Diagnosis Of Hereditary Spastic Paraplegias (hsp) By Detection Of A Mutation In The Kiaa1840 Gene Or Protein

Abstract

An ex vivo method of diagnosing or predicting an hereditary spastic paraplegias (HSP) in a subject is provided which comprises detecting a mutation in the KIAA1840 gene or protein (spatacsin), wherein that mutation is indicative of an hereditary spastic paraplegias (HSP).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional application of U.S. application Ser. No. 13/567,790, filed Aug. 6, 2012, which is a continuation application of U.S. application Ser. No. 12/440,644, filed Jan. 4, 2010, which was a 371 application of PCT/IB2007/003535, filed Sep. 11, 2007, all of said applications incorporated herein by reference.

[0002] The invention relates to the identification of mutations in the KIAA1840 gene or protein, associated with a hereditary spastic paraplegias (HSP), and to diagnostic applications that benefit from this identification.

[0003] Hereditary spastic paraplegias (HSP) are genetically heterogeneous Mendelian disorders characterized by weakness, spasticity and loss of vibratory sense in the lower limbs (Harding et al. 1983 and Tallaksen et al. 2001). They reveal themselves clinically through difficulties in walking possibly evolving into total paralysis of both legs. The physiopathology of this set of diseases is, to date, relatively undocumented; however, anatomopathological data make it possible to conclude that the attack is limited to the pyramidal tracts responsible for voluntary motricity in the spinal cord (Reid, 1997). The incidence of HSPs, which remains difficult to estimate because of rare epidemiological studies and the considerable clinical variability, varies from 0.9:100000 in Denmark, 3 to 9.6:100000 in certain regions of Spain (Polo et al., 1991) or 14:100000 in Norway (Skre, 1974) (approximately 3:100000 in France). Various clinical and genetic forms of HSP exist. The so-called "pure" HSPs, which correspond to isolated spasticity of the lower limbs, are clinically distinguished from the "complex" HSPs, for which the spasticity of the legs is associated with other clinical signs of neurological or non-neurological type (Bruyn et al., 1991).

[0004] Although forms of HSP have been recognized for over a century, new phenotypes are regularly described, demonstrating wide clinical heterogeneity. Genetically, autosomal dominant (AD), autosomal recessive (AR) and X-linked inheritance are observed and almost 32 genetic loci have been identified, but only 12 genes have been cloned (Flink et al. 2006). According to the putative roles of these genes, mitochondrial function, protein folding and axonal transport have been implicated in the dying back of pyramidal tract axons in these disorders.

[0005] The most common forms of AD-HSP, accounting for about 40-50% of cases, are caused by mutations in the SPG4 and SPG3A genes that encode for spastin and atlastin, respectively (Hazan et al. 1990, Zhao et al. 2001 and international patent application WO 01/18198). In contrast to AD forms, no major gene accounts for AR-HSP, which is less common and more varied in clinical presentation, implying greater genetic heterogeneity. The four AR-HSP genes cloned so far, encoding for paraplegin (SPG7, MIM#607259 (OMIM database, www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM)), (Casari et al. 1998) spartin (SPG20; MIM#275900), (Patel et al. 2002) and maspardin (SPG21, MIM 248900) (Simpson et al. 2003) as well as the gene responsible for the related spastic ataxia of Charlevoix Saguenay (ARSACS, MIM#270550) (Engert et al. 2000) probably represent less than 5% of all cases (Fink et al. 2003).

[0006] A very common form of AR-HSP associates spastic paraplegia, mental or cognitive deficit and thin corpus callosum (Winner et al. 2005). The majority of the families appear to be linked to SPG11 on chromosome 15, which was the third AR-HSP locus to be identified (Martinez et al. 1999). This entity is particularly prevalent in Japan (Shibasaki et al. 2000), but is also found in North-America, the Middle-East and Europe (Martinez et al 1999 and Lossos et al. 2006 and Casali et al. 2004 and Winner et al. 2004 and Stevanin et al. 2006). The typical clinical features of SPG11 consist of early-onset spastic paraplegia (usually <20 years), urinary bladder dysfunction, deep sensory deficits in the legs and cognitive impairment that progress insidiously to severe functional disability over a period of 10-20 years. Some patients also develop arm involvement, dysarthria, contractures and muscle atrophy. Auxiliary studies frequently identify a thin corpus callosum (TCC) with white matter lesions and variable cerebral cortical atrophy on magnetic resonance imaging (MRI), variable cortical and thalamic glucose hypometabolism on positron emission tomography and predominantly axonal motor or sensorimotor peripheral neuropathy on nerve conduction studies (Winner et al. 2004).

[0007] Linkage to chromosome 15q has been reported so far in 31 families in which the patients presented with the typical SPG11 phenotype. In the initial study, a maximum multipoint combined LOD score of 3.14 was detected in seven AR-HSP families in a region between D15S1007 and D15S1012, although patients from only 2 kindreds of North-American and Italian ancestries presented with a TCC (Martinez et al. 1999). A second study reported a group of 10 out of 13 Japanese families with a homogeneous phenotype of AR-HSP-TCC with a cumulative LOD score of 9.68 in the D15S971 to D15S117 interval (Shibasaki et al. 2000). Casali et al. also reported 5 Italian kindreds that showed significant linkage (Z=3.35) to the interval flanked by markers D15S1007 and D15S978 (Casali et al. 2004). More recently, the analysis of 8 additional kindreds (Z=11.5) including 3 large consanguineous families, allowed the locus to be restricted by the inventors to the 6 cM interval between markers D15S1044 and D15S143 (Lossos et al. 2006 and Stevanin et al. 2006) a region that did not overlap with the interval defined in the originally mapped families (Martinez et al. 1999), therefore showing genetic heterogeneity among families linked to 15q and more closely resembling the locus for amyotrophic lateral sclerosis ALS5 (Hentati et al, 1998). It is of note that in the work published by Martinez et al (1999), only 2 of 8 pedigrees presented with the typical SPG11 phenotype with TCC and patients from these 2 families were linked to a larger region on chromosome 15 overlapping the region described in recent reports (Lossos et al. 2006 and Stevanin et al. 2006). More recently, the SPG11 locus was further refined to the 4.6 cM region (according to the Marschfield genetic map, http://research.marshfieldclinic.org/genetics/GeneticResearch/compMaps.as- p) between markers D15S968-D15S132 (Olmez et al, 2006) confirming the results of the inventors (FIG. 2).

[0008] The inventors have now identified the gene responsible for the most frequent form of Autosomal Recessive Hereditary Spastic Paraplegia (AR-HSP). They have indeed demonstrated that the disease is caused by mutations in the KIAA1840 gene (also known as FLJ21439), affecting the spatacsin protein expression (Stevanin et al., 2007). This is supported by four pieces of evidence. First, the inventors have excluded 17 out of about 40 genes assigned to the SPG11 candidate interval after significant reduction of its size to the 3.2 cM interval (according to the Marschfield genetic map) between markers D15S778 and D15S659 (FIGS. 1 to 4). The analysis of 2 of these genes has been reported previously (Stevanin et al, 2006). Secondly, the inventors have identified 43 different mutations segregating in 47 families (FIGS. 5 to 9), 16 of which linked previously to the SPG11 locus with a highly significant 28.1 maximal combined lod score (FIGS. 1 and 2), 8 of them already published as linked (Casali et al, 2004; Lossos et al, 2006 and Stevanin et al, 2006). Thirdly, the inventors have identified mutations, absent in at least 140 control chromosomes, that were all, leading to abnormal splicing of the messenger RNA and/or leading to a truncated protein. Finally, the inventors have demonstrated that all mutated families, except 2 in which magnetic resonance imaging could not be performed (TUN2 and TUN14), presented with the typical AR-HSP-TCC phenotype. In addition, several of these families shared the same mutation with similar surrounding haplotypes when they came from the same geographical origins, suggesting regional founder effects (FIGS. 6 and 7). Mutations in KIAA1840 affected 47 of 91 AR-HSP-TCC families in the study carried out by the inventors making this genetic entity very frequent among AR-HSP-TCC (75% was estimated in a previous study, Stevanin et al, 2006). The invention therefore provides the identification of the major gene responsible of AR-HSP-TCC and probably of AR-HSPs in general and opens thereby new opportunities to improve diagnosis and genetic counseling of said disease. Moreover, the invention also provides a mean to improve the medical care management of patient affected with said disease. In addition, since most patients with spastic paraplegia have isolated forms, it is conceivable that this new gene could account for a small proportion of these patients as well. Indeed, in Europe, due to the small size of the families, recessively inherited diseases are often found in apparently isolated cases.

[0009] A first aspect of the invention thus relates to the identification of mutations in the KIAA1840 gene or protein, associated with a hereditary spastic paraplegias (HSP), and to diagnostic application that benefits from this identification.

[0010] A second aspect of the invention relates to an isolated nucleic acid, specifically hybridizable to a region of KIAA1840 gene sequence that contains a mutation selected from the group consisting of [0011] the substitutions: c.6100C>T, c.2198T>G, c. 118C>T, c. 1235C>G, c.2833A>G, c.1951C>T, c.869+1G>A, c. 1679C>G, c.2316+1G>A, c.2444G>T, c.2444+1G>C, c.2697G>A, c.5470C>T, c.5870C>G, c.6091C>T, c.6477+4 A>G, c.6856C>T, c.1282A>T and c.5974C>T, [0012] the deletions: c.529-533delATATT, c.6451delG, c.6832_6833 delAG, c.1203delA, c.1549_1550 delCT, c.6737_6740 delTTGA, c.1471_1472 delCT, c.1692delA, c.2716delC, c.1668delT, c.704_705 delAT, c.5989_5992 delCTGT, c.5532_5533delCA, c.5769delT, c.6739_6742delGAGT, c.4307_4308delAA and c.733_734delAT, and [0013] the insertions: c.7029_7030insT, c.2850_2851insT, c.3741_3742insA, c.5982_5983insCTCT, c.5986_5987insT, c.3075_3076insA and c.2842_2843insG.

[0014] Such an isolated nucleic acid can be used as a primer or probe.

[0015] More preferentially the invention relates to an isolated nucleic acid, which comprises a KIAA1840 gene sequence that contains one or several mutation(s) selected from the group consisting of [0016] the substitutions: c.6100C>T, c.2198T>G, c.118C>T, c.1235C>G, c.2833A>G, c.1951C>T, c.869+1G>A, c. 1679 C>G, c.2316+1G>A, c.2444G>T, c.2444+1G>C, c.2697G>A, c.5470C>T, c.5870C>G, c.6091C>T, c.6477+4 A>G, c.6856C>T, c.1282A>T c.5974C>T, [0017] the deletions: c.529-533delATATT, c.6451delG, c.6832_6833 delAG, c.1203delA, c.1549_1550 delCT, c.6737_6740 delTTGA, c.1471_1472 delCT, c.1692delA, c.2716delC, c.1668delT, c.704_705 delAT, c.5989_5992 delCTGT, c.5532_5533delCA, c.5769delT, c.6739_6742delGAGT, c.4307_4308delAA c.733_734delAT, and [0018] the insertions: c.7029_7030insT, c.2850_2851insT, c.3741_3742insA, c.5982_5983insCTCT, c.5986_5987insT, c.3075_3076insA c.2842_2843insG or a sequence complementary thereto.

[0019] Another aspect of the invention relates to an isolated polypeptide which comprises the amino acid sequence of KIAA1840 containing one or several mutation(s) selected from the group consisting of p.Q40X, p.I177_F178delfsX178, p.H235RfsX246, p.M245VfsX246, p.K401KfsX415, p.S412X, p.K428X, p.L491DfsX556, p.L517LfsX556, p.F556LfsX577, p.S560X, p.V564VfsX577, p.R651X, p.L733X, p.R815M, p.W899X, p.Q906SfsX920, p.R945G, p.R945GfsX950, p.L950FfsX953, p.V948GfsX953, p.E1026RfsX1029, p.P1248TfsX1264, p.Q1436RfsX1442, p.R1824X, p.S1844SfsX1857, p.S1923RfsX1950, p.S1957X, p.R1992X, p.L1995LfsX2000, p.C1996LfsX1999, p.L1997_1998 delfsX2056, p.R2031X, p.R2034X, p.A2151PfsX2172, p.I2246_E2247delfsX2260, p.E2247_S2248delfsX2260, p.S2278LfsX2338, p.R2286X and p.V2344CfsX2349. [0020] Another aspect of the invention relates to an isolated monoclonal or polyclonal antibody that specifically recognizes a KIAA1840 protein containing a mutation selected from the group consisting of p.Q40X, p.I177_F178delfsX178, p.H235RfsX246, p.M245VfsX246, p.K401KfsX415, p.S412X, p.K428X, p.L491DfsX556, p.L517LfsX556, p.F556LfsX577, p.S560X, p.V564VfsX577, p.R651X, p.L733X, p.R815M, p.W899X, p.Q906SfsX920, p.R945G, p.R945GfsX950, p.L950FfsX953, p.V948GfsX953, p.E1026RfsX1029, p.P1248TfsX1264, p.Q1436RfsX1442, p.R1824X, p.S1844SfsX1857, p.S1923RfsX1950, p.S1957X, p.R1992X, p.L1995LfsX2000, p.C1996LfsX1999, p.L1997_1998 delfsX2056, p.R2031X, p.R2034X, p.A2151PfsX2172, p.I2246_E2247delfsX2260, p.E2247_S2248delfsX2260, p.S2278LfsX2338, p.R2286X and p.V2344CfsX2349.

[0021] Another aspect of the present invention relates to the use of a monoclonal or polyclonal antibody recognizing the wild type protein to identify truncated forms of the protein.

DEFINITIONS

[0022] A "coding sequence" or a sequence "encoding" an expression product, such as a RNA, polypeptide, protein, or enzyme, is a nucleotide sequence that, when expressed, results in the production of that RNA, polypeptide, protein, or enzyme, i.e., the nucleotide sequence encodes an amino acid sequence for that polypeptide, protein or enzyme. A coding sequence for a protein may include a start codon (usually ATG) and a stop codon.

[0023] The term "gene" means a DNA sequence that codes for or corresponds to a particular sequence of amino acids which comprise all or part of one or more proteins or enzymes, and may or may not include regulatory DNA sequences, such as promoter sequences, which determine for example the conditions under which the gene is expressed. Some genes, which are not structural genes, may be transcribed from DNA to RNA, but are not translated into an amino acid sequence. Other genes may function as regulators of structural genes or as regulators of DNA transcription. In particular, the term gene may be intended for the genomic sequence encoding a protein, i.e. a sequence comprising regulator, promoter, intron and exon sequences.

[0024] As used herein, the term "oligonucleotide" refers to a nucleic acid, generally of at least 10, preferably at least 15, and more preferably at least 20 nucleotides, preferably no more than 100 nucleotides, still preferably no more than 70 nucleotides, and which is hybridizable to a KIAA1840 genomic DNA, cDNA, or mRNA. Oligonucleotides can be labelled according to any technique known in the art, such as with radiolabels, fluorescent labels, enzymatic labels, sequence tags, etc. A labelled oligonucleotide may be used as a probe to detect the presence of a mutated KIAA1840 nucleic acid. Alternatively, oligonucleotides (one or both of which may be labelled) can be used for amplifying a KIAA1840 nucleic acid, for instance by PCR (Saiki et al., 1988), to detect the presence of a mutation. Generally, oligonucleotides are prepared synthetically, preferably on a nucleic acid synthesizer. Accordingly, oligonucleotides can be prepared with non-naturally occurring phosphoester analog bonds, such as thioester bonds, etc.

[0025] A nucleic acid molecule is "hybridizable" or "hybridizes" to another nucleic acid molecule, such as a cDNA, genomic DNA, or RNA, when a single stranded form of the nucleic acid molecule can anneal to the other nucleic acid molecule under the appropriate conditions of temperature and solution ionic strength (Sambrook et al., 1989).

[0026] The conditions of temperature and ionic strength determine the "stringency" of the hybridization. For preliminary screening for homologous nucleic acids, low stringency hybridization conditions, corresponding to a Tm (melting temperature) of 55.degree. C., can be used, e.g., 5.times.SSC, 0.1% SDS, 0.25% milk, and no formamide; or 30 formamide, 5.times.SSC, 0.5% SDS). Moderate stringency hybridization conditions correspond to a higher Tm, e.g., 40% formamide, with 5.times. or 6.times.SCC. High stringency hybridization conditions correspond to the highest Tm, e.g., 50% formamide, 5.times. or 6.times.SCC. SCC is a 0.15 M NaCl, 0.015 M Na-citrate. Hybridization requires that the two nucleic acids contain complementary sequences, although depending on the stringency of the hybridization, mismatches between bases are possible. The appropriate stringency for hybridizing nucleic acids depends on the length of the nucleic acids and the degree of complementation, variables well known in the art. The greater the degree of similarity or homology between two nucleotide sequences, the greater the value of Tm for hybrids of nucleic acids having those sequences. The relative stability (corresponding to higher Tm) of nucleic acid hybridizations decreases in the following order: RNA:RNA, DNA:RNA, DNA:DNA. For hybrids of greater than 100 nucleotides in length, equations for calculating Tm have been derived (see Sambrook et al., 1989, 9.50-9.51). For hybridization with shorter nucleic acids, i.e., oligonucleotides, the position of mismatches becomes more important, and the length of the oligonucleotide determines its specificity (see Sambrook et al., 1989 II.7-11.8). A minimum length for a hybridizable nucleic acid is at least about 10 nucleotides, preferably at least about 15 nucleotides, and more preferably the length is at least about 20 nucleotides.

[0027] In a specific embodiment, the term "standard hybridization conditions" refers to a Tm of 55.degree. C., and utilizes conditions as set forth above. In a preferred embodiment, the Tm is 60.degree. C. In a more preferred embodiment, the Tm is 65.degree. C. In a specific embodiment, "high stringency" refers to hybridization and/or washing conditions at 68.degree. C. in 0.2.times.SSC, at 42.degree. C. in 50% formamide, 4.times.SSC, or under conditions that afford levels of hybridization equivalent to those observed under either of these two conditions.

[0028] As used herein, an "amplification primer" is an oligonucleotide for amplification of a target sequence by extension of the oligonucleotide after hybridization to the target sequence or by ligation of multiple oligonucleotides which are adjacent when hybridized to the target sequence. At least a portion of the amplification primer hybridizes to the target. This portion is referred to as the target binding sequence and it determines the target-specificity of the primer. In addition to the target binding sequence, certain amplification methods require specialized non-target binding sequences in the amplification primer. These specialized sequences are necessary for the amplification reaction to proceed and typically serve to append the specialized sequence to the target. For example, the amplification primers used in Strand Displacement Amplification (SDA) include a restriction endonuclease recognition site 5' to the target binding sequence (U.S. Pat. No. 5,455,166 and U.S. Pat. No. 5,270,184). Nucleic Acid Based Amplification (NASBA), self-sustaining sequence replication (3SR) and transcription based amplification primers require an RNA polymerase promoter linked to the target binding sequence of the primer. Linking such specialized sequences to a target binding sequence for use in a selected amplification reaction is routine in the art. In contrast, amplification methods such as PCR which do not require specialized sequences at the ends of the target, generally employ amplification primers consisting of only target binding sequence.

[0029] As used herein, the terms "primer" and "probe" refer to the function of the oligonucleotide. A primer is typically extended by polymerase or ligation following hybridization to the target but a probe typically is not. A hybridized oligonucleotide may function as a probe if it is used to capture or detect a target sequence, and the same oligonucleotide may function as a primer when it is employed as a target binding sequence in an amplification primer. It will therefore be appreciated that any of the target binding sequences disclosed herein for amplification, detection or quantisation of KIAA1840 may be used either as hybridization probes or as target binding sequences in primers for detection or amplification, optionally linked to a specialized sequence required by the selected amplification reaction or to facilitate detection.

[0030] As used herein, the terms "KIAA1840 gene" (or its synonyms: FLJ21439, ENSG00000104133 or SPG11) denotes a KIAA1840 gene of any species, especially human, but also other mammals or vertebrates to which the methods of the invention can apply. The human KIAA1840 gene encodes a large protein of 2443 amino-acids (aa) of unknown function that the inventors have named Spatacsin (SEQ ID NO: 2). Homo sapiens KIAA1840 gene is localized on chromosome 15 and its Coding Sequence (CDS) is deposited in Genebank under accession number NM_025137, or AB058743 (5'-3' forward strand shown SEQ ID NO: 1). Human KIAA1840 gene shares 85% identity with the homologous protein in dog, and 76% and 73% identity with the mouse and rat homologues and 59% with the chicken homologue. Homology is less than 25% with orthologous proteins, of smaller sizes, in tetraodon and drosophila. KIAA1840 homologous proteins at NCBI database are: dog XP_544657, gallus XP_413940.1, mouse BAE27954, rat XP_242139.3, and at Ensembl database; drosophila CG13531, tetraodon GSTENG00003909001. The human KIAA1840 gene contains 40 exons spanning 101 Kbases of genomic DNA on chromosome 15q21.1. The intron-exon structure of the complementary strand of the KIAA1840 gene is further indicated in Table 1 below and in FIG. 5.

