Patent Publication Number: US-6211336-B1

Title: Ataxia-telangiectasia gene

Description:
CROSS REFERENCE 
     This application is a National Phase Application of International Application No. PCT/US96/07040, filed May 16, 1996, which is a continuation-in-part of U.S. Ser. No. 08/508,836, filed Jul. 28, 1995, now U.S. Pat. No. 5,777,093, which is a continuation-in-part of U.S. Ser. No. 08/493,092, filed Jun. 21, 1995, now U.S. Pat. No. 5,728,807 which is a continuation-in-part of U.S. Ser. No. 08/441,822, filed May 16, 1995, now U.S. Pat. No. 5,756,288. 
    
    
     TECHNICAL FIELD 
     The present invention relates to the determination of the gene sequence, mutations of which cause ataxia-telangiectasia (A-T), designated ATM, and the use of the gene and gene products in detection of carriers of the A-T gene, and preparing native and transgenic organisms in which the gene products encoded by the ATM gene or its homolog in other species are artificially produced, or the expression of the native ATM gene is modified. 
     BACKGROUND OF THE INVENTION 
     Ataxia-telangiectasia (A-T) is a progressive genetic disorder affecting the central nervous and immune systems, and involving chromosomal instability, cancer predisposition, radiation sensitivity, and cell cycle abnormalities. Studies of the cellular phenotype of A-T have pointed to a defect in a putative system that processes a specific type of DNA damage and initiates a signal transduction pathway controlling cell cycle progression and repair. For a general review of Ataxia-telangiectasia, reference is hereby made to the review  Ataxia - Telangiectasis: Closer to Unraveling the Mystery,  Eur. J. Hum. Genet. (Shiloh, 1995) which, along with its cited references, is hereby incorporated by reference as well as to the reviews by Harnden (1994) and Taylor et al (1994). 
     Despite extensive investigation over the last two decades, A-T has remained a clinical and molecular enigma. A-T is a multi-system disease inherited in an autosomal recessive manner, with an average worldwide frequency of 1:40,000-1:100,000 live births and an estimated carrier frequency of 1% in the American population. Notable concentrations of A-T patients outside the United States are in Turkey, Italy and Israel. Israeli A-T patients are Moroccan Jews, Palestinian Arabs, Bedouins and Druzes. 
     Cerebellar ataxia that gradually develops into general motor dysfunction is the first clinical hallmark and results from progressive loss of Purkinje cells in the cerebellum. Oculocutaneous telangiectasia (dilation of blood vessels) develops in the bulbar conjunctiva and facial skin, and is later accompanied by graying of the hair and atrophic changes in the skin. The co-occurrence of cerebellar ataxia and telangiectases in the conjunctivae and occasionally on the facial skin—the second early hallmark of the disease—usually establishes the differential diagnosis of A-T from other cerebellar ataxias. Somatic growth is retarded in most patients, and ovarian dysgenesis is typical for female patients. Among occasional endocrine abnormalities, insulin-resistant diabetes is predominant, and serum levels of alpha-fetoprotein and carcinoembryonic antigen are elevated. The thymus is either absent or vestigial, and other immunological defects include reduced levels of serum IgA, IgE or IgG2, peripheral lymphopenia, and reduced responses to viral antigens and allogeneic cells, that cause many patients to suffer from recurrent sinopulmonary infections. 
     Cancer predisposition in A-T is striking: 38% of patients develop malignancies, mainly lymphoreticular neoplasms and leukemias. But, A-T patients manifest acute radiosensitivity and must be treated with reduced radiation doses, and not with radiomimetic chemotherapy. The most common cause of death in A-T, typically during the second or third decade of life, is sinopulmonary infections with or without malignancy. 
