp Ile Arg Asn 770 775 780 Phe Gln Pro Gln Val Ser Leu His Asn Ala Ser Glu Tyr Ser His Cys 785 790 795 800 Gly Glu Ser Pro Asp Asp Ile Leu Asn Val Gln 805 810 <210> 17 <211> 1250 <212> PRT <213> Homo sapiens <400> 17 Met Lys Pro Pro Gln Gln Ser Leu Tyr Leu Leu Val Asp Ser Val Asp 1 5 10 15 Glu Gly Cys Asn Ile Thr Glu Gly Glu Gln Thr Ser Thr Ser Leu Ser 20 25 30 Gly Thr Val Ala Ala Leu Leu Ala Gly His His Glu Phe Phe Pro Pro 35 40 45 Trp Leu Leu Leu Leu Cys Ser Ala Arg Lys Gln Ser Lys Ala Val Thr 50 55 60 Lys Met Phe Thr Gly Phe Arg Lys Ile Ser Leu Asp Asp Leu Arg Lys 65 70 75 80 Ala Tyr Ile Val Lys Asp Val Gln Gln Tyr Ile Leu His Arg Leu Asp 85 90 95 Gln Glu Glu Ala Leu Arg Gln His Leu Thr Lys Glu Thr Ala Glu Met 100 105 110 Leu Asn Gln Leu His Ile Lys Ser Ser Gly Cys Phe Leu Tyr Leu Glu 115 120 125 Arg Val Leu Asp Gly Val Val Glu Asn Phe Ile Met Leu Arg Glu Ile 130 135 140 Arg Asp Ile Pro Gly Thr Leu Asn Gly Leu Tyr Leu Trp Leu Cys Gln 145 150 155 160 Arg Leu Phe Val Arg Lys Gln Phe Ala Lys Val Gln Pro Ile Leu Asn 165 170 175 Val Ile Leu Ala Ala Cys Arg Pro Leu Thr Ile Thr Glu Leu Tyr His 180 185 190 Ala Val Trp Thr Lys Asn Met Ser Leu Thr Leu Glu Asp Phe Gln Arg 195 200 205 Lys Leu Asp Ile Leu Ser Lys Leu Leu Val Asp Gly Leu Gly Asn Thr 210 215 220 Lys Ile Leu Phe His Tyr Ser Phe Ala Glu Trp Leu Leu Asp Val Lys 225 230 235 240 His Cys Thr Gln Lys Tyr Leu Cys Asn Ala Ala Glu Gly His Arg Met 245 250 255 Leu Ala Met Ser Tyr Thr Cys Gln Ala Lys Asn Leu Thr Pro Leu Glu 260 265 270 Ala Gln Glu Phe Ala Leu His Leu Ile Asn Ser Asn Leu Gln Leu Glu 275 280 285 Thr Ala Glu Leu Ala Leu Trp Met Ile Trp Asn Gly Thr Pro Val Arg 290 295 300 Asp Ser Leu Ser Thr Leu Ile Pro Lys Glu Gln Glu Val Leu Gln Leu 305 310 315 320 Leu Val Lys Ala Gly Ala His Val Asn Ser Glu Asp Asp Arg Thr Ser 325 330 335 Cys Ile Val Arg Gln Ala Leu Glu Arg Glu Asp Ser Ile Arg Thr Leu 340 345 350 Leu Asp Asn Gly Ala Ser Val Asn Gln Cys Asp Ser Asn Gly Arg Thr 355 360 365 Leu Leu Ala Asn Ala Ala Tyr Ser Gly Ser Leu Asp Val Val Asn Leu 370 375 380 Leu Val Ser Arg Gly Ala Asp Leu Glu Ile Glu Asp Ala His Gly His 385 390 395 400 Thr Pro Leu Thr Leu Ala Ala Arg Gln Gly His Thr Lys Val Val Asn 405 410 415 Cys Leu Ile Gly Cys Gly Ala Asn Ile Asn His Thr Asp Gln Asp Gly 420 425 430 Trp Thr Ala Leu Arg Ser Ala Ala Trp Gly Gly His Thr Glu Val Val 435 440 445 Ser Ala Leu Leu Tyr Ala Gly Val Lys Val Asp Cys Ala Asp Ala Asp 450 455 460 Ser Arg Thr Ala Leu Arg Ala Ala Ala Trp Gly Gly His Glu Asp Ile 465 470 475 480 Val Leu Asn Leu Leu Gln His Gly Ala Glu Val Asn Lys Ala Asp Asn 485 490 495 Glu Gly Arg Thr Ala Leu Ile Ala Ala Ala Tyr Met Gly His Arg Glu 500 505 510 Ile Val Glu His Leu Leu Asp His Gly Ala Glu Val Asn His Glu Asp 515 520 525 Val Asp Gly Arg Thr Ala Leu Ser Val Ala Ala Leu Cys Val Pro Ala 530 535 540 Ser Lys Gly His Ala Ser Val Val Ser Leu Leu Ile Asp Arg Gly Ala 545 550 555 560 Glu Val Asp His Cys Asp Lys Asp Gly Met Thr Pro Leu Leu Val Ala 565 570 575 Ala Tyr Glu Gly His Val Asp Val Val Asp Leu Leu Leu Glu Gly Gly 580 585 590 Ala Asp Val Asp His Thr Asp Asn Asn Gly Arg Thr Pro Leu Leu Ala 595 600 605 Ala Ala Ser Met Gly His Ala Ser Val Val Asn Thr Leu Leu Phe Trp 610 615 620 Gly Ala Ala Val Asp Ser Ile Asp Ser Glu Gly Arg Thr Val Leu Ser 625 630 635 640 Ile Ala Ser Ala Gln Gly Asn Val Glu Val Val Arg Thr Leu Leu Asp 645 650 655 Arg Gly Leu Asp Glu Asn His Arg Asp Asp Ala Gly Trp Thr Pro Leu 660 665 670 His Met Ala Ala Phe Glu Gly His Arg Leu Ile Cys Glu Ala Leu Ile 675 680 685 Glu Gln Gly Ala Arg Thr Asn Glu Ile Asp Asn Asp Gly Arg Ile Pro 690 695 700 Phe Ile Leu Ala Ser Gln Glu Gly His Tyr Asp Cys Val Gln Ile Leu 705 710 715 720 Leu Glu Asn Lys Ser Asn Ile Asp Gln Arg Gly Tyr Asp Gly Arg Asn 725 730 735 Ala Leu Arg Val Ala Ala Leu Glu Gly His Arg Asp Ile Val Glu Leu 740 745 750 Leu Phe Ser His Gly Ala Asp Val Asn Cys Lys Asp Ala Asp Gly Arg 755 760 765 Pro Thr Leu Tyr Ile Leu Ala Leu Glu Asn Gln Leu Thr Met Ala Glu 770 775 780 Tyr Phe Leu Glu Asn Gly Ala Asn Val Glu Ala Ser Asp Ala Glu Gly 785 790 795 800 Arg Thr Ala Leu His Val Ser Cys Trp Gln Gly His Met Glu Met Val 805 810 815 Gln Val Leu Ile Ala Tyr His Ala Asp Val Asn Ala Ala Asp Asn Glu 820 825 830 Lys Arg Ser Ala Leu Gln Ser Ala Ala Trp Gln Gly His Val Lys Val 835 840 845 Val Gln Leu Leu Ile Glu His Gly Ala Val Val Asp His Thr Cys Asn 850 855 860 Gln Gly Ala Thr Ala Leu Cys Ile Ala Ala Gln Glu Gly His Ile Asp 865 870 875 880 Val Val Gln Val Leu Leu Glu His Gly Ala Asp Pro Asn His Ala Asp 885 890 895 Gln Phe Gly Arg Thr Ala Met Arg Val Ala Ala Lys Asn Gly His Ser 900 905 910 Gln Ile Ile Lys Leu Leu Glu Lys Tyr Gly Ala Ser Ser Leu Asn Gly 915 920 925 Cys Ser Pro Ser Pro Val His Thr Met Glu Gln Lys Pro Leu Gln Ser 930 935 940 Leu Ser Ser Lys Val Gln Ser Leu Thr Ile Lys Ser Asn Ser Ser Gly 945 950 955 960 Ser Thr Gly Gly Gly Asp Met Gln Pro Ser Leu Arg Gly Leu Pro Asn 965 970 975 Gly Pro Thr His Ala Phe Ser Ser Pro Ser Glu Ser Pro Asp Ser Thr 980 985 990 Val Asp Arg Gln Lys Ser Ser Leu Ser Asn Asn Ser Leu Lys Ser Ser 995 1000 1005 Lys Asn Ser Ser Leu Arg Thr Thr Ser Ser Thr Ala Thr Ala Gln Thr 1010 1015 1020 Val Pro Ile Asp Ser Phe His Asn Leu Ser Phe Thr Glu Gln Ile Gln 1025 1030 1035 1040 Gln His Ser Leu Pro Arg Ser Arg Ser Arg Gln Ser Ile Val Ser Pro 1045 1050 1055 Ser Ser Thr Thr Gln Ser Leu Gly Gln Ser His Asn Ser Pro Ser Ser 1060 1065 1070 Glu Phe Glu Trp Ser Gln Val Lys Pro Ser Leu Lys Ser Thr Lys Ala 1075 1080 1085 Ser Lys Gly Gly Lys Ser Glu Asn Ser Ala Lys Ser Gly Ser Ala Gly 1090 1095 1100 Lys Lys Ala Lys Gln Ser Asn Ser Ser Gln Pro Lys Val Leu Glu Tyr 1105 1110 1115 1120 Glu Met Thr Gln Phe Asp Arg Arg Gly Pro Ile Ala Lys Ser Gly Thr 1125 1130 1135 Ala Ala Pro Pro Lys Gln Met Pro Ala Glu Ser Gln Cys Lys Ile Met 1140 1145 1150 Ile Pro Ser Ala Gln Gln Glu Ile Gly Arg Ser Gln Gln Gln Phe Leu 1155 1160 1165 Ile His Gln Gln Ser Gly Glu Gln Lys Lys Arg Asn Gly Ile Met Thr 1170 1175 1180 Asn Pro Asn Tyr His Leu Gln Ser Asn Gln Val Phe Leu Gly Arg Val 1185 1190 1195 1200 Ser Val Pro Arg Thr Met Gln Asp Arg Gly His Gln Glu Val Leu Glu 1205 1210 1215 Gly Tyr Pro Ser Ser Glu Thr Glu Leu Ser Leu Lys Gln Ala Leu Lys 1220 1225 1230 Leu Gln Ile Glu Gly Ser Asp Pro Ser Phe Asn Tyr Lys Lys Glu Thr 1235 1240 1245 Pro Leu 1250 <210> 18 <211> 454 <212> PRT <213> Homo sapiens <400> 18 Met Phe Leu Ala Gln Arg Ser Leu Cys Ser Leu Ser Gly Arg Ala Lys 1 5 10 15 Phe Leu Lys Thr Ile Ser Ser Ser Lys Ile Leu Gly Phe Ser Thr Ser 20 25 30 Ala Lys Met Ser Leu Lys Phe Thr Asn Ala Lys Arg Ile Glu Gly Leu 35 40 45 Asp Ser Asn Val Trp Ile Glu Phe Thr Lys Leu Ala Ala Asp Pro Ser 50 55 60 Val Val Asn Leu Gly Gln Gly Phe Pro Asp Ile Ser Pro Pro Thr Tyr 65 70 75 80 Val Lys Glu Glu Leu Ser Lys Ile Ala Ala Ile Asp Ser Leu Asn Gln 85 90 95 Tyr Thr Arg Gly Phe Gly His Pro Ser Leu Val Lys Ala Leu Ser Tyr 100 105 110 Leu Tyr Glu Lys Leu Tyr Gln Lys Gln Ile Asp Ser Asn Lys Glu Ile 115 120 125 Leu Val Thr Val Gly Ala Tyr Gly Ser Leu Phe Asn Thr Ile Gln Ala 130 135 140 Leu Ile Asp Glu Gly Asp Glu Val Ile Leu Ile Val Pro Phe Tyr Asp 145 150 155 160 Cys Tyr Glu Pro Met Val Arg Met Ala Gly Ala Thr Pro Val Phe Ile 165 170 175 Pro Leu Arg Ser Lys Pro Val Tyr Gly Lys Arg Trp Ser Ser Ser Asp 180 185 190 Trp Thr Leu Asp Pro Gln Glu Leu Glu Ser Lys Phe Asn Ser Lys Thr 195 200 205 Lys Ala Ile Ile Leu Asn Thr Pro His Asn Pro Leu Gly Lys Val Tyr 210 215 220 Asn Arg Glu Glu Leu Gln Val Ile Ala Asp Leu Cys Ile Lys Tyr Asp 225 230 235 240 Thr Leu Cys Ile Ser Asp Glu Val Tyr Glu Trp Leu Val Tyr Ser Gly 245 250 255 Asn Lys His Leu Lys Ile Ala Thr Phe Pro Gly Met Trp Glu Arg Thr 260 265 270 Ile Thr Ile Gly Ser Ala Gly Lys Thr Phe Ser Val Thr Gly Trp Lys 275 280 285 Leu Gly Trp Ser Ile Gly Pro Asn His Leu Ile Lys His Leu Gln Thr 290 295 300 Val Gln Gln Asn Thr Ile Tyr Thr Cys Ala Thr Pro Leu Gln Glu Ala 305 310 315 320 Leu Ala Gln Ala Phe Trp Ile Asp Ile Lys Arg Met Asp Asp Pro Glu 325 330 335 Cys Tyr Phe Asn Ser Leu Pro Lys Glu Leu Glu Val Lys Arg Asp Arg 340 345 350 Met Val Arg Leu Leu Glu Ser Val Gly Leu Lys Pro Ile Val Pro Asp 355 360 365 Gly Gly Tyr Phe Ile Ile Ala Asp Val Ser Leu Leu Asp Pro Asp Leu 370 375 380 Ser Asp Met Lys Asn Asn Glu Pro Tyr Asp Tyr Lys Phe Val Lys Trp 385 390 395 400 Met Thr Lys His Lys Lys Leu Ser Ala Ile Pro Val Ser Ala Phe Cys 405 410 415 Asn Ser Glu Thr Lys Ser Gln Phe Glu Lys Phe Val Arg Phe Cys Phe 420 425 430 Ile Lys Lys Asp Ser Thr Leu Asp Ala Ala Glu Glu Ile Ile Lys Ala 435 440 445 Trp Ser Val Gln Lys Ser 450 <210> 19 <211> 299 <212> PRT <213> Homo sapiens <400> 19 Met Leu Gly Trp Val Gln Arg Val Leu Pro Gln Pro Pro Gly Thr Pro 1 5 10 15 Arg Lys Thr Lys Met Gln Glu Glu Glu Glu Val Glu Pro Glu Pro Glu 20 25 30 Met Glu Ala Glu Val Glu Pro Glu Pro Asn Pro Glu Glu Ala Glu Thr 35 40 45 Glu Ser Glu Ser Met Pro Pro Glu Glu Ser Phe Lys Glu Glu Glu Val 50 55 60 Ala Val Ala Asp Pro Ser Pro Gln Glu Thr Lys Glu Ala Ala Leu Thr 65 70 75 80 Ser Thr Ile Ser Leu Arg Ala Gln Gly Ala Glu Ile Ser Glu Met Asn 85 90 95 Ser Pro Ser Arg Arg Val Leu Thr Trp Leu Met Lys Gly Val Glu Lys 100 105 110 Val Ile