TABLE-US-00001 TABLE 1 Exon-intron boundaries of the human KIAA 1840 gene (according to the Ensembl database) Postition in SEQ Length No Exon/Intron ID NO: 1 (bp) Sequence 5' upstream ..........cgacgcagtcaggttccggcgaaagtgaccggaagtaaccgccgggccaa sequence 1 ENSE00001183257 0 258 GATGGCTGCAGAGGAAGGGGTCGCGAGTGCTGCTTCCGCCGGCGGTAGCTGGGGCACCGCGGCCATGGGG CGGGTTCTACCGATGCTGTTGGTGCCAGTCCCCGCCGAGGCGATGGGGCAGCTCGGCTCCCGGGCGCAGC- T GCGCACACAGCCGGAGGCTCTGGGGAGCCTGACGGCTGCGGGCAGCCTCCAAGTGCTTTCTTTGACGCCT- G GCAGCCGGGGCGGGGGTCGCTGCTGCCTGGAGGGCCCCTTCTGGCA Intro 1-2 2,774 gtaagtgctgagggagagttgggcc..........aataaatctaaactttttttcttag 2 ENSE00001183253 258 185 CTTTCTATGGGAGGATTCTCGTAACAGCAGCACACCAACTGAAAAGCCCAAACTGCTCGCTCTTGGTGAAAAT TATGAACTGCTTATCTATGAATTTAATTTGAAAGATGGAAGATGTGATGCAACCATTTTGTATAGCTGTA- GTAGG GAGGCATTGCAAAAGCTCATTGACGATCAAGATATCA Intro 2-3 1,128 gtaagtatctacaggtggtctttca..........gaaataatatccttttgttttgtag 3 ENSE00001183250 443 225 GTATTTCCTTATTGTCTTTGAGAATCCTGTCATTTCACAATAACACATCATTACTGTTCATCAACAAATGTGT- CAT CCTACATATTATATTTCCTGAAAGAGATGCTGCAATTAGAGTACTCAACTGTTTCACACTTCCCTTGCCT- GCACA GGCAGTGGACATGATTATTGACACGCAGCTCTGCAGAGGAATTCTTTTTGTTTTGAGTAGTTTAGGCTGG- ATCT Intro 3-4 1,782 gtatccttggtggtagaagtgttga..........attttcttttaactctaactaaaag 4 ENSE00001183246 668 202 ACATTTTTGATGTTGTGGATGGTACATATGTAGCTCATGTGGATTTAGCACTTCACAAAGAAGACATGTGTAA- T GAGCAGCAACAGGAGCCAGCCAAGATTTCTTCATTTACTTCACTGAAAGTTTCTCAAGACCTCGATGTTG- CAGT GATTGTCAGCTCCTCCAACTCCGCAGTTGCTCTTAACTTAAATTTGTATTTCAG Intro 4-5 4,828 gtatgtagatgactgcagtttctaa..........tgtctatcattatttttaaatgtag 5 ENSE00001183241 870 138 GCAACACCCAGGACACCTACTGTGTGAAAGAATACTAGAAGATCTTCCTATTCAAGGACCTAAGGGCGTAGAT GAAGATGATCCTGTTAACTCTGCCTACAACATGAAACTGGCCAAGTTTTCCTTCCAAATTGATAG Intro 5-6 189 gtacagaaacttccttttcatgtag..........aagttatattttaccttgtttccag 6 ENSE00001183238 1008 449 GTCTTGGAAAGCCCAGCTATCATCATTGAATGAAACAATAAAGGAACTCCAAACTGGAGGTTTCCTGTTGTGC- TC CATGGTTCCAGGATATTTTGCATTTGGAGTCACCTGAATCTGGTAACCACAGTACAAGTGTGCAGAGCTG- GGC CTTCATTCCACAGGACATAATGCATGGGCAATATAATGTTCTACACGAAAGATCATGCCAAGACCAGTGA- TCCAG GAAGATCATGGAAAATAATGCACATCAGTGAACAAGAGGAACCCATAGAGCTTAAATGTGTGTCTGTGAC- AGG ATTCAC TGCACTGTTTACTTGGGAAGTGGAAAGGATGGGCTATACCATTACCCTCTGGGATTTGGACACCCAGCCC- CATG CAGTGTTTTTCCCTTGGCACAAAGTGTATTCCTGTAGACAGTAGTGGAGACCAGCAGCTGTGCTTTGTTT- TGAC AG Intro 6-7 2,479 gtgagactgtcttgtattagattga..........aagctaacttttatttttcctatag 7 ENSE00001183236 1457 146 AGAATGGACTCTCTCTGATTTTGTTTGGTTTGACTCAAGAAGAGTTTTTAAACAGACTCATGATCCATGGAAG- T GCCAGCACTGTGGACACTCTTTGTCATCTCAATGGCTGGGGAAGGTGCTCAATTCCCATACATGCACTAG- AG Intro 7-8 15,288 gtaacagaattaaatgcccaagaac..........atttttattttcctcctcatttcag 8 ENSE00001105929 1603 133 GCCGGGATAGAAAATCGTCAGCTGGACACAGTAAATTTCTTTTTGAAGAGCAAGGAAAATCTTTTTAATCCAT- C CTCAAAATCTTCTGTATCTGATCAGTTTGATCACTTGTCATCCCATTTATATTTAAGAA Intro 8-9 4,116 gtaagtggaataaagatttctacat..........gttaatttctttggttctttctcag 9 ENSE00001105933 1736 156 ATGTGGAAGAGCTGATACCAGCATTGGATTTACTTTGCTCGGCAATTAGAGAAAGTTATTCTGAACCCCAAAG- C AAACACTTTTCAGAACAATTGCTTAATCTTACACTGTCTTTCCTTAACAACCAAATAAAGGAGCTTTTCA- TTCACA CTGAAG Intro 9-10 388 gtaagaatagcagctaggaaggggg..........attggcacattggtattttccatag 10 ENSE00001105923 1892 176 AACTAGATGAACATCTGCAAAAAGGAGTGAACATTTTGACTAGCTACATTAATGAACTTCGAACCTTCATGAT- AA AGTTTCCTTGGAAGCTAACAGATGCTATAGATGAATATGATGTACATGAAAATGTCCCCAAAGTAAAGGA- GAGC AATATATGGAAGAAACTCAGCTTTGAG Intro 10-11 2,161 gtaagtacgaataatcatcacttct..........aaggcaaacgtttttcttttcctag 11 ENSE00001105941 2068 177 GAAGTTATTGCCAGCGCCATTTTAAACAACAAAATACCAGAGGCACAGACTTTCTTCAGGATTGATAGTCATT- C TGCTCAAAAACTTGAGGAGCTTATTGGCATAGGCCTAAATTTGGTCTTTGACAATTTAAAAAAGAACAAT- ATAAA GGAAGCCTCTGAACTTTTGAAGAATATG Intro 11-12 3,531 gtgagtggtgtaatccataaagtct..........ttttggttttctatgtttattttag 12 ENSE00001183220 2245 72 GGGTTTGATGTAAAAGGCCAATTGCTCAAGATCTGCTTCTATACAACTAATAAAAATATACGTGACTTTTTG Intro 12-13 380 gtaggtaaaggtgagactacatagt..........ctgctttaattactttttattcaag 13 ENSE00001183213 2317 128 GTTGAAATTTTAAAAGAAAAAAATTATTTTTCTGAAAAAGAGAAAAGAACTATAGACTTCGTGCATCAAGTTG- AG AAGCTTTATTTGGGACATTTCCAAGAAAATATGCAAATCCAGTCATTTCCCAG Intro 13-14 285 gtagtctcattagtcctcttttgat..........aaaaaatttatatcactgtttttag 14 ENSE00001183208 2445 176 GTACTGGATAAAGGAACAAGATTTTTTCAAGCACAAGTCTGTTTTGGACTCATTCCTGAAATATGATTGTAAA- GA TGAATTTAACAAACAGGACCATAGAATTGTGTTAAATTGGGCTCTGTGGTGGGATCAACTAACACAAGAA- TCCA TCCTTCTCCCCAGGATAAGTCCAGAAG Intro 14-15 1,355 gcaagtgtgagagagcctgaaatat..........ttaaaatgtgttttttttcatgtag 15 ENSE00001183204 2621 214 AATACAAATCATATTCCCCTGAAGCCCTCTGGAGATACCTCACAGCTCGCCATGATTGGTTAAACATTATCTT- A TGGATTGGAGAATTTCAAACCCAGCATAGTTATGCTTCACTTCAGCAGAACAAATGGCCCCTTCTGACTG- TTGA TGTTATTAACCAGAATACTTCCTGTAACAACTACATGAGGAATGAAATTTTAGATAAGCTGGCCAG Intro 15-16 4,623 gtattataactgttgaactaatacc..........tgacatcctataaatctgtccatag 16 ENSE00001047610 2835 204 GAATGGGGTTTTTTTGGCATCTGAACTGGAAGACTTTGAATGCTTCCTCCTAAGACTGAGCCGTATTGGAGGT GTAATACAGGATACCCTCCCTGTTCAAAACTACAAGACCAAAGAAGGTTGGGATTTCCATTCTCAATTCA- TTCT CTATTGTTTGGAGCACAGTCTGCAGCATCTTCTTTATGTCTACCTTGACTGTTACAA Intro 16-17 1,826 gtgagtactgagaatgcatttgtcc..........aggtttttgtttgttttatatacag 17 ENSE00001287244 3039 107 ACTTAGTCCTGAAAATTGTCCCTTTTTGGAAAAAAAAGAGTTACATGAAGCACACCCTTGGTTTGAATTTTTA- GT TCAGTGTCGACAAGTTGCCAGTAACTTAACAG Intro 17-18 2,444 gtatgggtatactgtattaaacaca..........aaaaacactgtcttttattttccag 18 ENSE00001047605 3146 146 ATCCCAAACTGATCTTCCAGGCTAGCCTTGCAAATGCTCAGATTTTGATTCCCACCAATCAGGCCAGTGTAAG- C AGTATGCTATTGGAAGGACATACCCTCCTGGCCCTTGCTACTACAATGTATTCTCCTGGGGGTGTCAGTC- AG Intro 18-19 2,234 gtatggatagcactttatgacaaaa..........acctgttatctgtttttttacttag 19 ENSE00001047617 3292 162 GTTGTTCAGAATGAAGAAAATGAAAACTGTTTGAAGAAAGTGGATCCCCAGCTATTGAAGATGGCATTAACTC- C TTACCCCAAGCTAAAAACTGCTCTCTTCCCACAGTGCACTCCTCCTAGTGTCCTGCCATCTGATATTACA- ATCT ACCACCTTATTCAG Intro 19-20 2,352 gtacagtatttaggtggccaatatt..........ctgtttaacttttcccctttttcag 20 ENSE00001047612 3454 67 TCATTATCACCCTTTGATCCTAGCAGATTGTTTGGCTGGCAGTCTGCTAACACACTAGCTATAGGAG Intro 20-21 5,392 gtaagtcatcatgggtacttcttga..........taatattgttttactttccccctag 21 ENSE00001047594 3521 166 ATGCATGGAGTCATCTCCCACATTTCTCTAGCCCTGACCTGGTTAATAAATATGCTATAGTGGAACGTCTGAA- T TTTGCTTATTATTTACATAATGGGCGGCCATCATTTGCATTTGGTACTTTTCTGGTCCAGGAATTAATCA- AGAGC AAGACTCCCAAGCAGCT Intro 21-22 1,630 gtgagtatttaaaatataattttgt..........tgattttgattcctttctttttcag 22 ENSE00001047598 3687 206 GATCCAGCAAGTAGGCAATGAAGCCTATGTTATAGGGCTCTCCTCCTTCCACATACCTTCAATAGGAGCTGCA TGTGTTTGTTTCTTAGAATTGCTTGGCCTTGACAGCCTCAAGCTCAGAGTTGATATGAAAGTGGCCAATA- TAAT TTTGAGCTACAAGTGCAGAAATGAAGATGCTCAGTACAGCTTTATCAGAGAGTCTGTAG Intro 22-23 257 gtacagcaccttttatctggcctgc..........attttgttgtttatatttcttacag 23 ENSE00001047622 3893 109 CCGAAAAACTATCTAAACTAGCTGATGGTGAAAAGACAACCACAGAAGAATTGCTTGTTCTCTTAGAAGAAGG- T ACATGGAACAGCATTCAGCAACAGGAAATAAAGAG Intro 23-24 1,321 gtttgtgagttgcagtctcagcctc..........cccccacctctaattctgattatag 24 ENSE00001047619 4002 160 GTTATCCAGTGAATCTAGCAGCCAATGGGGCATTAGTGGTGCAGTTCTGCAGGCTACACAATATGAAACTAAG- C ATATCTTACCTTAGAGAATGTGCCAAAGCAAATGATTGGCTGCAGTTCATTATTCACAGCCAACTCCACA- ACTA CCACCCAGCAGAG Intro 24-25 428 gtaagccactaattgttagcagtca..........tttaatcatctgatatgccttctag 25 ENSE00001047603 4162 273 GTGAAATCCCTTATCCAGTACTTCAGCCCAGTCATTCAAGACCACTTAAGGCTGGCTTTTGAGAACTTGCCCT- C AGTGCCCACCTCCAAAATGGACAGCGATCAAGTCTGCAATAAGTGCCCCCAGGAACTTCAAGGAAGCAAA- CAA GAGATGACCGATTTATTTGAAATTCTGCTCCAATGCTCAGAGGAGCCAGACTCCTGGCACTGGCTTCTGG- TTG AAGCAGTGAAACAACAGGCCCCTATCCTCAGTGTTCTGGCCTCATGTCTCCAG Intro 25-26 623 gtgaggatcatgagaagcctgaagt..........tgttattttatttatcccgtggcag 26 ENSE00001047590 4435 201 GGTGCCAGTGCCATTTCTTGTCTCTGTGTTTGGATCATCACTTCTGTGGAGGACAATGTTGCAACTGAAGCAA- T GGGACACATTCAGGACTCAACAGAGGACCATACCTGGAACCTTGAGGATCTTTCAGTCATCTGGAGAACA- TTA TTAACAAGACAAAAGAGCAAAACTCTCATCAGAGGTTTCCAGCTTTTCTTTAAG Intro 26-27 2,820 gtagtgatagttgcttcacttcttt..........atttttttcaaactctttgtcaaag 27 ENSE00001047613 4636 108 GATTCCCCGTTACTACTGGTGATGGAGATGTATGAACTGTGTATGTTCTTCAGGAATTATAAAGAAGCTGAAG- C TAAACTTCTGGAGTTTCAGAAGAGCCTTGAAACG Intro 27-28 2,916 gtaagttggaattatggtgctcttt..........ctaagcttctctttttctttcatag 28 ENSE00001047595 4744 163 CTTAACACAGCAGCCACAAAGGTCCACCCTGTCATCCCTGCCATGTGGCTGGAGGATCAGGTGTGTTTCCTTT TGAAGCTTATGCTACAGCAGTGTAAGACCCAGTATGAGCTGGGGAAGCTTTTACAGCTCTTTGTTGAAAG- AGA

GCATCTCTTCTCTGATG Intro 28-29 3,401 gtaagacaatccttacagttaagtt..........ttatatccttttctctttggcacag 29 ENSE00001047608 4907 215 GTCCAGATGTGAAAAAGCTTTGCATCCTTTGCCAGATTTTGAAGGATACATCCATAGCCATTAATCATACAAT- TA TTACCAGCTACAGCATTGAGAATCTTCAGCATGAATGTGATCTATTTTGGAAAGACTGCAGACAGATGGA- CAA TTCGCTTTGGCCAGGAGGGTAGCAGAATTAGCTGAGTTACCTGTGGACAACTTGGTTATTAAAGAG Intro 29-30 1,077 gtatcatcggtcttttttttttttt..........aaatctgctttgttaaatttcacag 30 ENSE00001047607 5122 745 ATAACACAGGAAATGCAGACCCTAAAACACATTGAACAGTGGTCACTAAAACAAGCAAGAATTGACTTCTGGA- A AAAATGCCATGAGAATTTTAAGAAAAATTCAATTTCAAGCAAAGCAGCTTCTTCCTTTTTCTCAACCCAG- GCCCA TGTGGCATGTGAGCACCCAACTGGATGGAGCAGCATGGAGGAGCGCCATCTGCTGCTCACCTTGGCAGGG- C ACTGGCTTGCCCAGGAGGACGTGGTGCCCTTGGATAAGCTGGAGGAGCTGGAGAAGCAGATCTGGCTGTG- C CGCATCACCCAGCACACTCTTGGAAGAAATCAGGAGGAAACAGAGCCCAGATTTTCTCGACAGATCTCAA- CTA GTGGTGAACTTTCCTTTGATAGTTTAGCCAGTGAGTTTTCCTTCTCCAAGTTGGCTGCTCTGAACACATC- AAAA TACTTAGAACTTAACAGCCTTCCATCCAAAGAGACATGCGAGAATAGATTGGATTGGAAAGAGCAGGAGT- CAC TAAACTTTTTGATTGGGCGCCTACTGGATGATGGCTGTGTGCATGAAGCAAGTAGAGTATGCCGGTATTT- TCAT TTTTATAATCCAGATGTCGCCTTGGTATTGCACTGCAGAGCACTGGCCTCAGGGGAAGCTAGTATGGAGG- ATC TGCACCCAGAGATCCATGCTCTCCTACAAAGTGCTGAGCTGCTTGAGGAAGAAGCACCCGACATTCCCCT- AAG GAGAGTCCACAGCA Intro 30-31 8,772 gtaagtgaaggagatcagatggccc..........ccctcagacttgtatttgcttccag 31 ENSE00001047614 5867 140 CTTCAAGTCTGGATAGTCAGAAGTTTGTGACAGTGCCCTCCAGTAATGAAGTGGTAACTAACCTGGAAGTGCT GACAAGCAAATGCCTCCATGGGAAGAACTACTGTCGACAGGTCCTCTGTCTGTATGATCTTGCCAAG Intro 31-32 1,156 gtatgtgccaaggggtggggctcct..........ttgactggctttgtcttcctctcag 32 ENSE00001123435 6007 199 GAGTTGGGCTGTTCCTACACAGATGTTGCTGCTCAGGATGGTGAAGCCATGCTCCGGAAAATCTTGGCCTCTC AGCAGCCTGACCGATGCAAACGAGCCCAGGCCTTCATCAGCACACAGGGCCTTAAGCCAGATACTGTGGC- TG AACTCGTGGCAGAAGAGGTGACACGGGAGCTGCTTACTTCATCACAGGGAACAG Intro 32-33 726 gtgccctaccccccggggattccca..........cctgtcttcacacctctctgtacag 33 ENSE00001123426 6206 138 GACATAAGCAGATGTTCAACCCAACAGAGGAAAGCCAGACATTTCTTCAGCTGACCACTCTGTGTCAAGACCG CACATTGGTAGGCATGAAGTTGTTGGATAAGATTTCCTCCGTTCCCCATGGGGAACTGTCTTGCA Intro 33-34 2,024 gtaagttattgacctttttcttaca..........atcttaccagtgcccaccctcccag 34 ENSE00001123415 6344 134 CCACAGAGCTCCTGATCCTGGCCCATCATTGCTTCACCCTGACGTGCCACATGGAGGGCATCATCCGAGTCC TACAGGCCGCCCACATGCTCACAGATAACCACCTGGCCCCCAGTGAGGAGTATGGGCTGGTG Intro 34-35 1,019 gtaagtagccccctcaaccccagtc..........tgcgagctgtcctcccacttcacag 35 ENSE00001123405 6478 108 GTACGGCTCCTCACTGGCATTGGAAGGTACAACGAGATGACATACATATTTGATTTGCTGCATAAAAAGCACT- A CTTTGAAGTGCTAATGAGGAAGAAGTTGGATCCG Intro 35-36 1,805 gtaggtgcaaagtaatgagctccag..........gctttttcccttttattctgggcag 36 ENSE00001123397 6586 169 AGTGGTACCCTGAAAACAGCCCTGCTGGACTACATCAAACGCTGCCGTCCTGGAGACAGTGAAAAGCACAAT ATGATTGCCCTGTGCTTCAGCATGTGCCGGGAGATTGGCGAGAACCACGAGGCAGCTGCCCGCATCCAAC- TG AAATTGATTGAGTCTCAGCCCTGGG Intro 36-37 1,118 gtgagtgaggtcacagccacactac..........caaatcttctttatttcccctacag 37 ENSE0000684756 6755 89 AGGACAGCCTCAAGGATGGGCACCAGCTGAAACAACTGCTGCTGAAGGCCCTGACTCTGATGTTGGATGCAG CAGAGAGTTATGCCAAG Intro 37-38 207 gtaacccaaaggcttttttcagact..........gtgcctctccacccttgttcctcag 38 ENSE0000684735 6844 156 GACTCCTGTGTGCGACAGGCCCAGCACTGTCAGCGGCTCACCAAGTTGATAACTCTGCAGATTCACTTTCTGA ACACTGGCCAGAACACAATGCTCATCAACTTGGGCCGCCACAAGCTGATGGACTGTATTCTGGCCCTACC- TCG GTTCTACCAG Intro 38-39 1,155 gtgagcaagaaagcaaactgtagcc..........gtccttcttcacctctccttttaag 39 ENSE0000684706 7000 152 GCTTCTATTGTGGCTGAGGCCTACGATTTTGTTCCAGATTGGGCTGAAATTTTATACCAGCAAGTGATTCTTA- A AGGAGACTTTAATTACTTGGAAGAATTTAAGCAGCAAAGGTTATTAAAGTCCAGTATATTTGAAGAGATT- TCCAA AAA Intro 39-40 1,245 gtaagtattaaaagttgactgtaaa..........ctgtacattatgtttctttatctag 40 ENSE0000884381 7152 600 ATATAAACAACATCAGCCTACTGACATGGTCATGGAAAACCTGAAGAAATTACTCACATATTGTGAAGATGTT- TA CCTGTATTACAAGTTGGCATACGAACACAAGTTTTATGAAATTGTAAATGTGCTTCTGAAGGACCCTCAG- ACAG GTTGCTGTCTAAAGGACATGCTAGCAGGTTAGATGATTTCATAGGTGTCTGTTTTCTTGTACTGTTAGCA- GATT CTGACAGATGTGATGAGAAGAAGAATGCATTGGAGATCTTTGCTAAAGTTGAACAATCCCGGTACTGTAC- CATA TCAGTCCTTTGTGGGTAGTAGGTAGCAAGTAAGAAACTTTTCAGGAGGAAATTCCTATTTAAAATAGATT- GATTT TAGATGATTGTTCATCCACACCATTTTATATAGATACTAGTATTAAGATCAAAAGCTTCCTCTTCCTCAG- GACAG CTTCTACTTTAGATGATCCAATAATGATTAAAGAATACCTGTACCTGCAGATTCCAGTTTCAAAGAAATT- TAATTA TTATTTACACAGTTAAGGAACAGGTGATACATTTTCATTTGTTAGAAACTGATCTTTCTGTAATAAAATA- GATTTT C 3' downstream aattcagtgtatgtcattattactgctaaggaaatcttagcccttgtctg.......... sequence

[0031] As used herein, the term "Spatacsin" denotes the SPAsticity with Thin or Corpus callosum Syndrom protein, which is encoded by the KIAA1840 gene. The sequence of the human form is shown in SEQ ID NO:2.

[0032] The terms "mutant" and "mutation" mean any detectable change in genetic material, e.g. DNA, RNA, cDNA, or any process, mechanism, or result of such a change. This includes gene mutations, in which the structure (e.g. DNA sequence) of a gene is altered, any gene or DNA arising from any mutation process, and any expression product (e.g. protein or enzyme) expressed by a modified gene or DNA sequence. Generally a mutation is identified in a subject by comparing the sequence of a nucleic acid or polypeptide expressed by said subject with the corresponding nucleic acid or polypeptide expressed in a control population. A mutation in the genetic material may also be "silent", i.e. the mutation does not result in an alteration of the amino acid sequence of the expression product.

[0033] In the context of the instant application, mutations identified in KIAA1840 gene are designated pursuant to the nomenclature of Den Dunnen et al. 2001 (http://www.genomic.unimelb.edu.au/mdi/mutnomen/). As defined by Dunnen and Antonarakis at the nucleic acid level, substitutions are designated by "c. position(nt)>(nt)", e.g. "c.118C>G denotes that at nucleotide 118 of the reference sequence C is changed to a G. The mutation at the protein level is denoted p.Q40X: which means that a glutamine (Q) at position 40 encoded by CAG is replaced by a STOP (TAG) codon (Q40X). Deletions are designated by "del" after the deleted interval (followed by the deleted nucleotides). For instance 529_533delATATT denotes a ATATT deletion from nucleotides 529 to 533. The consequence of this deletion, p.I177_F178delfsX, is a deletion of aminoacids at positions 177 and 178 and a frameshift (fs) in the coding sequence leading to the appearance of a premature STOP codon (X). An alternative nomenclature is to indicate the position of the stop codon in the resulting protein after the X; p.I177_178 delfsX178 indicates that the stop codon resulting from the mutation is at codon 178. Insertions are designated by "ins," followed by the inserted nucleotides. For example, c.7029_7030 insT denotes that a T was inserted after nucleotide 7029. This leads to the replacement of valine (V) by cysteine (C) at position 2344 and to a frameshift of the coding sequence and a premature STOP codon at amino-acid 2349 (fsX): p.V2344CfsX or p.V2344CfsX2349. When a mutation is predicted to alter the splicing of the mRNA because the variant modifies a nucleotide of the consensus sequence for splicing (acceptor or donor site), the "r.?" denotes that the consequences of the mutation could not be checked at the RNA level, but is likely (as verified at http://rulai.cshl.edu/new_alt_exon_db2/HTML/score.html).

[0034] The term "hereditary spastic paraplegias (HSP)" denotes genetically heterogeneous Mendelian disorders characterized by weakness, spasticity and loss of vibratory sense in the lower limbs. The term "Autosomal Recessive Hereditary Spastic Paraplegia" or "AR-HSP" denotes spastic paraplegia that is transmitted as an autosomal recessive trait. Patients with HSP or AR-HSP can have a pure phenotype, or, more often, a complex phenotype that associates various neurological signs (cerebellar ataxia, mental retardation, peripheral neuropathy, etc). The term "AR-HSP-TCC" denotes an AR-HSP with Thin Corpus Callosum usually associated with, mental or cognitive deficit and peripheral neuropathy. Families without proved TCC can also be mutated in this gene either because of slow progression of the disease in the patient or because magnetic resonance imaging (MRI) couldn't be performed due to patient refusal or impossibility (patients leaving far from cities in North-Africa--this is the case for families FSP400, FSP393 and FSP343).

[0035] As used herein, the term "subject" denotes a mammal, such as a rodent, a feline, a canine, and a primate. Preferably a subject according to the invention is a human.

Mutations in the KIAA1840 Gene and Spatacsin Protein

[0036] The inventors identified various mutations in the KIAA1840 gene.

[0037] Fortythree different mutations on human KIAA1840 gene were indeed identified in 47 families, including the 16 linked ones, all at the homozygous state, except in 16 kindreds. They were either nonsense mutations (n=13), deletions (n=17), insertions (n=7), or splice site mutations (n=6) in the coding sequence, and resulted theoretically in an abnormally spliced mRNA or a truncated protein in all cases.

[0038] In one family, linked with a maximal 3.1 multipoint lod score to SPG11, a missense R945G mutation segregated at the homozygous state in both patients and was not detected in 150 control chromosomes. The mutation is probably not only affecting the nature of the amino-acid. Position of this variant was in the 5'-splice site consensus sequence (2 bases before the end of exon 15). The score of the 5'-splicing sequence changed from 4.9 for the wild type to 2.7 for the variant (Alternative Splicing Database:: http://rulai.cshl.edu/new_at_exon_db2/HTML/score.html) suggesting that this variant could act at both the RNA level (splicing effect) and at the protein level (missense change). Indeed, this was confirmed by direct sequencing (using primers GCTCTGTGGTGGGATCAACT and TGCTTACACTGGCCTGATTG) on mRNA isolated from lymphoblasts of an affected family member (FSP670-5) in which an alternative splice site is generated downstream in intron 15 leading to a 65 bp insertion and a premature stop codon (c.2833A>G, r.2834+1_2834+65 ins, p.R945GfsX950). It cannot be excluded, however, that splicing occurs at its normal place in a small amount of messenger RNA and that a full length protein is generated with the G variant at position 945. Similarly, the mutation c.2444G>T, p.R815M likely affects not only the amino-acid but also splicing of exon 13 since the splice score down from 3.7 to 0.2 for the mutation. In addition, the c.869+1G>A, c.2316+1G>A, c.2444+1G>C and c.6477+4A>G, are all clearly affecting the acceptor splicing consensus sequence (see splice scores in table 2) and likely alter the splicing of exons 4, 12, 13 and 34, respectively. The mutations identified by the inventors are presented on the following Table 2.

TABLE-US-00002 TABLE 2 Mutations identified in the KIAA1840 CDS (SEQ ID NO: 1) and protein (SEQ ID NO:2) Mutations Family code Family code Ex- mRNA or Protein SEQ (Origins) at the (Origins) at the ons Nucleotide variants variants ID NO: homozygous state heterozygous state 1 c.118C>T, p.Q40X 149 FSP672 (Israel) 3 c.529_533delATATT p.I177_F178>S177fsX1 150 FSP386 (Portugal) ITA17 (Brazil) 78 FSP754 (Portugal) FSP831 (Portugal) 4 c.704_705delAT p.H235RfsX246 166 SPD199 (Turkey) 4 c.733_734delAT, p.M245VfsX246 151 TUN2 (Tunisia) FSP117 (France) TUN3 (Tunisia) TUN4 (Tunisia) TUN22 (Tunisia) In- c.869+1G>A r.? FSP847 (Argentina) tron 4 Splice score down from 9.8 to -0.9 6 c.1203delA, p.K401KfsX415 152 PE (Italy) 6 cv.1235C>G, p.S412X 153 FSP393 (Portugal) 6 c.1282A>T p.K428X 167 FSP830 (Portugal) 7 c.1471_1472delCT p.L491DfsX556 168 FSP522 (France) 7 c.1549_1550delCT, p.L517LfsX556 154 FSP343 (Algeria) (non typical) 8 c.1668delT p.F556LfsX577 169 SAL646 (France) 8 c.1679C>G p.S560X 170 ITA16SB (Italy) 8 c.1692delA p.V564VfsX577 171 DKD (Italy) 10 c.1951C>T, p.R651X 155 MP (Italy) FSP683 (Romania) ITA28VAC (Italy) 11 c.2198T>G, p.L733X 156 OS (Italy) In- c.2316+1G>A r.? FSP892 (Norway) tron 12 Splice score down from 6.2 to -4.5 13 c.2444G>T p.R815M and/or r.? 172 ITA28VAC (Italy) Splice score down from 3.7 to 0.2 In- c.2444+1G>C r.? ITA16 (Brazil) tron 13 Splice score down from 3.7 to -7 15 c.2697G>A p.W899X 173 ITA10 (Italy) 15 c.2716delC p.Q906SfsX920 174 ITA9 (Italy) 15 c.2833A>G, r.2834+1_2834+65ins, 165 FSP670 (Israel) ITA14 (Italy) p.R945G or 188 p.R945GfsX950 Splice score down from 4.9 to 2.7 16 c.2842_2843insG, p.V948GfsX953 157 PE (Italy) 16 c.2850_2851insT, p.L950FfsX953 158 MP (Italy) 17 c.3075_3076insA p.E1026RfsX1029 175 ITA8 (Germany) 22 c.3741_3742insA p.P1248TfsX1264 176 ITA17 (Brazil) 25 c.4307_4308delAA p.Q1436RfsX1442 177 FSP398 (Israel) ITA16 (Brazil) 30 c.5470C>T p.R1824X 178 ITA8 (Germany) 30 c.5532_5533delCA p.S1844SfsX1857 179 FSP522 (France) 30 c.5769delT p.S1923RfsX1950 180 FSP838(Saudi-Arabia) 31 c.5870C>G p.S1957X 181 ITA16SB (Italy) 31 c.5974C>T, p.R1992X 159 FSP117 (France) 31 c.5982_5983insCTCT p.L1995LfsX2000 182 DKD (Italy) 31 c.5986_5987insT p.C1996LfsX1999 183 FSP398 (Israel) 31 c.5989_5992delCTGT p.L1997_Y1998>M1997f 184 FSP683 (Romania) sX2056 32 c.6091C>T p.R2031X 185 ITA1 (Turkey) 32 c.6100C>T, p.R2034X 160 FSP446 (Morocco), FSP221 (Algeria), FSP732 (Algeria), FSP400 (Algeria) FSP792 (Algeria) FSP845 (Morocco) TUN9 (Tunisia) TUN12 (Tunisia) TUN14 (Tunisia) 34 c.6451delG, p. A2151 P fsX2172 161 SAL1608 (France) In- c.6477+4 A>G r.? FSP830 (Portugal) tron 34 Splice score down from 9.6 to 6.6 36 c.6737_6740delTTGA, p.I2246_E2247>S2246f 162 FSP920 (Japan) FSP343 (Algeria) sX2260 36 c.6739_6742delGAGT p.E2247_S2248>L2247f 186 SAL646 (France) sX2260 37 c.6832_6833delAG, p.S2278LfsX2338 163 FSP75 (Portugal) 38 c.6856C>T p.R2286X 187 ITA14 (Italy) 39 c.7029_7030insT, p.V2344CfsX2349 164 FSP515 (Tunisia)

[0039] Each mutation are herein numbered according to human KIAA1840 CDS and amino acid sequence as shown in SEQ ID NO: 1 and SEQ ID NO:2.