     The complexity of the disease is reflected also in the cellular phenotype. Chromosomal instability is expressed as increased chromosomal breakage and the appearance in lymphocytes of clonal translocations specifically involving the loci of the immune system genes. Such clones may later become predominant when a lymphoreticular malignancy appears. Primary fibroblast lines from A-T patients show accelerated senescence, increased demand for certain growth factors, and defective cytoskeletal structure. Most notable is the abnormal response of A-T cells to ionizing radiation and certain radiomimetic chemicals. While hypersensitive to the cytotoxic and clastogenic effects of these agents, DNA synthesis is inhibited by these agents to a lesser extent than in normal cells. The concomitant lack of radiation-induced cell cycle delay and reduction of radiation-induced elevation of p53 protein are evidence of defective checkpoints at the G1, S and G2 phases of the cell cycle. The G1 and G2 checkpoint defects are evident as reduced delay in cell cycle progression following treatment with ionizing radiation or radiomimetic chemicals, while the rise in the p53 protein level usually associated in normal cells with radiation-induced G1 arrest is delayed in A-T cells. The defective checkpoint at the S phase is readily observed as radioresistant DNA synthesis (RDS). Increased intrachromosomal recombination in A-T cells was also noted recently. Cellular sensitivity to DNA damaging agents and RDS are usually considered an integral part of the A-T phenotype. 
     Although these clinical and cellular features are considered common to all “classical” A-T patients, variations have been noted. Milder forms of the disease with later onset, slower clinical progression, reduced radiosensitivity and occasional absence of RDS have been described in several ethnic groups (Fiorilli, 1985; Taylor et al., 1987; Ziv et al., 1989; Chessa et al., 1992). Additional phenotypic variability possibly related to A-T is suggested by several disorders that show “partial A-T phenotype” with varying combinations of ataxia, immunodeficiency and chromosomal instability without telangiectases (12-16) (Ying &amp; Decoteau, 1983; Byrne et al., 1984; Aicardi et al., 1988; Maserati et a;., 1988; Friedman &amp; Weitberg, 1993). Still, other disorders display the A-T phenotype and additional features; most notable is the Nijmegen breakage syndrome that combines A-T features with microcephaly, sometimes with mental retardation, but without telangiectases (Weemaes et al., 1994). 
     Prenatal diagnoses of A-T using cytogenetic analysis or measurements of DNA synthesis have been reported, but these tests are laborious and subject to background fluctuations and, therefore, not widely used. 
     A-T homozygotes have two defective copies of the A-T gene and are affected with the disease. A-T heterozygotes (carriers) have one normal copy of the gene and one defective copy of the gene and are generally healthy. When two carriers have children, there is a 25% risk in every pregnancy of giving birth to an A-T affected child. 
     A-T heterozygotes show a significant excess of various malignancies, with a 3- to 4-fold increased risk for all cancers between the ages of 20 and 80, and a 5-fold increased risk of breast cancer in women. These observations turn A-T into a public health problem and add an important dimension to A-T research, particularly to heterozygote identification. Cultured cells from A-T heterozygotes indeed show an intermediate degree of X-ray sensitivity, but the difference from normal cells is not always large enough to warrant using this criterion as a laboratory assay for carrier detection. The main reason for the unreliability of this assay is the various degrees of overlap between A-T heterozygotes and non-heterozygotes with respect to radiosensitivity. Cytogenetic assays for carriers have the same problems as for prenatal diagnosis, they are labor intensive and not always consistent. 
     The nature of the protein missing in A-T is unknown. Cell fusion studies have established four complementation groups in A-T, designated A, C, D and E, suggesting the probable involvement of at least four genes or four types of mutations in one gene, with inter-allelic complementation. These four groups are clinically indistinguishable and were found to account for 55%, 28%, 14% and 3% of some 80 patients typed to date. In Israel, several Moroccan Jewish patients were assigned to group C, while Palestinian Arab patients were assigned to group A. 
     The general chromosomal localization of the putative A-T gene(s) has been determined, but not the sequence. An A-T locus containing the A-T(A) mutations was localized by Gatti et al. (1988) to chromosome 11, region q22-23, using linkage analysis. The A-T(C) locus was localized by applicant to the same region of chromosome 11, region q22-23, by linkage analysis of an extended Jewish Moroccan A-T family (Ziv et al., 1991). Further studies, conducted by an international consortium in which applicant participated (McConville et al., 1990; Foroud et al., 1991; Ziv et al., 1992), reconfirmed this localization in a series of studies and gradually narrowed the A-T locus to an interval estimated at 4 centimorgan, which probably contains also the A-T(E) mutations. 