Pro Gln Pro Val His Ser Ile Thr Glu Asp Pro Ala Gln Ile 115 120 125 Leu Gly His Gly Ser Thr Gly Asp Thr Gly Cys Thr Asp Glu Pro Asn 130 135 140 Glu Ala Leu Glu Ala Gln Asp Thr Arg Pro Gly Leu Arg Leu Leu Leu 145 150 155 160 Trp Leu Glu Gln Asn Leu Glu Arg Val Leu Pro Gln Pro Pro Lys Ser 165 170 175 Ser Glu Val Trp Arg Asp Glu Pro Ala Val Ala Thr Gly Ala Ala Ser 180 185 190 Asp Pro Ala Pro Pro Gly Arg Pro Gln Glu Met Gly Pro Lys Leu Gln 195 200 205 Ala Arg Glu Thr Pro Ser Leu Pro Thr Pro Ile Pro Leu Gln Pro Lys 210 215 220 Glu Glu Pro Lys Glu Ala Pro Ala Pro Glu Pro Gln Pro Gly Ser Gln 225 230 235 240 Ala Gln Thr Ser Ser Leu Pro Pro Thr Arg Asp Pro Ala Arg Leu Val 245 250 255 Ala Trp Val Leu His Arg Leu Glu Met Ala Leu Pro Gln Pro Val Leu 260 265 270 His Gly Lys Ile Gly Glu Gln Glu Pro Asp Ser Pro Gly Ile Cys Asp 275 280 285 Val Gln Thr Arg Val Met Gly Ala Gly Gly Leu 290 295 <210> 20 <211> 226 <212> PRT <213> Homo sapiens <400> 20 Met Ala Asp Pro Gln Ala Gly Ser Ala Ala Gly Asp Trp Glu Ile Asp 1 5 10 15 Val Glu Ser Leu Glu Leu Glu Glu Asp Val Cys Gly Ala Pro Arg Ser 20 25 30 Thr Pro Pro Gly Pro Ser Pro Pro Pro Ala Asp Gly Asp Cys Glu Asp 35 40 45 Asp Glu Asp Asp Asp Gly Val Asp Glu Asp Ala Glu Glu Glu Gly Asp 50 55 60 Gly Glu Glu Ala Gly Ala Ser Pro Gly Met Pro Gly Gln Pro Glu Gln 65 70 75 80 Arg Gly Gly Pro Gln Pro Arg Pro Pro Leu Ala Pro Gln Ala Ser Pro 85 90 95 Ala Gly Thr Gly Pro Arg Glu Arg Cys Thr Pro Ala Gly Gly Gly Ala 100 105 110 Glu Pro Arg Lys Leu Ser Arg Thr Pro Lys Cys Ala Arg Cys Arg Asn 115 120 125 His Gly Val Val Ser Cys Leu Lys Gly His Lys Arg Phe Cys Arg Trp 130 135 140 Arg Asp Cys Gln Cys Ala Asn Cys Leu Leu Val Val Glu Arg Gln Arg 145 150 155 160 Val Met Ala Ala Gln Val Ala Leu Arg Arg Gln Gln Ala Thr Glu Asp 165 170 175 Lys Lys Gly Leu Ser Gly Lys Gln Asn Asn Phe Glu Arg Lys Ala Val 180 185 190 Tyr Gln Arg Gln Val Arg Ala Pro Ser Leu Leu Ala Lys Ser Ile Leu 195 200 205 Glu Val Leu Leu Gly Leu Phe Tyr Ser Tyr Tyr Val Tyr Ile Met Asn 210 215 220 His Leu 225 <210> 21 <211> 341 <212> PRT <213> Homo sapiens <400> 21 Met Ile Glu Met Asp Gly Thr Glu Asn Lys Ser Lys Phe Gly Ala Asn 1 5 10 15 Ala Ile Leu Gly Val Ser Leu Ala Val Cys Lys Ala Gly Ala Val Glu 20 25 30 Lys Gly Val Pro Leu Tyr Arg His Ile Ala Asp Leu Ala Gly Asn Ser 35 40 45 Glu Val Ile Leu Pro Val Pro Ala Phe Asn Val Ile Asn Gly Gly Ser 50 55 60 His Ala Gly Asn Lys Leu Ala Met Gln Glu Phe Met Ile Leu Pro Val 65 70 75 80 Gly Ala Ala Asn Phe Arg Glu Ala Met Arg Ile Gly Ala Glu Val Tyr 85 90 95 His Asn Leu Lys Asn Val Ile Lys Glu Lys Tyr Gly Lys Asp Ala Thr 100 105 110 Asn Val Gly Asp Glu Gly Gly Phe Ala Pro Asn Ile Leu Glu Asn Lys 115 120 125 Glu Gly Leu Glu Leu Leu Lys Thr Ala Ile Gly Lys Ala Gly Tyr Thr 130 135 140 Asp Lys Val Val Ile Gly Met Asp Val Ala Ala Ser Glu Phe Phe Arg 145 150 155 160 Ser Gly Lys Tyr Asp Leu Asp Phe Lys Ser Pro Asp Asp Pro Ser Arg 165 170 175 Tyr Ile Ser Pro Asp Gln Leu Ala Asp Leu Tyr Lys Ser Phe Ile Lys 180 185 190 Asp Tyr Pro Val Val Ser Ile Glu Asp Pro Phe Asp Gln Asp Asp Trp 195 200 205 Gly Ala Trp Gln Lys Phe Thr Ala Ser Ala Gly Ile Gln Val Val Gly 210 215 220 Asp Asp Leu Thr Val Thr Asn Pro Lys Arg Ile Ala Lys Ala Val Asn 225 230 235 240 Glu Lys Ser Cys Asn Cys Leu Leu Leu Lys Val Asn Gln Ile Gly Ser 245 250 255 Val Thr Glu Ser Leu Gln Ala Cys Lys Leu Ala Gln Ala Asn Gly Trp 260 265 270 Gly Val Met Val Ser His Arg Ser Gly Glu Thr Glu Asp Thr Phe Ile 275 280 285 Ala Asp Leu Val Val Gly Leu Cys Thr Gly Gln Ile Lys Thr Gly Ala 290 295 300 Pro Cys Arg Ser Glu Arg Leu Ala Lys Tyr Asn Gln Leu Leu Arg Ile 305 310 315 320 Glu Glu Glu Leu Gly Ser Lys Ala Lys Phe Ala Gly Arg Asn Phe Arg 325 330 335 Asn Pro Leu Ala Lys 340 <210> 22 <211> 537 <212> PRT <213> Homo sapiens <400> 22 Met Glu Glu Leu Val Val Glu Val Arg Gly Ser Asn Gly Ala Phe Tyr 1 5 10 15 Lys Ala Phe Val Lys Asp Val His Glu Asp Ser Ile Thr Val Ala Phe 20 25 30 Glu Asn Asn Trp Gln Pro Asp Arg Gln Ile Pro Phe His Asp Val Arg 35 40 45 Phe Pro Pro Pro Val Gly Tyr Asn Lys Asp Ile Asn Glu Ser Asp Glu 50 55 60 Val Glu Val Tyr Ser Arg Ala Asn Glu Lys Glu Pro Cys Cys Trp Trp 65 70 75 80 Leu Ala Lys Val Arg Met Ile Lys Gly Glu Phe Tyr Val Ile Glu Tyr 85 90 95 Ala Ala Cys Asp Ala Thr Tyr Asn Glu Ile Val Thr Ile Glu Arg Leu 100 105 110 Arg Ser Val Asn Pro Asn Lys Pro Ala Thr Lys Asp Thr Phe His Lys 115 120 125 Ile Lys Leu Asp Val Pro Glu Asp Leu Arg Gln Met Cys Ala Lys Glu 130 135 140 Ala Ala His Lys Asp Phe Lys Lys Ala Val Gly Ala Phe Ser Val Thr 145 150 155 160 Tyr Asp Pro Glu Asn Tyr Gln Leu Val Ile Leu Ser Ile Asn Glu Val 165 170 175 Thr Ser Lys Arg Ala His Met Leu Ile Asp Met His Phe Arg Ser Leu 180 185 190 Arg Thr Lys Leu Ser Leu Ile Met Arg Asn Glu Glu Ala Ser Lys Gln 195 200 205 Leu Glu Ser Ser Arg Gln Leu Ala Ser Arg Phe His Glu Gln Phe Ile 210 215 220 Val Arg Glu Asp Leu Met Gly Leu Ala Ile Gly Thr His Gly Ala Asn 225 230 235 240 Ile Gln Gln Ala Arg Lys Val Pro Gly Val Thr Ala Ile Asp Leu Asp 245 250 255 Glu Asp Thr Cys Thr Phe His Ile Tyr Gly Glu Asp Gln Asp Ala Val 260 265 270 Lys Lys Ala Arg Ser Phe Leu Glu Phe Ala Glu Asp Val Ile Gln Val 275 280 285 Pro Arg Asn Leu Val Gly Lys Val Ile Gly Lys Asn Gly Lys Leu Ile 290 295 300 Gln Glu Ile Val Asp Lys Ser Gly Val Val Arg Val Arg Ile Glu Ala 305 310 315 320 Glu Asn Glu Lys Asn Val Pro Gln Glu Glu Glu Ile Met Pro Pro Asn 325 330 335 Ser Leu Pro Ser Asn Asn Ser Arg Val Gly Pro Asn Ala Pro Glu Glu 340 345 350 Lys Lys His Leu Asp Ile Lys Glu Asn Ser Thr His Phe Ser Gln Pro 355 360 365 Asn Ser Thr Lys Val Gln Arg Val Leu Val Ala Ser Ser Val Val Ala 370 375 380 Gly Glu Ser Gln Lys Pro Glu Leu Lys Ala Trp Gln Gly Met Val Pro 385 390 395 400 Phe Val Phe Val Gly Thr Lys Asp Ser Ile Ala Asn Ala Thr Val Leu 405 410 415 Leu Asp Tyr His Leu Asn Tyr Leu Lys Leu Gln Gln Arg Lys Arg Gly 420 425 430 Arg Ala Ser Cys Ala Glu Glu Thr Asp Gly Gly Val Glu Gly Glu Glu 435 440 445 Glu Asp Lys Glu Glu Glu Asp Val Glu Glu Ala Ser Lys Glu Thr Thr 450 455 460 Ile Thr Pro Glu Gln Ile Ile Val His Val Ile Gln Glu Arg Leu Lys 465 470 475 480 Glu Glu Gln Gln Met Asp Pro Phe Arg Ser Glu Leu Thr Ala Ile Met 485 490 495 Lys Gly Val Ser Thr Leu Lys His Tyr Arg Ile Pro Val Lys Val 500 505 510 Val Gly Cys Ala Arg Val Lys Ile Val Thr Arg Arg Lys Arg Ser Gln 515 520 525 Thr Ala Trp Met Val Ser Asn His Ser 530 535 <210> 23 <211> 1690 <212> PRT <213> Homo sapiens <400> 23 Met Ala Gly Val Gly Pro Gly Gly Tyr Ala Ala Glu Phe Val Pro Pro 1 5 10 15 Pro Glu Cys Pro Val Phe Glu Pro Ser Trp Glu Glu Phe Thr Asp Pro 20 25 30 Leu Ser Phe Ile Gly Arg Ile Arg Pro Leu Ala Glu Lys Thr Gly Ile 35 40 45 Cys Lys Ile Arg Pro Pro Lys Asp Trp Gln Pro Pro Phe Ala Cys Glu 50 55 60 Val Lys Ser Phe Arg Phe Thr Pro Arg Val Gln Arg Leu Asn Glu Leu 65 70 75 80 Glu Ala Met Thr Arg Val Arg Leu Asp Phe Leu Asp Gln Leu Ala Lys 85 90 95 Phe Trp Glu Leu Gln Gly Ser Thr Leu Lys Ile Pro Val Val Glu Arg 100 105 110 Lys Ile Leu Asp Leu Tyr Ala Leu Ser Lys Ile Val Ala Ser Lys Gly 115 120 125 Gly Phe Glu Met Val Thr Lys Glu Lys Lys Trp Ser Lys Val Gly Ser 130 135 140 Arg Leu Gly Tyr Leu Pro Gly Lys Gly Thr Gly Ser Leu Leu Lys Ser 145 150 155 160 His Tyr Glu Arg Ile Leu Tyr Pro Tyr Glu Leu Phe Gln Ser Gly Val 165 170 175 Ser Leu Met Gly Val Gln Met Pro Asn Leu Asp Leu Lys Glu Lys Val 180 185 190 Glu Pro Glu Val Leu Ser Thr Asp Thr Gln Thr Ser Pro Glu Pro Gly 195 200 205 Thr Arg Met Asn Ile Leu Pro Lys Arg Thr Arg Arg Val Lys Thr Gln 210 215 220 Ser Glu Ser Gly Asp Val Ser Arg Asn Thr Glu Leu Lys Lys Leu Gln 225 230 235 240 Ile Phe Gly Ala Gly Pro Lys Val Val Gly Leu Ala Met Gly Thr Lys 245 250 255 Asp Lys Glu Asp Glu Val Thr Arg Arg Arg Lys Val Thr Asn Arg Ser 260 265 270 Asp Ala Phe Asn Met Gln Met Arg Gln Arg Lys Gly Thr Leu Ser Val 275 280 285 Asn Phe Val Asp Leu Tyr Val Cys Met Phe Cys Gly Arg Gly Asn Asn 290 295 300 Glu Asp Lys Leu Leu Leu Cys Asp Gly Cys Asp Asp Ser Tyr His Thr 305 310 315 320 Phe Cys Leu Ile Pro Pro Leu Pro Asp Val Pro Lys Gly Asp Trp Arg 325 330 335 Cys Pro Lys Cys Val Ala Glu Glu Cys Ser Lys Pro Arg Glu Ala Phe 340 345 350 Gly Phe Glu Gln Ala Val Arg Glu Tyr Thr Leu Gln Ser Phe Gly Glu 355 360 365 Met Ala Asp Asn Phe Lys Ser Asp Tyr Phe Asn Met Pro Val His Met 370 375 380 Val Pro Thr Glu Leu Val Glu Lys Glu Phe Trp Arg Leu Val Ser Ser 385 390 395 400 Ile Glu Glu Asp Val Ile Val Glu Tyr Gly Ala Asp Ile Ser Ser Lys 405 410 415 Asp Phe Gly Ser Gly Phe Pro Val Lys Asp Gly Arg Arg Lys Ile Leu 420 425 430 Pro Glu Glu Glu Glu Tyr Ala Leu Ser Gly Trp Asn Leu Asn Asn Met 435 440 445 Pro Val Leu Glu Gln Ser Val Leu Ala His Ile Asn Val Asp Ile Ser 450 455 460 Gly Met Lys Val Pro Trp Leu Tyr Val Gly Met Cys Phe Ser Ser Phe 465 470 475 480 Cys Trp His Ile Glu Asp His Trp Ser Tyr Ser Ile Asn Tyr Leu His 485 490 495 Trp Gly Glu Pro Lys Thr Trp Tyr Gly Val Pro Ser His Ala Ala Glu 500 505 510 Gln Leu Glu Glu Val Met Arg Glu Leu Ala Pro Glu Leu Phe Glu Ser 515 520 525 Gln Pro Asp Leu Leu His Gln Leu Val Thr Ile Met Asn Pro Asn Val 530 535 540 Leu Met Glu His Gly Val Pro Val Tyr Arg Thr Asn Gln Cys Ala Gly 545 550 555 560 Glu Phe Val Val Thr