[0040] Accordingly, the invention relates to an isolated nucleic acid specifically hybridizable to a region of KIAA1840 gene coding sequence (SEQ ID NO:1) that contains a mutation selected from the group consisting of [0041] the substitutions c.6100C>T, c.2198T>G, c.118C>T, c.1235C>G, c.2833A>G, c.1951C>T, c.869+1G>A, c. 1679 C>G, c.2316+1G>A, c.2444G>T, c.2444+1G>C, c.2697G>A, c.5470C>T, c.5870C>G, c.6091C>T, c.6477+4 A>G, c.6856C>T, c.1282A>T and c.5974C>T, [0042] the deletions: c.529-533delATATT, c.6451delG, c.6832_6833 delAG, c.1203delA, c.1549_1550 delCT, c.6737_6740 delTTGA, c.1471_1472 delCT, c.1692delA, c.2716delC, c.1668delT, c.704_705delAT, c. 5989_5992delCTGT, c. 5532_5533delCA, c.5769delT, c.6739_6742delGAGT, c.4307_4308 delAA and c. 733_734delAT, and [0043] the insertions: c.7029_7030insT, c.2850_2851insT, c.3741_3742insA, c. 5982_5983insCTCT, c. 5986_5987insT, c. 3075_3076insA and c.2842_2843insG.

[0044] In one embodiment of this aspect of the invention, the isolated nucleic acid according to the invention consists of at least 10 nucleotides, preferably 20 nucleotides, more preferably 40 nucleotides.

[0045] In a preferred embodiment, such an isolated nucleic acid is specifically hybridizable to a region consisting of 10 nucleotides upstream and 10 nucleotides downstream of a mutation selected from the group consisting of [0046] the substitutions: c.6100C>T, c.2198T>G, c.118C>T, c.1235C>G, c.2833A>G, c.1951C>T, c.869+1G>A, c. 1679 C>G, c.2316+1G>A, c.2444G>T, c.2444+1G>C, c.2697G>A, c.5470C>T, c.5870C>G, c.6091C>T, c.6477+4 A>G, c.6856C>T, c.1282A>T c.5974C>T, [0047] the deletions: c.529-533delATATT, c.6451delG, c.6832_6833 delAG, c.1203delA, c.1549_1550 delCT, c.6737_6740 delTTGA, c.1471_1472 delCT, c.1692delA, c.2716delC, c.1668delT, c.704_705delAT, c. 5989_5992delCTGT, c. 5532_5533delCA, c.5769delT, c.6739_6742delGAGT, c.4307_4308 delAA c. 733_734delAT, and [0048] the insertions: c.7029_7030insT, c.2850_2851insT, c.3741_3742insA, c. 5982_5983insCTCT, c. 5986_5987insT, c. 3075_3076insA c.2842_2843insG, of the KIAA1840 gene sequence.

[0049] Preferably, "specifically hybridizable" means "hybridizable under conditions at 68.degree. C. in 0.2.times.SSC, at 42.degree. C. in 50% formamide, 4.times.SSC, or under conditions that afford levels of hybridization equivalent to those observed under either of these two conditions".

[0050] In an alternative manner, a sequence "specifically hybridizable" to a target sequence means a sequence showing a percentage of sequence identity with the sequence complementary of said target sequence of at least about 70%, preferably at least about 80%, more preferably at least about 90%, most preferably at least about 95%.

[0051] Said nucleic acid according to the invention may be an oligonucleotide.

[0052] Preferably, said nucleic acid or oligonucleotide is complementary to a region of the KIAA1840 gene that contains at least one of the identified mutations.

[0053] In one embodiment of this aspect of the invention, the isolated nucleic acid according to the invention consists of at least 10 nucleotides, preferably 20 nucleotides, more preferably 40 nucleotides.

[0054] Such a nucleic acid according to the invention may advantageously be used as a primer or probe.

[0055] A further object of the present invention relates to an isolated nucleic acid, which comprises or consists in a KIAA1840 gene coding sequence (SEQ ID NO:1) that contains one or several mutation(s) selected from the group consisting of [0056] the substitutions: c.6100C>T, c.2198T>G, c.118C>T, c.1235C>G, c.2833A>G, c.1951C>T, c.869+1G>A, c. 1679 C>G, c.2316+1G>A, c.2444G>T, c.2444+1G>C, c.2697G>A, c.5470C>T, c.5870C>G, c.6091C>T, c.6477+4 A>G, c.6856C>T, c.1282A>T c.5974C>T, [0057] the deletions: c.529-533delATATT, c.6451delG, c.6832_6833 delAG, c.1203delA, c.1549_1550 delCT, c.6737_6740 delTTGA, c.1471_1472 delCT, c.1692delA, c.2716delC, c.1668delT, c.704_705delAT, c. 5989_5992delCTGT, c. 5532_5533delCA, c.5769delT, c.6739_6742delGAGT, c.4307_4308 delAA c. 733_734delAT, and [0058] the insertions: c.7029_7030insT, c.2850_2851insT, c.3741_3742insA, c. 5982_5983insCTCT, c. 5986_5987insT, c. 3075_3076insA c.2842_2843insG or a sequence complementary thereto.

[0059] In one embodiment of this aspect of the invention, the isolated nucleic acid according to the invention consists of at least 10 nucleotides, preferably 20 nucleotides, more preferably 40 nucleotides.

[0060] In another embodiment, the invention relates to an isolated polypeptide which comprises the polypeptide sequence of KIAA1840 containing one or several mutation(s) selected from the group consisting of p.Q40X, p.I177_F178delfsX178, p.H235RfsX246, p.M245VfsX246, p.K401KfsX415, p.S412X, p.K428X, p.L491DfsX556, p.L517LfsX556, p.F556LfsX577, p.S560X, p.V564VfsX577, p.R651X, p.L733X, p.R815M, p.W899X, p.Q906SfsX920, p.R945G, p.R945GfsX950, p.L950FfsX953, p.V948GfsX953, p.E1026RfsX1029, p.P1248TfsX1264, p.Q1436RfsX1442, p.R1824X, p.S1844SfsX1857, p.S1923RfsX1950, p.S1957X, p.R1992X, p.L1995LfsX2000, p.C1996LfsX1999, p.L1997_1998 delfsX2056, p.R2031X, p.R2034X, p.A2151 PfsX2172, p.I2246_E2247delfsX2260, p. E2247_S2248delfsX2260, p.S2278LfsX2338, p.R2286X and p.V2344CfsX2349.

Diagnostic Method

[0061] The inventors have further shown that KIAA1840mutants are associated with a hereditary spastic paraplegias (HSP) which is characterized by weakness, spasticity and often loss of vibration sense in the lower limbs. More particular, the inventors have shown that KIAA1840 mutations as above described correlate in all patients with mild mental impairment, a thin corpus callosum (TCC) (AR-HSP-TCC) and frequent polyneuropathy (72% of the patients) in a series of 45 families with the full clinical criteria of SPG11. In the 2 other kindreds, cerebral imaging was not available to verify the presence of a thin corpus callosum (TUN2 and TUN14).

[0062] Therefore the invention provides an ex vivo method of diagnosing or predicting a hereditary spastic paraplegia (HSP) in a subject, which method comprises detecting a mutation in the KIAA1840 gene or protein (spatacsin), as compared to a control population, wherein the presence of a mutation is indicative of an hereditary spastic paraplegia (HSP).

Nucleic Acids Assays:

[0063] According to a first embodiment the mutations may be detected by analysing a KIAA1840 nucleic acid molecule. In the context of the invention, KIAA1840 nucleic acid molecules include mRNA, genomic DNA and cDNA derived from mRNA. DNA or RNA can be single stranded or double stranded. These may be utilized for detection by amplification and/or hybridization with a probe, for instance.

[0064] Thus the invention provides an ex vivo method of diagnosing or predicting a hereditary spastic paraplegia (HSP), in a subject, which method may comprise the step consisting of detecting a KIAA1840 mutation in a nucleic acid sample obtained from the subject, wherein the presence of a mutation is indicative of a hereditary spastic paraplegia (HSP).

[0065] The nucleic acid sample may be obtained from any cell source or tissue biopsy. Non-limiting examples of cell sources available include without limitation blood cells, buccal cells, epithelial cells, fibroblasts, or any cells present in a tissue obtained by biopsy or post-mortem. Cells may also be obtained from body fluids, such as blood, plasma, serum, lymph, etc. DNA may be extracted using any methods known in the art, such as described in Sambrook et al., 1989. RNA may also be isolated, for instance from tissue biopsy, using standard methods well known to the one skilled in the art such as guanidium thiocyanate-phenol-chloroform extraction (Chomocyznski et al., 1987).

[0066] A KIAA1840 mutation according to the invention may be found and located in many exons, including exon 1 and exon 39 (Table 2).

[0067] KIAA1840 mutations may be detected in a RNA or DNA sample, preferably after amplification. For instance, the isolated RNA may be subjected to coupled reverse transcription and amplification, such as reverse transcription and amplification by polymerase chain reaction (RT-PCR), using specific oligonucleotide primers that are specific for a mutated site or that enable amplification of a region containing the mutated site. According to a first alternative, conditions for primer annealing may be chosen to ensure specific reverse transcription (where appropriate) and amplification; so that the appearance of an amplification product be a diagnostic of the presence of a particular KIAA1840 mutation. Otherwise, RNA may be reverse-transcribed and amplified, or DNA may be amplified, after which a mutated site may be detected in the amplified sequence by hybridization with a suitable probe or by direct sequencing, or any other appropriate method known in the art. For instance, a cDNA obtained from RNA may be cloned and sequenced to identify a mutation in KIAA1840 sequence.

[0068] Actually numerous strategies for genotype analysis are available (Antonarakis et al., 1989 Cooper et al., 1991 Grompe, 1993). Briefly, the nucleic acid molecule may be tested for the presence or absence of a restriction site. When a base substitution mutation creates or abolishes the recognition site of a restriction enzyme, this allows a simple direct enzymatic test for the mutation. Further strategies include, but are not limited to, direct sequencing, restriction fragment length polymorphism (RFLP) analysis; hybridization with allele-specific oligonucleotides (ASO) that are short synthetic probes which hybridize only to a perfectly matched sequence under suitably stringent hybridization conditions; allele-specific PCR; PCR using mutagenic primers; ligase-PCR, HOT cleavage; denaturing gradient gel electrophoresis (DGGE), temperature denaturing gradient gel electrophoresis (TGGE), single-stranded conformational polymorphism (SSCP) and denaturing high performance liquid chromatography (DHPLC) (Kuklin et al., 1997). Direct sequencing may be accomplished by any method, including without limitation chemical sequencing, using the Maxam-Gilbert method by enzymatic sequencing, using the Sanger method mass spectrometry sequencing sequencing using a chip-based technology (see e.g. Little et al., 1996); and real-time quantitative PCR. Preferably, DNA from a subject is first subjected to amplification by polymerase chain reaction (PCR) using specific amplification primers. However several other methods are available, allowing DNA to be studied independently of PCR, such as the rolling circle amplification (RCA), the InvaderTMassay, or oligonucleotide ligation assay (OLA). OLA may be used for revealing base substitution mutations. According to this method, two oligonucleotides are constructed that hybridize to adjacent sequences in the target nucleic acid, with the join sited at the position of the mutation. DNA ligase will covalently join the two oligonucleotides only if they are perfectly hybridized (Nickerson et al., 1990).

[0069] The inventors designed a series of primers, manually or using Oligo6 (MBI, Cascade, Colo.), in order to amplify all coding exons of 18 genes from the candidate interval (primers and conditions available on request), including the mutated KIAA1840 gene (see Table 4). PCR-amplified fragments of genomic DNA were then purified using exonuclease 1 (New England Biolabs, 2 U/5 .mu.l PCR product) and shrimp alkaline phosphatase (Roche, 1 U/5 .mu.l of PCR product) and sequenced using the fluorescent dideoxy-terminator method (BigDye v3, Applied Biosystem) on an automated ABI-3730 sequencer according to the manufacturer's recommendations. With the use of the software package SeqScape (Applied Biosystems), sequences were aligned and compared to consensus sequences.

[0070] Protein Assays

[0071] According to a second embodiment said mutation may be detected in KIAA1840 protein or a truncated form of the KIAA1840 protein may be detected, as compared to a control population.

[0072] All of the identified mutations of the KIAA840 gene create some deletions of the C-terminal part of the spatacsin protein, in some cases because of aberrant splicing (FIG. 5). These deletions result in truncated proteins of sequences SEQ ID NO: 149 to SEQ ID NO:164 and SEQ ID NO:166 to SEQ ID NO:188, respectively. Those due to aberrant splicing, either very likely, could not be precised because the modification of the splicing could not be evidenced in mRNA directly, except in family FSP670 (r.2834+1_2834+65 ins, p.R945GfsX950). It can not be excluded, however, that a shorten protein fragment may be synthesized due to the activation of new ATGs after the stop codon.

[0073] Said mutation may be detected according to any appropriate method known in the art. In particular a sample, such as a tissue biopsy, obtained from a subject may be contacted with antibodies specific of the mutated form of KIAA1840 protein, i.e. antibodies that are capable of distinguishing between a mutated form of KIAA1840 and the wild-type protein (or any other protein), to determine the presence or absence of a KIAA1840 specified by the antibody. An antibody recognizing the wild type protein could also be used to check the presence of the protein or its abnormal location or size and could then be used as a diagnostic tool as well.

[0074] Antibodies that specifically recognize a mutated KIAA1840 protein also make part of the invention. The antibodies are specific of mutated KIAA1840 protein, that is to say they do not cross-react with the wild-type KIAA1840 protein.

[0075] A monoclonal or polyclonal antibody recognizing the wild-type KIAA1840 protein may be used to detect the presence of the wild-type protein or one of its truncated forms. For instance, an antibody recognizing the N-terminal part of the wild-type KIAA1840 protein may also recognize one or several truncated forms and can be used to reveal by immunoblotting, the different forms, wild-type and truncated, according to their molecular weights. An antibody recognizing the wild-type KIAA1840 protein, but not recognizing the truncated forms, can be used for immunoblotting or in immunoassay as ELISA; in that case, an absence of signal reveals the presence of a truncated form in the sample or the absence of synthesis of a stable protein as compared with a positive control comprising the wild-type KIAA1840 protein.

[0076] The antibodies of the present invention may be monoclonal or polyclonal antibodies, single chain or double chain, chimeric antibodies, humanized antibodies, or portions of an immunoglobulin molecule, including those portions known in the art as antigen binding fragments Fab, Fab', F(ab').sub.2 and F(v). They can also be immunoconjugated, e.g. with a toxin, or labelled antibodies.

[0077] Whereas polyclonal antibodies may be used, monoclonal antibodies are preferred for since they are more reproducible in the long run.

[0078] Procedures for raising "polyclonal antibodies" are also well known. Polyclonal antibodies can be obtained from serum of an animal immunized against the spatacsin complex, which may be produced by genetic engineering for example according to standard methods well-known by one skilled in the art. Typically, such antibodies can be raised by administering mutated KIAA1840 protein or peptides of this protein subcutaneously to New Zealand white rabbits which have first been bled to obtain pre-immune serum. The antigens can be injected at a total volume of 100 .mu.l per site at six different sites. Each injected material may contain adjuvants with or without pulverized acrylamide gel containing the protein or polypeptide after SDS-polyacrylamide gel electrophoresis. The rabbits are then bled two weeks after the first injection and periodically boosted with the same antigen three times every six weeks. A sample of serum is then collected 10 days after each boost. Polyclonal antibodies are then recovered from the serum by affinity chromatography using the corresponding antigen to capture the antibody. This and other procedures for raising polyclonal antibodies are disclosed by Harlow et al. (1988) which is hereby incorporated in the references.

[0079] A "monoclonal antibody" in its various grammatical forms refers to a population of antibody molecules that contains only one species of antibody combining site capable of immunoreacting with a particular epitope. A monoclonal antibody thus typically displays a single binding affinity for any epitope with which it immunoreacts. A monoclonal antibody may therefore contain an antibody molecule having a plurality of antibody combining sites, each immunospecific for a different epitope, e.g. a bispecific monoclonal antibody. Although historically a monoclonal antibody was produced by immortalization of a clonally pure immunoglobulin secreting cell line, a monoclonally pure population of antibody molecules can also be prepared by the methods of the present invention.

[0080] Laboratory methods for preparing monoclonal antibodies are well known in the art (see, for example, Harlow et al., 1988). Monoclonal antibodies (mAbs) may be prepared by immunizing purified mutated KIAA1840 protein into a mammal, e.g. a mouse, rat, human and the like mammals. The antibody-producing cells in the immunized mammal are isolated and fused with myeloma or heteromyeloma cells to produce hybrid cells (hybridoma). The hybridoma cells producing the monoclonal antibodies are utilized as a source of the desired monoclonal antibody. This standard method of hybridoma culture is described in Kohler and Milstein (1975).

[0081] While mAbs can be produced by hybridoma culture the invention is not to be so limited. Also contemplated is the use of mAbs produced by an expressing nucleic acid cloned from a hybridoma of this invention. That is, the nucleic acid expressing the molecules secreted by a hybridoma of this invention can be transferred into another cell line to produce a transformant. The transformant is genotypically distinct from the original hybridoma but is also capable of producing antibody molecules of this invention, including immunologically active fragments of whole antibody molecules, corresponding to those secreted by the hybridoma. See, for example, U.S. Pat. No. 4,642,334 to Reading; PCT Publication No.; European Patent Publications No. 0239400 to Winter et al. and No. 0125023 to Cabilly et al.

[0082] Antibody generation techniques not involving immunisation are also contemplated such as for example using phage display technology to examine naive libraries (from non-immunised animals); see Barbas et al. (1992), and Waterhouse et al. (1993).

[0083] Antibodies raised against mutated KIAA1840 protein may be cross reactive with wild-type KIAA1840 protein. Accordingly a selection of antibodies specific for mutated KIAA1840 protein is required. This may be achieved by depleting the pool of antibodies from those that are reactive with the wild-type KIAA1840 protein, for instance by submitting the raised antibodies to an affinity chromatography against wild-type KIAA1840 protein.

[0084] Alternatively, binding agents other than antibodies may be used for the purpose of the invention. These may be for instance aptamers, which are a class of molecule that represents an alternative to antibodies in term of molecular recognition. Aptamers are oligonucleotide or oligopeptide sequences with the capacity to recognize virtually any class of target molecules with high affinity and specificity. Such ligands may be isolated through Systematic Evolution of Ligands by EXponential enrichment (SELEX) of a random sequence library, as described in Tuerk C. and Gold L., 1990. The random sequence library is obtainable by combinatorial chemical synthesis of DNA. In this library, each member is a linear oligomer, eventually chemically modified, of a unique sequence. Possible modifications, uses and advantages of this class of molecules have been reviewed in Jayasena S. D., 1999. Peptide aptamers consists of a conformationally constrained antibody variable region displayed by a platform protein, such as E. coli Thioredoxin A that are selected from combinatorial libraries by two hybrid methods (Colas et al., 1996).

Kits

[0085] According to another aspect of the invention, the KIAA1840 mutation is detected by contacting the DNA of the subject with a nucleic acid probe, which is optionally labeled.

[0086] Primers may also be useful to amplify, analyse (dHPLC, Southern . . . ) or sequence the portion of the KIAA1840 gene containing the mutated positions of interest.

[0087] Such probes or primers are nucleic acids that are capable of specifically hybridizing with a portion of the KIAA1840 gene sequence containing the mutated positions of interest. That means that they are sequences that hybridize with the portion mutated KIAA1840 nucleic acid sequence to which they refer under conditions of high stringency.

[0088] The present invention further provides kits suitable for determining at least one of the mutations of the KIAA1840 gene.

[0089] The kits may include the following components:

[0090] (i) a probe, usually made of DNA, and that may be pre-labelled. Alternatively, the probe may be unlabelled and the ingredients for labelling may be included in the kit in separate containers; and

[0091] (ii) hybridization reagents: the kit may also contain other suitably packaged reagents and materials needed for the particular hybridization protocol, including solid-phase matrices, if applicable, and standards.

[0092] In another embodiment, the kits may include:

[0093] (i) sequence determination or amplification primers: sequencing primers may be pre-labelled or may contain an affinity purification or attachment moiety and

[0094] (2) sequence determination or amplification reagents: the kit may also contain other suitably packaged reagents and materials needed for the particular sequencing amplification protocol. In one preferred embodiment, the kit comprises a panel of sequencing or amplification primers, whose sequences correspond to sequences adjacent to at least one of the polymorphic positions, as well as a means for detecting the presence of each polymorphic sequence.

In a particular embodiment, it is provided a kit which comprises a pair of oligonucleotide primers specific for amplifying all or part of the KIAA1840 gene comprising at least one of the mutated positions that are identified above (see Table 2).

[0095] More preferably, the kits of the invention comprise a pair of primers selected from the pairs shown in Table 3 either for detection by direct sequencing or by screening by dHPLC when they could be set-up (second set of primer pairs).

TABLE-US-00003 TABLE 3 Primers used for PCR or for dHPLC (in parentheses) SEQ ID Exons Mutations For/Rev primers NO: 1 c.118C>T, p.Q40X ccacaggaaacgaatggaat/ggttctgtgaggaaaccacg 3/4 3 c.529_533delATATT, cagggacattgtaggccatc/tcccagctcccaaaactaaa 5/7 p.I177_F178delfsX (ccagttgtaaaattgtgacc)/(tcaatcaacacttctaccac) (6)/(8) 4 c.733_734delAT, caggttctttcttgtggcatca/cgaggatatttttaacctcttatca 9/10 p.M245VfsX (gttaggcatacttacaaaactggc)/(cgaggatatttttaacctcttatca) (11)/(12) c.704_705delAT, p.H235RfsX246 c.869+1G>A, r.? 6 c.1203delA, p.K401KfsX; gaacatctttgccctggttt/caggcactgaggcagaagta 13/15 c.1235C>G, p.S412X (ctgtgacaggtgttaagtta)/(atctaatacaagacagtctc) (16) c.1282A>T, p.K428X 7 c.1549_1550delCT, aaaaatcaattcctaaatcataatcc/tcttttaaagccaaaaagggtaaa 17/19 p.L517LfsX (tagtactgaagtattgagta)/(ttaagtaatgttcttgggca) (20) 8 c.1668delT, cttgccccagattgcataat/tccaaaaagtacgtaaaatccca 57/58 p.F556LfsX577 c.1679C>G, p.S560X c.1692delA, p.V564VfsX577 10 c.1951C>T, p.R651X cccaggactaatcatgaagga/atccccaaaccgataaaacc 21/22 11 c.2198T>G, p.L733X cggtgtgtcttccactagctc/acccagccattctcagtgtt 23/25 (gttacataaatgtataatccctg)/(cattttaagactttatggattac) (24)/(26) 12 c.2316+1G>A, r.? tttgaaagagcagaaagctatgg/tgaaggggttgtcacactttt 61/62 13 c.2444G>T, p.R815M ttgtggcaaaagaaaatttgtg/gagaatgcaggctcagttcc 63/64 and/or r.? c.2444+1G>C, r.? 15 c.2833A>G, cacagcgagatcctgtctca/cctcactgtaagatgatgccc 27/28 r.2834+1_2834+65ins, p.R945GfsX950 or p.R945G c.2697G>A, p.W899X c.2716delC, pQ906SfsX920 16 c.2842_2843insG, cctttaaatactacagtggtgcaga/ccaactgttgagatggagaaaa 29/31 p.V948GfsX; (tgtgggcatgatttggtcta)/(acctgctcaaggacaaatgc) (30)/(32) c.2850_2851insT, p.L950FfsX 17 c.3075_3076insA, ttgtttccagatcatgaagaatatg/tcagatagctgaccacagcc 67/68 p.E1026RfsX1029 22 c.3741_3742insA, agtcagcttaagggaagcgg/gaagataaccattttctcccca 77/78 p.P1248TfsX1264 25 c.4307_4308delAA, aaaaggcaccatacagctttg/ggaaacacatgctggaacct 83/84 p.Q1436RfsX1442 30 c.5470C>T, p.R1824X tgaggtgggaggatctcttg/gatgtgttcagagcagccaa 93/94 c.5532_5533delCA, and p.S1844SfsX1857 taagctggaggagctggaga/ttgttgtccccttaacttgg 95/96 c.5769delT, p.S1923RfsX1950 31 c.5974C>T, p.R1992X tttgaagtatcccagggtgg/ccaccattccccaaagataa 33/34 c.5870C>G, p.S1957X c.5982_5983insCTCT, p.L1995LfsX2000 c.5986_5987insT, p.C1996LfsX1999 c.5989_5992delCTGT, p.L1997_Y1998>M1997fs X2056 32 c.6100C>T, R2034X ttacctggatttggctttgg/tgcaatccagaaacttgagaga 35/37 c.6091C>T, p.R2031X (cctggcttctaaaagtggcc)/(aagcacaacatccaaatcctt) (36)(38) 34 c.6451delG, p.A2151PfsX atgttggcaggaactccatc/ctcctttggagcaacctctg 39/40 c.6477+4 A>G, r.? 36 c.6737_6740delTTGA, ttccaacaggaaagcacaca/cagctacttgggaggctgag 41/43 p.I2246_E2247delfsX (caacaggaaagcacacatgc)/(gtgtggctgtgacctcactc) (42)/(44) c.6739_6742delGAGT, p.E2247_S2248>L2247fs X2260 37 c.6832_6833delAG, gcattagaaggggcactgaa/ctcacaacggtattcacccc 45/47 p.S2278LfxX (aacatggctgggatgtttct)/(ttcctggttggcctatgatg) (46)/(48) 38 c.6856C>T, p.R2286X ttttgtccttgggctctttc/cctggttctgtcactagccc 101/102 39 c.7029_7030insT, aagggtttaagataatttgggga/ggattcttgatactgctttgcc 49/51 p.V2344CfsX (aatgccaaacacacacctga)/(ctcaaagcagaggcaaggag) (50)/(52)

Therapeutic Methods

[0096] The inventors have demonstrated that the all, except one, mutations identified in the KIAA1840 gene cause truncation of the protein, suggesting that pathogenicity results from loss of function.