     A proposed gene for complementation group D is disclosed in U.S. Pat. No. 5,395,767 to Murnane et al., issued Mar. 7, 1995. This sequence was found not to be mutated in any complementation group of A-T. Further, the gene sequence was mapped physically distant from the presumptive A-T locus. 
     Therefore, in order to better understand the nature and effects of A-T, as well as to more accurately and consistently determine those individuals who may carry the defective gene for A-T, it would be advantageous to isolate and determine the gene sequence, mutations of which are responsible for causing A-T, and utilize this sequence as a basis for detecting carriers of A-T and thereby be able to more beneficially manage the underlying conditions and predispositions of those carriers of the defective gene. 
     SUMMARY OF THE INVENTION AND ADVANTAGES 
     According to the present invention, a gene designated ATM and mutations of this gene which cause ataxia-telangiectasia (A-T), has been purified, isolated and determined as well as mutations of the gene. 
     The present invention further includes the method for identifying carriers of the defective A-T gene in a population and defective A-T gene products. 
     Further, the present invention provides transgenic and knockout nonhuman animal and cellular models. 
     The role of the ATM gene in cancer predisposition makes this gene an important target for screening. The detection of A-T mutation carriers is particularly significant in light of their radiation-sensitivity so that carrier exposure to radiation can be properly monitored and avoided. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     Other advantages of the present invention will be readily appreciated as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings wherein: 
     FIGS. 1A-E illustrate the positional cloning steps to identify the A-T gene(s) wherein 
     FIG. 1A is a high-density marker map of the A-T region on chromosome 11q22-23 (Vanagaite et al., 1995), constructed by generating microsatellite markers within genomic contigs spanning the region and by physical mapping of available markers using the same contigs, the prefix “D11” has been omitted from the marker designations, FDX: the adrenal ferredoxin gene, ACAT: the acetoacetyl-coenzyme A thiolase gene, the stippled box denotes the A-T interval, defined recently by individual recombinants between the markers S1818 and S1819 in a consortium linkage study (Lange et al., 1995), the solid box indicates the two-lod confidence interval for A-T obtained in that study, between S1294 and S384; 
     FIG. 1B illustrates a part of a YAC contig constructed across this region (Rotman et al., 1994c); 
     FIG. 1C illustrates part of a cosmid contig spanning the S384-S1818 interval, generated by screening a chromosome 11 specific cosmid library with YAC clones Y16 and Y67, and subsequent contig assembly of the cosmid clones by physical mapping (Shiloh, 1995); 
     FIG. 1D illustrates products of gene hunting experiments wherein solid boxes denote cDNA fragments obtained by using cosmid and YAC clones for hybrid selection of cDNAs (Lovett et al. 1991; Tagle et al., 1993) from a variety of tissues, open boxes denote putative exons isolated from these cosmids by exon trapping (Church et al., 1993), these sequences hybridized back to specific cosmids (broken lines), which allowed their physical localization to specific subregions of the contig (dotted frames); and 
     FIG. 1E illustrates a 5.9 kb cDNA clone, designated 7-9 (SEQ ID No:1), identified in a fibroblast cDNA library using the cDNA fragments and exons in ID as a probe wherein the open box denotes an open reading frame of 5124 nucleotides, solid lines denote untranslated regions, striped arrowheads denote two Alu elements at the 3′ end, and wherein dotted lines drawn between cDNA fragments and exons the cDNA indicate colinearity of sequences; 
     FIG. 2 is a diagram of the physical map of the ATM region and relationship to the cDNA wherein the top line represents a linear map of the region containing known genetic markers (the prefix D11 has been omitted from marker designations) and shown below the linear map is a portion of a cosmid contig spanning the region with the arch between ends of cosmids A12 and B4 represents a genomic PCR product, a contig of cDNA clones which span the ATM ORF is shown at the bottom of the figure, broken lines denote the position of specific cDNA sequences with the cosmid contig; 