Phe Pro Arg Ala Tyr His Ser Gly Phe Asn Gln 565 570 575 Gly Tyr Asn Phe Ala Glu Ala Val Asn Phe Cys Thr Ala Asp Trp Leu 580 585 590 Pro Ile Gly Arg Gln Cys Val Asn His Tyr Arg Arg Leu Arg Arg His 595 600 605 Cys Val Phe Ser His Glu Glu Leu Ile Phe Lys Met Ala Ala Asp Pro 610 615 620 Glu Cys Leu Asp Val Gly Leu Ala Ala Met Val Cys Lys Glu Leu Thr 625 630 635 640 Leu Met Thr Glu Glu Glu Thr Arg Leu Arg Glu Ser Val Val Gln Met 645 650 655 Gly Val Leu Met Ser Glu Glu Glu Val Phe Glu Leu Val Pro Asp Asp 660 665 670 Glu Arg Gln Cys Ser Ala Cys Arg Thr Thr Cys Phe Leu Ser Ala Leu 675 680 685 Thr Cys Ser Cys Asn Pro Glu Arg Leu Val Cys Leu Tyr His Pro Thr 690 695 700 Asp Leu Cys Pro Cys Pro Met Gln Lys Lys Cys Leu Arg Tyr Arg Tyr 705 710 715 720 Pro Leu Glu Asp Leu Pro Ser Leu Leu Tyr Gly Val Lys Val Arg Ala 725 730 735 Gln Ser Tyr Asp Thr Trp Val Ser Arg Val Thr Glu Ala Leu Ser Ala 740 745 750 Asn Phe Asn His Lys Lys Asp Leu Ile Glu Leu Arg Val Met Leu Glu 755 760 765 Asp Ala Glu Asp Arg Lys Tyr Pro Glu Asn Asp Leu Phe Arg Lys Leu 770 775 780 Arg Asp Ala Val Lys Glu Ala Glu Thr Cys Ala Ser Val Ala Gln Leu 785 790 795 800 Leu Leu Ser Lys Lys Gln Lys His Arg Gln Ser Pro Asp Ser Gly Arg 805 810 815 Thr Arg Thr Lys Leu Thr Val Glu Glu Leu Lys Ala Phe Val Gln Gln 820 825 830 Leu Phe Ser Leu Pro Cys Val Ile Ser Gln Ala Arg Gln Val Lys Asn 835 840 845 Leu Leu Asp Asp Val Glu Glu Phe His Glu Arg Ala Gln Glu Ala Met 850 855 860 Met Asp Glu Thr Pro Asp Ser Ser Lys Leu Gln Met Leu Ile Asp Met 865 870 875 880 Gly Ser Ser Leu Tyr Val Glu Leu Pro Glu Leu Pro Arg Leu Lys Gln 885 890 895 Glu Leu Gln Gln Ala Arg Trp Leu Asp Glu Val Arg Leu Thr Leu Ser 900 905 910 Asp Pro Gln Gln Val Thr Leu Asp Val Met Lys Lys Leu Ile Asp Ser 915 920 925 Gly Val Gly Leu Ala Pro His His Ala Val Glu Lys Ala Met Ala Glu 930 935 940 Leu Gln Glu Leu Leu Thr Val Ser Glu Arg Trp Glu Glu Lys Ala Lys 945 950 955 960 Val Cys Leu Gln Ala Arg Pro Arg His Ser Val Ala Ser Leu Glu Ser 965 970 975 Ile Val Asn Glu Ala Lys Asn Ile Pro Ala Phe Leu Pro Asn Val Leu 980 985 990 Ser Leu Lys Glu Ala Leu Gln Lys Ala Arg Glu Trp Thr Ala Lys Val 995 1000 1005 Glu Ala Ile Gln Ser Gly Ser Asn Tyr Ala Tyr Leu Glu Gln Leu Glu 1010 1015 1020 Ser Leu Ser Ala Lys Gly Arg Pro Ile Pro Val Arg Leu Glu Ala Leu 1025 1030 1035 1040 Pro Gln Val Glu Ser Gln Val Ala Ala Ala Arg Ala Trp Arg Glu Arg 1045 1050 1055 Thr Gly Arg Thr Phe Leu Lys Lys Asn Ser Ser His Thr Leu Leu Gln 1060 1065 1070 Val Leu Ser Pro Arg Thr Asp Ile Gly Val Tyr Gly Ser Gly Lys Asn 1075 1080 1085 Arg Arg Lys Lys Val Lys Glu Leu Ile Glu Lys Glu Lys Glu Lys Asp 1090 1095 1100 Leu Asp Leu Glu Pro Leu Ser Asp Leu Glu Glu Gly Leu Glu Glu Thr 1105 1110 1115 1120 Arg Asp Thr Ala Met Val Val Ala Val Phe Lys Glu Arg Glu Gln Lys 1125 1130 1135 Glu Ile Glu Ala Met His Ser Leu Arg Ala Ala Asn Leu Ala Lys Met 1140 1145 1150 Thr Met Val Asp Arg Ile Glu Glu Val Lys Phe Cys Ile Cys Arg Lys 1155 1160 1165 Thr Ala Ser Gly Phe Met Leu Gln Cys Glu Leu Cys Lys Asp Trp Phe 1170 1175 1180 His Asn Ser Cys Val Pro Leu Pro Lys Ser Ser Ser Gln Lys Lys Gly 1185 1190 1195 1200 Ser Ser Trp Gln Ala Lys Glu Val Lys Phe Leu Cys Pro Leu Cys Met 1205 1210 1215 Arg Ser Arg Arg Pro Arg Leu Glu Thr Ile Leu Ser Leu Leu Val Ser 1220 1225 1230 Leu Gln Lys Leu Pro Val Arg Leu Pro Glu Gly Glu Ala Leu Gln Cys 1235 1240 1245 Leu Thr Glu Arg Ala Met Ser Trp Gln Asp Arg Ala Arg Gln Ala Leu 1250 1255 1260 Ala Thr Asp Glu Leu Ser Ser Ala Leu Ala Lys Leu Ser Val Leu Ser 1265 1270 1275 1280 Gln Arg Met Val Glu Gln Ala Ala Arg Glu Lys Thr Glu Lys Ile Ile 1285 1290 1295 Ser Ala Glu Leu Gln Lys Ala Ala Ala Asn Pro Asp Leu Gln Gly His 1300 1305 1310 Leu Pro Ser Phe Gln Gln Ser Ala Phe Asn Arg Val Val Ser Ser Val 1315 1320 1325 Ser Ser Ser Pro Arg Gln Thr Met Asp Tyr Asp Asp Glu Glu Thr Asp 1330 1335 1340 Ser Asp Glu Asp Ile Arg Glu Thr Tyr Gly Tyr Asp Met Lys Asp Thr 1345 1350 1355 1360 Ala Ser Val Lys Ser Ser Ser Ser Leu Glu Pro Asn Leu Phe Cys Asp 1365 1370 1375 Glu Glu Ile Pro Ile Lys Ser Glu Glu Val Val Thr His Met Trp Thr 1380 1385 1390 Ala Pro Ser Phe Cys Ala Glu His Ala Tyr Ser Ser Ala Ser Lys Ser 1395 1400 1405 Cys Ser Gln Gly Ser Ser Thr Pro Arg Lys Gln Pro Arg Lys Ser Pro 1410 1415 1420 Leu Val Pro Arg Ser Leu Glu Pro Pro Val Leu Glu Leu Ser Pro Gly 1425 1430 1435 1440 Ala Lys Ala Gln Leu Glu Glu Leu Met Met Val Gly Asp Leu Leu Glu 1445 1450 1455 Val Ser Leu Asp Glu Thr Gln His Ile Trp Arg Ile Leu Gln Ala Thr 1460 1465 1470 His Pro Pro Ser Glu Asp Arg Phe Leu His Ile Met Glu Asp Asp Ser 1475 1480 1485 Met Glu Glu Lys Pro Leu Lys Val Lys Gly Lys Asp Ser Ser Glu Lys 1490 1495 1500 Lys Arg Lys Arg Lys Leu Glu Lys Val Glu Gln Leu Phe Gly Glu Gly 1505 1510 1515 1520 Lys Gln Lys Ser Lys Glu Leu Lys Lys Met Asp Lys Pro Arg Lys Lys 1525 1530 1535 Lys Leu Lys Leu Gly Ala Asp Lys Ser Lys Glu Leu Asn Lys Leu Ala 1540 1545 1550 Lys Lys Leu Ala Lys Glu Glu Glu Arg Lys Lys Lys Lys Glu Lys Ala 1555 1560 1565 Ala Ala Ala Lys Val Glu Leu Val Lys Glu Ser Thr Glu Lys Lys Arg 1570 1575 1580 Glu Lys Lys Val Leu Asp Ile Pro Ser Lys Tyr Asp Trp Ser Gly Ala 1585 1590 1595 1600 Glu Glu Ser Asp Asp Glu Asn Ala Val Cys Ala Ala Gln Asn Cys Gln 1605 1610 1615 Arg Pro Cys Lys Asp Lys Val Asp Trp Val Gln Cys Asp Gly Gly Cys 1620 1625 1630 Asp Glu Trp Phe His Gln Val Cys Val Gly Val Ser Pro Glu Met Ala 1635 1640 1645 Glu Asn Glu Asp Tyr Ile Cys Ile Asn Cys Ala Lys Lys Gln Gly Pro 1650 1655 1660 Val Ser Pro Gly Pro Ala Pro Pro Pro Ser Phe Ile Met Ser Tyr Lys 1665 1670 1675 1680 Leu Pro Met Glu Asp Leu Lys Glu Thr Ser 1685 1690 <210> 24 <211> 338 <212> PRT <213> Homo sapiens <400> 24 Met Ser Leu Ser Ala Phe Thr Leu Phe Leu Ala Leu Ile Gly Gly Thr 1 5 10 15 Ser Gly Gln Tyr Tyr Asp Tyr Asp Phe Pro Leu Ser Ile Tyr Gly Gln 20 25 30 Ser Ser Pro Asn Cys Ala Pro Glu Cys Asn Cys Pro Glu Ser Tyr Pro 35 40 45 Ser Ala Met Tyr Cys Asp Glu Leu Lys Leu Lys Ser Val Pro Met Val 50 55 60 Pro Pro Gly Ile Lys Tyr Leu Tyr Leu Arg Asn Asn Gln Ile Asp His 65 70 75 80 Ile Asp Glu Lys Ala Phe Glu Asn Val Thr Asp Leu Gln Trp Leu Ile 85 90 95 Leu Asp His Asn Leu Leu Glu Asn Ser Lys Ile Lys Gly Arg Val Phe 100 105 110 Ser Lys Leu Lys Gln Leu Lys Lys Leu His Ile Asn His Asn Asn Leu 115 120 125 Thr Glu Ser Val Gly Pro Leu Pro Lys Ser Leu Glu Asp Leu Gln Leu 130 135 140 Thr His Asn Lys Ile Thr Lys Leu Gly Ser Phe Glu Gly Leu Val Asn 145 150 155 160 Leu Thr Phe Ile His Leu Gln His Asn Arg Leu Lys Glu Asp Ala Val 165 170 175 Ser Ala Ala Phe Lys Gly Leu Lys Ser Leu Glu Tyr Leu Asp Leu Ser 180 185 190 Phe Asn Gln Ile Ala Arg Leu Pro Ser Gly Leu Pro Val Ser Leu Leu 195 200 205 Thr Leu Tyr Leu Asp Asn Asn Lys Ile Ser Asn Ile Pro Asp Glu Tyr 210 215 220 Phe Lys Arg Phe Asn Ala Leu Gln Tyr Leu Arg Leu Ser His Asn Glu 225 230 235 240 Leu Ala Asp Ser Gly Ile Pro Gly Asn Ser Phe Asn Val Ser Ser Leu 245 250 255 Val Glu Leu Asp Leu Ser Tyr Asn Lys Leu Lys Asn Ile Pro Thr Val 260 265 270 Asn Glu Asn Leu Glu Asn Tyr Tyr Leu Glu Val Asn Gln Leu Glu Lys 275 280 285 Phe Asp Ile Lys Ser Phe Cys Lys Ile Leu Gly Pro Leu Ser Tyr Ser 290 295 300 Lys Ile Lys His Leu Arg Leu Asp Gly Asn Arg Ile Ser Glu Thr Ser 305 310 315 320 Leu Pro Pro Asp Met Tyr Glu Cys Leu Arg Val Ala Asn Glu Val Thr 325 330 335 Leu Asn <210> 25 <211> 750 <212> PRT <213> Homo sapiens <400> 25 Met Ala Lys Pro Arg Leu Leu Val Leu Tyr Phe Ala Leu Ile Val Val 1 5 10 15 Pro Ala Trp Val Ser Ser Ile Val Leu Thr Gly Thr Ser Glu Pro Pro 20 25 30 Asp Ala Gln Thr Val Ala Pro Ala Glu Asp Glu Thr Leu Gln Asn Glu 35 40 45 Ala Asp Asn Gln Glu Asn Val Leu Ser Gln Leu Leu Gly Asp Tyr Asp 50 55 60 Lys Val Lys Ala Met Ser Glu Gly Ser Asp Cys Gln Cys Lys Cys Val 65 70 75 80 Val Arg Pro Leu Gly Arg Asp Ala Cys Gln Arg Ile Asn Ala Gly Ala 85 90 95 Ser Arg Lys Glu Asp Phe Tyr Thr Val Glu Thr Ile Thr Ser Gly Ser 100 105 110 Ser Cys Lys Cys Ala Cys Val Ala Pro Pro Ser Ala Leu Asn Pro Cys 115 120 125 Glu Gly Asp Phe Arg Leu Gln Lys Leu Arg Glu Ala Asp Ser Gln Asp 130 135 140 Leu Lys Leu Ser Thr Ile Ile Asp Met Leu Glu Gly Ala Phe Tyr Gly 145 150 155 160 Leu Asp Leu Leu Lys Leu His Ser Val Thr Thr Lys Leu Val Gly Arg 165 170 175 Val Asp Lys Leu Glu Glu Glu Val Ser Lys Asn Leu Thr Lys Glu Asn 180 185 190 Glu Gln Ile Lys Glu Asp Met Glu Glu Ile Arg Thr Glu Met Asn Lys 195 200 205 Arg Gly Lys Glu Asn Cys Ser Glu Asn Ile Leu Asp Ser Met Pro Asp 210 215 220 Ile Arg Ser Ala Leu Gln Arg Asp Ala Ala Ala Ala Tyr Ala His Pro 225 230 235 240 Glu Tyr Glu Glu Arg Phe Leu Gln Glu Glu Thr Val Ser Gln Gln Ile 245 250 255 Asn Ser Ile Glu Leu Leu Gln Thr Arg Pro Leu Ala Leu Pro Glu Val 260 265 270 Val Lys Ser Gln Arg Pro Leu Gln Arg Gln Val His Leu Arg Gly Arg 275 280 285 Pro Ala Ser Gln Pro Thr Val Ile Arg Gly Ile Thr Tyr Tyr Lys Ala 290 295 300 Lys Val Ser Glu Glu Glu Asn Asp Ile Glu Glu Gln Gln Asp Glu Phe 305 310 315 320 Phe Ser Gly Asp Asn Gly Val Asp Leu Leu Ile Glu Asp Gln Leu Leu 325 330 335 Arg His Asn Gly Leu Met Thr Ser Val Thr Arg Arg Pro Ala Ala Thr 340 345 350 Arg Gln Gly His Ser Thr Ala Val Thr Ser Asp Leu Asn Ala Arg Thr 355 360 365 Ala Pro Trp Ser Ser Ala Leu Pro Gln Pro Ser