[0097] These results identify mutated KIAA1840 gene as target for the preventive or curative treatment of a hereditary spastic paraplegia.

[0098] Thus the invention further relates to a method of treatment of an HSP which comprises the step of administering a subject in need thereof with a KIAA1840 nucleic acid, i.e. a nucleic acid sequence that encodes a wild-type KIAA1840 protein, so that spatacsin is expressed in vivo by the cells of the subject that have been transfected with said nucleic acid. Accordingly, said method leads to an overexpression of wild-type spatacsin which compensates expression of defective mutated KIAA1840 protein.

[0099] The invention also relates to the use of a KIAA1840 nucleic acid for the manufacture of a medicament intended for the treatment of an HSP.

[0100] In the context of the invention, the term "treating" or "treatment", as used herein, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0101] Preferably said KIAA1840 nucleic acid is administered in a therapeutically effective amount. A "therapeutically effective amount" is intended for a minimal amount of active agent (e.g., KIAA1840 nucleic acid) which is necessary to impart therapeutic benefit to a subject. For example, a "therapeutically effective amount" to a mammal is such an amount which induces, ameliorates or otherwise causes an improvement in the pathological symptoms, disease progression or physiological conditions associated with or resistance to succumbing to a disorder.

[0102] The administered polynucleotide comprises the nucleotide sequence SEQ ID NO:1, or any homologous or similar sequence as defined below:

[0103] a) a sequence showing at least 70%, preferably at least 75% or 80% or 85% or 90% or 95% or 99%, sequence similarity with SEQ ID NO:1;

[0104] b) a sequence hybridizing with SEQ ID NO:1, or its complementary sequence, under stringent conditions;

[0105] c) a sequence encoding a protein of sequence SEQ ID NO:2, or any sequence substantially similar with SEQ ID NO:2.

[0106] The term "sequence similarity" in all its grammatical forms refers to the degree of identity or correspondence between nucleic acid or amino acid sequences of proteins that may or may not share a common evolutionary origin. Preferably the degree of sequence identity is calculated compared with the totality of a reference sequence.

[0107] In a specific embodiment, two DNA sequences are "substantially homologous" or "substantially similar" when at least 70%, preferably at least 75% or 80% or 85% or 90% or 95% or 99%, of the nucleotides match over the defined length of the DNA sequences, as determined by sequence comparison algorithms, such as BLAST, FASTA, DNA Strider, etc. Sequences that are substantially homologous can be identified by comparing the sequences using standard software available in sequence data banks, or in a Southern hybridization experiment under, for example, stringent conditions as defined for that particular system.

[0108] Similarly, in a particular embodiment, two amino acid sequences are "substantially similar" when greater than 80%, preferably than 85% or 90% or 95% or 99%, of the amino acids are similar (functionally identical). "Functionally identical" polypeptides are those in which a given amino acid residue has been changed without altering the overall conformation and function of the polypeptide, including, but not limited to, replacement of an amino acid with one having similar properties (such as, for example, polarity, hydrogen bonding potential, acidic, basic, hydrophobic, aromatic, and the like). Amino acids with similar properties are well known in the art. For example, arginine, histidine and lysine are hydrophilic-basic amino acids and may be interchangeable. Similarly, isoleucine, a hydrophobic amino acid, may be replaced with leucine, methionine or valine. Such changes are expected to have little or no effect on the apparent molecular weight or isoelectric point of the protein or polypeptide. Preferably, the similar sequences are identified by alignment using, for example, the GCG (Genetics Computer Group, Program Manual for the GCG Package, Version 7, Madison, Wis.) pileup program, or any of the programs described above (BLAST, FASTA, etc.).

[0109] Preferably the KIAA1840 nucleic acid sequence according to the invention is associated with elements that enable for regulation of its expression, such as a promoter sequence.

[0110] Such a nucleic acid may be in the form of a DNA vector. The terms "vector" means the vehicle by which a DNA or RNA sequence (e.g. a foreign gene) can be introduced into a host cell, so as to transform the host and promote expression (e.g. transcription and translation) of the introduced sequence. A common type of vector is a "plasmid", which generally is a self-contained molecule of double-stranded DNA, usually of bacterial origin, that can readily accept additional (foreign) DNA and which can readily introduced into a suitable host cell. A plasmid vector often contains coding DNA and promoter DNA and has one or more restriction sites suitable for inserting foreign DNA.

[0111] The KIAA1840 nucleic acid may be introduced into a target cell by means of any procedure known for the delivery of nucleic acids to the nucleus of cells, ex vivo, on cells in culture or removed from an animal or a patient, or in vivo.

[0112] Ex vivo introduction may be performed by any standard method well known by one skilled in the art, e.g. transfection, electroporation, lipofection, microinjection, transduction, cell fusion, DEAE dextran, calcium phosphate precipitation, or use of a gene gun.

[0113] The above methods do not limit the scope of the invention and it is to be understood that the one skilled in the art may readily make use of any other known appropriate methods for delivering a nucleic acid to a cell in vivo or in vitro.

[0114] The invention also relates to the use of wild-type KIAA1840 protein (spatacsin) for the manufacture of a medicament intended for the treatment of an HSP.

[0115] Thus the invention further relates to a method of treatment of an HSP which comprises the step of administering a subject in need thereof with a therapeutically effective amount of wild-type KIAA1840 protein.

[0116] The KIAA1840 protein may be introduced to a target cell by means of any procedure known for the delivery of proteins to cells, ex vivo, on cells in culture or removed from an animal or a patient, or in vivo.

[0117] Protein delivery is the process by which a protein crosses the cell plasma membrane. Traditionally, methods to introduce antibodies, peptides or other membrane-impermeable molecules into cells include micro-injection and electroporation.

[0118] A number of protein-transduction domains (PTDs) have also been developed that mediate protein delivery into cells. These PTDs or signal peptide sequences are naturally occurring polypeptides of 15 to 30 amino acids, which normally mediate protein secretion in the cells. They are composed of a positively charged amino terminus, a central hydrophobic core and a carboxyl-terminal cleavage site recognized by a signal peptidase. Examples of such membrane-transducing peptides include Trojan peptides, human immunodeficiency virus (HIV)-1 transcriptional activator (TAT) protein or its functional domain peptides, and other peptides containing protein-transduction domains (PTDs) derived from translocation proteins such as Drosophilia homeotic transcription factor Antennapedia (Antp) and herpes simplex virus DNA-binding protein, VP22, and the like. Some commercially available peptides, for example, penetratin 1, Pep-1 (Chariot reagent, Active Motif Inc., CA) and HIV GP41 fragment (519-541), can be used for protein delivery.

[0119] Recently, the use of lipid liposomes or the like that can complex with a protein of interest and promote the delivery of the protein into the cell has also been demonstrated. Products available commercially can be used, such as BioPORTER (Gene Therapy Systems), or ProVectin (Imgenex, San Diego, Calif.).

[0120] The above methods do not limit the scope of the invention and it is to be understood that the one skilled in the art may readily make use of any other known appropriate methods for delivering a protein to a cell in vivo or in vitro.

[0121] The invention will be further illustrated by the following figures and examples.

FIGURES

[0122] FIGS. 1 and 2: Multipoint linkage analysis performed in 16 families for 34 microsatellite markers from chromosome 15q. cM=centimorgan.

[0123] (FIG. 1) Multipoint LOD score values for each family. *Relative position on the genetic map of chromosome 15 (according to http://research.marshfieldclinic.org/genetics).

[0124] (FIG. 2) Cumulative multipoint LOD scores in the 16 linked-families plotted according to the genetic map of chromosome 15.

[0125] FIGS. 3 and 4: Pedigrees of 2 SPG11 families that reduced the candidate interval. Black circles (women) and squares (men) indicate affected members compared to previous publications. The numbers are an internal reference for each sampled individual. Asterisks indicate sampled subjects. Haplotype reconstruction for selected microsatellite markers positioned according to the human genome draft sequence (www.ncbi.nlm.nih.gov, www.ensembl.org) is shown. The homozygous haplotype, in which the mutated gene has been located, is flanked by black boxes. Arrowheads indicate the position of probable recombination events. cM=centimorgan (according to http://research.marshfieldclinic.org/genetics).

[0126] FIG. 5: Critical region of SPG11. (a) Physical map of human chromosome 15q15-21 with selected genetic markers and candidate genes that were sequenced. Distances in megabases are indicated relative to chromosome 15 according to the Ensembl database. Markers defining the reduced candidate interval are in bold. # indicates that these genes (SEMA6D and MAP1A) were analyzed in a previous study (Stevanin et al, 2006). > and < indicate the orientation of the open reading frame (ORF) of each gene. (b) Exon-intron structure of the 101 Kb of the KIAA1840 gene, also known as FLJ21439, with positions of mutations identified in 17 SPG11 families. (c) Putative functional domains (boxes) and their positions on the protein sequence. TM=transmembrane domains. Regions I and II correspond to structurally similar domains based on their hydrophobicity status analysed with DomHCA software.

[0127] FIGS. 6 to 17: Pedigrees and segregation of the 17 mutations detected in KIAA1840. Square symbols are men, the circles are women. The filled symbols are affected individuals, grey or ? symbols indicate patients with an unknown status. The numbers are an internal reference for each sampled individual. Stars indicate sampled subjects. M or m=mutation; +=wild type. Electrophoregrams are shown for the homozygous mutations only. (6,7) Families with common origins sharing the same mutations. Haplotypes for three close microsatellites segregating with the mutations are highlighted. The correspondence between the numbering of alleles and their size in base pairs is indicated. (8, 10 to 14) Other homozygous mutations. (15) New homozygous mutations. (9, 16, 17) Compound heterozygous mutations.

[0128] FIG. 18: Internal structural duplication in spatacsin

[0129] (a) Hydrophobic cluster analysis (HCA) plots of the internal duplication of two regions in the human sequence. The HCA method is based on the use of a bidimensional plot (HCA plot) from the drawing of the 1D sequence on an alpha helix (3.6 residue/turn, connectivity distance of 4 residues separating two different clusters) which has been shown to offer the best correspondence between clusters and regular secondary structures. Examination of the HCA plot of a protein sequence enables globular regions to be easily distinguished from non globular ones and, in globular regions, secondary structures to be identified. This 2D signature, which is much more highly conserved than the 1D sequence and can be enriched from the comparison of families of highly divergent sequences, enables relevant similarities to be successfully detected at low levels of sequence identity. The form of the clusters is generally indicative of the type of secondary structures (vertical clusters are often associated with beta strands whereas horizontal ones often correspond to alpha helices). DomHCA software: http://www.lmcp.jussieu.fr/%7Emornon/hca.html. Special symbols are used for some amino acids: star for proline, square and dotted square for threonine and serine, diamond for glycine.

[0130] (b) Multiple alignment of the structural repeat domains (I and II, FIG. 3) corresponding to the HCA plots (DomHCA software). Under the multiple alignment, highly conserved residues are indicated by a capital letter when strictly conserved or in lower case if there is some homology. The character "&" means that this position is always occupied by a hydrophobic residue (amino acids FILMVW and Y).

[0131] FIG. 19: Expression profile of KIAA1840 examined by northern blot in human adult brain. The transcripts were present in all brain tissues. Note the 8-Kb transcript more intensely expressed in the cerebellum while the 5.5-Kb transcript is mainly found in the cerebral cortex.

[0132] Table 1: Exon-intron boundaries in the KIAA1840 gene

[0133] Table 2: Mutations found in the KIAA1840 gene in families with AR-HSP-TCC.

[0134] Table 3:Primers used for detecting the mutations either by direct sequencing or by dHPLC

[0135] Table 4: Primers used for the amplification of all exons of the KIAA1840 gene and PCR amplification conditions

[0136] Table 5: PCR conditions and dHPLC conditions to analyze exons of KIAA1840.

[0137] Table 6: dHPLC primers to analyze exons of KIAA1840

EXAMPLE

Method

[0138] Subjects: 211 individuals, including 83 affected members and 44 non mutated members, from 91 families.

[0139] All patients were examined by a neurologist. They were selected among 216 families with hereditary spastic paraparesis compatible with recessive transmission collected in our neurogenetic reference center in collaboration with the SPATAX network. They presented a typical "SPG11" phenotype defined as the presence of progressive spastic paraparesis associated with thin corpus callosum on cerebral MRI and mental retardation and neuropathy.

[0140] Blood samples was obtained after written consent from all affected patients and their relatives with approval of the local Ethic committee of Paris-Necker (approval n.sup.o 03.12.07 of the comite Consultatif pour la Protection des Personnes et la Recherche Biomedicale, to A.D). Genomic DNA was extracted from leukocytes using standard procedures.

[0141] Linkage analysis: The genome scan in family FSP221 was performed using 400 microsatellites, regularly spaced on all chromosomes (ABI-Prism mapping set v2, Applied Biosystems, Foster City, Calif.) and 50 additional polymorphic markers were used to analyze the results. Genotypes were determined by PCR with a fluorescently-labeled primer, electrophoretic migration in an ABI-3730 sequencer (Applied Biosystems) and analysis with Genescan 3.5 (Applied Biosystems). Allegro 1.2c was used to calculate two-point and multipoint lod scores between the disease phenotype and each of the markers or the map of the markers assuming a complete penetrance, equal allele frequencies for the markers and a mutated allele frequency of 0.0005 (Gudbjartsson et al. 2000). Marker order and genetic distances were obtained from the Ensembl (http://www.ensembl.org) and Marshfield databases (http://research.marshfieldclinic.org/genetics), respectively.

[0142] Mutation Detection:

[0143] A series of primers was designed manually or using Oligo6 (MBI, Cascade, Colo.) in order to amplify all coding exons of 18 genes from the candidate interval (primers and conditions available on request). PCR-amplified fragments of genomic DNA were then purified using exonuclease 1 (New England Biolabs, 2 U/5 .mu.l PCR product) and shrimp alkaline phosphatase (Roche, 1 U/5 .mu.l of PCR product) and sequenced using the fluorescent dideoxy-terminator method (BigDye v3, Applied Biosystem) on an automated ABI-3730 sequencer according to the manufacturer's recommendations. With the use of the software package SeqScape (Applied Biosystems), sequences were aligned and compared to consensus sequences.

[0144] Primers used for the amplification of the KIAA1840 gene are listed in the following Table 4.

[0145] The conditions of the PCR programme are as follows:

[0146] 95.degree. C., 12 min

[0147] then 40 cycles of: [0148] 95.degree. C., 30 s [0149] Annealing Temperature (see Table 4), 30 s, [0150] 72.degree. C., 30 s

[0151] then

[0152] 72.degree. C., 10 min, and

[0153] 15.degree. C., 15 min.

[0154] PCR were performed in 25 .mu.l final volume using 10 pmol of each primer, at final concerntrations of 1.5 mM MgCl2 and 0.24 mM dNTP.

[0155] Taq pol, which is commercially available from Quiagen was used except for exons 6, 12 and 40B where Taq GOLD (Applied Biosystems) was used.

TABLE-US-00004 TABLE 4 Annealing SEQ ID Exon temperature NO: Forward primer Reverse primer ex1 60.degree. C. 3/4 ccacaggaaacgaatggaat ggttctgtgaggaaaccacg ex2 60.degree. C. 53/54 ctgagccccacatttttgtt caagtgctcaatagccccat ex3 60.degree. C. 5/7 cagggacattgtaggccatc tcccagctcccaaaactaaa ex4 60.degree. C. 9/10 caggttctttattgtggcatca cgaggatatttttaacctcttatca ex5 62.degree. C. 55/56 gctaactgcccttaatagagtaaaa aaagggtacagcgtcagcat ex6 TD62-58 13/15 gaacatctttgccctggttt caggcactgaggcagaagta ex7 60.degree. C. 17/19 aaaaatcaattcctaaatcataatcc tcttttaaagccaaaaagggtaaa ex8 60.degree. C. 57/58 cttgccccagattgcataat tccaaaaagtacgtaaaatccca ex9 60.degree. C. 59/60 cagcaaaagggtaatagcagtg cccaaatgtagtaaatggcg ex10 60.degree. C. 21/22 cccaggactaatcatgaagga atccccaaaccgataaaacc ex11 60.degree. C. 23/25 cggtgtgtcttccactagctc acccagccattctcagtgtt ex12 TD62-58 61/62 tttgaaagagcagaaagctatgg tgaaggggttgtcacactttt ex13 60.degree. C. 63/64 ttgtggcaaaagaaaatttgtg gagaatgcaggctcagttcc ex14 60.degree. C. 65/66 atgtggaactgagcctgcat cgacttgcattttaaagaacctg ex15 60.degree. C. 27/28 cacagcgagatcctgtctca cctcactgtaagatgatgccc ex16 62.degree. C. 29/31 cctttaaatactacagtggtgcaga ccaactgttgagatggagaaaa ex17 56.degree. C. 67/68 ttgtttccagatcatgaagaatatg tcagatagctgaccacagcc ex18 60.degree. C. 69/70 tccctcttaaggagaaaaacactg accgggccgagatataaaat ex19 60.degree. C. 71/72 gctagtttgtcttagaaccagaaca ttttgggttgtctcactatcaca ex20 60.degree. C. 73/74 aaggaacatagccagttctgtttt tgcgaactatttttcctttgg ex21 60.degree. C. 75/76 tgcaacttctcaggtacacatct aggctagagtgcagtggcat ex22 60.degree. C. 77/78 agtcagcttaagggaagcgg gaagataaccattttctcccca ex23 60.degree. C. 79/80 ttgtgagtgtttggggagaa ggggatttagtgaaaacacca ex24 64.degree. C. 81/82 tttgttggagaatacactgtgctt catgtctacacaacagaaagaatgc ex25 60.degree. C. 83/84 aaaaggcaccatacagctttg ggaaacacatgctggaacct ex26C 55.degree. C. 85/86 cttctgtctgcttcttggtctt tatcatcattatctgttgttgg ex27 60.degree. C. 87/88 ttaggtgatcccactggctc cccaggagttcaaggctgta ex28 60.degree. C. 89/90 ctgaggagggcttgtttttg tctgtaacttgtttactcccagttg ex29 60.degree. C. 91/92 gatcacaccactgcattcca ggcacctgtagtcccagcta ex30A 60.degree. C. 93/94 tgaggtgggaggatctcttg gatgtgttcagagcagccaa ex30B 60.degree. C. 95/96 taagctggaggagctggaga ttgttgtccccttaacttgg ex31 60.degree. C. 33/34 tttgaagtatcccagggtgg ccaccattccccaaagataa ex32 60.degree. C. 35/37 ttacctggatttggctttgg tgcaatccagaaacttgagaga ex33 60.degree. C. 97/98 caataggccaagggtttcaa tataactcctgctggagggc ex34 62.degree. C. 39/40 atgttggcaggaactccatc ctcctttggagcaacctctg ex35 60.degree. C. 99/100 ggtagcctggaaattagccc tgaaccagaatctgaagcca ex36 62.degree. C. 41/43 ttccaacaggaaagcacaca cagctacttgggaggctgag ex37 60.degree. C. 45/47 gcattagaaggggcactgaa ctcacaacggtattcacccc ex38 60.degree. C. 101/102 ttttgtccttgggctctttc cctggttctgtcactagccc ex39 60.degree. C. 49/51 aagggtttaagataatttgggga ggattcttgatactgctttgcc ex40A 60.degree. C. 103/104 aattagccagggtggtgaca cccacaaaggactgatatgg ex40B TD62-58 105/106 aaggaccctcagacaggttg tcctttaaggcagacaaggg TD = TouchDown 10 cycles decrease of annealing temperature, then 25 stable cycles. Temperatures in Celsius degrees.

[0156] For some exons, it was possible to set up dHPLC conditions to detect variants. Primers different from those used for direct sequencing were specifically designed but they can also be used for direct sequencing. The PCR conditions and dHPLC conditions are indicated on table 5.

TABLE-US-00005 TABLE 5 dHPLC conditions to analyze exons of KIAA1840. Temperature in Celsius degrees. Exon Size T.degree. PCR T.degree. DHPLC 2 323 62.degree. - 1' - 35x 55.3.degree. 3 305 58.degree. - 1' - 35x 55.1.degree. 4 320 62.degree. - 1' - 35x 54.8.degree.-52.8.degree. 5 330 60.degree. - 1' - 35x 54.9.degree. 6 450 58.degree. - 1' - 35x 54.degree.-53.degree. 7 275 58.degree. - 1' - 35x 50.6.degree.-52.6.degree. 9 342 62.degree. - 1' - 35x 54.1.sup. 11 293 57.degree. - 1' - 35x 54.6.degree. 12 210 62.degree. - 1' - 35x 52.5.degree. 13 289 62.degree. - 1' - 35x 51.5.degree. 14 246 62.degree. - 1' - 35x 55.8.degree. 16 309 62.degree. - 1' - 35x 55.2.degree. 17 239 62.degree. - 1' - 35x 53.9.degree. 18 324 58.degree. - 1' - 35x 53.degree.-50.degree. 20 311 62.degree. - 1' - 35x 52.3.degree. 22 383 62.degree. - 1' - 35x 55.8.degree. 23 356 62.degree. - 1' - 35x 53.1.degree. 24 267 60.degree. - 1' - 35x 57.1.degree. 25 361 60.degree. - 1' - 35x 56.6.degree. 27 330 62.degree. - 1' - 35x 53.6.degree. 28 329 62.degree. - 1' - 35x 53.5.degree. 29 330 56.degree. - 1' - 35x 54.2.degree.-56.2.degree. 32 323 60.degree. - 1' - 35x 58.8.degree. 33 349 62.degree. - 1' - 35x 57.6.degree. 35 312 62.degree. - 1' - 35x 54.degree. 36 376 62.degree. - 1' - 35x 52.degree. 37 313 62.degree. - 1' - 35x 57.6.degree. 38 315 62.degree. - 1' - 35x 56.9.degree. 39 380 62.degree. - 1' - 35x 53.2.degree. 40 390 62.degree. - 1' - 35x 54.4.degree. 40 321 58.degree. - 1' - 35x 54.2.degree.

TABLE-US-00006 TABLE 6 dHPLC primers to analyze exons of KIAA1840 Exon PRIMERS F (5'-3')/R (5'-3') SEQ ID NO: 2 accaggtcaactaaactgttctct/tatgctgaaagaccacctgtaga 107/108 3 ccagttgtaaaattgtgacc/tcaatcaacacttctaccac 6/8 4 gttaggcatacttacaaaactggc/cgaggatatttttaacctcttatca 11/12 5 caggagcagtagtaacacaa/aaagggtacagcgtcagcat 109/110 6 ctgtgacaggtgttaagtta/atctaatacaagacagtctc 14/16 7 tagtactgaagtattgagta/ttaagtaatgttcttgggca 18/20 9 gcaggtaataagcctgcagaa/cccccttcctagctgctatt 111/112 11 gttacataaatgtataatccctg/cattttaagactttatggattac 24/26 12 tgttcaaaatagttccattacaaaa/tttcttccaaggttttcttcca 113/114 13 tttgcaaaagtgcttgatttt/tgcaggctcagttccacata 115/116 14 ggaatgatgcctttttctcc/tctcacacttgccttctgga 117/118 16 tgtgggcatgatttggtcta/acctgctcaaggacaaatgc 30/32 17 aatcatcgcctgagcaaaat/ccagtgactgatccaaagca 119/120 18 ccctcttaaggagaaaaacac/cagccttatcctctgctctt 121/122 20 tggaaaaggggagcagacta/tgcgaactatttttcctttgg 123/124 22 gaggaggccacaaatcacat/gccttagacctcgtcacacc 125/126 23 tgctcaggttttgactttttctc/tttcactgatggcaagatgc 127/128 24 accacccccacctctaattc/ctacacaacagaaagaatgc 129/130 25 ccagctgaaactgaaagttgg/ctgggtacttacttcaggct 131/132 27 cactgtgccctgccttatta/tgtgcctgagtaaccgagtg 133/134 28 tcccagatttggaggttttg/tgcattttaatttcctaactaccc 135/136 29 gctgtagtggcattttattg/cctgggtgacagagcaagac 137/138 32 cctggcttctaaaagtggcc/aagcacaacatccaaatcctt 36/38 33 agctgcagagctccataagc/taggcatccagagcaggaac 139/140 35 ggcatctgaaagcaaccact/ccctccattttcccaagagt 141/142 36 caacaggaaagcacacatgc/gtgtggctgtgacctcactc 42/44 37 aacatggctgggatgtttct/ttcctggttggcctatgatg 46/48 38 ggggtgaataccgttgtgag/acctctgggttccatgagtg 143/144 39 aatgccaaacacacacctga/ctcaaagcagaggcaaggag 50/52 40 agactgctcctctgcactcc/ccgggattgttcaactttagc 145/146 40 cagtatcttaacctgtacat/ccgggattgttcaactttagc 147/148

[0157] Overexpression Studies:

[0158] The KIAA1840 cDNA from clone pf01011 (Kazusa DNA research Institute, Japan) was excised from the pBluescript II SK(+) vector using XhoI/NotI restriction enzymes and cloned in fusion with EGFP in a SalI/Bsp120I digested pEGFP-C1 vector (Clontech). The construction was verified by direct sequencing after ligation, transformation and plasmid extraction using standard procedures.