     FIG. 3 is a diagram of the molecular cloning of the coding region of the Atm transcript wherein the top bar depicts the entire length of the cloned sequence, double crosshatched bars are cDNA clones, dotted bars are RT-PCR products, and bars with diagonal lines are PCR products obtained from a cDNA library; 
     FIG. 4 is a diagram of the comparison of amino acid sequences of the human ATM and mouse Atm proteins wherein the alignment of amino acid sequences spanning the carboxy terminal portions that contain the PI 3-kinase domains of the two proteins are depicted with identical amino acids aligned by vertical bars, and similar amino acids by one or two dots; and 
     FIGS. 5A-B diagrams the chromosomal location of Atm in the mouse genome with (A) showing the segregation patterns of Atm and flanking genes wherein each column represents the chromosome identified in the backcross progeny that was inherited from the (C57BL/6J× M. spretus ) F 1  parent, and shaded boxes represent the presence of a C57BL/6J allele and empty boxes represent the presence of a  M. spretus  allele, the number of offspring inheriting each type of chromosome is listed at the bottom of each column, and (B) is a diagram of a partial chromosome 9 linkage map showing the location of Atm in relation to linked genes with the number of recombinant N 2  animals over the total number of N 2  animals typed plus the recombination frequencies, expressed as genetic distance in centimorgans (±one standard error) is shown for each pair of loci to the left of the map, where no recombinants were found between loci, the upper 95% confidence limit of the recombination distance is given in parentheses, the positions of loci in human chromosomes are shown to the right of the map. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
     The present invention consists of a purified, isolated and cloned nucleic acid sequence encoding a gene, designated ATM, mutations in which cause ataxia-telangiectasia and genetic polymorphisms thereof. The nucleic acid can be genomic DNA, cDNA or mRNA. 
     The complete coding sequence of the ATM gene is set forth in SEQ ID No:2 and was submitted to the GenBank database under accession number U33841. There is extensive alternate splicing at the 5′ untranslated region (5′UTR) of the ATM transcript giving rise to twelve different 5′ UTRs. The sequence of the longest 5′UTR is set forth in SEQ ID No:9. The first exon in this sequence is designated 1b. There is an alternative leader exon, designated 1a (SEQ ID No:10). The sequence of the complete 3′UTR is set forth in SEQ ID No:8. Together these sequences contain the complete sequence of the ATM transcript. 
     Polymorphisms are variants in the sequence generally found between different ethnic and geographic locations which, while having a different sequence, produce functionally equivalent gene products. 
     Current mutation data (as shown in Tables 1 and 2) indicate that A-T is a disease characterized by considerable allelic heterogenicity. Mutations imparting defects into the A-T gene can be point mutations, deletions, insertions or rearrangements. The mutations can be present within the nucleotide sequence of either/or both alleles of the ATM gene such that the resulting amino acid sequence of the ATM protein product is altered in one or both copies of the gene product; when present in both copies imparting ataxia-telangiectasia. Alternatively, a mutation event selected from the group consisting of point mutations, deletions, insertions and rearrangements could have occurred within the flanking sequences and/or regulatory sequences of ATM such that regulation of ATM is altered imparting ataxia-telangiectasia. 
     Table 1 illustrates several mutations in the ATM gene found in A-T patients. Mutations in the ATM gene were found in all of the complementation groups suggesting that ATM is the sole gene responsible for all A-T cases. 
     Table 2 illustrates the 44 mutations identified to date in applicant&#39;s patient cohort and include 34 new ones and 10 previously listed in Table 1. These mutations were found amongst 55 A-T families: many are unique to a single family, while others are shared by several families, most notably the 4 nt deletion, 7517del4, which is common to 6 A-T families from South-Central Italy. The nature and location of A-T mutations, as set forth in Table 2, provide insight into the function of the ATM protein and the molecular basis of this pleiotropic disease. 