Thr Ser Asp Pro Ser 370 375 380 Ile Ala Asn His Ala Ser Val Gly Pro Thr Leu Gln Thr Thr Ser Val 385 390 395 400 Ser Pro Asp Pro Thr Arg Glu Ser Val Leu Gln Pro Ser Pro Gln Val 405 410 415 Pro Ala Thr Thr Val Ala His Thr Ala Thr Gln Gln Pro Ala Ala Pro 420 425 430 Ala Pro Pro Ala Val Ser Pro Arg Glu Ala Leu Met Glu Ala Met His 435 440 445 Thr Val Pro Val Pro Pro Thr Thr Val Arg Thr Asp Ser Leu Gly Lys 450 455 460 Asp Ala Pro Ala Gly Trp Gly Thr Thr Pro Ala Ser Pro Thr Leu Ser 465 470 475 480 Pro Glu Glu Glu Asp Asp Ile Arg Asn Val Ile Gly Arg Cys Lys Asp 485 490 495 Thr Leu Ser Thr Ile Thr Gly Pro Thr Thr Gln Asn Thr Tyr Gly Arg 500 505 510 Asn Glu Gly Ala Trp Met Lys Asp Pro Leu Ala Lys Asp Glu Arg Ile 515 520 525 Tyr Val Thr Asn Tyr Tyr Tyr Gly Asn Thr Leu Val Glu Phe Arg Asn 530 535 540 Leu Glu Asn Phe Lys Gln Gly Arg Trp Ser Asn Ser Tyr Lys Leu Pro 545 550 555 560 Tyr Ser Trp Ile Gly Thr Gly His Val Val Tyr Asn Gly Ala Phe Tyr 565 570 575 Tyr Asn Arg Ala Phe Thr Arg Asn Ile Ile Lys Tyr Asp Leu Lys Gln 580 585 590 Arg Tyr Val Ala Ala Trp Ala Met Leu His Asp Val Ala Tyr Glu Glu 595 600 605 Ala Thr Pro Trp Arg Trp Gln Gly His Ser Asp Val Asp Phe Ala Val 610 615 620 Asp Glu Asn Gly Leu Trp Leu Ile Tyr Pro Ala Leu Asp Asp Glu Gly 625 630 635 640 Phe Ser Gln Glu Val Ile Val Leu Ser Lys Leu Asn Ala Ala Asp Leu 645 650 655 Ser Thr Gln Lys Glu Thr Thr Trp Arg Thr Gly Leu Arg Arg Asn Phe 660 665 670 Tyr Gly Asn Cys Phe Val Ile Cys Gly Val Leu Tyr Ala Val Asp Ser 675 680 685 Tyr Asn Gln Arg Asn Ala Asn Ile Ser Tyr Ala Phe Asp Thr His Thr 690 695 700 Asn Thr Gln Ile Val Pro Arg Leu Leu Phe Glu Asn Glu Tyr Ser Tyr 705 710 715 720 Thr Thr Gln Ile Asp Tyr Asn Pro Lys Asp Arg Leu Leu Tyr Ala Trp 725 730 735 Asp Asn Gly His Gln Val Thr Tyr His Val Ile Phe Ala Tyr 740 745 750 <210> 26 <211> 301 <212> PRT <213> Homo sapiens <400> 26 Met Glu Phe Val Leu Leu Gly Phe Ser Asp Ile Pro Asn Leu His Trp 1 5 10 15 Met Leu Phe Ser Ile Phe Leu Leu Met Tyr Leu Met Ile Leu Met Cys 20 25 30 Asn Gly Ile Ile Ile Leu Leu Ile Lys Ile His Pro Ala Leu Gln Thr 35 40 45 Pro Met Tyr Phe Phe Leu Ser Asn Phe Ser Leu Leu Glu Ile Cys Tyr 50 55 60 Val Thr Ile Ile Ile Pro Arg Met Leu Met Asp Ile Trp Thr Gln Lys 65 70 75 80 Gly Asn Ile Ser Leu Phe Ala Cys Ala Thr Gln Met Cys Phe Phe Leu 85 90 95 Met Leu Gly Gly Thr Glu Cys Leu Leu Leu Thr Val Met Ala Tyr Asp 100 105 110 Arg Tyr Val Ala Ile Cys Lys Pro Leu Gln Tyr Pro Leu Val Met Asn 115 120 125 His Lys Val Cys Ile Gln Leu Ile Ile Ala Ser Trp Thr Ile Thr Ile 130 135 140 Pro Val Val Ile Gly Glu Thr Cys Gln Ile Phe Leu Leu Pro Phe Cys 145 150 155 160 Gly Thr Asn Thr Ile Asn His Phe Phe Cys Asp Ile Pro Pro Ile Leu 165 170 175 Lys Leu Ala Cys Gly Asn Ile Phe Val Asn Glu Ile Thr Val His Val 180 185 190 Val Ala Val Val Phe Ile Thr Val Pro Phe Leu Leu Ile Val Val Ser 195 200 205 Tyr Gly Lys Ile Ile Ser Asn Ile Leu Lys Leu Ser Ser Ala Arg Gly 210 215 220 Lys Ala Lys Ala Phe Ser Thr Cys Ser Ser His Leu Ile Val Val Ile 225 230 235 240 Leu Phe Phe Gly Ala Gly Thr Ile Thr Tyr Leu Gln Pro Lys Pro His 245 250 255 Gln Phe Gln Arg Met Gly Lys Leu Ile Ser Leu Phe Tyr Thr Ile Leu 260 265 270 Ile Pro Thr Leu Asn Pro Ile Ile Tyr Thr Leu Arg Asn Lys Asp Ile 275 280 285 Met Val Ala Leu Arg Lys Leu Leu Ala Lys Leu Leu Thr 290 295 300 <210> 27 <211> 311 <212> PRT <213> Homo sapiens <400> 27 Met Ser Asn Ala Thr Leu Leu Thr Ala Phe Ile Leu Thr Gly Leu Pro 1 5 10 15 His Ala Pro Gly Leu Asp Ala Pro Leu Phe Gly Ile Phe Leu Val Val 20 25 30 Tyr Val Leu Thr Val Leu Gly Asn Leu Leu Ile Leu Leu Val Ile Arg 35 40 45 Val Asp Ser His Leu His Thr Pro Met Tyr Tyr Phe Leu Thr Asn Leu 50 55 60 Ser Phe Ile Asp Met Trp Phe Ser Thr Val Thr Val Pro Lys Met Leu 65 70 75 80 Met Thr Leu Val Ser Pro Ser Gly Arg Thr Ile Ser Phe His Ser Cys 85 90 95 Val Ala Gln Leu Tyr Phe Phe His Phe Leu Gly Ser Thr Glu Cys Phe 100 105 110 Leu Tyr Thr Val Met Ser Tyr Asp Arg Tyr Leu Ala Ile Ser Tyr Pro 115 120 125 Leu Arg Tyr Thr Asn Met Met Thr Gly Arg Ser Cys Ala Leu Leu Ala 130 135 140 Thr Gly Thr Trp Leu Ser Gly Ser Leu His Ser Ala Val Gln Thr Ile 145 150 155 160 Leu Thr Phe His Leu Pro Tyr Cys Gly Pro Asn Gln Ile Gln His Tyr 165 170 175 Phe Cys Asp Ala Pro Pro Ile Leu Lys Leu Ala Cys Ala Asp Thr Ser 180 185 190 Ala Asn Glu Met Val Ile Phe Val Asn Ile Gly Leu Val Ala Ser Gly 195 200 205 Cys Phe Val Leu Ile Val Leu Ser Tyr Val Ser Ile Val Cys Ser Ile 210 215 220 Leu Arg Ile Arg Thr Ser Glu Gly Arg His Arg Ala Phe Gln Thr Cys 225 230 235 240 Ala Ser His Cys Ile Val Val Leu Cys Phe Phe Gly Pro Gly Leu Phe 245 250 255 Ile Tyr Leu Arg Pro Gly Ser Arg Asp Ala Leu His Gly Val Val Ala 260 265 270 Val Phe Tyr Thr Thr Leu Thr Pro Leu Phe Asn Pro Val Val Tyr Thr 275 280 285 Leu Arg Asn Lys Glu Val Lys Lys Ala Leu Leu Lys Leu Lys Asn Gly 290 295 300 Ser Val Phe Ala Gln Gly Glu 305 310 <210> 28 <211> 692 <212> PRT <213> Homo sapiens <400> 28 Met Gly Thr Val Ser Ser Arg Arg Ser Trp Trp Pro Leu Pro Leu Leu 1 5 10 15 Leu Leu Leu Leu Leu Leu Leu Gly Pro Ala Gly Ala Arg Ala Gln Glu 20 25 30 Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val Leu Ala Leu Arg Ser Glu 35 40 45 Glu Asp Gly Leu Ala Glu Ala Pro Glu His Gly Thr Thr Ala Thr Phe 50 55 60 His Arg Cys Ala Lys Asp Pro Trp Arg Leu Pro Gly Thr Tyr Val Val 65 70 75 80 Val Leu Lys Glu Glu Thr His Leu Ser Gln Ser Glu Arg Thr Ala Arg 85 90 95 Arg Leu Gln Ala Gln Ala Ala Arg Arg Gly Tyr Leu Thr Lys Ile Leu 100 105 110 His Val Phe His Gly Leu Leu Pro Gly Phe Leu Val Lys Met Ser Gly 115 120 125 Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro His Val Asp Tyr Ile Glu 130 135 140 Glu Asp Ser Ser Val Phe Ala Gln Ser Ile Pro Trp Asn Leu Glu Arg 145 150 155 160 Ile Thr Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gln Pro Pro Asp Gly 165 170 175 Gly Ser Leu Val Glu Val Tyr Leu Leu Asp Thr Ser Ile Gln Ser Asp 180 185 190 His Arg Glu Ile Glu Gly Arg Val Met Val Thr Asp Phe Glu Asn Val 195 200 205 Pro Glu Glu Asp Gly Thr Arg Phe His Arg Gln Ala Ser Lys Cys Asp 210 215 220 Ser His Gly Thr His Leu Ala Gly Val Val Ser Gly Arg Asp Ala Gly 225 230 235 240 Val Ala Lys Gly Ala Ser Met Arg Ser Leu Arg Val Leu Asn Cys Gln 245 250 255 Gly Lys Gly Thr Val Ser Gly Thr Leu Ile Gly Leu Glu Phe Ile Arg 260 265 270 Lys Ser Gln Leu Val Gln Pro Val Gly Pro Leu Val Val Leu Leu Pro 275 280 285 Leu Ala Gly Gly Tyr Ser Arg Val Leu Asn Ala Ala Cys Gln Arg Leu 290 295 300 Ala Arg Ala Gly Val Val Leu Val Thr Ala Ala Gly Asn Phe Arg Asp 305 310 315 320 Asp Ala Cys Leu Tyr Ser Pro Ala Ser Ala Pro Glu Val Ile Thr Val 325 330 335 Gly Ala Thr Asn Ala Gln Asp Gln Pro Val Thr Leu Gly Thr Leu Gly 340 345 350 Thr Asn Phe Gly Arg Cys Val Asp Leu Phe Ala Pro Gly Glu Asp Ile 355 360 365 Ile Gly Ala Ser Ser Asp Cys Ser Thr Cys Phe Val Ser Gln Ser Gly 370 375 380 Thr Ser Gln Ala Ala Ala His Val Ala Gly Ile Ala Ala Met Met Leu 385 390 395 400 Ser Ala Glu Pro Glu Leu Thr Leu Ala Glu Leu Arg Gln Arg Leu Ile 405 410 415 His Phe Ser Ala Lys Asp Val Ile Asn Glu Ala Trp Phe Pro Glu Asp 420 425 430 Gln Arg Val Leu Thr Pro Asn Leu Val Ala Ala Leu Pro Pro Ser Thr 435 440 445 His Gly Ala Gly Trp Gln Leu Phe Cys Arg Thr Val Trp Ser Ala His 450 455 460 Ser Gly Pro Thr Arg Met Ala Thr Ala Val Ala Arg Cys Ala Pro Asp 465 470 475 480 Glu Glu Leu Leu Ser Cys Ser Ser Phe Ser Arg Ser Gly Lys Arg Arg 485 490 495 Gly Glu Arg Met Glu Ala Gln Gly Gly Lys Leu Val Cys Arg Ala His 500 505 510 Asn Ala Phe Gly Gly Glu Gly Val Tyr Ala Ile Ala Arg Cys Cys Leu 515 520 525 Leu Pro Gln Ala Asn Cys Ser Val His Thr Ala Pro Pro Ala Glu Ala 530 535 540 Ser Met Gly Thr Arg Val His Cys His Gln Gln Gly His Val Leu Thr 545 550 555 560 Gly Cys Ser Ser His Trp Glu Val Glu Asp Leu Gly Thr His Lys Pro 565 570 575 Pro Val Leu Arg Pro Arg Gly Gln Pro Asn Gln Cys Val Gly His Arg 580 585 590 Glu Ala Ser Ile His Ala Ser Cys Cys His Ala Pro Gly Leu Glu Cys 595 600 605 Lys Val Lys Glu His Gly Ile Pro Ala Pro Gln Glu Gln Val Thr Val 610 615 620 Ala Cys Glu Glu Gly Trp Thr Leu Thr Gly Cys Ser Ala Leu Pro Gly 625 630 635 640 Thr Ser His Val Leu Gly Ala Tyr Ala Val Asp Asn Thr Cys Val Val 645 650 655 Arg Ser Arg Asp Val Ser Thr Thr Gly Ser Thr Ser Glu Gly Ala Val 660 665 670 Thr Ala Val Ala Ile Cys Cys Arg Ser Arg His Leu Ala Gln Ala Ser 675 680 685 Gln Glu Leu Gln 690 <210> 29 <211> 671 <212> PRT <213> Homo sapiens <400> 29 Met Thr Ile Arg His Gln Gly Gln Gln Tyr Arg Pro Arg Met Ala Phe 1 5 10 15 Leu Gln Lys Ile Glu Ala Leu Val Lys Asp Met Gln Asn Pro Glu Thr 20 25 30 Gly Val Arg Met Gln Asn Gln Arg Val Leu Val Thr Ser Val Pro His 35 40 45 Ala Met Thr Gly Ser Asp Val Leu Gln Trp Ile Val Gln Arg Leu Trp 50 55 60 Ile Ser Ser Leu Glu Ala Gln Asn Leu Gly Asn Phe Ile Val Arg Tyr 65 70 75 80 Gly Tyr Ile Tyr Pro Leu Gln Asp Pro Lys Asn Leu Ile Leu Lys Pro 85 90 95 Asp Gly Ser Leu Tyr Arg Phe Gln Thr Pro Tyr Phe Trp Pro Thr Gln 100 105 110 Gln Trp Pro Ala Glu Asp Thr Asp Tyr Ala Ile Tyr Leu Ala Lys Arg 115 120 125 Asn Ile Lys Lys Lys Gly Ile Leu Glu Glu Tyr Glu Lys Glu Asn Tyr 130 135 140 Asn Phe Leu Asn Gln Lys Met Asn Tyr Lys Trp Asp Phe Val Ile Met 145 150 155 160 Gln Ala Lys Glu Gln Tyr