[0159] COS-7 cells were maintained in DMEM (Invitrogen) supplemented with 10% fetal bovine serum, penicillin (100 UI/ml) and streptomycin (100 .mu.g/ml). Cells were plated 24 h before transfection on cover slips coated with polyethylenimine and transfected with Lipofectamine-PLUS reagents according to the manufacturer's instructions (Invitrogen). For 6-well plates, 1-2 .mu.g of plasmid DNA was used per well. Cells were analyzed by immunofluorescence 120 h post-transfection. The spatacsin-EGFP fusion protein was observed directly after fixation for 15 min with 4% formaldehyde. Immunocytochemistry was performed, using classical procedures with the following antibodies: rabbit anti-Cox2 (1/200, kind gift of A. Lombes, Paris) and rabbit anti-alpha-COP (1/1000.sup.e; Affinity Bioreagent). Cells were counterstained with DAPI (1 .mu.g/ml, Sigma) and mounted with Fluoromount-G (Southern Biotech). Samples were observed with a Leica SP1 confocal microscope. Leica confocal software was used to acquire the images.

[0160] Northern-Blot analysis (Human): Total RNA was extracted from the human post-mortem brain cortex of an healthy individual (Brain Bank of INSERM U679) using the RNAeasy Mini kit (Qiagen). The corresponding cDNAs were synthesized using random hexamers in the presence of Thermoscript reverse transcriptase as recommended by the supplier (Invitrogen). A series of 7 probes of 1.2 Kb covering the entire KIAA1840 cDNA was amplified by PCR at an annealing temperature of 60.degree. C. (primer sequences available on request). Human multiple tissue northern blots (Clontech) were hybridized at 68.degree. C. for 1 hour with a mix of these probes aP.sup.32-labeled by random priming (Prime-it II Random Primer Labeling kit, Stratagene) and purified using ProbeQuant G-50 micro columns (Amersham Biosciences) in accordance to the manufacturer's recommendations to reach a specific activity of at least 1.times.10.sup.9 cpm/.mu.g. Membranes were then washed as recommended by Clontech then exposed to X-Ray film for autoradiography.

[0161] In Situ Hybridization (Rat):

[0162] Young (P1, P6, P15 and P21, n=1 each) and adult (P68, 200 g, n=2) Sprague Dawley rats (Charles River) were killed by decapitation and their brains were rapidly extracted and frozen in isopentane at -50.degree. C. Sections were prepared with a cryostat at -20.degree. C., from medulla to striatum (+1.7 from bregma) 600 .mu.m-spaced, thaw-mounted on glass slides and stored at -80.degree. C. until usage. KIAA1840 mRNA expression was analyzed using 3 antisens oligonucleotides designed using Helios ETC oligo design software (Helios Biosciences, Paris, France) on the mRNA sequence (XM-242139) of Rattus norvegicus similar to hypothetical protein FLJ21439 (LOC311372). Each oligonucleotide or a mix of the 3 oligonucleotides were used for the hybridization step and gave identical results. A mix of three sens oligonucleotides was used as a negative control.

[0163] In situ hybridization was performed as described in Moutsimilli et al. (2005) Briefly, oligonucleotides were labeled with [35S]-dATP (Amersham Biosciences) using terminal transferase (Amersham Biosciences) to a specific activity of 5.times.10.sup.8 dpm/.mu.g. The day of the experiment, slides were fixed in 4% formaldehyde in PBS, washed with PBS, rinsed with water, dehydrated in 70% ethanol and air-dried. Sections were then covered with 140 .mu.l of hybridization medium (Helios Biosciences, Paris, France) containing 3-5.times.10.sup.5 dpm of the labeled oligonucleotide mix. Slides were incubated overnight at 42.degree. C., washed and exposed to a BAS-SR Fujifilm Imaging Plate for 5-10 days. The plates were scanned with a Fujifilm Biolmaging Analyzer BAS-5000 and analyzed with Multi Gauge Software (Fuji).

[0164] For double labeling experiments, brains were processed as for in situ hybridization. After the last wash step, sections were fixed in 4% paraformaldehyde in PBS and preincubated in PBS containing 6% goat serum and 0,1% triton. Sections were next incubated with mouse antibodies directed against Neu-N(Chemicon International, 1/250), in the same buffer, processed with biotinylated horse anti-mouse IgG antibodies and ABC reagents (Vector Laboratories, Burlingame, Calif.) and submitted to emulsion autoradiography. The labeling with the antisense probe in comparison with the Neu-N neuronal specific counterstaining was observed.

[0165] Bioinformatics:

[0166] Functional domains were searched using bioinformatics tools available online at BABEL (http://babel.infobiogen.fr:1984/), Ressource Parisienne en Bioinformatique Structurale (http://bioserv.rpbs.jussieu.fr/RPBS) and PSORT (http://psort.nibb.ac.jp/). Psi-blast (www.ncbi.nlm.nih.gov) was used to look for homologous proteins or peptides. Alignment of homologous proteins was performed using CLUSTALW (http://www.ebi.ac.uk/clustalw/). Alteration of splicing sites was verified in the Alternative Splicing Database at http://rulai.cshl.edu/new_alt_exon_db2/HTML/score.html.

[0167] HCA is a method that allows to represent a protein sequence on a bidimensional scaffold that increases the density of the amino acids, and consequently, evidences local compacity of hydrophobic residues. They form clusters according to a connectivity that is the one of an alpha helix. It has been shown that the centers of the clusters and the centers of the secondary structures statistically match, (Woodcocks et al. 1992) and on the other hand the shape of a cluster is related to the nature of the secondary structure (Callebaut et al. 1997). HCA is a very efficient tool for recovery of highly divergent internal duplication of domains and for the detection of globular domain limits.

[0168] Results:

[0169] We selected a series of 91 families of European or North-African origins, all without mutations in the SPG7 gene and with a typical AR-HSP-TCC phenotype. Six of these families were previously reported as linked to SPG11 using a subset of polymorphic markers from the interval (Casali et al, 2004; Stevanin et al, 2006; Lossos et al, 2006). The other families were new. All available family members of 16 most informative families were genotyped using 34 microsatellite markers for linkage to three successive loci on chromosome 15 which have been associated with thin corpus callosum; SPG11, SPG21 and the locus for agenesis of corpus callosum with polyneuropathy (ACCPN). Positive multipoint LOD scores ranging from 0.60 to 3.85 and corresponding to the maximal expected values in the pedigrees were obtained in the 16 most informative families (FIGS. 1 and 2). Mutations in the ACCPN or SPG21 loci were excluded by direct sequencing in all families that showed positive linkage to these regions (data not shown). A significant combined multipoint LOD score of 28.1 was reached in the 3.3 cM interval flanked by markers D15S778 and D15S659 in the linked kindreds (FIGS. 1 and 2). Haplotype reconstructions identified two critical recombination events that allowed to restrict the candidate interval to 6.6 cM between markers D15S1044 and D15S123. The 3.2 cM of the D15S778-D15S659 interval was considered to be the region most likely containing the responsible gene on the basis of homozygosity in all consanguineous patients of two significantly linked families; family FSP221 linked to SPG11 with a maximal LOD score of 3.85 and family FSP672 linked to the same locus with a 2.6 LOD score value (FIGS. 3 and 4). In addition, a genome wide screen performed in family FSP221 at a resolution of 10 cM on all chromosomes only identified three other possible locations with multipoint lod scores of 2.2 to 2.5 that were excluded using 18 additional microsatellite markers (data not shown), therefore highly supporting linkage to SPG11.

[0170] The narrowed interval contained 40 genes in accordance with the National Center for Biotechnology Information (NCBI) and the Ensembl databases. Two were excluded in previous studies (SEMA6D and MAP1A, Stevanin et al, 2006). We evaluated 16 additional genes from the interval as candidates for SPG11, prioritizing those with a known or putative function in mitochondrial metabolism, intra-cellular trafficking or cytoskeleton integrity (FIG. 5). All coding and non-coding exons as well as their splicing sites with at least 50 bp of intronic sequences on each side were sequenced on genomic DNA of 5 index patients from 5 linked families. No mutations were found in 15 genes but sequence variations were found in the KIAA1840 gene. We then screened one affected member from the 16 linked families as well as of the uninformative kindreds and checked all other members of the families, when available, for sequence variations. 43 different mutations were identified in 47 families, including the 16 linked ones, 31 at the homozygous state, (FIGS. 5 to 9). They were either nonsense mutations (n=13), deletions (n=17), insertions (n=7) or splice site mutations (n=6) in the coding sequence, and resulted in an abnormally truncated protein or predicted to alter the splicing of the messenger RNA in all cases. In two families (FSP670 and ITA28 VAC, FIG. 8), we found a missense change (R945G or R815M) affecting a nucleotide of the 5'-splice site consensus and predicted to alter the splicing of the mRNA. This could be confirmed in family FSP670 by the analysis of mRNA from one patient (c.2833A>G, r.2834+1_2834+65 ins, p.R945GfsX950). Four mutations affected the intronic part of the consensus sequence for the acceptor splicing site (see Table 2) that also likely affect the splicing of the mRNA. The mutations segregated completely in the families with the disease and were not found on at least 140 chromosomes from unrelated control individuals of European and North-African origin suggesting that these mutations were not polymorphisms. Only 4 mutations were found in more than one pedigree (FIGS. 6 and 7). A c.6100C>T substitution that replaces an arginine by a stop codon in exon 32 (R2034X), shortening the protein from 2443 to 2034 amino acids (SEQ ID NO:160), was identified, in the homozygous state, in 4 Algerian, 3 Tunisian and 2 Moroccan consanguineous kindreds (FIG. 6). A 5 bp deletion in exon 3 (c.529_533delATATT) leading to a frameshift and a stop codon at aa 178 (SEQ ID NO:150) was found at the homozygous state in all patients of 3 Portuguese families and at the heterozygous state in one Brazilian kindred (FIG. 7). Interestingly, alleles at close flanking markers were partially similar in families with identical mutations (when it could be tested) suggesting founder effects in North-Africa and Portugal for these mutations. The c.733_734 del AT mutation was also found in 4 Tunisian pedigrees, sharing partial common haplotypes (data not shown) and one French kindred. Finally, the c.1951C>T variant was found at the heterozygous state in 2 Italian and one Kindred from Romania for which we are extending the pedigrees to check for haplotype conservation.

[0171] No mutations were found in 44 families, suggesting that the responsible mutations were either in non-coding regions of KIAA1840 or in another unidentified gene.

[0172] SPG11 mutations were thus found in the majority of the families with the typical AR-HSP-TCC studied here (47/91). Most families originated from the Mediterranean basin. Complete examination of 22 affected members (Stevanin et al, 2007), 12 men and 10 women, showed a mean age of 24.8.+-.9.5 years ranging from 12 to 49. Onset of the disease always occurred before age 24 years (mean age 11.8.+-.5.5 years; range 2-23) and consisted in either spastic gait (57%, 12/21) or cognitive impairment (19%, 4/21), sometimes diagnosed as mental retardation. After about 10 years of evolution, the full-blown clinical picture consisted in progressive and severe spastic paraplegia with distal wasting and cognitive problems. In several cases (n=6), cognitive dysfunction clearly worsened with disease progression. Cerebral imaging showed a thin corpus callosum, but also periventricular white matter changes and cortical atrophy, in the majority of the patients. Pseudo-bulbar dysarthria was frequent (54%, n=12) and dystonic voice was noted in one patient. Interestingly, although a few patients had normal electromyographic recordings, peripheral neuropathy was frequent (72%, 13 out of 18 patients) and was mostly associated with pure motor changes. Additional signs, such as optic atrophy, retinitis pigmentosa, mild cerebellar signs, cataract, and clinodactily were occasionally observed, a finding that expands the clinical spectrum of this entity.

[0173] The human KIAA1840 gene contains 40 exons spanning 101 Kbases of genomic DNA on chromosome 15q21.1. The full length transcript encodes a predicted protein of 2443 amino acids of unknown function called spatacsin for SPAsticity with Thin or Atrophied Corpus callosum Syndrome proteIN. The sequence of spatacsin is strongly conserved through evolution with orthologues in mammalians and other vertebrates: human KIAA1840 shares 85% identity with the homologous protein in dog, 76 and 73% with the mouse and rat homologues and 59% with the chicken homologue, all of similar sizes. Less similarity was found with homologous proteins of smaller sizes from fugu (44%), tetraodon (39%), and drosophila (22%).

[0174] Neither the gene nor the predicted protein it encodes in many species show any significant sequence similarity to known cDNA or protein sequences. We then looked for protein motifs and domains (FIG. 3). Four putative transmembrane domains were predicted by various algorithms (aa 163-194, 200-240, 1239-1267 and 1471-1493). A glycosyl hydrolase F1 signature was also detected (aa 482-490). This motif is based on a conserved glutamic acid residue which has been shown in the beta-glucosidase of various bacteria and plants and mammalian lactase-phlorizin hydrolase, an integral membrane glycoprotein that splits lactose in the small intestine. Interestingly, this protein is assigned to the aromatic compound dioxygenase superfamily because of a 22% identity with the consensus sequence between aa 2104-2381. A leucine zipper (aa 611 to 632), involved in dimerization of many gene-regulatory proteins (C/EBP, CREB, CRE-BP1, ATFs and Jun/AP1 family of transcription factors) and a Myb domain (aa 1766 to 1774), involved in the DNA-binding of drosophila and vertebrate myb and related proteins, were also identified. Interestingly, there is a 47% identity, over 44 aa, with thymosyl-like peptides, small peptides which play an important role in the organization of the cytoskeleton; these peptides, bind to and sequester actin monomers, thereby inhibiting actin polymerization (Low and Golstein 1985). Furthermore, a probable coiled-coil domain of 33 residues from 1556 to 1590 was also present and such domains are reported in structural or motor proteins such as spectrin, laminin, dynein or neurofilament proteins.

[0175] We then looked at the structure of the predicted protein. The level of hydrophobicity (34.2%) over the entire sequence was typical of a globular protein. Because of it's size, a succession of globular domains is likely and we tried to identify them by the identification of inter domain regions, corresponding to a low density of hydrophobic clusters with the DomHCA software (Prat-Albeau et al, 2006). Except a small linker located between positions 1410 and 1440, no domain separation was evidenced. From the HCA plots, one of the putative transmembrane regions was confirmed at amino acids 200 to 240 on spatacsin from 5 vertebrates, but it was lacking in the homologous sequences from tetraodon and drosophila, as these last two sequences presented a shortened N-terminal domain. A thorough analysis of putative duplication highlighted two structurally similar regions (aa 560-700 and 2250-2390) in all vertebrate homologues of the protein with 19% sequence identity in human sequences (FIG. 10). Amino acid proportion shows a non standard distribution in some cases: high amount of leucines (13,8% vs 9,6% in standard reference databases), a low level of methionines (1.9% instead of 2.38%) and glycines (3.9% vs 6.93% in Swiss Prot). The proportion of cysteins was over 2 fold higher (2,9%) compared to the mean in databases but did not gave rise to disulfide bridges, according to the predictions of the CysState software (Mucchielli-Girgi, 2002). Cluster shapes claim for a mainly helical behavior of this protein, which is confirmed by standard prediction tools.

[0176] The spatacsin protein, fused with GFP, had a diffuse cytosolic and nuclear distribution that sometimes excluded the nucleus of COS-7 cells. In rare cases (<5%), spatacsin formed small perinuclear dots or aggresome-like structures in cells with high expression levels after 4 days post-transfection that did not colocalized with the mitochondrial marker Cox2 or the Golgi marker alpha-COP.

[0177] Previous expression profiling of the SPG11 gene showed that it is expressed ubiquitously at low levels in mouse tissues, including the brain (Nagase et al, 2001). Ubiquitous low level expression, even in structures apparently not related to the phenotype, has been shown for other genes responsible for neurodegenerative diseases (Paisan-Ruiz et al, 2004). We successfully amplified seven overlapping cDNA fragments from the KIAA1840 mRNA extracted from human cerebral cortex and used them to probe human adult multiple-tissue northern blots. At least three alternative transcripts were detected in all structures of adult brain. The full-length transcript (.about.8 Kb) was most highly expressed in the cerebellum, the 5.5-Kb transcript in the cerebral cortex (FIG. 11).

[0178] When the temporal and regional expression of the mouse KIAA1840 mRNA was investigated by in situ hybridization in rat brain, it was undetectable in newborn rats (P1). It was detected in the cerebellum, however, from P6 to P21. At adulthood (P68), expression was found throughout the brain. Expression was generally low, but stronger signals were observed in the pineal gland, the edges of the lateral ventricles, the granular layer of the cerebellum and the hippocampus. In contrast to human adult northern blots, only a weak expression was detected in the cerebral cortex. Understanding the function of spatacsin in these structures would help to explain the major features of the disease phenotype: e.g., expression in the hippocampus could be related to the cognitive impairment observed in the patients. In addition, whether the labeling of the edges of the lateral ventricles, where oligodendrocyte progenitors are located, is related to the white matter changes in patients remains to be investigated.

[0179] Our study identified the gene responsible for spastic paraplegia with thin corpus callosum linked to SPG11, KIAA1840. This is supported by four pieces of evidence; first, we have excluded 17 out of the 40 genes assigned to the SPG11 candidate interval; second, we have identified 43 different mutations segregating in 47 families, 16 of which linked previously to the SPG11 locus, and not found in at least 140 control chromosomes; third, all, these mutations were leading to a truncated protein and/or abnormally spliced mRNA, and fourth all mutated families presented with the typical AR-HSP-TCC phenotype or at least a compatible phenotype in 2 families in which cerebral imaging was not available. Mutations in KIAA1840 affected 47 of 91 AR-HSP-TCC families in this study making this genetic entity very frequent among AR-HSP-TCC (52%), 75% was estimated in a previous study (Stevanin et al, 2006), but also among recessive spastic paraplegias. At least another gene might however exist as previously shown (Lossos et al, 2006; Stevanin et al, 2006; Casali et al, 2004).

[0180] This gene has a widespread low level expression, including in the brain where it is more strongly expressed in the cerebellum, the cerebral cortex, the hippocampus, the pineal gland and the edges of the ventricles. Spastic paraplegias are supposed to results from a dying back mechanism of the exons and mitochondrial metabolism or axonal transport has been implicated in several genetic entities of HSP (Crosby et al, 2002). Indeed, three causative genes identified in AR-HSP have been implicated in defective intracellular trafficking: mutations in the mitochondrial metalloprotease protein paraplegin impair axonal transport in SPG7; spartin (SPG20) mutations affect endosomal trafficking and microtubule dynamics; maspardin (SPG21) mutations may interfere with endosomal/trans-Golgi vesicle transportation. Although, the function of spatacsin remains unknown, given it's basal expression in all tissues and it's high conservation in all species, this protein might have a crucial function which might explain the degeneration of the corticospinal tracts which might rely on the post-translational modifications or modeling/carriage of other proteins involved in axonal transport, mitochondrial metabolism as well as cerebral development. The presence of at least one transmembrane domain suggests that spatacsin may act as a receptor of a transporter.

[0181] All mutations identified so far in the KIAA1840 gene cause or are predicted to cause truncation of the protein, suggesting that pathogenicity results from loss of function. They are located in many exons, including exon 1 and exon 39 suggesting that the C-terminal domain of the protein has also an important function or effect on the structure of the protein. It is also conceivable that, given its position in the 5'splice site consensus sequence, the missense mutation R815M would also affect the transcription of the gene as demonstrated for mutation c.2833A>G, r.2834+1_2834+65 ins, p.R945GfsX950. Similarly, the mutations found in the intronic part of the acceptor splicing sites in introns 4, 12, 13 and 34 (Table 2) are likely altering the splicing of the surrounding exons and therefore the synthesis and/or stability of the mRNA or protein. No tissues from patients were available yet, however, to validate this hypothesis.

[0182] The identification of the SPG11 gene will now improve the diagnostic procedure, as well as patient management, and permit more accurate genetic counseling. This is invaluable for patients and their families.

REFERENCES

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[0199] Harlow E. et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York, (1988). [0200] Hazan, J. et al. Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nature Genet. 23, 296-303 (1999). [0201] Kohler and Milstein (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature; 256, 495-7. [0202] Kuklin et al. Detection of single-nucleotide polymorphisms with the WAVE DNA fragment analysis system Genet. Test (1997-98), 1(3):201-6 [0203] Lossos, A. et al. Hereditary spastic paraplegia with thin corpus callosum: reduction of the SPG11 interval and evidence for further heterogeneity. Arch Neurol 63(5):756-60 (2006). [0204] Martinez, M. F. et al. Genetic localization of a new locus for recessive familial spastic paraparesis to 15q13-15. Neurology 53, 50-56 (1999). [0205] Moutsimilli, L. et al. Selective cortical VGLUT1 increase as a marker for antidepressant activity. Neuropharmacology 49, 890-900 (2005). [0206] Nickerson et al., 1990 [0207] Olmez et al. Further Clinical and Genetic Characterization of SPG11: Hereditary Spastic Paraplegia with Thin Corpus Callosum. Neuropediatrics. 2006;37:59-66. [0208] Patel, H. et al. SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nature Genet. 31, 347-348 (2002). [0209] Saiki et al., Science 1988, 239:487 [0210] Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. [0211] Shibasaki, Y. et al. Linkage of autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum to chromosome 15A13-15. Ann Neurol 48, 108-112 (2000). [0212] Simpson, M. A. et al. Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia. Am. J. Hum. Genet. 73, 1147-1156 (2003). [0213] Stevanin, G. et al. Spastic paraplegia with thin corpus callosum: description of 20 new families, refinement of the SPG11 locus, candidate gene analysis and evidence of genetic heterogeneity. Neurogenetics, 7, 149-156 (2006). [0214] Stevanin, G. et al., Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum Nat Genet Mar; 39(3):366-72. Epub 2007 Feb. 18. (2007) [0215] Tallaksen, C. M., Durr, A., & Brice, A. Recent advances in hereditary spastic paraplegia. Curr. Opin. Neurol. 14, 457-463 (2001). [0216] Waterhouse P, Griffiths A D, Johnson K S, Winter G. (1993) Combinatorial infection and in vivo recombination: a strategy for making large phage antibody repertoires. Nucleic Acids Research, 21, 2265-2266. [0217] Winner, B. et al. Clinical progression and genetic analysis in hereditary spastic paraplegia with thin corpus callosum in spastic gait gene 11 (SPG11). Arch. Neurol. 61, 117-121 (2004). [0218] Winner, B. et al. 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Sequence CWU 1