     This series of 44 A-T mutations is dominated by deletions and insertions. The smaller ones, of less than 12 nt, reflect identical sequence alterations in genomic DNA. Deletions spanning larger segments of the ATM transcript were found to reflect exon skipping, not corresponding genomic deletions. Of the 44 A-T mutations identified, 39 (89%) are expected to inactivate the ATM protein by truncating it, by abolishing correct initiation or termination of translation, or by deleting large segments. Additional mutations are four smaller in-frame deletions and insertions, and one substitution of a highly conserved amino acid at the PI 3-kinase domain. The emerging profile of mutations causing A-T is thus dominated by those expected to completely inactivate the ATM protein. ATM mutations with milder effects appear to result in phenotypes related, but not identical, to A-T. In view of the pleiotropic nature of the ATM gene, the range of phenotypes associated with various ATM genotypes may be even broader, and include mild progressive conditions not always defined as clear clinical entities as discussed herein below in Example 3. Screening for mutations in this gene in such cases will reveal wider boundaries for the molecular pathology associated with the ATM gene. The present invention therefore allows the identification of these mutations in subjects with related phenotypes to A-T. 
     The ATM gene leaves a great deal of room for mutations: it encodes a large transcript. The variety of mutations identified in this study indeed indicates a rich mutation repertoire. Despite this wealth of mutations, their structural characteristics point to a definite bias towards those that inactivate or eliminate the ATM protein. The nature or distribution of the genomic deletions among these mutations do not suggest a special preponderance of the ATM gene for such mutations, such as that of the dystrophin (Anderson and Kunkel, 1992) or steroid sulfatase (Ballabio et al., 1989) genes which are particularly prone to such deletions. Thus, one would have expected also a strong representation of missense mutations, which usually constitute a significant portion of the molecular lesions in many disease genes (Cooper and Krawczak, 1993; Sommer, 1995). However, only one such mutation was identified in the present study. Other point mutations reflected in this series are those that probably underlie the exon skipping deletions observed in many patients, again, exerting a severe structural effect on the ATM protein. 
     In cloning the gene for A-T (Example 2), the strategy used was a standard strategy in identifying a disease gene with an unknown protein product known as positional cloning, as is well known in the art. In positional cloning, the target gene is localized to a specific chromosomal region by establishing linkage between the disease and random genetic markers defined by DNA polymorphisms. Definition of the smallest search interval for the gene by genetic analysis is followed by long-range genomic cloning and identification of transcribed sequences within the interval. The disease gene is then identified among these sequences, mainly by searching for mutations in patients. 
     Several important and long sought disease genes were isolated recently in this way (Collins, 1992; Attree et al., 1992; Berger et al., 1992; Chelly et al., 1993; Vetrie et al., 1993; Trofatter et al., 1993; The Huntington&#39;s Disease Collaborative Research Group, 1993; The European Polycystic Kidney Disease Consortium, 1994; Miki et al., 1994). 
     Two complementary methods were used for the identification of transcribed sequences (gene hunting): hybrid selection based on direct hybridization of genomic DNA with cDNAs from various sources (Parimoo et al., 1991; Lovett et al., 1991); and exon trapping (also called exon amplification), which identifies putative exons in genomic DNA by virtue of their splicing capacity (Church et al., 1993). In hybrid selection experiments, cosmid and YAC clones served to capture cross-hybridizing sequences in cDNA collections from placenta, thymus and fetal brain, using the magnetic bead capture protocol (Morgan et al., 1992; Tagle et al., 1993). In parallel experiments, YAC clones were bound to a solid matrix and used to select cDNA fragments from a heterogeneous cDNA collection representing several human tissues (Parimoo et al., 1993). The cosmids were also used for exon trapping with the pSPL3 vector (Church et al., 1994). The captured cDNA fragments and trapped exons were mapped back to the A-T region by hybridization to several radiation hybrids containing various portions of the 11q22-23 region (Richard et al., 1993; James et al., 1994), and to high-density grids containing all the YACs and cosmids spanning this interval. An extensive transcriptional map of the A-T region was thus constructed (Shiloh et al., 1994). 
     Pools of adjacent cDNA fragments and exons, expected to converge into the same transcriptional units, were used to screen cDNA libraries. A cluster of 5 cDNA fragments and 3 exons mapped in close proximity to the marker D11S535, where the location score for A-T had peaked (Lange et al., 1995). All these sequences hybridized to the same 5.9 kb of the cDNA clone, 7-9, (SEQ ID No:1) obtained from a fibroblast cDNA library. 