Arg Ala Gly Lys Glu Arg Asn Lys Ala Asp 165 170 175 Arg Tyr Ala Leu Asp Cys Gln Glu Lys Ala Tyr Trp Leu Val His Arg 180 185 190 Cys Pro Pro Gly Met Asp Asn Val Leu Asp Tyr Gly Leu Asp Arg Val 195 200 205 Thr Asn Pro Asn Glu Val Lys Lys Gln Thr Val Val Ala Val Lys Lys 210 215 220 Glu Ile Met Tyr Tyr Gln Gln Ala Leu Met Arg Ser Thr Val Lys Ser 225 230 235 240 Ser Val Ser Leu Gly Gly Ile Val Lys Tyr Ser Glu Gln Phe Ser Ser 245 250 255 Asn Asp Ala Ile Met Ser Gly Cys Leu Pro Ser Asn Pro Trp Ile Thr 260 265 270 Asp Asp Thr Gln Phe Trp Asp Leu Asn Ala Lys Leu Val Glu Ile Pro 275 280 285 Thr Lys Met Arg Val Glu Arg Trp Ala Phe Asn Phe Ser Glu Leu Ile 290 295 300 Arg Asp Pro Lys Gly Arg Gln Ser Phe Gln Tyr Phe Leu Lys Lys Glu 305 310 315 320 Phe Ser Gly Glu Asn Leu Gly Phe Trp Glu Ala Cys Glu Asp Leu Lys 325 330 335 Tyr Gly Asp Gln Ser Lys Val Lys Glu Lys Ala Glu Glu Ile Tyr Lys 340 345 350 Leu Phe Leu Ala Pro Gly Ala Arg Arg Trp Ile Asn Ile Asp Gly Lys 355 360 365 Thr Met Asp Ile Thr Val Lys Gly Leu Lys His Pro His Arg Tyr Val 370 375 380 Leu Asp Ala Ala Gln Thr His Ile Tyr Met Leu Met Lys Lys Asp Ser 385 390 395 400 Tyr Ala Arg Tyr Leu Lys Ser Pro Ile Tyr Lys Asp Met Leu Ala Lys 405 410 415 Ala Ile Glu Pro Gln Glu Thr Thr Lys Lys Ser Ser Thr Leu Pro Phe 420 425 430 Met Arg Arg His Leu Arg Ser Ser Pro Ser Pro Val Ile Leu Arg Gln 435 440 445 Leu Glu Glu Glu Ala Lys Ala Arg Glu Ala Ala Asn Thr Val Asp Ile 450 455 460 Thr Gln Pro Gly Gln His Met Ala Pro Ser Pro His Leu Thr Val Tyr 465 470 475 480 Thr Gly Thr Cys Met Pro Pro Ser Pro Ser Ser Pro Phe Ser Ser Ser 485 490 495 Cys Arg Ser Pro Arg Lys Pro Phe Ala Ser Pro Ser Arg Phe Ile Arg 500 505 510 Arg Pro Ser Thr Thr Ile Cys Pro Ser Pro Ile Arg Val Ala Leu Glu 515 520 525 Ser Ser Ser Gly Leu Glu Gln Lys Gly Glu Cys Ser Gly Ser Met Ala 530 535 540 Pro Arg Gly Pro Ser Val Thr Glu Ser Ser Glu Ala Ser Leu Asp Thr 545 550 555 560 Ser Trp Pro Arg Ser Arg Pro Arg Ala Pro Pro Lys Ala Arg Met Ala 565 570 575 Leu Ser Phe Ser Arg Phe Leu Arg Arg Gly Cys Leu Ala Ser Pro Val 580 585 590 Phe Ala Arg Leu Ser Pro Lys Cys Pro Ala Val Ser His Gly Arg Val 595 600 605 Gln Pro Leu Gly Asp Val Gly Gln Gln Leu Pro Arg Leu Lys Ser Lys 610 615 620 Arg Val Ala Asn Phe Phe Gln Ile Lys Met Asp Val Pro Thr Gly Ser 625 630 635 640 Gly Thr Cys Leu Met Asp Ser Glu Asp Ala Gly Thr Gly Glu Ser Gly 645 650 655 Asp Arg Ala Thr Glu Lys Glu Val Ile Cys Pro Trp Glu Ser Leu 660 665 670 <210> 30 <211> 1032 <212> PRT <213> Homo sapiens <400> 30 Met Ala Glu Pro Ser Ala Ala Thr Gln Ser His Ser Ile Ser Ser Ser 1 5 10 15 Ser Phe Gly Ala Glu Pro Ser Ala Pro Gly Gly Gly Gly Ser Pro Gly 20 25 30 Ala Cys Pro Ala Leu Gly Thr Lys Ser Cys Ser Ser Ser Cys Ala Asp 35 40 45 Ser Phe Val Ser Ser Ser Ser Ser Gln Pro Val Ser Leu Phe Ser Thr 50 55 60 Ser Gln Glu Gly Leu Ser Ser Leu Cys Ser Asp Glu Pro Ser Ser Glu 65 70 75 80 Ile Met Thr Ser Ser Phe Leu Ser Ser Ser Glu Ile His Asn Thr Gly 85 90 95 Leu Thr Ile Leu His Gly Glu Lys Ser His Val Leu Gly Ser Gln Pro 100 105 110 Ile Leu Ala Lys Glu Gly Lys Asp His Leu Asp Leu Leu Asp Met Lys 115 120 125 Lys Met Glu Lys Pro Gln Gly Thr Ser Asn Asn Val Ser Asp Ser Ser 130 135 140 Val Ser Leu Ala Ala Gly Val His Cys Asp Arg Pro Ser Ile Pro Ala 145 150 155 160 Ser Phe Pro Glu His Pro Ala Phe Leu Ser Lys Lys Ile Gly Gln Val 165 170 175 Glu Glu Gln Ile Asp Lys Glu Thr Lys Asn Pro Asn Gly Val Ser Ser 180 185 190 Arg Glu Ala Lys Thr Ala Leu Asp Ala Asp Asp Arg Phe Thr Leu Leu 195 200 205 Thr Ala Gln Lys Pro Pro Thr Glu Tyr Ser Lys Val Glu Gly Ile Tyr 210 215 220 Thr Tyr Ser Leu Ser Pro Ser Lys Val Ser Gly Asp Asp Val Ile Glu 225 230 235 240 Lys Asp Ser Pro Glu Ser Pro Phe Glu Val Ile Ile Asp Lys Ala Ala 245 250 255 Phe Asp Lys Glu Phe Lys Asp Ser Tyr Lys Glu Ser Thr Asp Asp Phe 260 265 270 Gly Ser Trp Ser Val His Thr Asp Lys Glu Ser Ser Glu Asp Ile Ser 275 280 285 Glu Thr Asn Asp Lys Leu Phe Pro Leu Arg Asn Lys Glu Ala Gly Arg 290 295 300 Tyr Pro Met Ser Ala Leu Leu Ser Arg Gln Phe Ser His Thr Asn Ala 305 310 315 320 Ala Leu Glu Glu Val Ser Arg Cys Val Asn Asp Met His Asn Phe Thr 325 330 335 Asn Glu Ile Leu Thr Trp Asp Leu Val Pro Gln Val Lys Gln Gln Thr 340 345 350 Asp Lys Ser Ser Asp Cys Ile Thr Lys Thr Thr Gly Leu Asp Met Ser 355 360 365 Glu Tyr Asn Ser Glu Ile Pro Val Val Asn Leu Lys Thr Ser Thr His 370 375 380 Gln Lys Thr Pro Val Cys Ser Ile Asp Gly Ser Thr Pro Ile Thr Lys 385 390 395 400 Ser Thr Gly Asp Trp Ala Glu Ala Ser Leu Gln Gln Glu Asn Ala Ile 405 410 415 Thr Gly Lys Pro Val Pro Asp Ser Leu Asn Ser Thr Lys Glu Phe Ser 420 425 430 Ile Lys Gly Val Gln Gly Asn Met Gln Lys Gln Asp Asp Thr Leu Ala 435 440 445 Glu Leu Pro Gly Ser Pro Pro Glu Lys Cys Asp Ser Leu Gly Ser Gly 450 455 460 Val Ala Thr Val Lys Val Val Leu Pro Asp Asp His Leu Lys Asp Glu 465 470 475 480 Met Asp Trp Gln Ser Ser Ala Leu Gly Glu Ile Thr Glu Ala Asp Ser 485 490 495 Ser Gly Glu Ser Asp Asp Thr Val Ile Glu Asp Ile Thr Ala Asp Thr 500 505 510 Ser Phe Glu Asn Asn Lys Ile Gln Ala Glu Lys Pro Val Ser Ile Pro 515 520 525 Ser Ala Val Val Lys Thr Gly Glu Arg Glu Ile Lys Glu Ile Pro Ser 530 535 540 Cys Glu Arg Glu Glu Lys Thr Ser Lys Asn Phe Glu Glu Leu Val Ser 545 550 555 560 Asp Ser Glu Leu His Gln Asp Gln Pro Asp Ile Leu Gly Arg Ser Pro 565 570 575 Ala Ser Glu Ala Ala Cys Ser Lys Val Pro Asp Thr Asn Val Ser Leu 580 585 590 Glu Asp Val Ser Glu Val Ala Pro Glu Lys Pro Ile Thr Thr Glu Asn 595 600 605 Pro Lys Leu Pro Ser Thr Val Ser Pro Asn Val Phe Asn Glu Thr Glu 610 615 620 Phe Ser Leu Asn Val Thr Thr Ser Ala Tyr Leu Glu Ser Leu His Gly 625 630 635 640 Lys Asn Val Lys His Ile Asp Asp Ser Ser Pro Glu Asp Leu Ile Ala 645 650 655 Ala Phe Thr Glu Thr Arg Asp Lys Gly Ile Val Asp Ser Glu Arg Asn 660 665 670 Ala Phe Lys Ala Ile Ser Glu Lys Met Thr Asp Phe Lys Thr Thr Pro 675 680 685 Pro Val Glu Val Leu His Glu Asn Glu Ser Gly Gly Ser Glu Ile Lys 690 695 700 Asp Ile Gly Ser Lys Tyr Ser Glu Gln Ser Lys Glu Thr Asn Gly Ser 705 710 715 720 Glu Pro Leu Gly Val Phe Pro Thr Gln Gly Thr Pro Val Ala Ser Leu 725 730 735 Asp Leu Glu Gln Glu Gln Leu Thr Ile Lys Ala Leu Lys Glu Leu Gly 740 745 750 Glu Arg Gln Val Glu Lys Ser Thr Ser Ala Gln Arg Asp Ala Glu Leu 755 760 765 Pro Ser Glu Glu Val Leu Lys Gln Thr Phe Thr Phe Ala Pro Glu Ser 770 775 780 Trp Pro Gln Arg Ser Tyr Asp Ile Leu Glu Arg Asn Val Lys Asn Gly 785 790 795 800 Ser Asp Leu Gly Ile Ser Gln Lys Pro Ile Thr Ile Arg Glu Thr Thr 805 810 815 Arg Val Asp Ala Val Ser Ser Leu Ser Lys Thr Glu Leu Val Lys Lys 820 825 830 His Val Leu Ala Arg Leu Leu Thr Asp Phe Ser Val His Asp Leu Ile 835 840 845 Phe Trp Arg Asp Val Lys Lys Thr Gly Phe Val Phe Gly Thr Thr Leu 850 855 860 Ile Met Leu Leu Ser Leu Ala Ala Phe Ser Val Ile Ser Val Val Ser 865 870 875 880 Tyr Leu Ile Leu Ala Leu Leu Ser Val Thr Ile Ser Phe Arg Ile Tyr 885 890 895 Lys Ser Val Ile Gln Ala Val Gln Lys Ser Glu Glu Gly His Pro Phe 900 905 910 Lys Ala Tyr Leu Asp Val Asp Ile Thr Leu Ser Ser Glu Ala Phe His 915 920 925 Asn Tyr Met Asn Ala Ala Met Val His Ile Asn Arg Ala Leu Lys Leu 930 935 940 Ile Ile Arg Leu Phe Leu Val Glu Asp Leu Val Asp Ser Leu Lys Leu 945 950 955 960 Ala Val Phe Met Trp Leu Met Thr Tyr Val Gly Ala Val Phe Asn Gly 965 970 975 Ile Thr Leu Leu Ile Leu Ala Glu Leu Leu Ile Phe Ser Val Pro Ile 980 985 990 Val Tyr Glu Lys Tyr Lys Thr Gln Ile Asp His Tyr Val Gly Ile Ala 995 1000 1005 Arg Asp Gln Thr Lys Ser Ile Val Glu Lys Ile Gln Ala Lys Leu Pro 1010 1015 1020 Gly Ile Ala Lys Lys Lys Ala Glu 1025 1030 <210> 31 <211> 786 <212> PRT <213> Homo sapiens <400> 31 Met Ser Phe Ser Arg Ala Leu Leu Trp Ala Arg Leu Pro Ala Gly Arg 1 5 10 15 Gln Ala Gly His Arg Ala Ala Ile Cys Ser Ala Leu Arg Pro His Phe 20 25 30 Gly Pro Phe Pro Gly Val Leu Gly Gln Val Ser Val Leu Ala Thr Ala 35 40 45 Ser Ser Ser Ala Ser Gly Gly Ser Lys Ile Pro Asn Thr Ser Leu Phe 50 55 60 Val Pro Leu Thr Val Lys Pro Gln Gly Pro Ser Ala Asp Gly Asp Val 65 70 75 80 Gly Ala Glu Leu Thr Arg Pro Leu Asp Lys Asn Glu Val Lys Lys Val 85 90 95 Leu Asp Lys Phe Tyr Lys Arg Lys Glu Ile Gln Lys Leu Gly Ala Asp 100 105 110 Tyr Gly Leu Asp Ala Arg Leu Phe His Gln Ala Phe Ile Ser Phe Arg 115 120 125 Asn Tyr Ile Met Gln Ser His Ser Leu Asp Val Asp Ile His Ile Val 130 135 140 Leu Asn Asp Ile Cys Phe Gly Ala Ala His Ala Asp Asp Leu Phe Pro 145 150 155 160 Phe Phe Leu Arg His Ala Lys Gln Ile Phe Pro Val Leu Asp Cys Lys 165 170 175 Asp Asp Leu Arg Lys Ile Ser Asp Leu Arg Ile Pro Pro Asn Trp Tyr 180 185 190 Pro Asp Ala Arg Ala Met Gln Arg Lys Ile Ile Phe His Ser Gly Pro 195 200 205 Thr Asn Ser Gly Lys Thr Tyr His Ala Ile Gln Lys Tyr Phe Ser Ala 210 215 220 Lys Ser Gly Val Tyr Cys Gly Pro Leu Lys Leu Leu Ala His Glu Ile 225 230 235 240 Phe Glu Lys Ser Asn Ala Ala Gly Val Pro Cys Asp Leu Val Thr Gly 245 250 255 Glu Glu Arg Val Thr Val Gln Pro Asn Gly Lys Gln Ala Ser His Val 260 265 270 Ser Cys Thr Val Glu Met Cys Ser Val Thr Thr Pro Tyr Glu Val Ala 275 280 285 Val Ile Asp Glu Ile Gln Met Ile Arg Asp Pro Ala Arg Gly Trp Ala 290 295 300 Trp Thr Arg Ala Leu Leu Gly Leu Cys Ala Glu Glu Val His Leu Cys 305 310 315 320 Gly Glu Pro Ala Ala Ile Asp Leu Val Met Glu