1

18817751DNAhomo sapiens 1atggctgcag aggaaggggt cgcgagtgct gcttccgccg gcggtagctg gggcaccgcg 60gccatggggc gggttctacc gatgctgttg gtgccagtcc ccgccgaggc gatggggcag 120ctcggctccc gggcgcagct gcgcacacag ccggaggctc tggggagcct gacggctgcg 180ggcagcctcc aagtgctttc tttgacgcct ggcagccggg gcgggggtcg ctgctgcctg 240gagggcccct tctggcactt tctatgggag gattctcgta acagcagcac accaactgaa 300aagcccaaac tgctcgctct tggtgaaaat tatgaactgc ttatctatga atttaatttg 360aaagatggaa gatgtgatgc aaccattttg tatagctgta gtagggaggc attgcaaaag 420ctcattgacg atcaagatat cagtatttcc ttattgtctt tgagaatcct gtcatttcac 480aataacacat cattactgtt catcaacaaa tgtgtcatcc tacatattat atttcctgaa 540agagatgctg caattagagt actcaactgt ttcacacttc ccttgcctgc acaggcagtg 600gacatgatta ttgacacgca gctctgcaga ggaattcttt ttgttttgag tagtttaggc 660tggatctaca tttttgatgt tgtggatggt acatatgtag ctcatgtgga tttagcactt 720cacaaagaag acatgtgtaa tgagcagcaa caggagccag ccaagatttc ttcatttact 780tcactgaaag tttctcaaga cctcgatgtt gcagtgattg tcagctcctc caactccgca 840gttgctctta acttaaattt gtatttcagg caacacccag gacacctact gtgtgaaaga 900atactagaag atcttcctat tcaaggacct aagggcgtag atgaagatga tcctgttaac 960tctgcctaca acatgaaact ggccaagttt tccttccaaa ttgataggtc ttggaaagcc 1020cagctatcat cattgaatga aacaataaag aactccaaac tggaggtttc ctgttgtgct 1080ccatggttcc aggatatttt gcatttggag tcacctgaat ctggtaacca cagtacaagt 1140gtgcagagct gggccttcat tccacaggac ataatgcatg ggcaatataa tgttctacag 1200aaagatcatg ccaagaccag tgatccagga agatcatgga aaataatgca catcagtgaa 1260caagaggaac ccatagagct taaatgtgtg tctgtgacag gattcactgc actgtttact 1320tgggaagtgg aaaggatggg ctataccatt accctctggg atttggagac ccagggcatg 1380cagtgttttt cccttggcac aaagtgtatt cctgtagaca gtagtggaga ccagcagctg 1440tgctttgttt tgacagagaa tggactctct ctgattttgt ttggtttgac tcaagaagag 1500tttttaaaca gactcatgat ccatggaagt gccagcactg tggacactct ttgtcatctc 1560aatggctggg gaaggtgctc aattcccata catgcactag aggccgggat agaaaatcgt 1620cagctggaca cagtaaattt ctttttgaag agcaaggaaa atctttttaa tccatcctca 1680aaatcttctg tatctgatca gtttgatcac ttgtcatccc atttatattt aagaaatgtg 1740gaagagctga taccagcatt ggatttactt tgctcggcaa ttagagaaag ttattctgaa 1800ccccaaagca aacacttttc agaacaattg cttaatctta cactgtcttt ccttaacaac 1860caaataaagg agcttttcat tcacactgaa gaactagatg aacatctgca aaaaggagtg 1920aacattttga ctagctacat taatgaactt cgaaccttca tgataaagtt tccttggaag 1980ctaacagatg ctatagatga atatgatgta catgaaaatg tccccaaagt aaaggagagc 2040aatatatgga agaaactcag ctttgaggaa gttattgcca gcgccatttt aaacaacaaa 2100ataccagagg cacagacttt cttcaggatt gatagtcatt ctgctcaaaa acttgaggag 2160cttattggca taggcctaaa tttggtcttt gacaatttaa aaaagaacaa tataaaggaa 2220gcctctgaac ttttgaagaa tatggggttt gatgtaaaag gccaattgct caagatctgc 2280ttctatacaa ctaataaaaa tatacgtgac tttttggttg aaattttaaa agaaaaaaat 2340tatttttctg aaaaagagaa aagaactata gacttcgtgc atcaagttga gaagctttat 2400ttgggacatt tccaagaaaa tatgcaaatc cagtcatttc ccaggtactg gataaaggaa 2460caagattttt tcaagcacaa gtctgttttg gactcattcc tgaaatatga ttgtaaagat 2520gaatttaaca aacaggacca tagaattgtg ttaaattggg ctctgtggtg ggatcaacta 2580acacaagaat ccatccttct ccccaggata agtccagaag aatacaaatc atattcccct 2640gaagccctct ggagatacct cacagctcgc catgattggt taaacattat cttatggatt 2700ggagaatttc aaacccagca tagttatgct tcacttcagc agaacaaatg gccccttctg 2760actgttgatg ttattaacca gaatacttcc tgtaacaact acatgaggaa tgaaatttta 2820gataagctgg ccaggaatgg ggtttttttg gcatctgaac tggaagactt tgaatgcttc 2880ctcctaagac tgagccgtat tggaggtgta atacaggata ccctccctgt tcaaaactac 2940aagaccaaag aaggttggga tttccattct caattcattc tctattgttt ggagcacagt 3000ctgcagcatc ttctttatgt ctaccttgac tgttacaaac ttagtcctga aaattgtccc 3060tttttggaaa aaaaagagtt acatgaagca cacccttggt ttgaattttt agttcagtgt 3120cgacaagttg ccagtaactt aacagatccc aaactgatct tccaggctag ccttgcaaat 3180gctcagattt tgattcccac caatcaggcc agtgtaagca gtatgctatt ggaaggacat 3240accctcctgg cccttgctac tacaatgtat tctcctgggg gtgtcagtca ggttgttcag 3300aatgaagaaa atgaaaactg tttgaagaaa gtggatcccc agctattgaa gatggcatta 3360actccttacc ccaagctaaa aactgctctc ttcccacagt gcactcctcc tagtgtcctg 3420ccatctgata ttacaatcta ccaccttatt cagtcattat caccctttga tcctagcaga 3480ttgtttggct ggcagtctgc taacacacta gctataggag atgcatggag tcatctccca 3540catttctcta gccctgacct ggttaataaa tatgctatag tggaacgtct gaattttgct 3600tattatttac ataatgggcg gccatcattt gcatttggta cttttctggt ccaggaatta 3660atcaagagca agactcccaa gcagctgatc cagcaagtag gcaatgaagc ctatgttata 3720gggctctcct ccttccacat accttcaata ggagctgcat gtgtttgttt cttagaattg 3780cttggccttg acagcctcaa gctcagagtt gatatgaaag tggccaatat aattttgagc 3840tacaagtgca gaaatgaaga tgctcagtac agctttatca gagagtctgt agccgaaaaa 3900ctatctaaac tagctgatgg tgaaaagaca accacagaag aattgcttgt tctcttagaa 3960gaaggtacat ggaacagcat tcagcaacag gaaataaaga ggttatccag tgaatctagc 4020agccaatggg cattagtggt gcagttctgc aggctacaca atatgaaact aagcatatct 4080taccttagag aatgtgccaa agcaaatgat tggctgcagt tcattattca cagccaactc 4140cacaactacc acccagcaga ggtgaaatcc cttatccagt acttcagccc agtcattcaa 4200gaccacttaa ggctggcttt tgagaacttg ccctcagtgc ccacctccaa aatggacagc 4260gatcaagtct gcaataagtg cccccaggaa cttcaaggaa gcaaacaaga gatgaccgat 4320ttatttgaaa ttctgctcca atgctcagag gagccagact cctggcactg gcttctggtt 4380gaagcagtga aacaacaggc ccctatcctc agtgttctgg cctcatgtct ccagggtgcc 4440agtgccattt cttgtctctg tgtttggatc atcacttctg tggaggacaa tgttgcaact 4500gaagcaatgg gacacattca ggactcaaca gaggaccata cctggaacct tgaggatctt 4560tcagtcatct ggagaacatt attaacaaga caaaagagca aaactctcat cagaggtttc 4620cagcttttct ttaaggattc cccgttacta ctggtgatgg agatgtatga actgtgtatg 4680ttcttcagga attataaaga agctgaagct aaacttctgg agtttcagaa gagccttgaa 4740acgcttaaca cagcagccac aaaggtccac cctgtcatcc ctgccatgtg gctggaggat 4800caggtgtgtt tccttttgaa gcttatgcta cagcagtgta agacccagta tgagctgggg 4860aagcttttac agctctttgt tgaaagagag catctcttct ctgatggtcc agatgtgaaa 4920aagctttgca tcctttgcca gattttgaag gatacatcca tagccattaa tcatacaatt 4980attaccagct acagcattga gaatcttcag catgaatgta gatctatttt ggaaagactg 5040cagacagatg gacaattcgc tttggccagg agggtagcag aattagctga gttacctgtg 5100gacaacttgg ttattaaaga gataacacag gaaatgcaga ccctaaaaca cattgaacag 5160tggtcactaa aacaagcaag aattgacttc tggaaaaaat gccatgagaa ttttaagaaa 5220aattcaattt caagcaaagc agcttcttcc tttttctcaa cccaggccca tgtggcatgt 5280gagcacccaa ctggatggag cagcatggag gagcgccatc tgctgctcac cttggcaggg 5340cactggcttg cccaggagga cgtggtgccc ttggataagc tggaggagct ggagaagcag 5400atctggctgt gccgcatcac ccagcacact cttggaagaa atcaggagga aacagagccc 5460agattttctc gacagatctc aactagtggt gaactttcct ttgatagttt agccagtgag 5520ttttccttct ccaagttggc tgctctgaac acatcaaaat acttagaact taacagcctt 5580ccatccaaag agacatgcga gaatagattg gattggaaag agcaggagtc actaaacttt 5640ttgattgggc gcctactgga tgatggctgt gtgcatgaag caagtagagt atgccggtat 5700tttcattttt ataatccaga tgtcgccttg gtattgcact gcagagcact ggcctcaggg 5760gaagctagta tggaggatct gcacccagag atccatgctc tcctacaaag tgctgagctg 5820cttgaggaag aagcacccga cattccccta aggagagtcc acagcacttc aagtctggat 5880agtcagaagt ttgtgacagt gccctccagt aatgaagtgg taactaacct ggaagtgctg 5940acaagcaaat gcctccatgg gaagaactac tgtcgacagg tcctctgtct gtatgatctt 6000gccaaggagt tgggctgttc ctacacagat gttgctgctc aggatggtga agccatgctc 6060cggaaaatct tggcctctca gcagcctgac cgatgcaaac gagcccaggc cttcatcagc 6120acacagggcc ttaagccaga tactgtggct gaactcgtgg cagaagaggt gacacgggag 6180ctgcttactt catcacaggg aacaggacat aagcagatgt tcaacccaac agaggaaagc 6240cagacatttc ttcagctgac cactctgtgt caagaccgca cattggtagg catgaagttg 6300ttggataaga tttcctccgt tccccatggg gaactgtctt gcaccacaga gctcctgatc 6360ctggcccatc attgcttcac cctgacgtgc cacatggagg gcatcatccg agtcctacag 6420gccgcccaca tgctcacaga taaccacctg gcccccagtg aggagtatgg gctggtggta 6480cggctcctca ctggcattgg aaggtacaac gagatgacat acatatttga tttgctgcat 6540aaaaagcact actttgaagt gctaatgagg aagaagttgg atccgagtgg taccctgaaa 6600acagccctgc tggactacat caaacgctgc cgtcctggag acagtgaaaa gcacaatatg 6660attgccctgt gcttcagcat gtgccgggag attggcgaga accacgaggc agctgcccgc 6720atccaactga aattgattga gtctcagccc tgggaggaca gcctcaagga tgggcaccag 6780ctgaaacaac tgctgctgaa ggccctgact ctgatgttgg atgcagcaga gagttatgcc 6840aaggactcct gtgtgcgaca ggcccagcac tgtcagcggc tcaccaagtt gataactctg 6900cagattcact ttctgaacac tggccagaac acaatgctca tcaacttggg ccgccacaag 6960ctgatggact gtattctggc cctacctcgg ttctaccagg cttctattgt ggctgaggcc 7020tacgattttg ttccagattg ggctgaaatt ttataccagc aagtgattct taaaggagac 7080tttaattact tggaagaatt taagcagcaa aggttattaa agtccagtat atttgaagag 7140atttccaaaa aatataaaca acatcagcct actgacatgg tcatggaaaa cctgaagaaa 7200ttactcacat attgtgaaga tgtttacctg tattacaagt tggcatacga acacaagttt 7260tatgaaattg taaatgtgct tctgaaggac cctcagacag gttgctgtct aaaggacatg 7320ctagcaggtt agatgatttc ataggtgtct gttttcttgt actgttagca gattctgaca 7380gatgtgatga gaagaagaat gcattggaga tctttgctaa agttgaacaa tcccggtact 7440gtaccatatc agtcctttgt gggtagtagg tagcaagtaa gaaacttttc aggaggaaat 7500tcctatttaa aatagattga ttttagatga ttgttcatcc acaccatttt atatagatac 7560tagtattaag atcaaaagct tcctcttcct caggacagct tctactttag atgatccaat 7620aatgattaaa gaatacctgt acctgcagat tccagtttca aagaaattta attattattt 7680acacagttaa ggaacaggtg atacattttc atttgttaga aactgatctt tctgtaataa 7740aatagatttt c 775122443PRThomo sapiens 2Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Phe Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075 1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090

1095 Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240 1245 Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255 1260 Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265 1270 1275 Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285 1290 Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295 1300 1305 Lys Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315 1320 Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325 1330 1335 Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340 1345 1350 Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360 1365 Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375 1380 His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390 1395 Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405 1410 Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420 1425 Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430 1435 1440 Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450 1455 Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460 1465 1470 Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480 1485 Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490 1495 1500 Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505 1510 1515 Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525 1530 Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540 1545 Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555 1560 Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570 1575 Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580 1585 1590 Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595 1600 1605 Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615 1620 Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625 1630 1635 Val Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645 1650 Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655 1660 1665 Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670 1675 1680 Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690 1695 Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705 1710 Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720 1725 Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735 1740 Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750 1755 Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760 1765 1770 Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780 1785 Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790 1795 1800 Cys Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810 1815 Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820 1825 1830 Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835 1840 1845 Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855 1860 Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870 1875 Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885 1890 Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900 1905 Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu Ala Ser 1910 1915 1920 Met Glu Asp Leu His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925 1930 1935 Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro Leu Arg Arg Val 1940 1945 1950 His Ser Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955 1960 1965 Ser Ser Asn Glu Val Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970 1975 1980 Cys Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Cys Leu Tyr 1985 1990 1995 Asp Leu Ala Lys Glu Leu Gly Cys Ser Tyr Thr Asp Val Ala Ala 2000 2005 2010 Gln Asp Gly Glu Ala Met Leu Arg Lys Ile Leu Ala Ser Gln Gln 2015 2020 2025 Pro Asp Arg Cys Lys Arg Ala Gln Ala Phe Ile Ser Thr Gln Gly 2030 2035 2040 Leu Lys Pro Asp Thr Val Ala Glu Leu Val Ala Glu Glu Val Thr 2045 2050 2055 Arg Glu Leu Leu Thr Ser Ser Gln Gly Thr Gly His Lys Gln Met 2060 2065 2070 Phe Asn Pro Thr Glu Glu Ser Gln Thr Phe Leu Gln Leu Thr Thr 2075 2080 2085 Leu Cys Gln Asp Arg Thr Leu Val Gly Met Lys Leu Leu Asp Lys 2090 2095 2100 Ile Ser Ser Val Pro His Gly Glu Leu Ser Cys Thr Thr Glu Leu 2105 2110 2115 Leu Ile Leu Ala His His Cys Phe Thr Leu Thr Cys His Met Glu 2120 2125 2130 Gly Ile Ile Arg Val Leu Gln Ala Ala His Met Leu Thr Asp Asn 2135 2140 2145 His Leu Ala Pro Ser Glu Glu Tyr Gly Leu Val Val Arg Leu Leu 2150 2155 2160 Thr Gly Ile Gly Arg Tyr Asn Glu Met Thr Tyr Ile Phe Asp Leu 2165 2170 2175 Leu His Lys Lys His Tyr Phe Glu Val Leu Met Arg Lys Lys Leu 2180 2185 2190 Asp Pro Ser Gly Thr Leu Lys Thr Ala Leu Leu Asp Tyr Ile Lys 2195 2200 2205 Arg Cys Arg Pro Gly Asp Ser Glu Lys His Asn Met Ile Ala Leu 2210 2215 2220 Cys Phe Ser Met Cys Arg Glu Ile Gly Glu Asn His Glu Ala Ala 2225 2230 2235 Ala Arg Ile Gln Leu Lys Leu Ile Glu Ser Gln Pro Trp Glu Asp 2240 2245 2250 Ser Leu Lys Asp Gly His Gln Leu Lys Gln Leu Leu Leu Lys Ala 2255 2260 2265 Leu Thr Leu Met Leu Asp Ala Ala Glu Ser Tyr Ala Lys Asp Ser 2270 2275 2280 Cys Val Arg Gln Ala Gln His Cys Gln Arg Leu Thr Lys Leu Ile 2285 2290 2295 Thr Leu Gln Ile His Phe Leu Asn Thr Gly Gln Asn Thr Met Leu 2300 2305 2310 Ile Asn Leu Gly Arg His Lys Leu Met Asp Cys Ile Leu Ala Leu 2315 2320 2325 Pro Arg Phe Tyr Gln Ala Ser Ile Val Ala Glu Ala Tyr Asp Phe 2330 2335 2340 Val Pro Asp Trp Ala Glu Ile Leu Tyr Gln Gln Val Ile Leu Lys 2345 2350 2355 Gly Asp Phe Asn Tyr Leu Glu Glu Phe Lys Gln Gln Arg Leu Leu 2360 2365 2370 Lys Ser Ser Ile Phe Glu Glu Ile Ser Lys Lys Tyr Lys Gln His 2375 2380 2385 Gln Pro Thr Asp Met Val Met Glu Asn Leu Lys Lys Leu Leu Thr 2390 2395 2400 Tyr Cys Glu Asp Val Tyr Leu Tyr Tyr Lys Leu Ala Tyr Glu His 2405 2410 2415 Lys Phe Tyr Glu Ile Val Asn Val Leu Leu Lys Asp Pro Gln Thr 2420 2425 2430 Gly Cys Cys Leu Lys Asp Met Leu Ala Gly 2435 2440 320DNAArtificialprimer 3ccacaggaaa cgaatggaat 20420DNAArtificialprimer 4ggttctgtga ggaaaccacg 20520DNAArtificialprimer 5cagggacatt gtaggccatc 20620DNAArtificialprimer 6ccagttgtaa aattgtgacc 20720DNAArtificialprimer 7tcccagctcc caaaactaaa 20820DNAArtificialprimer 8tcaatcaaca cttctaccac 20922DNAArtificialprimer 9caggttcttt cttgtggcat ca 221025DNAArtificialprimer 10cgaggatatt tttaacctct tatca 251124DNAArtificialprimer 11gttaggcata cttacaaaac tggc 241225DNAArtificialprimer 12cgaggatatt tttaacctct tatca 251320DNAArtificialprimer 13gaacatcttt gccctggttt 201420DNAArtificialprimer 14ctgtgacagg tgttaagtta 201520DNAArtificialprimer 15caggcactga ggcagaagta 201620DNAArtificialprimer 16atctaataca agacagtctc 201726DNAArtificialprimer 17aaaaatcaat tcctaaatca taatcc 261820DNAArtificialprimer 18tagtactgaa gtattgagta 201924DNAArtificialprimer 19tcttttaaag ccaaaaaggg taaa 242020DNAArtificialprimer 20ttaagtaatg ttcttgggca 202121DNAArtificialprimer 21cccaggacta atcatgaagg a 212220DNAArtificialprimer 22atccccaaac cgataaaacc 202321DNAArtificialprimer 23cggtgtgtct tccactagct c 212423DNAArtificialprimer 24gttacataaa tgtataatcc ctg 232520DNAArtificialprimer 25acccagccat tctcagtgtt 202623DNAArtificialprimer 26cattttaaga ctttatggat tac 232720DNAArtificialprimer 27cacagcgaga tcctgtctca 202821DNAArtificialprimer 28cctcactgta agatgatgcc c 212925DNAArtificialprimer 29cctttaaata ctacagtggt gcaga 253020DNAArtificialprimer 30tgtgggcatg atttggtcta 203122DNAArtificialprimer 31ccaactgttg agatggagaa aa 223220DNAArtificialprimer 32acctgctcaa ggacaaatgc 203320DNAArtificialprimer 33tttgaagtat cccagggtgg 203420DNAArtificialprimer 34ccaccattcc ccaaagataa 203520DNAArtificialprimer 35ttacctggat ttggctttgg 203620DNAArtificialprimer 36cctggcttct aaaagtggcc 203722DNAArtificialprimer 37tgcaatccag aaacttgaga ga 223821DNAArtificialprimer 38aagcacaaca tccaaatcct t 213920DNAArtificialprimer 39atgttggcag gaactccatc 204020DNAArtificialprimer 40ctcctttgga gcaacctctg 204120DNAArtificialprimer 41ttccaacagg aaagcacaca 204220DNAArtificialprimer 42caacaggaaa gcacacatgc 204320DNAArtificialprimer 43cagctacttg ggaggctgag 204420DNAArtificialprimer 44gtgtggctgt gacctcactc 204520DNAArtificialprimer 45gcattagaag gggcactgaa 204620DNAArtificialprimer 46aacatggctg ggatgtttct 204720DNAArtificialprimer 47ctcacaacgg tattcacccc 204820DNAArtificialprimer 48ttcctggttg gcctatgatg 204923DNAArtificialprimer 49aagggtttaa gataatttgg gga 235020DNAArtificialprimer 50aatgccaaac acacacctga 205122DNAArtificialprimer 51ggattcttga tactgctttg cc 225220DNAArtificialprimer 52ctcaaagcag aggcaaggag 205320DNAArtificialprimer 53ctgagcccca catttttgtt 205420DNAArtificialprimer 54caagtgctca atagccccat 205525DNAArtificialprimer 55gctaactgcc cttaatagag taaaa 255620DNAArtificialprimer 56aaagggtaca gcgtcagcat 205720DNAArtificialprimer 57cttgccccag attgcataat 205823DNAArtificialprimer 58tccaaaaagt acgtaaaatc cca 235922DNAArtificialprimer 59cagcaaaagg gtaatagcag tg 226020DNAArtificialprimer 60cccaaatgta gtaaatggcg 206123DNAArtificialprimer 61tttgaaagag cagaaagcta tgg 236221DNAArtificialprimer 62tgaaggggtt gtcacacttt t 216322DNAArtificialprimer 63ttgtggcaaa agaaaatttg tg 226420DNAArtificialprimer 64gagaatgcag gctcagttcc 206520DNAArtificialprimer 65atgtggaact gagcctgcat 206623DNAArtificialprimer 66cgacttgcat tttaaagaac ctg 236725DNAArtificialprimer 67ttgtttccag atcatgaaga atatg 256820DNAArtificialprimer 68tcagatagct gaccacagcc 206924DNAArtificialprimer 69tccctcttaa ggagaaaaac actg 247020DNAArtificialprimer 70accgggccga gatataaaat 207125DNAArtificialprimer 71gctagtttgt cttagaacca gaaca 257223DNAArtificialprimer 72ttttgggttg tctcactatc aca 237324DNAArtificialprimer 73aaggaacata gccagttctg tttt 247421DNAArtificialprimer 74tgcgaactat ttttcctttg g 217523DNAArtificialprimer 75tgcaacttct caggtacaca tct

237620DNAArtificialprimer 76aggctagagt gcagtggcat 207720DNAArtificialprimer 77agtcagctta agggaagcgg 207822DNAArtificialprimer 78gaagataacc attttctccc ca 227920DNAArtificialprimer 79ttgtgagtgt ttggggagaa 208021DNAArtificialprimer 80ggggatttag tgaaaacacc a 218124DNAArtificialprimer 81tttgttggag aatacactgt gctt 248225DNAArtificialprimer 82catgtctaca caacagaaag aatgc 258321DNAArtificialprimer 83aaaaggcacc atacagcttt g 218420DNAArtificialprimer 84ggaaacacat gctggaacct 208522DNAArtificialprimer 85cttctgtctg cttcttggtc tt 228622DNAArtificialprimer 86tatcatcatt atctgttgtt gg 228720DNAArtificialprimer 87ttaggtgatc ccactggctc 208820DNAArtificialprimer 88cccaggagtt caaggctgta 208920DNAArtificialprimer 89ctgaggaggg cttgtttttg 209025DNAArtificialprimer 90tctgtaactt gtttactccc agttg 259120DNAArtificialprimer 91gatcacacca ctgcattcca 209220DNAArtificialprimer 92ggcacctgta gtcccagcta 209320DNAArtificialprimer 93tgaggtggga ggatctcttg 209420DNAArtificialprimer 94gatgtgttca gagcagccaa 209520DNAArtificialprimer 95taagctggag gagctggaga 209620DNAArtificialprimer 96ttgttgtccc cttaacttgg 209720DNAArtificialprimer 97caataggcca agggtttcaa 209820DNAArtificialprimer 98tataactcct gctggagggc 209920DNAArtificialprimer 99ggtagcctgg aaattagccc 2010020DNAArtificialprimer 100tgaaccagaa tctgaagcca 2010120DNAArtificialprimer 101ttttgtcctt gggctctttc 2010220DNAArtificialprimer 102cctggttctg tcactagccc 2010320DNAArtificialprimer 103aattagccag ggtggtgaca 2010420DNAArtificialprimer 104cccacaaagg actgatatgg 2010520DNAArtificialprimer 105aaggaccctc agacaggttg 2010620DNAArtificialprimer 106tcctttaagg cagacaaggg 2010724DNAArtificialprimer 107accaggtcaa ctaaactgtt ctct 2410823DNAArtificialprimer 108tatgctgaaa gaccacctgt aga 2310920DNAArtificialprimer 109caggagcagt agtaacacaa 2011020DNAArtificialprimer 110aaagggtaca gcgtcagcat 2011121DNAArtificialprimer 111gcaggtaata agcctgcaga a 2111220DNAArtificialprimer 112cccccttcct agctgctatt 2011325DNAArtificialprimer 113tgttcaaaat agttccatta caaaa 2511422DNAArtificialprimer 114tttcttccaa ggttttcttc ca 2211521DNAArtificialprimer 115tttgcaaaag tgcttgattt t 2111620DNAArtificialprimer 116tgcaggctca gttccacata 2011720DNAArtificialprimer 117ggaatgatgc ctttttctcc 2011820DNAArtificialprimer 118tctcacactt gccttctgga 2011920DNAArtificialprimer 119aatcatcgcc tgagcaaaat 2012020DNAArtificialprimer 120ccagtgactg atccaaagca 2012121DNAArtificialprimer 121ccctcttaag gagaaaaaca c 2112220DNAArtificialprimer 122cagccttatc ctctgctctt 2012320DNAArtificialprimer 123tggaaaaggg gagcagacta 2012421DNAArtificialprimer 124tgcgaactat ttttcctttg g 2112520DNAArtificialprimer 125gaggaggcca caaatcacat 2012620DNAArtificialprimer 126gccttagacc tcgtcacacc 2012723DNAArtificialprimer 127tgctcaggtt ttgacttttt ctc 2312820DNAArtificialprimer 128tttcactgat ggcaagatgc 2012920DNAArtificialprimer 129accaccccca cctctaattc 2013020DNAArtificialprimer 130ctacacaaca gaaagaatgc 2013121DNAArtificialprimer 131ccagctgaaa ctgaaagttg g 2113220DNAArtificialprimer 132ctgggtactt acttcaggct 2013320DNAArtificialprimer 133cactgtgccc tgccttatta 2013420DNAArtificialprimer 134tgtgcctgag taaccgagtg 2013520DNAArtificialprimer 135tcccagattt ggaggttttg 2013624DNAArtificialprimer 136tgcattttaa tttcctaact accc 2413720DNAArtificialprimer 137gctgtagtgg cattttattg 2013820DNAArtificialprimer 138cctgggtgac agagcaagac 2013920DNAArtificialprimer 139agctgcagag ctccataagc 2014020DNAArtificialprimer 140taggcatcca gagcaggaac 2014120DNAArtificialprimer 141ggcatctgaa agcaaccact 2014220DNAArtificialprimer 142ccctccattt tcccaagagt 2014320DNAArtificialprimer 143ggggtgaata ccgttgtgag 2014420DNAArtificialprimer 144acctctgggt tccatgagtg 2014520DNAArtificialprimer 145agactgctcc tctgcactcc 2014621DNAArtificialprimer 146ccgggattgt tcaactttag c 2114720DNAArtificialprimer 147cagtatctta acctgtacat 2014821DNAArtificialprimer 148ccgggattgt tcaactttag c 2114940PRTHomo sapiensmisc_feature(40)..(40)Xaa can be any naturally occurring amino acid 149Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Xaa 35 40 150178PRTHomo sapiensmisc_feature(178)..(178)Xaa can be any naturally occurring amino acid 150Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ser Xaa 151246PRTHomo sapiensmisc_feature(246)..(246)Xaa can be any naturally occurring amino acid 151Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Val Xaa 245 152415PRTHomo sapiensmisc_feature(415)..(415)Xaa can be any naturally occurring amino acid 152Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Ile Met Pro Arg Pro Val Ile Gln Glu Asp His Gly Lys Xaa 405 410 415 153412PRTHomo sapiensmisc_feature(412)..(412)Xaa can be any naturally occurring amino acid 153Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380

Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Xaa 405 410 154556PRTHomo sapiensmisc_feature(556)..(556)Xaa can be any naturally occurring amino acid 154Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Ser Ser Gln Trp Leu Gly Lys Val Leu Asn Ser 515 520 525 His Thr Cys Thr Arg Gly Arg Asp Arg Lys Ser Ser Ala Gly His Ser 530 535 540 Lys Phe Leu Phe Glu Glu Gln Gly Lys Ser Phe Xaa 545 550 555 155651PRTHomo sapiensmisc_feature(651)..(651)Xaa can be any naturally occurring amino acid 155Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Xaa 645 650 156733PRTHomo sapiensmisc_feature(733)..(733)Xaa can be any naturally occurring amino acid 156Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Xaa 725 730 157953PRTHomo sapiensmisc_feature(953)..(953)Xaa can be any naturally occurring amino acid 157Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn

Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Gly Phe Phe Gly Ile Xaa 945 950 158953PRTHomo sapiensmisc_feature(953)..(953)Xaa can be any naturally occurring amino acid 158Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Phe Gly Ile Xaa 945 950 1591992PRTHomo sapiensmisc_feature(1992)..(1992)Xaa can be any naturally occurring amino acid 159Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635