Leu Met Tyr Thr Thr 325 330 335 Gly Glu Glu Val Glu Val Arg Asp Tyr Lys Arg Leu Thr Pro Ile Ser 340 345 350 Val Leu Asp His Ala Leu Glu Ser Leu Asp Asn Leu Arg Pro Gly Asp 355 360 365 Cys Ile Val Cys Phe Ser Lys Asn Asp Ile Tyr Ser Val Ser Arg Gln 370 375 380 Ile Glu Ile Arg Gly Leu Glu Ser Ala Val Ile Tyr Gly Ser Leu Pro 385 390 395 400 Pro Gly Thr Lys Leu Ala Gln Ala Lys Lys Phe Asn Asp Pro Asn Asp 405 410 415 Pro Cys Lys Ile Leu Val Ala Thr Asp Ala Ile Gly Met Gly Leu Asn 420 425 430 Leu Ser Ile Arg Arg Ile Ile Phe Tyr Ser Leu Ile Lys Pro Ser Ile 435 440 445 Asn Glu Lys Gly Glu Arg Glu Leu Glu Pro Ile Thr Thr Ser Gln Ala 450 455 460 Leu Gln Ile Ala Gly Arg Ala Gly Arg Phe Ser Ser Arg Phe Lys Glu 465 470 475 480 Gly Glu Val Thr Thr Met Asn His Glu Asp Leu Ser Leu Leu Lys Glu 485 490 495 Ile Leu Lys Arg Pro Val Asp Pro Ile Arg Ala Ala Gly Leu His Pro 500 505 510 Thr Ala Glu Gln Ile Glu Met Phe Ala Tyr His Leu Pro Asp Ala Thr 515 520 525 Leu Ser Asn Leu Ile Asp Ile Phe Val Asp Phe Ser Gln Val Asp Gly 530 535 540 Gln Tyr Phe Val Cys Asn Met Asp Asp Phe Lys Phe Ser Ala Glu Leu 545 550 555 560 Ile Gln His Ile Pro Leu Ser Leu Arg Val Arg Tyr Val Phe Cys Thr 565 570 575 Ala Pro Ile Asn Lys Lys Gln Pro Phe Val Cys Ser Ser Leu Leu Gln 580 585 590 Phe Ala Arg Gln Tyr Ser Arg Asn Glu Pro Leu Thr Phe Ala Trp Leu 595 600 605 Arg Arg Tyr Ile Lys Trp Pro Leu Leu Pro Pro Lys Asn Ile Lys Asp 610 615 620 Leu Met Asp Leu Glu Ala Val His Asp Val Leu Asp Leu Tyr Leu Trp 625 630 635 640 Leu Ser Tyr Arg Phe Met Asp Met Phe Pro Asp Ala Ser Leu Ile Arg 645 650 655 Asp Leu Gln Lys Glu Leu Asp Gly Ile Ile Gln Asp Gly Val His Asn 660 665 670 Ile Thr Lys Leu Ile Lys Met Ser Glu Thr His Lys Leu Leu Asn Leu 675 680 685 Glu Gly Phe Pro Ser Gly Ser Gln Ser Arg Leu Ser Gly Thr Leu Lys 690 695 700 Ser Gln Ala Arg Arg Thr Arg Gly Thr Lys Ala Leu Gly Ser Lys Ala 705 710 715 720 Thr Glu Pro Pro Ser Pro Asp Ala Gly Glu Leu Ser Leu Ala Ser Arg 725 730 735 Leu Val Gln Gln Gly Leu Leu Thr Pro Asp Met Leu Lys Gln Leu Glu 740 745 750 Lys Glu Trp Met Thr Gln Gln Thr Glu His Asn Lys Glu Lys Thr Glu 755 760 765 Ser Gly Thr His Pro Lys Gly Thr Arg Arg Lys Lys Lys Glu Pro Asp 770 775 780 Ser Asp 785 <210> 32 <211> 436 <212> PRT <213> Homo sapiens <400> 32 Met Trp Arg Cys Pro Leu Gly Leu Leu Leu Leu Leu Pro Leu Ala Gly 1 5 10 15 His Leu Ala Leu Gly Ala Gln Gln Gly Arg Gly Arg Arg Glu Leu Ala 20 25 30 Pro Gly Leu His Leu Arg Gly Ile Arg Asp Ala Gly Gly Arg Tyr Cys 35 40 45 Gln Glu Gln Asp Leu Cys Cys Arg Gly Arg Ala Asp Asp Cys Ala Leu 50 55 60 Pro Tyr Leu Gly Ala Ile Cys Tyr Cys Asp Leu Phe Cys Asn Arg Thr 65 70 75 80 Val Ser Asp Cys Cys Pro Asp Phe Trp Asp Phe Cys Leu Gly Val Pro 85 90 95 Pro Pro Phe Pro Pro Ile Gln Gly Cys Met His Gly Gly Arg Ile Tyr 100 105 110 Pro Val Leu Gly Thr Tyr Trp Asp Asn Cys Asn Arg Cys Trp Gln Ala 115 120 125 Gly Asn His Ser Ala Phe Trp Gly Met Thr Leu Asp Glu Gly Ile Arg 130 135 140 Tyr Arg Leu Gly Thr Ile Arg Pro Ser Ser Ser Val Met Asn Met His 145 150 155 160 Glu Ile Tyr Thr Val Leu Asn Pro Gly Glu Val Leu Pro Thr Ala Phe 165 170 175 Glu Ala Ser Glu Lys Trp Pro Asn Leu Ile His Glu Pro Leu Asp Gln 180 185 190 Gly Asn Cys Ala Gly Ser Trp Ala Phe Ser Thr Ala Ala Val Ala Ser 195 200 205 Asp Arg Val Ser Ile His Ser Leu Gly His Met Thr Pro Val Leu Ser 210 215 220 Pro Gln Asn Leu Leu Ser Cys Asp Thr His Gln Gln Gln Gly Cys Arg 225 230 235 240 Gly Gly Arg Leu Asp Gly Ala Trp Trp Phe Leu Arg Arg Arg Gly Val 245 250 255 Val Ser Asp His Cys Tyr Pro Phe Ser Gly Arg Glu Arg Asp Glu Ala 260 265 270 Gly Pro Ala Pro Pro Cys Met Met His Ser Arg Ala Met Gly Arg Gly 275 280 285 Lys Arg Gln Ala Thr Ala His Cys Pro Asn Ser Tyr Val Asn Asn Asn 290 295 300 Asp Ile Tyr Gln Val Thr Pro Val Tyr Arg Leu Gly Ser Asn Asp Lys 305 310 315 320 Glu Ile Met Lys Glu Leu Met Glu Asn Gly Pro Val Gln Ala Leu Met 325 330 335 Glu Val His Glu Asp Phe Phe Leu Tyr Lys Gly Gly Ile Tyr Ser His 340 345 350 Thr Pro Val Ser Leu Gly Arg Pro Glu Arg Tyr Arg Arg His Gly Thr 355 360 365 His Ser Val Lys Ile Thr Gly Trp Gly Glu Glu Thr Leu Pro Asp Gly 370 375 380 Arg Thr Leu Lys Tyr Trp Thr Ala Ala Asn Ser Trp Gly Pro Ala Trp 385 390 395 400 Gly Glu Arg Gly His Phe Arg Ile Val Arg Gly Val Asn Glu Cys Asp 405 410 415 Ile Glu Ser Phe Val Leu Gly Val Trp Gly Arg Val Gly Met Glu Asp 420 425 430 Met Gly His His 435 <210> 33 <211> 467 <212> PRT <213> Homo sapiens <400> 33 Met Ala Ser Val Ala Ala Ala Arg Ala Val Pro Val Gly Ser Gly Leu 1 5 10 15 Arg Gly Leu Gln Arg Thr Leu Pro Leu Val Val Ile Leu Gly Ala Thr 20 25 30 Gly Thr Gly Lys Ser Thr Leu Ala Leu Gln Leu Gly Gln Arg Leu Gly 35 40 45 Gly Glu Ile Val Ser Ala Asp Ser Met Gln Val Tyr Glu Gly Leu Asp 50 55 60 Ile Ile Thr Asn Lys Val Ser Ala Gln Glu Gln Arg Ile Cys Arg His 65 70 75 80 His Met Ile Ser Phe Val Asp Pro Leu Val Thr Asn Tyr Thr Val Val 85 90 95 Asp Phe Arg Asn Arg Ala Thr Ala Leu Ile Glu Asp Ile Phe Ala Arg 100 105 110 Asp Lys Ile Pro Ile Val Val Gly Gly Thr Asn Tyr Tyr Ile Glu Ser 115 120 125 Leu Leu Trp Lys Val Leu Val Asn Thr Lys Pro Gln Glu Met Gly Thr 130 135 140 Glu Lys Val Ile Asp Arg Lys Val Glu Leu Glu Lys Glu Asp Gly Leu 145 150 155 160 Val Leu His Lys Arg Leu Ser Gln Val Asp Pro Glu Met Ala Ala Lys 165 170 175 Leu His Pro His Asp Lys Arg Lys Val Ala Arg Ser Leu Gln Val Phe 180 185 190 Glu Glu Thr Gly Ile Ser His Ser Glu Phe Leu His Arg Gln His Thr 195 200 205 Glu Glu Gly Gly Gly Pro Leu Gly Gly Pro Leu Lys Phe Ser Asn Pro 210 215 220 Cys Ile Leu Trp Leu His Ala Asp Gln Ala Val Leu Asp Glu Arg Leu 225 230 235 240 Asp Lys Arg Val Asp Asp Met Leu Ala Ala Gly Leu Leu Glu Glu Leu 245 250 255 Arg Asp Phe His Arg Arg Tyr Asn Gln Lys Asn Val Ser Glu Asn Ser 260 265 270 Gln Asp Tyr Gln His Gly Ile Phe Gln Ser Ile Gly Phe Lys Glu Phe 275 280 285 His Glu Tyr Leu Ile Thr Glu Gly Lys Cys Thr Leu Glu Thr Ser Asn 290 295 300 Gln Leu Leu Lys Lys Gly Ile Glu Ala Leu Lys Gln Val Thr Lys Arg 305 310 315 320 Tyr Ala Arg Lys Gln Asn Arg Trp Val Lys Asn Arg Phe Leu Ser Arg 325 330 335 Pro Gly Pro Ile Val Pro Pro Val Tyr Gly Leu Glu Val Ser Asp Val 340 345 350 Ser Lys Trp Glu Glu Ser Val Leu Glu Pro Ala Leu Glu Ile Val Gln 355 360 365 Ser Phe Ile Gln Gly His Lys Pro Thr Ala Thr Pro Ile Lys Met Pro 370 375 380 Tyr Asn Glu Ala Glu Asn Lys Arg Ser Tyr His Leu Cys Asp Leu Cys 385 390 395 400 Asp Arg Ile Ile Ile Gly Asp Arg Glu Trp Ala Ala His Ile Lys Ser 405 410 415 Lys Ser His Leu Asn Gln Leu Lys Lys Arg Arg Arg Leu Asp Ser Asp 420 425 430 Ala Val Asn Thr Ile Glu Ser Gln Ser Val Ser Pro Asp His Asn Lys 435 440 445 Glu Pro Lys Glu Lys Gly Ser Pro Gly Gln Asn Asp Gln Glu Leu Lys 450 455 460 Cys Ser Val 465 <210> 34 <211> 953 <212> PRT <213> Homo sapiens <400> 34 Met Gly Arg Ala Ala Ala Thr Ala Gly Gly Gly Gly Gly Ala Arg Arg 1 5 10 15 Trp Leu Pro Trp Leu Gly Leu Cys Phe Trp Ala Ala Gly Thr Ala Ala 20 25 30 Ala Arg Gly Thr Asp Asn Gly Glu Ala Leu Pro Glu Ser Ile Pro Ser 35 40 45 Ala Pro Gly Thr Leu Pro His Phe Ile Glu Glu Pro Asp Asp Ala Tyr 50 55 60 Ile Ile Lys Ser Asn Pro Ile Ala Leu Arg Cys Lys Ala Arg Pro Ala 65 70 75 80 Met Gln Ile Phe Phe Lys Cys Asn Gly Glu Trp Val His Gln Asn Glu 85 90 95 His Val Ser Glu Glu Thr Leu Asp Glu Ser Ser Gly Leu Lys Val Arg 100 105 110 Glu Val Phe Ile Asn Val Thr Arg Gln Gln Val Glu Asp Phe His Gly 115 120 125 Pro Glu Asp Tyr Trp Cys Gln Cys Val Ala Trp Ser His Leu Gly Thr 130 135 140 Ser Lys Ser Arg Lys Ala Ser Val Arg Ile Ala Tyr Leu Arg Lys Asn 145 150 155 160 Phe Glu Gln Asp Pro Gln Gly Arg Glu Val Pro Ile Glu Gly Met Ile 165 170 175 Val Leu His Cys Arg Pro Pro Glu Gly Val Pro Ala Ala Glu Val Glu 180 185 190 Trp Leu Lys Asn Glu Glu Pro Ile Asp Ser Glu Gln Asp Glu Asn Ile 195 200 205 Asp Thr Arg Ala Asp His Asn Leu Ile Ile Arg Gln Ala Arg Leu Ser 210 215 220 Asp Ser Gly Asn Tyr Thr Cys Met Ala Ala Asn Ile Val Ala Lys Arg 225 230 235 240 Arg Ser Leu Ser Ala Thr Val Val Val Tyr Val Asn Gly Gly Trp Ser 245 250 255 Ser Trp Thr Glu Trp Ser Ala Cys Asn Val Arg Cys Gly Arg Gly Trp 260 265 270 Gln Lys Arg Ser Arg Thr Cys Thr Asn Pro Ala Pro Leu Asn Gly Gly 275 280 285 Ala Phe Cys Glu Gly Met Ser Val Gln Lys Ile Thr Cys Thr Ser Leu 290 295 300 Cys Pro Val Asp Gly Ser Trp Glu Val Trp Ser Glu Trp Ser Val Cys 305 310 315 320 Ser Pro Glu Cys Glu His Leu Arg Ile Arg Glu Cys Thr Ala Pro Pro 325 330 335 Pro Arg Asn Gly Gly Lys Phe Cys Glu Gly Leu Ser Gln Glu Ser Glu 340 345 350 Asn Cys Thr Asp Gly Leu Cys Ile Leu Asp Lys Lys Pro Leu His Glu 355 360 365 Ile Lys Pro Gln Ser Ile Glu Asn Ala Ser Asp Ile Ala Leu Tyr Ser 370 375 380 Gly Leu Gly Ala Ala Val Val Ala Val Ala Val Leu Val Ile Gly Val 385 390 395 400 Thr Leu Tyr Arg Arg Ser Gln Ser Asp Tyr Gly Val Asp Val Ile Asp 405 410 415 Ser Ser Ala Leu Thr Gly Gly Phe Gln Thr Phe Asn Phe Lys Thr Val 420 425 430 Arg Gln Gly Asn Ser Leu Leu Leu Asn Ser Ala Met Gln Pro Asp Leu 435 440 445 Thr Val Ser Arg Thr Tyr Ser Gly Pro Ile Cys Leu Gln Asp Pro Leu 450 455 460 Asp Lys Glu Leu Met Thr Glu Ser Ser Leu Phe Asn Pro Leu Ser Asp 465 470 475 480 Ile Lys Val Lys Val Gln Ser Ser Phe Met Val Ser Leu Gly Val Ser 485 490 495 Glu Arg Ala Glu Tyr His Gly Lys Asn His Ser Arg Thr Phe Pro His 500 505 510 Gly Asn Asn His Ser Phe Ser Thr Met His Pro Arg Asn Lys Met Pro 515 520 525 Tyr Ile Gln Asn Leu Ser Ser Leu Pro Thr Arg Thr Glu Leu Arg Thr 530 535 540 Thr Gly Val Phe Gly His Leu Gly Gly Arg Leu Val Met Pro Asn Thr 545 550 555 560 Gly Val Ser Leu Leu Ile Pro His Gly Ala Ile Pro Glu Glu Asn Ser 565 570 575 Trp Glu Ile Tyr Met Ser Ile Asn Gln Gly Glu Pro Ser Leu Gln Ser 580 585 590 Asp Gly Ser Glu Val Leu Leu Ser Pro Glu Val Thr Cys Gly Pro Pro 595 600 605 Asp Met Ile Val Thr Thr Pro Phe Ala Leu Thr Ile Pro His Cys Ala 610 615 620 Asp Val Ser Ser Glu His Trp Asn Ile His Leu Lys Lys Arg Thr Gln 625 630 635 640 Gln Gly Lys Trp Glu Glu Val Met Ser Val Glu Asp Glu Ser Thr Ser 645 650 655 Cys Tyr Cys Leu Leu Asp Pro Phe Ala Cys His Val Leu Leu Asp Ser 660 665 670 Phe Gly Thr Tyr Ala Leu Thr Gly Glu Pro Ile Thr Asp Cys Ala Val 675 680 685 Lys Gln Leu Lys Val Ala Val Phe Gly Cys Met Ser Cys Asn Ser Leu 690 695 700 Asp Tyr Asn Leu Arg Val Tyr Cys Val Asp Asn Thr Pro Cys Ala Phe 705 710 715 720 Gln Glu Val Val Ser Asp Glu Arg His Gln Gly Gly Gln Leu Leu Glu 725 730 735 Glu Pro Lys Leu Leu His Phe Lys Gly Asn Thr Phe Ser Leu Gln Ile 740 745 750 Ser Val Leu Asp Ile Pro Pro Phe Leu Trp Arg Ile Lys Pro Phe Thr 755 760 765 Ala Cys Gln Glu Val Pro Phe Ser Arg Val Trp Cys Ser Asn Arg Gln 770 775 780 Pro Leu His Cys Ala Phe Ser Leu Glu Arg Tyr Thr Pro Thr Thr Thr 785 790 795 800 Gln Leu Ser Cys Lys Ile Cys Ile Arg Gln Leu Lys Gly His Glu Gln 805 810 815 Ile Leu Gln Val Gln Thr Ser Ile Leu Glu Ser Glu Arg Glu Thr Ile 820 825 830 Thr Phe Phe Ala Gln Glu Asp Ser Thr Phe Pro Ala Gln Thr Gly Pro 835 840 845 Lys Ala Phe Lys Ile Pro Tyr Ser Ile Arg Gln Arg Ile Cys Ala Thr 850 855 860 Phe Asp Thr Pro Asn Ala Lys Gly Lys Asp Trp Gln Met Leu Ala Gln 865 870 875 880 Lys Asn Ser Ile Asn Arg Asn Leu Ser Tyr Phe Ala Thr Gln Ser Ser 885 890 895 Pro Ser Ala Val Ile Leu Asn Leu Trp Glu Ala Arg His Gln His Asp 900 905 910 Gly Asp Leu Asp Ser Leu Ala Cys Ala Leu Glu Glu Ile Gly Arg Thr 915 920 925 His Thr Lys Leu Ser Asn Ile Ser Glu Ser Gln Leu Asp Glu Ala Asp 930 935 940 Phe Asn Tyr Ser Arg Gln Asn Gly Leu 945 950 <210> 35 <211> 1247 <212> PRT <213> Homo sapiens <400> 35 Met Ser Leu Phe Leu Arg Val Val Phe Ser Phe Thr Met Phe Gly Asp 1 5 10 15 Leu Phe Glu Glu Glu Tyr Ser Thr Val Ser Asn Asn Gln Tyr Gly Lys 20 25 30 Gly Lys Lys Leu Lys Thr Lys Ala Leu Glu Pro Pro Ala Pro Arg Glu 35 40 45 Phe Thr Asn Leu Ser Gly Ile Arg Asn Gln Gly Gly Thr Cys Tyr Leu 50 55 60 Asn Ser Leu Leu Gln Thr Leu His Phe Thr Pro Glu Phe Arg Glu Ala 65 70 75 80 Leu Phe Ser Leu Gly Pro Glu Glu Leu Gly Leu Phe Glu Asp Lys Asp 85 90 95 Lys Pro Asp Ala Lys Val Arg Ile Ile Pro Leu Gln Leu Gln Arg Leu 100 105 110 Phe Ala Gln Leu Leu Leu Leu Asp Gln Glu Ala Ala Ser Thr Ala Asp 115 120 125 Leu Thr Asp Ser Phe Gly Trp Thr Ser Asn Glu Glu Met Arg Gln His 130 135 140 Asp Val Gln Glu Leu Asn Arg Ile Leu Phe Ser Ala Leu Glu Thr Ser 145 150 155 160 Leu Val Gly Thr Ser Gly His Asp Leu Ile Tyr Arg Leu Tyr His Gly 165 170 175 Thr Ile Val Asn Gln Ile Val Cys Lys Glu Cys Lys Asn Val Ser Glu 180 185 190 Arg Gln Glu Asp Phe Leu Asp Leu Thr Val Ala Val Lys Asn Val Ser 195 200 205 Gly Leu Glu Asp Ala Leu Trp Asn Met Tyr Val Glu Glu Glu Val Phe 210 215 220 Asp Cys Asp Asn Leu Tyr His Cys Gly Thr Cys Asp Arg Leu Val Lys 225 230 235 240 Ala Ala Lys Ser Ala Lys Leu Arg Lys Leu Pro Pro Phe Leu Thr Val 245 250 255 Ser Leu Leu Arg Phe Asn Phe Asp Phe Val Lys Cys Glu Arg Tyr Lys 260 265 270 Glu Thr Ser Cys Tyr Thr Phe Pro Leu Arg Ile Asn Leu Lys Pro Phe 275 280 285 Cys Glu Gln Ser Glu Leu Asp Asp Leu Glu Tyr Ile Tyr Asp Leu Phe 290 295 300 Ser Val Ile Ile His Lys Gly Gly Cys Tyr Gly Gly His Tyr His Val 305 310 315 320 Tyr Ile Lys Asp Val Asp His Leu Gly Asn Trp Gln Phe Gln Glu Glu 325 330 335 Lys Ser Lys Pro Asp Val Asn Leu Lys Asp Leu Gln Ser Glu Glu Glu 340 345 350 Ile Asp His Pro Leu Met Ile Leu Lys Ala Ile Leu Leu Glu Glu Asn 355 360 365 Asn Leu Ile Pro Val Asp Gln Leu Gly Gln Lys Leu Leu Lys Lys Ile 370 375 380 Gly Ile Ser Trp Asn Lys Lys Tyr Arg Lys Gln His Gly Pro Leu Arg 385 390 395 400 Lys Phe Leu Gln Leu His Ser Gln Ile Phe Leu Leu Ser Ser Asp Glu 405 410 415 Ser Thr Val Arg Leu Leu Lys Asn Ser Ser Leu Gln Ala Glu Ser Asp 420 425 430 Phe Gln Arg Asn Asp Gln Gln Ile Phe Lys Met Leu Pro Pro Glu Ser 435 440 445 Pro Gly Leu Asn Asn Ser Ile Ser Cys Pro His Trp Phe Asp Ile Asn 450 455 460 Asp Ser Lys Val Gln Pro Ile Arg Glu Lys Asp Ile Glu Gln Gln Phe 465 470 475 480 Gln Gly Lys Glu Ser Ala Tyr Met Leu Phe Tyr Arg Lys Ser Gln Leu 485 490 495 Gln Arg Pro Pro Glu Ala Arg Ala Asn Pro Arg Tyr Gly Val Pro Cys 500 505 510 His Leu Leu Asn Glu Met Asp Ala Ala Asn Ile Glu Leu Gln Thr Lys 515 520 525 Arg Ala Glu Cys Asp Ser Ala Asn Asn Thr Phe Glu Leu His Leu His 530 535 540 Leu Gly Pro Gln Tyr His Phe Phe Asn Gly Ala Leu His Pro Val Val 545 550 555 560 Ser Gln Thr Glu Ser Val Trp Asp Leu Thr Phe Asp Lys Arg Lys Thr 565 570 575 Leu Gly Asp Leu Arg Gln Ser Ile Phe Gln Leu Leu Glu Phe Trp Glu 580 585 590 Gly Asp Met Val Leu Ser Val Ala Lys Leu Val Pro Ala Gly Leu His 595 600 605 Ile Tyr Gln Ser Leu Gly Gly Asp Glu Leu Thr Leu Cys Glu Thr Glu 610 615 620 Ile Ala Asp Gly Glu Asp Ile Phe Val Trp Asn Gly Val Glu Val Gly 625 630 635 640 Gly Val His Ile Gln Thr Gly Ile Asp Cys Glu Pro Leu Leu Leu Asn 645 650 655 Val Leu His Leu Asp Thr Ser Ser Asp Gly Glu Lys Cys Cys Gln Val 660 665 670 Ile Glu Ser Pro His Val Phe Pro Ala Asn Ala Glu Val Gly Thr Val 675 680 685 Leu Thr Ala Leu Ala Ile Pro Ala Gly Val Ile Phe Ile Asn Ser Ala 690 695 700 Gly Cys Pro Gly Gly Glu Gly Trp Thr Ala Ile Pro Lys Glu Asp Met 705 710 715 720 Arg Lys Thr Phe Arg Glu Gln Gly Leu Arg Asn Gly Ser Ser Ile Leu 725 730 735 Ile Gln Asp Ser His Asp Asp Asn Ser Leu Leu Thr Lys Glu Glu Lys 740 745 750 Trp Val Thr Ser Met Asn Glu Ile Asp Trp Leu His Val Lys Asn Leu 755 760 765 Cys Gln Leu Glu Ser Glu Glu Lys Gln Val Lys Ile Ser Ala Thr Val 770 775 780 Asn Thr Met Val Phe Asp Ile Arg Ile Lys Ala Ile Lys Glu Leu Lys 785 790 795 800 Leu Met Lys Glu Leu Ala Asp Asn Ser Cys Leu Arg Pro Ile Asp Arg 805 810 815 Asn Gly Lys Leu Leu Cys Pro Val Pro Asp Ser Tyr Thr Leu Lys Glu 820 825 830 Ala Glu Leu Lys Met Gly Ser Ser Leu Gly Leu Cys Leu Gly Lys Ala 835 840 845 Pro Ser Ser Ser Gln Leu Phe Leu Phe Phe Ala Met Gly Ser Asp Val 850 855 860 Gln Pro Gly Thr Glu Met Glu Ile Val Val Glu Glu Thr Ile Ser Val 865 870 875 880 Arg Asp Cys Leu Lys Leu Met Leu Lys Lys Ser Gly Leu Gln Gly Asp 885 890 895 Ala Trp His Leu Arg Lys Met Asp Trp Cys Tyr Glu Ala Gly Glu Pro 900 905 910 Leu Cys Glu Glu Asp Ala Thr Leu Lys Glu Leu Leu Ile Cys Ser Gly 915 920 925 Asp Thr Leu Leu Leu Ile Glu Gly Gln Leu Pro Pro Leu Gly Phe Leu 930 935 940 Lys Val Pro Ile Trp Trp Tyr Gln Leu Gln Gly Pro Ser Gly His Trp 945 950 955 960 Glu Ser His Gln Asp Gln Thr Asn Cys Thr Ser Ser Trp Gly Arg Val 965 970 975 Trp Arg Ala Thr Ser Ser Gln Gly Ala Ser Gly Asn Glu Pro Ala Gln 980 985 990 Val Ser Leu Leu Tyr Leu Gly Asp Ile Glu Ile Ser Glu Asp Ala Thr 995 1000 1005 Leu Ala Glu Leu Lys Ser Gln Ala Met Thr Leu Pro Pro Phe Leu Glu 1010 1015 1020 Phe Gly Val Pro Ser Pro Ala His Leu Arg Ala Trp Thr Val Glu Arg 1025 1030 1035 1040 Lys Arg Pro Gly Arg Leu Leu Arg Thr Asp Arg Gln Pro Leu Arg Glu 1045 1050 1055 Tyr Lys Leu Gly Arg Arg Ile Glu Ile Cys Leu Glu Pro Leu Gln Lys 1060 1065 1070 Gly Glu Asn Leu Gly Pro Gln Asp Val Leu Leu Arg Thr Gln Val Arg 1075 1080 1085 Ile Pro Gly Glu Arg Thr Tyr Ala Pro Ala Leu Asp Leu Val Trp Asn 1090 1095 1100 Ala Ala Gln Gly Gly Thr Ala Gly Ser Leu Arg Gln Arg Val Ala Asp 1105 1110 1115 1120 Phe Tyr Arg Leu Pro Val Glu Lys Ile Glu Ile Ala Lys Tyr Phe Pro 1125 1130 1135 Glu Lys Phe Glu Trp Leu Pro Ile Ser Ser Trp Asn Gln Gln Ile Thr 1140 1145 1150 Lys Arg Lys Lys Lys Lys Lys Gln Asp Tyr Leu Gln Gly Ala Pro Tyr 1155 1160 1165 Tyr Leu Lys Asp Gly Asp Thr Ile Gly Val Lys Asn Leu Leu Ile Asp 1170 1175 1180 Asp Asp Asp Asp Phe Ser Thr Ile Arg Asp Asp Thr Gly Lys Glu Lys 1185 1190 1195 1200 Gln Lys Gln Arg Ala Leu Gly Arg Arg Lys Ser Gln Glu Ala Leu His 1205 1210 1215 Glu Gln Ser Ser Tyr Ile Leu Ser Ser Ala Glu Thr Pro Ala Arg Pro 1220 1225 1230 Arg Ala Pro Glu Thr Ser Leu Ser Ile His Val Gly Ser Phe Arg 1235 1240 1245

Claims (11)

ALAS2, ARHGEF5, BAZ2B, C20orf26, CLCN2, FAM59A, KIAA1614, MCPH1, NLRP2, NOS1AP, PRSS38, RGPD5, USP29, XPO1, ZFAND2B, ZNF33A, ANKRD50, CCBL2, CNDM5GB1, DM1, OLFDM2GB1, DM1, EML2 OR10AG1, OR10G7, PCSK9, RGS9, RTN3, SUPV3L1, TINAGL1, TRIT1, UNC5D and USP40 Recurrence or prognosis of kidney cancer, comprising an agent for confirming the presence or absence of mutations in the gene encoding at least one selected from the group consisting of Composition for prediction. The method according to claim 1,
The mutation of the gene encoding ALAS2 is a missense mutation that is at least one of K100R and K97N, or a nonsense mutation that is E530* in the amino acid sequence of SEQ ID NO: 1;
The mutation of the gene encoding ARHGEF5 is a missense mutation that is at least one of E487G and V1574F in the amino acid sequence of SEQ ID NO: 2;