640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075 1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090 1095 Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240 1245 Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255 1260 Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265 1270 1275 Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285 1290 Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295 1300 1305 Lys Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315 1320 Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325 1330 1335 Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340 1345 1350 Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360 1365 Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375 1380 His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390 1395 Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405 1410 Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420 1425 Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430 1435 1440 Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450 1455 Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460 1465 1470 Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480 1485 Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490 1495 1500 Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505 1510 1515 Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525 1530 Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540 1545 Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555 1560 Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570 1575 Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580 1585 1590 Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595 1600 1605 Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615 1620 Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625 1630 1635 Val Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645 1650 Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655 1660 1665 Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670 1675 1680 Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690 1695 Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705 1710 Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720 1725 Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735 1740 Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750 1755 Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760 1765 1770 Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780 1785 Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790 1795 1800 Cys Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810 1815 Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820 1825 1830 Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835 1840 1845 Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855 1860 Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870 1875 Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885 1890 Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900 1905 Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu Ala Ser 1910 1915 1920 Met Glu Asp Leu His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925 1930 1935 Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro Leu Arg Arg Val 1940 1945 1950 His Ser Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955 1960 1965 Ser Ser Asn Glu Val Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970 1975 1980 Cys Leu His Gly Lys Asn Tyr Cys Xaa 1985 1990 1602034PRTHomo sapiensmisc_feature(2034)..(2034)Xaa can be any naturally occurring amino acid 160Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu

Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075 1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090 1095 Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240 1245 Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255 1260 Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265 1270 1275 Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285 1290 Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295 1300 1305 Lys Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315 1320 Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325 1330 1335 Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340 1345 1350 Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360 1365 Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375 1380 His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390 1395 Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405 1410 Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420 1425 Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430 1435 1440 Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450 1455 Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460 1465 1470 Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480 1485 Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490 1495 1500 Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505 1510 1515 Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525 1530 Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540 1545 Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555 1560 Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570 1575 Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580 1585 1590 Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595 1600 1605 Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615 1620 Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625 1630 1635 Val Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645 1650 Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655 1660 1665 Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670 1675 1680 Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690 1695 Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705 1710 Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720 1725 Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735 1740 Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750 1755 Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760 1765 1770 Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780 1785 Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790 1795 1800 Cys Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810 1815 Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820 1825 1830 Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835 1840 1845 Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855 1860 Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870 1875 Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885 1890 Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900 1905 Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu Ala Ser 1910 1915 1920 Met Glu Asp Leu His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925 1930 1935 Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro Leu Arg Arg Val 1940 1945 1950 His Ser Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955 1960 1965 Ser Ser Asn Glu Val Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970 1975 1980 Cys Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Cys Leu Tyr 1985 1990 1995 Asp Leu Ala Lys Glu Leu Gly Cys Ser Tyr Thr Asp Val Ala Ala 2000 2005 2010 Gln Asp Gly Glu Ala Met Leu Arg Lys Ile Leu Ala Ser Gln Gln 2015 2020 2025 Pro Asp Arg Cys Lys Xaa 2030 1612172PRTHomo sapiensmisc_feature(2172)..(2172)Xaa can be any naturally occurring amino acid 161Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075

1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090 1095 Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240 1245 Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255 1260 Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265 1270 1275 Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285 1290 Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295 1300 1305 Lys Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315 1320 Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325 1330 1335 Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340 1345 1350 Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360 1365 Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375 1380 His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390 1395 Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405 1410 Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420 1425 Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430 1435 1440 Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450 1455 Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460 1465 1470 Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480 1485 Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490 1495 1500 Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505 1510 1515 Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525 1530 Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540 1545 Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555 1560 Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570 1575 Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580 1585 1590 Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595 1600 1605 Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615 1620 Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625 1630 1635 Val Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645 1650 Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655 1660 1665 Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670 1675 1680 Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690 1695 Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705 1710 Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720 1725 Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735 1740 Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750 1755 Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760 1765 1770 Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780 1785 Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790 1795 1800 Cys Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810 1815 Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820 1825 1830 Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835 1840 1845 Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855 1860 Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870 1875 Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885 1890 Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900 1905 Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu Ala Ser 1910 1915 1920 Met Glu Asp Leu His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925 1930 1935 Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro Leu Arg Arg Val 1940 1945 1950 His Ser Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955 1960 1965 Ser Ser Asn Glu Val Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970 1975 1980 Cys Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Cys Leu Tyr 1985 1990 1995 Asp Leu Ala Lys Glu Leu Gly Cys Ser Tyr Thr Asp Val Ala Ala 2000 2005 2010 Gln Asp Gly Glu Ala Met Leu Arg Lys Ile Leu Ala Ser Gln Gln 2015 2020 2025 Pro Asp Arg Cys Lys Arg Ala Gln Ala Phe Ile Ser Thr Gln Gly 2030 2035 2040 Leu Lys Pro Asp Thr Val Ala Glu Leu Val Ala Glu Glu Val Thr 2045 2050 2055 Arg Glu Leu Leu Thr Ser Ser Gln Gly Thr Gly His Lys Gln Met 2060 2065 2070 Phe Asn Pro Thr Glu Glu Ser Gln Thr Phe Leu Gln Leu Thr Thr 2075 2080 2085 Leu Cys Gln Asp Arg Thr Leu Val Gly Met Lys Leu Leu Asp Lys 2090 2095 2100 Ile Ser Ser Val Pro His Gly Glu Leu Ser Cys Thr Thr Glu Leu 2105 2110 2115 Leu Ile Leu Ala His His Cys Phe Thr Leu Thr Cys His Met Glu 2120 2125 2130 Gly Ile Ile Arg Val Leu Gln Ala Ala His Met Leu Thr Asp Asn 2135 2140 2145 His Leu Pro Pro Val Arg Ser Met Gly Trp Trp Tyr Gly Ser Ser 2150 2155 2160 Leu Ala Leu Glu Gly Thr Thr Arg Xaa 2165 2170 1622260PRTHomo sapiensmisc_feature(2260)..(2260)Xaa can be any naturally occurring amino acid 162Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075 1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090 1095 Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp

1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240 1245 Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255 1260 Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265 1270 1275 Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285 1290 Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295 1300 1305 Lys Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315 1320 Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325 1330 1335 Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340 1345 1350 Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360 1365 Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375 1380 His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390 1395 Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405 1410 Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420 1425 Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430 1435 1440 Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450 1455 Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460 1465 1470 Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480 1485 Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490 1495 1500 Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505 1510 1515 Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525 1530 Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540 1545 Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555 1560 Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570 1575 Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580 1585 1590 Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595 1600 1605 Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615 1620 Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625 1630 1635 Val Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645 1650 Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655 1660 1665 Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670 1675 1680 Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690 1695 Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705 1710 Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720 1725 Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735 1740 Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750 1755 Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760 1765 1770 Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780 1785 Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790 1795 1800 Cys Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810 1815 Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820 1825 1830 Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835 1840 1845 Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855 1860 Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870 1875 Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885 1890 Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900 1905 Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu Ala Ser 1910 1915 1920 Met Glu Asp Leu His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925 1930 1935 Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro Leu Arg Arg Val 1940 1945 1950 His Ser Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955 1960 1965 Ser Ser Asn Glu Val Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970 1975 1980 Cys Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Cys Leu Tyr 1985 1990 1995 Asp Leu Ala Lys Glu Leu Gly Cys Ser Tyr Thr Asp Val Ala Ala 2000 2005 2010 Gln Asp Gly Glu Ala Met Leu Arg Lys Ile Leu Ala Ser Gln Gln 2015 2020 2025 Pro Asp Arg Cys Lys Arg Ala Gln Ala Phe Ile Ser Thr Gln Gly 2030 2035 2040 Leu Lys Pro Asp Thr Val Ala Glu Leu Val Ala Glu Glu Val Thr 2045 2050 2055 Arg Glu Leu Leu Thr Ser Ser Gln Gly Thr Gly His Lys Gln Met 2060 2065 2070 Phe Asn Pro Thr Glu Glu Ser Gln Thr Phe Leu Gln Leu Thr Thr 2075 2080 2085 Leu Cys Gln Asp Arg Thr Leu Val Gly Met Lys Leu Leu Asp Lys 2090 2095 2100 Ile Ser Ser Val Pro His Gly Glu Leu Ser Cys Thr Thr Glu Leu 2105 2110 2115 Leu Ile Leu Ala His His Cys Phe Thr Leu Thr Cys His Met Glu 2120 2125 2130 Gly Ile Ile Arg Val Leu Gln Ala Ala His Met Leu Thr Asp Asn 2135 2140 2145 His Leu Ala Pro Ser Glu Glu Tyr Gly Leu Val Val Arg Leu Leu 2150 2155 2160 Thr Gly Ile Gly Arg Tyr Asn Glu Met Thr Tyr Ile Phe Asp Leu 2165 2170 2175 Leu His Lys Lys His Tyr Phe Glu Val Leu Met Arg Lys Lys Leu 2180 2185 2190 Asp Pro Ser Gly Thr Leu Lys Thr Ala Leu Leu Asp Tyr Ile Lys 2195 2200 2205 Arg Cys Arg Pro Gly Asp Ser Glu Lys His Asn Met Ile Ala Leu 2210 2215 2220 Cys Phe Ser Met Cys Arg Glu Ile Gly Glu Asn His Glu Ala Ala 2225 2230 2235 Ala Arg Ile Gln Leu Lys Leu Ser Leu Ser Pro Gly Arg Thr Ala 2240 2245 2250 Ser Arg Met Gly Thr Ser Xaa 2255 2260 1632338PRTHomo sapiensmisc_feature(2338)..(2338)Xaa can be any naturally occurring amino acid 163Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075 1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090 1095 Val Gln Asn Glu Glu

Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240 1245 Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255 1260 Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265 1270 1275 Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285 1290 Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295 1300 1305 Lys Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315 1320 Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325 1330 1335 Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340 1345 1350 Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360 1365 Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375 1380 His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390 1395 Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405 1410 Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420 1425 Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430 1435 1440 Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450 1455 Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460 1465 1470 Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480 1485 Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490 1495 1500 Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505 1510 1515 Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525 1530 Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540 1545 Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555 1560 Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570 1575 Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580 1585 1590 Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595 1600 1605 Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615 1620 Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625 1630 1635 Val Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645 1650 Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655 1660 1665 Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670 1675 1680 Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690 1695 Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705 1710 Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720 1725 Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735 1740 Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750 1755 Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760 1765 1770 Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780 1785 Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790 1795 1800 Cys Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810 1815 Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820 1825 1830 Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835 1840 1845 Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855 1860 Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870 1875 Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885 1890 Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900 1905 Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu Ala Ser 1910 1915 1920 Met Glu Asp Leu His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925 1930 1935 Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro Leu Arg Arg Val 1940 1945 1950 His Ser Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955 1960 1965 Ser Ser Asn Glu Val Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970 1975 1980 Cys Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Cys Leu Tyr 1985 1990 1995 Asp Leu Ala Lys Glu Leu Gly Cys Ser Tyr Thr Asp Val Ala Ala 2000 2005 2010 Gln Asp Gly Glu Ala Met Leu Arg Lys Ile Leu Ala Ser Gln Gln 2015 2020 2025 Pro Asp Arg Cys Lys Arg Ala Gln Ala Phe Ile Ser Thr Gln Gly 2030 2035 2040 Leu Lys Pro Asp Thr Val Ala Glu Leu Val Ala Glu Glu Val Thr 2045 2050 2055 Arg Glu Leu Leu Thr Ser Ser Gln Gly Thr Gly His Lys Gln Met 2060 2065 2070 Phe Asn Pro Thr Glu Glu Ser Gln Thr Phe Leu Gln Leu Thr Thr 2075 2080 2085 Leu Cys Gln Asp Arg Thr Leu Val Gly Met Lys Leu Leu Asp Lys 2090 2095 2100 Ile Ser Ser Val Pro His Gly Glu Leu Ser Cys Thr Thr Glu Leu 2105 2110 2115 Leu Ile Leu Ala His His Cys Phe Thr Leu Thr Cys His Met Glu 2120 2125 2130 Gly Ile Ile Arg Val Leu Gln Ala Ala His Met Leu Thr Asp Asn 2135 2140 2145 His Leu Ala Pro Ser Glu Glu Tyr Gly Leu Val Val Arg Leu Leu 2150 2155 2160 Thr Gly Ile Gly Arg Tyr Asn Glu Met Thr Tyr Ile Phe Asp Leu 2165 2170 2175 Leu His Lys Lys His Tyr Phe Glu Val Leu Met Arg Lys Lys Leu 2180 2185 2190 Asp Pro Ser Gly Thr Leu Lys Thr Ala Leu Leu Asp Tyr Ile Lys 2195 2200 2205 Arg Cys Arg Pro Gly Asp Ser Glu Lys His Asn Met Ile Ala Leu 2210 2215 2220 Cys Phe Ser Met Cys Arg Glu Ile Gly Glu Asn His Glu Ala Ala 2225 2230 2235 Ala Arg Ile Gln Leu Lys Leu Ile Glu Ser Gln Pro Trp Glu Asp 2240 2245 2250 Ser Leu Lys Asp Gly His Gln Leu Lys Gln Leu Leu Leu Lys Ala 2255 2260 2265 Leu Thr Leu Met Leu Asp Ala Ala Glu Leu Cys Gln Gly Leu Leu 2270 2275 2280 Cys Ala Thr Gly Pro Ala Leu Ser Ala Ala His Gln Val Asp Asn 2285 2290 2295 Ser Ala Asp Ser Leu Ser Glu His Trp Pro Glu His Asn Ala His 2300 2305 2310 Gln Leu Gly Pro Pro Gln Ala Asp Gly Leu Tyr Ser Gly Pro Thr 2315 2320 2325 Ser Val Leu Pro Gly Phe Tyr Cys Gly Xaa 2330 2335 1642349PRTHomo sapiensmisc_feature(2349)..(2349)Xaa can be any naturally occurring amino acid 164Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980

985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075 1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090 1095 Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240 1245 Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255 1260 Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265 1270 1275 Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285 1290 Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295 1300 1305 Lys Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315 1320 Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325 1330 1335 Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340 1345 1350 Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360 1365 Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375 1380 His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390 1395 Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405 1410 Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420 1425 Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430 1435 1440 Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450 1455 Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460 1465 1470 Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480 1485 Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490 1495 1500 Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505 1510 1515 Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525 1530 Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540 1545 Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555 1560 Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570 1575 Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580 1585 1590 Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595 1600 1605 Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615 1620 Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625 1630 1635 Val Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645 1650 Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655 1660 1665 Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670 1675 1680 Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690 1695 Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705 1710 Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720 1725 Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735 1740 Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750 1755 Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760 1765 1770 Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780 1785 Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790 1795 1800 Cys Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810 1815 Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820 1825 1830 Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835 1840 1845 Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855 1860 Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870 1875 Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885 1890 Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900 1905 Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu Ala Ser 1910 1915 1920 Met Glu Asp Leu His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925 1930 1935 Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro Leu Arg Arg Val 1940 1945 1950 His Ser Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955 1960 1965 Ser Ser Asn Glu Val Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970 1975 1980 Cys Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Cys Leu Tyr 1985 1990 1995 Asp Leu Ala Lys Glu Leu Gly Cys Ser Tyr Thr Asp Val Ala Ala 2000 2005 2010 Gln Asp Gly Glu Ala Met Leu Arg Lys Ile Leu Ala Ser Gln Gln 2015 2020 2025 Pro Asp Arg Cys Lys Arg Ala Gln Ala Phe Ile Ser Thr Gln Gly 2030 2035 2040 Leu Lys Pro Asp Thr Val Ala Glu Leu Val Ala Glu Glu Val Thr 2045 2050 2055 Arg Glu Leu Leu Thr Ser Ser Gln Gly Thr Gly His Lys Gln Met 2060 2065 2070 Phe Asn Pro Thr Glu Glu Ser Gln Thr Phe Leu Gln Leu Thr Thr 2075 2080 2085 Leu Cys Gln Asp Arg Thr Leu Val Gly Met Lys Leu Leu Asp Lys 2090 2095 2100 Ile Ser Ser Val Pro His Gly Glu Leu Ser Cys Thr Thr Glu Leu 2105 2110 2115 Leu Ile Leu Ala His His Cys Phe Thr Leu Thr Cys His Met Glu 2120 2125 2130 Gly Ile Ile Arg Val Leu Gln Ala Ala His Met Leu Thr Asp Asn 2135 2140 2145 His Leu Ala Pro Ser Glu Glu Tyr Gly Leu Val Val Arg Leu Leu 2150 2155 2160 Thr Gly Ile Gly Arg Tyr Asn Glu Met Thr Tyr Ile Phe Asp Leu 2165 2170 2175 Leu His Lys Lys His Tyr Phe Glu Val Leu Met Arg Lys Lys Leu 2180 2185 2190 Asp Pro Ser Gly Thr Leu Lys Thr Ala Leu Leu Asp Tyr Ile Lys 2195 2200 2205 Arg Cys Arg Pro Gly Asp Ser Glu Lys His Asn Met Ile Ala Leu 2210 2215 2220 Cys Phe Ser Met Cys Arg Glu Ile Gly Glu Asn His Glu Ala Ala 2225 2230 2235 Ala Arg Ile Gln Leu Lys Leu Ile Glu Ser Gln Pro Trp Glu Asp 2240 2245 2250 Ser Leu Lys Asp Gly His Gln Leu Lys Gln Leu Leu Leu Lys Ala 2255 2260 2265 Leu Thr Leu Met Leu Asp Ala Ala Glu Ser Tyr Ala Lys Asp Ser 2270 2275 2280 Cys Val Arg Gln Ala Gln His Cys Gln Arg Leu Thr Lys Leu Ile 2285 2290 2295 Thr Leu Gln Ile His Phe Leu Asn Thr Gly Gln Asn Thr Met Leu 2300 2305 2310 Ile Asn Leu Gly Arg His Lys Leu Met Asp Cys Ile Leu Ala Leu 2315 2320 2325 Pro Arg Phe Tyr Gln Ala Ser Ile Val Ala Glu Ala Tyr Asp Phe 2330 2335 2340 Cys Ser Arg Leu Gly Xaa 2345 1652443PRThomo sapiens 165Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr

Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Gly Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075 1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090 1095 Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240 1245 Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255 1260 Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265 1270 1275 Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285 1290 Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295 1300 1305 Lys Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315 1320 Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325 1330 1335 Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340 1345 1350 Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360 1365 Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375 1380 His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390 1395 Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405 1410 Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420 1425 Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430 1435 1440 Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450 1455 Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460 1465 1470 Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480 1485 Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490 1495 1500 Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505 1510 1515 Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525 1530 Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540 1545 Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555 1560 Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570 1575 Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580 1585 1590 Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595 1600 1605 Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615 1620 Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625 1630 1635 Val Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645 1650 Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655 1660 1665 Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670 1675 1680 Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690 1695 Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705 1710 Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720 1725 Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735 1740 Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750 1755 Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760 1765 1770 Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780 1785 Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790 1795 1800 Cys Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810 1815 Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820 1825 1830 Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835 1840 1845 Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855 1860 Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870 1875 Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885 1890 Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900 1905 Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu Ala Ser 1910 1915 1920 Met Glu Asp Leu His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925 1930 1935 Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro Leu Arg Arg Val 1940 1945 1950 His Ser Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955 1960 1965 Ser Ser Asn Glu Val Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970 1975 1980 Cys Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Cys Leu Tyr 1985 1990 1995 Asp Leu Ala Lys Glu Leu Gly Cys Ser Tyr Thr Asp Val Ala Ala 2000 2005 2010 Gln Asp Gly Glu Ala Met Leu Arg Lys Ile Leu Ala Ser Gln Gln 2015 2020 2025 Pro Asp Arg Cys Lys Arg Ala Gln Ala Phe Ile Ser Thr Gln Gly 2030 2035 2040 Leu Lys Pro Asp Thr Val Ala Glu Leu Val Ala Glu Glu Val Thr 2045 2050 2055 Arg Glu Leu Leu Thr Ser Ser Gln Gly Thr Gly His Lys Gln Met 2060 2065 2070 Phe Asn Pro Thr Glu Glu Ser Gln Thr Phe Leu Gln Leu Thr Thr 2075 2080 2085 Leu Cys Gln Asp Arg Thr Leu Val Gly Met Lys Leu Leu Asp Lys 2090 2095 2100 Ile Ser Ser Val Pro His Gly Glu Leu Ser Cys Thr Thr Glu Leu 2105 2110 2115 Leu Ile Leu Ala His His Cys Phe Thr Leu Thr Cys His Met Glu 2120 2125 2130 Gly Ile Ile Arg Val Leu Gln Ala Ala His Met Leu Thr Asp Asn 2135 2140 2145 His Leu Ala Pro Ser Glu Glu Tyr Gly Leu Val Val Arg Leu Leu 2150 2155 2160 Thr Gly Ile Gly Arg Tyr Asn Glu Met Thr Tyr Ile Phe Asp Leu 2165 2170 2175 Leu His Lys Lys His Tyr Phe Glu Val Leu Met Arg Lys Lys Leu 2180 2185 2190 Asp Pro Ser Gly Thr Leu Lys Thr Ala Leu Leu Asp Tyr Ile Lys 2195 2200 2205 Arg Cys Arg Pro Gly Asp Ser Glu Lys His Asn Met Ile Ala Leu 2210 2215 2220 Cys Phe Ser Met Cys Arg Glu Ile Gly Glu Asn His Glu Ala Ala 2225 2230 2235 Ala Arg Ile Gln Leu Lys Leu Ile Glu Ser Gln Pro Trp Glu Asp 2240 2245 2250 Ser Leu Lys Asp Gly His Gln Leu Lys Gln Leu Leu Leu Lys Ala 2255 2260 2265 Leu Thr Leu Met Leu Asp Ala Ala Glu Ser Tyr Ala Lys Asp Ser 2270 2275 2280 Cys Val Arg Gln Ala Gln His Cys Gln Arg Leu Thr Lys Leu Ile 2285 2290 2295 Thr Leu Gln Ile His Phe Leu Asn Thr Gly Gln Asn Thr Met Leu 2300 2305 2310 Ile Asn Leu Gly Arg His Lys Leu Met Asp Cys Ile Leu Ala Leu 2315 2320 2325 Pro Arg Phe Tyr Gln Ala Ser Ile Val Ala Glu Ala Tyr Asp Phe 2330 2335 2340 Val Pro Asp Trp Ala Glu Ile Leu Tyr Gln Gln Val Ile Leu Lys 2345 2350 2355 Gly Asp Phe Asn Tyr Leu Glu Glu Phe Lys Gln Gln Arg Leu Leu 2360 2365 2370 Lys Ser Ser Ile Phe Glu Glu Ile Ser Lys Lys Tyr Lys Gln His 2375 2380 2385 Gln Pro Thr Asp Met Val Met Glu Asn Leu Lys Lys Leu Leu Thr 2390 2395 2400 Tyr Cys Glu Asp Val Tyr Leu Tyr Tyr Lys Leu Ala Tyr Glu His 2405 2410 2415 Lys Phe Tyr Glu Ile Val Asn Val Leu Leu Lys Asp Pro Gln Thr 2420 2425 2430 Gly Cys Cys Leu Lys Asp Met Leu Ala Gly 2435 2440 166245PRThomo sapiens 166Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala Arg Gly Phe Ser Thr Ser 225 230 235 240 Gln Arg Arg His Val 245 167427PRTHomo sapiens 167Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg

Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu 420 425 168555PRTHomo sapiens 168Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Asp Phe Val Trp Phe Asp 485 490 495 Ser Arg Arg Val Phe Lys Gln Thr His Asp Pro Trp Lys Cys Gln His 500 505 510 Cys Gly His Ser Leu Ser Ser Gln Trp Leu Gly Lys Val Leu Asn Ser 515 520 525 His Thr Cys Thr Arg Gly Arg Asp Arg Lys Ser Ser Ala Gly His Ser 530 535 540 Lys Phe Leu Phe Glu Glu Gln Gly Lys Ser Phe 545 550 555 169576PRTHomo sapiens 169Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Leu Ile His Pro Gln 545 550 555 560 Asn Leu Leu Tyr Leu Ile Ser Leu Ile Thr Cys His Pro Ile Tyr Ile 565 570 575 170559PRTHomo sapiens 170Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser 545 550 555 171576PRTHomo sapiens 171Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Leu Ile Ser Leu Ile Thr Cys His Pro Ile Tyr Ile 565

570 575 1722443PRTHomo sapiens 172Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Met Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075 1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090 1095 Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240 1245 Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255 1260 Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265 1270 1275 Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285 1290 Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295 1300 1305 Lys Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315 1320 Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325 1330 1335 Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340 1345 1350 Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360 1365 Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375 1380 His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390 1395 Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405 1410 Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420 1425 Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430 1435 1440 Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450 1455 Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460 1465 1470 Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480 1485 Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490 1495 1500 Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505 1510 1515 Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525 1530 Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540 1545 Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555 1560 Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570 1575 Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580 1585 1590 Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595 1600 1605 Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615 1620 Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625 1630 1635 Val Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645 1650 Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655 1660 1665 Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670 1675 1680 Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690 1695 Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705 1710 Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720 1725 Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735 1740 Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750 1755 Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760 1765 1770 Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780 1785 Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790 1795 1800 Cys Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810 1815 Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820 1825 1830 Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835 1840 1845 Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855 1860 Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870 1875 Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885 1890 Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900 1905 Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu Ala Ser 1910 1915 1920 Met Glu Asp Leu His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925 1930 1935 Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro Leu Arg Arg Val 1940 1945 1950 His Ser Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955 1960 1965 Ser Ser Asn Glu Val Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970 1975 1980 Cys Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Cys Leu Tyr 1985 1990 1995 Asp Leu Ala Lys Glu Leu Gly Cys Ser Tyr Thr Asp Val Ala Ala 2000 2005 2010 Gln Asp Gly Glu Ala Met Leu Arg Lys Ile Leu Ala Ser Gln Gln 2015 2020 2025 Pro Asp Arg Cys Lys Arg Ala Gln Ala Phe Ile Ser Thr Gln Gly 2030 2035 2040 Leu Lys Pro Asp Thr Val Ala Glu Leu Val Ala Glu Glu Val Thr 2045 2050 2055 Arg Glu Leu Leu Thr Ser Ser Gln Gly Thr Gly His Lys Gln Met 2060 2065 2070 Phe Asn Pro Thr Glu Glu Ser Gln Thr Phe Leu Gln Leu Thr Thr 2075 2080 2085 Leu Cys Gln Asp Arg Thr Leu Val Gly Met Lys Leu Leu Asp Lys 2090 2095 2100 Ile Ser Ser Val Pro His Gly Glu Leu Ser Cys Thr Thr Glu Leu 2105 2110 2115 Leu Ile Leu Ala His His Cys Phe Thr Leu Thr Cys His Met Glu 2120 2125 2130 Gly Ile Ile Arg Val Leu Gln Ala Ala His Met Leu Thr Asp Asn 2135 2140 2145 His Leu Ala Pro Ser Glu Glu Tyr Gly Leu Val Val Arg Leu Leu 2150 2155 2160 Thr Gly Ile Gly Arg Tyr Asn Glu Met Thr Tyr Ile Phe Asp Leu 2165 2170 2175 Leu His Lys Lys His Tyr Phe Glu Val Leu Met Arg Lys Lys Leu 2180 2185 2190 Asp Pro Ser Gly Thr Leu Lys Thr Ala Leu Leu Asp Tyr Ile Lys 2195 2200 2205 Arg Cys Arg Pro Gly Asp Ser Glu Lys His Asn Met Ile Ala Leu 2210 2215 2220 Cys Phe Ser Met Cys Arg Glu Ile Gly Glu Asn His Glu Ala Ala 2225