The mutation of the gene encoding BAZ2B is at least one missense mutation selected from the group consisting of E1064Q, G1717V, E616D, I1153K and H295Q in the amino acid sequence of SEQ ID NO: 3, or E1830* nonsense mutation;
The mutation of the gene encoding C20orf26 is at least one missense mutation selected from the group consisting of D195N, P341R, Q799L, R800W, and A68D in the amino acid sequence of SEQ ID NO: 4;
The mutation of the gene encoding CLCN2 is an in-frame insert (IF ins) mutation of R646dup, a missense mutation of R881H, or a frame shift deletion of E871Gfs*35 in the amino acid sequence of SEQ ID NO: 5 ( frame shift delete, FS del) mutation;
The mutation of the gene encoding FAM59A is at least one missense mutation selected from the group consisting of E853D, F297I, K180Q, Q228E and T380I in the amino acid sequence of SEQ ID NO: 6, or frame shift insertion of D412Rfs*8 insert, FS ins) mutant;
The mutation of the gene encoding KIAA1614 is at least one missense mutation selected from the group consisting of E592A, G1014S and P1037S in the amino acid sequence of SEQ ID NO: 7;
The mutation of the gene encoding MCPH1 is at least one missense mutation selected from the group consisting of R613G, N523S, and C510G in the amino acid sequence of SEQ ID NO: 8, or a FS del mutation of S293Kfs*16;
The mutation of the gene encoding NLRP2 is a nonsense mutation of R115* in the amino acid sequence of SEQ ID NO: 9, or at least one missense mutation selected from the group consisting of V120M, R103M, and L932V;
The mutation of the gene encoding NOS1AP is a missense mutation of at least one of A25T and G199V, or an FS ins mutation of R207Gfs*32 in the amino acid sequence of SEQ ID NO: 10;
The mutation of the gene encoding PRSS38 is in the amino acid sequence of SEQ ID NO: 11, a FS ins mutation of S314Qfs*21, a missense mutation of V315I, or a splice mutation of X104_splice (G is substituted at the chromosome 228004909 position). ;
The mutation of the gene encoding RGPD5 is at least one missense mutation selected from the group consisting of F946L, E1674K and E798G in the amino acid sequence of SEQ ID NO: 12;
The mutation of the gene encoding USP29 is a nonsense mutation of E259* in the amino acid sequence of SEQ ID NO: 13, or a missense mutation of at least one of R899L and G833E;
The mutation of the gene encoding XPO1 is at least one missense mutation selected from the group consisting of R1043P, H1050R, S984P and Q81H in the amino acid sequence of SEQ ID NO: 14;
The mutation of the gene encoding ZFAND2B is a missense mutation of at least one of I149T and S159G in the amino acid sequence of SEQ ID NO: 15;
The mutation of the gene encoding ZNF33A is a missense mutation of at least one of K165M and D271E, or a FS del mutation of Y161* in the amino acid sequence of SEQ ID NO: 16;
The mutation of the gene encoding ANKRD50 is a FS ins mutation of K1272Efs*19 in the amino acid sequence of SEQ ID NO: 17, or at least one missense mutation selected from the group consisting of R1193G, D1145A, S46T and L1376H;
The mutation of the gene encoding CCBL2 is a missense mutation of Q5H in the amino acid sequence of SEQ ID NO: 18;
The mutation of the gene encoding CNGB1 is a missense mutation of at least one of I688N and S283T, or an FS ins mutation of L849Afs*3 in the amino acid sequence of SEQ ID NO: 19;
The mutation of the gene encoding DMRT2 is a missense mutation of Q368E in the amino acid sequence of SEQ ID NO: 20;
The mutation of the gene encoding ENO1 is at least one missense mutation selected from the group consisting of M165I, V240A and V84I in the amino acid sequence of SEQ ID NO: 21;
The mutation of the gene encoding FMR1 is a missense mutation of P618T or an FS ins mutation of H481Afs*13 in the amino acid sequence of SEQ ID NO: 22;
The mutation of the gene encoding KDM5A is a FS ins mutation of E499Gfs*29 in the amino acid sequence of SEQ ID NO: 23, or at least one missense mutation selected from the group consisting of V537I, D1339V and R1217W;
The mutation of the gene encoding LUM is a nonsense mutation of Y20* in the amino acid sequence of SEQ ID NO: 24;
The mutation of the gene encoding OLFML2B is a missense mutation of at least one of V8D and E644D in the amino acid sequence of SEQ ID NO: 25;
The mutation of the gene encoding OR10AG1 is a missense mutation of at least one of L156F and L204F in the amino acid sequence of SEQ ID NO: 26;
The mutation of the gene encoding OR10G7 is at least one missense mutation selected from the group consisting of F163Y, T159A, F26Y and V273I in the amino acid sequence of SEQ ID NO: 27, or a FS ins mutation of L25Pfs*44;
The mutation of the gene encoding PCSK9 is a missense mutation of at least one of R167G and S666N in the amino acid sequence of SEQ ID NO: 28;
The mutation of the gene encoding RGS9 is a missense mutation of at least one of N38K and V60F in the amino acid sequence of SEQ ID NO: 29;
The mutation of the gene encoding RTN3 is a missense mutation of at least one of E260D and S312N in the amino acid sequence of SEQ ID NO: 30;
The mutation of the gene encoding SUPV3L1 is a missense mutation of at least one of K495Q and M295I in the amino acid sequence of SEQ ID NO: 31;
The mutation of the gene encoding TINAGL1 is a missense mutation of at least one of G45D and C226F in the amino acid sequence of SEQ ID NO: 32;
The mutation of the gene encoding TRIT1 is a missense mutation of V70G in the amino acid sequence of SEQ ID NO: 33;
The mutation of the gene encoding UNC5D is a missense mutation of at least one of D866N and E924D in the amino acid sequence of SEQ ID NO: 34;
The mutation of the gene encoding USP40 is a nonsense mutation of R91*, an IF ins mutation of K740dup, or a missense mutation of at least one of A681T and I748S in the amino acid sequence of SEQ ID NO: 35. A kit for predicting recurrence or prognosis of renal cancer, comprising a composition for predicting recurrence or prognosis of renal cancer of claim 1. Preparing sample DNA from a sample of a patient with recurrent kidney cancer;
Amplifying the sample DNA using the kit of claim 3;
Confirming the presence or absence of a recurrence-specific marker from the amplification result;
Treating a renal cancer patient whose recurrence-specific marker has been identified with any candidate for renal cancer treatment or by any method; And
Adopting any of the renal cancer treatment candidate substances or any treatment method to improve renal cancer or, when the treatment is treated, as a treatment candidate suitable for patients with relapsed renal cancer, or a treatment method for which a relapse specific marker has been identified A method of providing information necessary to determine the difference in the effect of renal cancer treatment according to the recurrence of renal cancer patients. The method of claim 4,
The recurrence specific marker is a mutation of a gene encoding one selected from the group consisting of ALAS2, ARHGEF5, BAZ2B, C20orf26, CLCN2, FAM59A, KIAA1614, MCPH1, NLRP2, NOS1AP, PRSS38, RGPD5, USP29, XPO1, ZFAND2B and ZNF33A. Way. Preparing sample DNA from a sample of a patient with recurrent kidney cancer;
Amplifying the sample DNA using the kit of claim 3; And
A method for providing information necessary for prognosis diagnosis of a renal cancer patient comprising; checking the presence or absence of a specific recurrence marker from the amplification result. The method of claim 6,
The recurrence specific markers are ALAS2, ANKRD50, ARHGEF5, BAZ2B, C20orf26, CCBL2, CLCN2, CNGB1, DMRT2, ENO1, FAM59A, FMR1, KDM5A, KIAA1614, LUM, MCPH1, NLRP2, NOS1AP, OLFML2B, OR10AG9, OR10B, PRSS38, RGS9, RTN3, SUPV3L1, TINAGL1, TRIT1, UNC5D, USP29, USP40, XPO1, ZFAND2B and ZNF33A A method that is a mutation of a gene encoding one selected from the group consisting of. The method of claim 6,
The method is a method of predicting the total survival rate or disease-free survival rate of a kidney cancer patient. The method of claim 8,
BAZ2B, CCBL2, CLCN2, CNGB1, DMRT2, FAM59A, KIAA1614, LUM, NLRP2, OR10AG1, RGS9, RTN3, SUPV3L1, TINAGL1, TRIT1, UNC5D, ZFAND2B and ZNF33A mutation encoding at least one selected from the group consisting of genes In the case of a confirmed kidney cancer patient, determining that the total survival rate of the kidney cancer patient is low or that the disease-free survival rate of the kidney cancer patient is low. The method of claim 8,
In the case of a kidney cancer patient in which a mutation in the gene encoding at least one of FMR1 and KDM5A is confirmed, determining that the total survival rate of the kidney cancer patient is low. The method of claim 8,
ALAS2, ANKRD50, ARHGEF5, C20orf26, ENO1, MCPH1, NOS1AP, OLFML2B, OR10G7, PCSK9, PRSS38, USP29, USP40 and XPO1 In the case of a kidney cancer patient whose mutation is confirmed in a gene encoding one selected from the group consisting of, The method further comprising; determining that the disease-free survival rate of the kidney cancer patient is low.

Images