2230 2235 Ala Arg Ile Gln Leu Lys Leu Ile Glu Ser Gln Pro Trp Glu Asp 2240 2245 2250 Ser Leu Lys Asp Gly His Gln Leu Lys Gln Leu Leu Leu Lys Ala 2255 2260 2265 Leu Thr Leu Met Leu Asp Ala Ala Glu Ser Tyr Ala Lys Asp Ser 2270 2275 2280 Cys Val Arg Gln Ala Gln His Cys Gln Arg Leu Thr Lys Leu Ile 2285 2290 2295 Thr Leu Gln Ile His Phe Leu Asn Thr Gly Gln Asn Thr Met Leu 2300 2305 2310 Ile Asn Leu Gly Arg His Lys Leu Met Asp Cys Ile Leu Ala Leu 2315 2320 2325 Pro Arg Phe Tyr Gln Ala Ser Ile Val Ala Glu Ala Tyr Asp Phe 2330 2335 2340 Val Pro Asp Trp Ala Glu Ile Leu Tyr Gln Gln Val Ile Leu Lys 2345 2350 2355 Gly Asp Phe Asn Tyr Leu Glu Glu Phe Lys Gln Gln Arg Leu Leu 2360 2365 2370 Lys Ser Ser Ile Phe Glu Glu Ile Ser Lys Lys Tyr Lys Gln His 2375 2380 2385 Gln Pro Thr Asp Met Val Met Glu Asn Leu Lys Lys Leu Leu Thr 2390 2395 2400 Tyr Cys Glu Asp Val Tyr Leu Tyr Tyr Lys Leu Ala Tyr Glu His 2405 2410 2415 Lys Phe Tyr Glu Ile Val Asn Val Leu Leu Lys Asp Pro Gln Thr 2420 2425 2430 Gly Cys Cys Leu Lys Asp Met Leu Ala Gly 2435 2440 173898PRTHomo sapiens 173Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu 174919PRTHomo sapiens 174Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Ser Ile Val Met Leu His Phe 900 905 910 Ser Arg Thr Asn Gly Pro Phe 915 1751028PRTHomo sapiens 175Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245

250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Arg Val Thr 1025 1761263PRTHomo sapiens 176Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075 1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090 1095 Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Thr 1235 1240 1245 Phe Asn Arg Ser Cys Met Cys Leu Phe Leu Arg Ile Ala Trp Pro 1250 1255 1260 1771441PRTHomo sapiens 177Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225

230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075 1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090 1095 Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240 1245 Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255 1260 Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265 1270 1275 Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285 1290 Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295 1300 1305 Lys Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315 1320 Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325 1330 1335 Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340 1345 1350 Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360 1365 Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375 1380 His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390 1395 Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405 1410 Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420 1425 Gln Glu Leu Gln Gly Ser Lys Arg Asp Asp Arg Phe Ile 1430 1435 1440 1781823PRTHomo sapiens 178Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro

Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075 1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090 1095 Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240 1245 Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255 1260 Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265 1270 1275 Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285 1290 Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295 1300 1305 Lys Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315 1320 Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325 1330 1335 Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340 1345 1350 Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360 1365 Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375 1380 His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390 1395 Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405 1410 Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420 1425 Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430 1435 1440 Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450 1455 Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460 1465 1470 Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480 1485 Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490 1495 1500 Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505 1510 1515 Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525 1530 Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540 1545 Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555 1560 Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570 1575 Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580 1585 1590 Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595 1600 1605 Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615 1620 Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625 1630 1635 Val Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645 1650 Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655 1660 1665 Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670 1675 1680 Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690 1695 Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705 1710 Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720 1725 Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735 1740 Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750 1755 Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760 1765 1770 Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780 1785 Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790 1795 1800 Cys Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810 1815 Glu Pro Arg Phe Ser 1820 1791856PRTHomo sapiens 179Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075 1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090 1095 Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240 1245 Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255 1260 Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265 1270 1275 Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285 1290 Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295 1300 1305 Lys Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315 1320 Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325 1330 1335 Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340 1345 1350 Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360 1365 Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375 1380 His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390 1395 Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405 1410 Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420 1425 Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430 1435 1440 Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450 1455 Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460 1465 1470

Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480 1485 Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490 1495 1500 Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505 1510 1515 Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525 1530 Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540 1545 Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555 1560 Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570 1575 Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580 1585 1590 Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595 1600 1605 Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615 1620 Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625 1630 1635 Val Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645 1650 Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655 1660 1665 Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670 1675 1680 Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690 1695 Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705 1710 Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720 1725 Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735 1740 Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750 1755 Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760 1765 1770 Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780 1785 Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790 1795 1800 Cys Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810 1815 Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820 1825 1830 Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Val Gly Cys Ser 1835 1840 1845 Glu His Ile Lys Ile Leu Arg Thr 1850 1855 1801949PRTHomo sapiens 180Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075 1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090 1095 Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240 1245 Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255 1260 Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265 1270 1275 Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285 1290 Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295 1300 1305 Lys Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315 1320 Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325 1330 1335 Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340 1345 1350 Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360 1365 Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375 1380 His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390 1395 Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405 1410 Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420 1425 Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430 1435 1440 Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450 1455 Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460 1465 1470 Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480 1485 Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490 1495 1500 Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505 1510 1515 Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525 1530 Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540 1545 Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555 1560 Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570 1575 Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580 1585 1590 Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595 1600 1605 Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615 1620 Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625 1630 1635 Val Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645 1650 Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655 1660 1665 Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670 1675 1680 Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690 1695 Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705 1710 Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720 1725 Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735 1740 Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750 1755 Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760 1765 1770 Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780 1785 Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790 1795 1800 Cys Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810 1815 Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820 1825 1830 Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835 1840 1845 Leu Asn Thr Ser Lys

Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855 1860 Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870 1875 Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885 1890 Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900 1905 Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu Ala Arg 1910 1915 1920 Trp Arg Ile Cys Thr Gln Arg Ser Met Leu Ser Tyr Lys Val Leu 1925 1930 1935 Ser Cys Leu Arg Lys Lys His Pro Thr Phe Pro 1940 1945 1811956PRTHomo sapiens 181Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075 1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090 1095 Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240 1245 Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255 1260 Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265 1270 1275 Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285 1290 Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295 1300 1305 Lys Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315 1320 Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325 1330 1335 Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340 1345 1350 Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360 1365 Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375 1380 His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390 1395 Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405 1410 Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420 1425 Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430 1435 1440 Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450 1455 Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460 1465 1470 Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480 1485 Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490 1495 1500 Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505 1510 1515 Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525 1530 Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540 1545 Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555 1560 Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570 1575 Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580 1585 1590 Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595 1600 1605 Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615 1620 Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625 1630 1635 Val Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645 1650 Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655 1660 1665 Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670 1675 1680 Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690 1695 Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705 1710 Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720 1725 Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735 1740 Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750 1755 Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760 1765 1770 Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780 1785 Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790 1795 1800 Cys Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810 1815 Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820 1825 1830 Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835 1840 1845 Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855 1860 Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870 1875 Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885 1890 Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900 1905 Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu Ala Ser 1910 1915 1920 Met Glu Asp Leu His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925 1930 1935 Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro Leu Arg Arg Val 1940 1945 1950 His Ser Thr 1955 1821999PRTHomo sapiens 182Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180

185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075 1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090 1095 Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240 1245 Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255 1260 Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265 1270 1275 Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285 1290 Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295 1300 1305 Lys Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315 1320 Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325 1330 1335 Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340 1345 1350 Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360 1365 Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375 1380 His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390 1395 Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405 1410 Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420 1425 Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430 1435 1440 Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450 1455 Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460 1465 1470 Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480 1485 Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490 1495 1500 Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505 1510 1515 Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525 1530 Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540 1545 Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555 1560 Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570 1575 Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580 1585 1590 Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595 1600 1605 Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615 1620 Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625 1630 1635 Val Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645 1650 Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655 1660 1665 Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670 1675 1680 Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690 1695 Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705 1710 Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720 1725 Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735 1740 Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750 1755 Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760 1765 1770 Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780 1785 Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790 1795 1800 Cys Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810 1815 Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820 1825 1830 Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835 1840 1845 Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855 1860 Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870 1875 Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885 1890 Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900 1905 Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu Ala Ser 1910 1915 1920 Met Glu Asp Leu His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925 1930 1935 Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro Leu Arg Arg Val 1940 1945 1950 His Ser Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955 1960 1965 Ser Ser Asn Glu Val Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970 1975 1980 Cys Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Ser Leu Ser 1985 1990 1995 Val 1831998PRTHomo sapiens 183Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly

Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075 1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090 1095 Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240 1245 Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255 1260 Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265 1270 1275 Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285 1290 Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295 1300 1305 Lys Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315 1320 Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325 1330 1335 Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340 1345 1350 Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360 1365 Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375 1380 His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390 1395 Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405 1410 Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420 1425 Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430 1435 1440 Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450 1455 Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460 1465 1470 Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480 1485 Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490 1495 1500 Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505 1510 1515 Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525 1530 Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540 1545 Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555 1560 Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570 1575 Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580 1585 1590 Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595 1600 1605 Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615 1620 Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625 1630 1635 Val Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645 1650 Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655 1660 1665 Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670 1675 1680 Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690 1695 Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705 1710 Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720 1725 Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735 1740 Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750 1755 Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760 1765 1770 Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780 1785 Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790 1795 1800 Cys Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810 1815 Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820 1825 1830 Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835 1840 1845 Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855 1860 Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870 1875 Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885 1890 Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900 1905 Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu Ala Ser 1910 1915 1920 Met Glu Asp Leu His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925 1930 1935 Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro Leu Arg Arg Val 1940 1945 1950 His Ser Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955 1960 1965 Ser Ser Asn Glu Val Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970 1975 1980 Cys Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Leu Ser Val 1985 1990 1995 1842055PRTHomo sapiens 184Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser

Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075 1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090 1095 Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240 1245 Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255 1260 Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265 1270 1275 Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285 1290 Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295 1300 1305 Lys Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315 1320 Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325 1330 1335 Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340 1345 1350 Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360 1365 Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375 1380 His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390 1395 Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405 1410 Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420 1425 Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430 1435 1440 Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450 1455 Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460 1465 1470 Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480 1485 Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490 1495 1500 Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505 1510 1515 Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525 1530 Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540 1545 Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555 1560 Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570 1575 Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580 1585 1590 Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595 1600 1605 Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615 1620 Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625 1630 1635 Val Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645 1650 Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655 1660 1665 Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670 1675 1680 Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690 1695 Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705 1710 Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720 1725 Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735 1740 Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750 1755 Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760 1765 1770 Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780 1785 Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790 1795 1800 Cys Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810 1815 Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820 1825 1830 Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835 1840 1845 Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855 1860 Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870 1875 Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885 1890 Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900 1905 Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu Ala Ser 1910 1915 1920 Met Glu Asp Leu His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925 1930 1935 Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro Leu Arg Arg Val 1940 1945 1950 His Ser Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955 1960 1965 Ser Ser Asn Glu Val Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970 1975 1980 Cys Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Cys Met Ile 1985 1990 1995 Leu Pro Arg Ser Trp Ala Val Pro Thr Gln Met Leu Leu Leu Arg 2000 2005 2010 Met Val Lys Pro Cys Ser Gly Lys Ser Trp Pro Leu Ser Ser Leu 2015 2020 2025 Thr Asp Ala Asn Glu Pro Arg Pro Ser Ser Ala His Arg Ala Leu 2030 2035 2040 Ser Gln Ile Leu Trp Leu Asn Ser Trp Gln Lys Arg 2045 2050 2055 1852030PRTHomo sapiens 185Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr

Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075 1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090 1095 Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240 1245 Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255 1260 Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265 1270 1275 Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285 1290 Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295 1300 1305 Lys Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315 1320 Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325 1330 1335 Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340 1345 1350 Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360 1365 Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375 1380 His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390 1395 Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405 1410 Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420 1425 Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430 1435 1440 Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450 1455 Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460 1465 1470 Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480 1485 Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490 1495 1500 Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505 1510 1515 Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525 1530 Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540 1545 Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555 1560 Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570 1575 Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580 1585 1590 Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595 1600 1605 Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615 1620 Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625 1630 1635 Val Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645 1650 Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655 1660 1665 Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670 1675 1680 Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690 1695 Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705 1710 Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720 1725 Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735 1740 Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750 1755 Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760 1765 1770 Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780 1785 Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790 1795 1800 Cys Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810 1815 Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820 1825 1830 Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835 1840 1845 Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855 1860 Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870 1875 Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885 1890 Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900 1905 Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu Ala Ser 1910 1915 1920 Met Glu Asp Leu His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925 1930 1935 Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro Leu Arg Arg Val 1940 1945 1950 His Ser Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955 1960 1965 Ser Ser Asn Glu Val Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970 1975 1980 Cys Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Cys Leu Tyr 1985 1990 1995 Asp Leu Ala Lys Glu Leu Gly Cys Ser Tyr Thr Asp Val Ala Ala 2000 2005 2010 Gln Asp Gly Glu Ala Met Leu Arg Lys Ile Leu Ala Ser Gln Gln 2015 2020 2025 Pro Asp 2030 1862259PRTHomo sapiens 186Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075

1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090 1095 Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240 1245 Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255 1260 Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265 1270 1275 Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285 1290 Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295 1300 1305 Lys Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315 1320 Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325 1330 1335 Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340 1345 1350 Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360 1365 Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375 1380 His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390 1395 Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405 1410 Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420 1425 Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430 1435 1440 Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450 1455 Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460 1465 1470 Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480 1485 Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490 1495 1500 Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505 1510 1515 Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525 1530 Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540 1545 Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555 1560 Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570 1575 Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580 1585 1590 Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595 1600 1605 Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615 1620 Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625 1630 1635 Val Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645 1650 Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655 1660 1665 Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670 1675 1680 Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690 1695 Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705 1710 Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720 1725 Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735 1740 Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750 1755 Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760 1765 1770 Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780 1785 Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790 1795 1800 Cys Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810 1815 Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820 1825 1830 Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835 1840 1845 Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855 1860 Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870 1875 Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885 1890 Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900 1905 Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu Ala Ser 1910 1915 1920 Met Glu Asp Leu His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925 1930 1935 Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro Leu Arg Arg Val 1940 1945 1950 His Ser Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955 1960 1965 Ser Ser Asn Glu Val Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970 1975 1980 Cys Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Cys Leu Tyr 1985 1990 1995 Asp Leu Ala Lys Glu Leu Gly Cys Ser Tyr Thr Asp Val Ala Ala 2000 2005 2010 Gln Asp Gly Glu Ala Met Leu Arg Lys Ile Leu Ala Ser Gln Gln 2015 2020 2025 Pro Asp Arg Cys Lys Arg Ala Gln Ala Phe Ile Ser Thr Gln Gly 2030 2035 2040 Leu Lys Pro Asp Thr Val Ala Glu Leu Val Ala Glu Glu Val Thr 2045 2050 2055 Arg Glu Leu Leu Thr Ser Ser Gln Gly Thr Gly His Lys Gln Met 2060 2065 2070 Phe Asn Pro Thr Glu Glu Ser Gln Thr Phe Leu Gln Leu Thr Thr 2075 2080 2085 Leu Cys Gln Asp Arg Thr Leu Val Gly Met Lys Leu Leu Asp Lys 2090 2095 2100 Ile Ser Ser Val Pro His Gly Glu Leu Ser Cys Thr Thr Glu Leu 2105 2110 2115 Leu Ile Leu Ala His His Cys Phe Thr Leu Thr Cys His Met Glu 2120 2125 2130 Gly Ile Ile Arg Val Leu Gln Ala Ala His Met Leu Thr Asp Asn 2135 2140 2145 His Leu Ala Pro Ser Glu Glu Tyr Gly Leu Val Val Arg Leu Leu 2150 2155 2160 Thr Gly Ile Gly Arg Tyr Asn Glu Met Thr Tyr Ile Phe Asp Leu 2165 2170 2175 Leu His Lys Lys His Tyr Phe Glu Val Leu Met Arg Lys Lys Leu 2180 2185 2190 Asp Pro Ser Gly Thr Leu Lys Thr Ala Leu Leu Asp Tyr Ile Lys 2195 2200 2205 Arg Cys Arg Pro Gly Asp Ser Glu Lys His Asn Met Ile Ala Leu 2210 2215 2220 Cys Phe Ser Met Cys Arg Glu Ile Gly Glu Asn His Glu Ala Ala 2225 2230 2235 Ala Arg Ile Gln Leu Lys Leu Ile Leu Ser Pro Gly Arg Thr Ala 2240 2245 2250 Ser Arg Met Gly Thr Ser 2255 1872285PRTHomo sapiens 187Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe 945 950 955 960 Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965 970 975 Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980 985 990 Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995 1000 1005 Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015 1020 Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030 1035 Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045 1050 Phe Gln

Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060 1065 Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075 1080 Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090 1095 Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100 1105 1110 Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120 1125 Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130 1135 1140 Ile Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150 1155 Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160 1165 1170 Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180 1185 Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195 1200 His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210 1215 Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225 1230 Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240 1245 Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255 1260 Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265 1270 1275 Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285 1290 Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295 1300 1305 Lys Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315 1320 Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325 1330 1335 Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340 1345 1350 Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360 1365 Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375 1380 His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390 1395 Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405 1410 Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420 1425 Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430 1435 1440 Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450 1455 Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460 1465 1470 Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480 1485 Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490 1495 1500 Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505 1510 1515 Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525 1530 Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540 1545 Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555 1560 Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570 1575 Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580 1585 1590 Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595 1600 1605 Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615 1620 Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625 1630 1635 Val Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645 1650 Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655 1660 1665 Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670 1675 1680 Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690 1695 Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705 1710 Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720 1725 Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735 1740 Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750 1755 Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760 1765 1770 Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780 1785 Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790 1795 1800 Cys Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810 1815 Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820 1825 1830 Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835 1840 1845 Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855 1860 Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870 1875 Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885 1890 Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900 1905 Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu Ala Ser 1910 1915 1920 Met Glu Asp Leu His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925 1930 1935 Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro Leu Arg Arg Val 1940 1945 1950 His Ser Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955 1960 1965 Ser Ser Asn Glu Val Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970 1975 1980 Cys Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Cys Leu Tyr 1985 1990 1995 Asp Leu Ala Lys Glu Leu Gly Cys Ser Tyr Thr Asp Val Ala Ala 2000 2005 2010 Gln Asp Gly Glu Ala Met Leu Arg Lys Ile Leu Ala Ser Gln Gln 2015 2020 2025 Pro Asp Arg Cys Lys Arg Ala Gln Ala Phe Ile Ser Thr Gln Gly 2030 2035 2040 Leu Lys Pro Asp Thr Val Ala Glu Leu Val Ala Glu Glu Val Thr 2045 2050 2055 Arg Glu Leu Leu Thr Ser Ser Gln Gly Thr Gly His Lys Gln Met 2060 2065 2070 Phe Asn Pro Thr Glu Glu Ser Gln Thr Phe Leu Gln Leu Thr Thr 2075 2080 2085 Leu Cys Gln Asp Arg Thr Leu Val Gly Met Lys Leu Leu Asp Lys 2090 2095 2100 Ile Ser Ser Val Pro His Gly Glu Leu Ser Cys Thr Thr Glu Leu 2105 2110 2115 Leu Ile Leu Ala His His Cys Phe Thr Leu Thr Cys His Met Glu 2120 2125 2130 Gly Ile Ile Arg Val Leu Gln Ala Ala His Met Leu Thr Asp Asn 2135 2140 2145 His Leu Ala Pro Ser Glu Glu Tyr Gly Leu Val Val Arg Leu Leu 2150 2155 2160 Thr Gly Ile Gly Arg Tyr Asn Glu Met Thr Tyr Ile Phe Asp Leu 2165 2170 2175 Leu His Lys Lys His Tyr Phe Glu Val Leu Met Arg Lys Lys Leu 2180 2185 2190 Asp Pro Ser Gly Thr Leu Lys Thr Ala Leu Leu Asp Tyr Ile Lys 2195 2200 2205 Arg Cys Arg Pro Gly Asp Ser Glu Lys His Asn Met Ile Ala Leu 2210 2215 2220 Cys Phe Ser Met Cys Arg Glu Ile Gly Glu Asn His Glu Ala Ala 2225 2230 2235 Ala Arg Ile Gln Leu Lys Leu Ile Glu Ser Gln Pro Trp Glu Asp 2240 2245 2250 Ser Leu Lys Asp Gly His Gln Leu Lys Gln Leu Leu Leu Lys Ala 2255 2260 2265 Leu Thr Leu Met Leu Asp Ala Ala Glu Ser Tyr Ala Lys Asp Ser 2270 2275 2280 Cys Val 2285 188949PRTHomo sapiens 188Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser 1 5 10 15 Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20 25 30 Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40 45 Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55 60 Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu 65 70 75 80 Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85 90 95 Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105 110 Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120 125 Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135 140 Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His 145 150 155 160 Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165 170 175 Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185 190 Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200 205 Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215 220 Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu 225 230 235 240 His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245 250 255 Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260 265 270 Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275 280 285 Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295 300 Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn 305 310 315 320 Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325 330 335 Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345 350 Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355 360 365 Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370 375 380 Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln 385 390 395 400 Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405 410 415 His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420 425 430 Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440 445 Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455 460 Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu 465 470 475 480 Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu 485 490 495 Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500 505 510 Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520 525 Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530 535 540 Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser 545 550 555 560 Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr 565 570 575 Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580 585 590 Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600 605 Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610 615 620 Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val 625 630 635 640 Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645 650 655 Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660 665 670 Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680 685 Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695 700 Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu 705 710 715 720 Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725 730 735 Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740 745 750 Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760 765 Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775 780 Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr 785 790 795 800 Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805 810 815 Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820 825 830 Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840 845 Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855 860 Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro 865 870 875 880 Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885 890 895 Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905 910 Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915 920 925 Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935 940 Gly Tyr Tyr Asn Cys 945

Claims

1-17. (canceled)

18. A method for detecting the presence of a KIAA1840 nucleic acid mutation in a subject with a family history of hereditary spastic paraplegia (HSP), which method comprises: assaying a sample containing a KIAA1840 nucleic acid from said subject to determine the presence of a mutated KIAA1840 nucleic acid as compared to a control population, wherein said mutated KIAA1840 nucleic acid sequence is at least 90% identical to SEQ ID NO:1 and encodes a truncated form of the KIAA protein, and detecting the mutation in the sample.

19. The method of claim 18, wherein the KIAA 1840 mutation is a substitution selected from the group consisting of c.6100C>T, c.2198T>G, c.118C>T, c.1235C>G, c.2833A>G, c.1951C>T, c.869+1G>A, c. 1679 C>G, c.2316+1G>A, c.2444G>T, c.2444+1G>C, c.2697G>A, c.5470C>T, c.5870C>G, c.6091C>T, c.6477+4 A>G, c.6856C>T, c.1282A>T, and c.5974C>T.

20. The method of claim 18, wherein the KIAA 1840 mutation is a deletion selected from the group consisting of c.529-533delATATT, c.6451delG, c.6832_6833delAG, c.1203delA, c.1549_1550delCT, c.6737_6740delTTGA, c.1471_1472delCT, c.1692delA, c.2716delC, c.1668delT, c.704_705delAT, c.5989_5992delCTGT, c.5532_5533delCA, c.5769delT, c.6739_6742delGAGT, c.4307_4308delAA and c.733_734delAT.

21. The method of claim 18, wherein the KIAA 1840 mutation is an insertion selected from the group consisting of c.7029_7030insT, c.2850_2851insT, c.3741_3742insA, c.5982_5983insCTCT, c.5986_5987insT, c.3075_3076insA and c.2842_2843insG.

22. The method of claim 18, wherein the encoded truncated KIAA1840 protein has an amino acid sequence selected from the group consisting of SEQ ID NO: 149 to SEQ ID NO:164 and SEQ ID NO:166 to SEQ ID NO:188.

23. The method of claim 18 wherein said sample is obtained from a source selected from the group consisting of blood, blood cells, plasma, serum, lymph, buccal cells, epithelial cells, fibroblasts, and cells present in a tissue obtained by biopsy.

24. The method of claim 23, wherein said sample is an DNA sample.

25. The method of claim 24, wherein the sample comprises genomic DNA and the nucleic acid in the sample is amplified using oligonucleotide primers that are specific for a mutated site in the KIAA 1840 nucleic acid or that are capable of amplifying a region containing the mutation.

26. The method of claim 25, wherein the method further comprises DNA sequencing.

27. The method of claim 23 wherein said sample is an RNA sample.

28. The method of claim 27, wherein the sample is subjected to coupled reverse transcription and nucleic acid amplification using oligonucleotide primers specific for a mutated site in the KIAA 1840 nucleic acid or amplify a region containing the mutation.

29. The method of claim 28, wherein the method further comprises DNA sequencing.

30. The method of claim 18, wherein the sample is assayed by at least one process selected from the group consisting of direct sequencing, restriction fragment length polymorphism (RFLP) analysis, hybridization with allele-specific oligonucleotides, allele-specific PCR, PCR using mutagenic primers, ligase-PCR, HOT cleavage, denaturing gradient gel electrophoresis, temperature denaturing gradient gel electrophoresis, single stranded conformational polymorphism and denaturing high performance liquid chromatography.

31. An ex vivo method of diagnosing or predicting a hereditary spastic paraplegia (HSP) in a subject with a family history of hereditary spastic paraplegia (HSP), which method comprises: assaying a sample containing a KIAA1840 nucleic acid from said subject to determine the presence of a mutated KIAA1840 nucleic acid as compared to a control population, wherein said mutated KIAA1840 nucleic acid sequence is at least 90% identical to SEQ ID NO:1 and encodes a truncated form of the KIAA protein, and detecting the mutation in the sample, thereby indicating the subject has, or is likely to develop, HSP.

32. The method of claim 31, wherein the KIAA 1840 mutation is a substitution selected from the group consisting of c.6100C>T, c.2198T>G, c.118C>T, c.1235C>G, c.2833A>G, c.1951C>T, c.869+1G>A, c. 1679 C>G, c.2316+1G>A, c.2444G>T, c.2444+1G>C, c.2697G>A, c.5470C>T, c.5870C>G, c.6091C>T, c.6477+4 A>G, c.6856C>T, c.1282A>T, and c.5974C>T.

33. The method of claim 31, wherein the KIAA 1840 mutation is a deletion selected from the group consisting of c.529-533delATATT, c.6451delG, c.6832_6833delAG, c.1203delA, c.1549_1550delCT, c.6737_6740delTTGA, c.1471_1472delCT, c.1692delA, c.2716delC, c.1668delT, c.704_705delAT, c.5989_5992delCTGT, c.5532_5533delCA, c.5769delT, c.6739_6742delGAGT, c.4307_4308delAA and c.733_734delAT.

34. The method of claim 31, wherein the KIAA 1840 mutation is an insertion selected from the group consisting of c.7029_7030insT, c.2850_2851insT, c.3741_3742insA, c.5982_5983insCTCT, c.5986_5987insT, c.3075_3076insA and c.2842_2843insG.

35. The method of claim 31, wherein the encoded truncated KIAA1840 protein has an amino acid sequence selected from the group consisting of SEQ ID NO: 149 to SEQ ID NO:164 and SEQ ID NO:166 to SEQ ID NO:188

36. The method of claim 31, wherein nucleic acid in the sample is amplified using oligonucleotide primers capable of amplifying a region containing the KIAA1840 mutation.

37. The method of claim 36 further comprising DNA sequencing.