     Hybridization of the 7-9 cDNA clone to the radiation hybrid panel indicated that the entire transcript was derived from the chromosome 11 locus. The full sequence of this clone (SEQ ID No:1) was obtained using a shotgun strategy, and found to contain 5921 bp which includes an open reading frame (ORF) of 5124 nucleotides, a 538 bp 3′ untranslated region (3′ UTR), and a 259 bp 5′ non-coding sequence containing stop codons in all reading frames. (Genbank Accession No. U26455). Two Alu repetitive elements were observed at the 3′ end of this clone and in nine smaller clones representing this gene from the same cDNA library. Since no polyadenylation signal was identified in these cDNA clones, their poly(A) tracts were assumed to be associated with the Alu element rather than being authentic poly(A) tails of these transcripts. This assumption was later supported when applicants identified a cDNA clone derived from the same gene in a leukocyte cDNA library, with an alternative 3′ UTR containing a typical polyadenylation signal. Alignment of the cDNA with the genomic physical map showed that the corresponding gene is transcribed from centromere to telomere. 
     Hybridization of a probe containing the entire ORF of clone 7-9 to northern blots from various tissues and cell lines revealed a major transcript of 12 kb, later shown to be 13 kb, in all tissues and cell types examined, and minor species of various sizes in several tissues, possibly representing alternatively spliced transcripts of the corresponding gene or other homologous sequences. Genomic sequencing later identified the 5′ non-coding region of clone 7-9 as sequences of the unspliced adjacent intron. Two other cDNA clones from a leukocyte cDNA library were found to contain this intronic sequence in their 5′ ends. These clones may represent splicing intermediates. 
     The 7-9 cDNA clone represents only part of the ATM gene transcript. Successive screening of randomly-primed cDNA libraries identified a series of partly overlapping cDNA clones and enabled the construction of a cDNA contig of about 10 Kb (FIG.  2 ). The gene coding for this transcript spans about 150 Kb of genomic DNA. 
     The composite cDNA of 9860 bp (GenBank Accession No. U33841; SEQ ID No:2) includes an open reading frame of 9168 nucleotides, a 538 bp 3′ untranslated region (UTR), and a 164 bp 5′ UTR containing stop codons in all reading frames. The sequence surrounding the first in-frame initiation codon (ACC ATG A) resembles the consensus sequence proposed by Kozak for optimal initiation of translation, (A/G)CC ATG G (ref. 20 in Savitsky et al, 1995b). No polyadenylation signal was found at the 3′ UTR. The same poly(A) tail was found in all cDNA clones and 3′ RACE products isolated to date in applicant&#39;s laboratory, however, this poly(A) tail most likely belongs to the Alu element contained in the 3′ UTR. 
     Sequencing and PCR analysis of 32 partial ATM cDNA clones, obtained from 11 cDNA libraries representing 8 different tissues, did not show coding sequences in addition to those presented herein. 
     The invention further provides a purified protein as encoded by the ATM gene (SEQ ID No:2) and analogs thereof. A consensus complete sequence is set forth in SEQ ID No:3. The present invention further provides for mutations in SEQ ID No:2 and SEQ ID No:3 which cause ataxia-telangiectasia, for example, as set forth in Tables 1 and 2. 
     This product (SEQ ID No:3) of the ATM Open Reading Frame (SEQ ID No:2) is a large protein of 3056 amino acids, with an expected molecular weight of 350.6 kDa. The ATM gene product (SEQ ID No:3) contains a PI-3 kinase signature at codons 2855-2875, and a potential leucine zipper at codons 1217-1238. The presence of this leucine zipper may suggest possible dimerization of the ATM protein or interaction with additional proteins. No nuclear localization signal, transmembrane domains or other motifs were observed in this protein sequence. 
     The ATM gene product is a member of a family of large proteins that share a highly conserved carboxy-terminal region of about 300 amino acids showing high sequence homology to the catalytic domain of PI-3 kinases. Among these proteins are Tel1p and Mec1p in budding yeast, rad3p in fission yeast, the TOR proteins in yeast and their mammalian counterpart, FRAP (RAFT1), MEI-41 in  Drosophila melanogaster , and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in mammals. All of these proteins are implicated in cell cycle control and some of them, like Mec1p, rad3p and DNA-PKcs are involved in response to DNA damage (Table 3). The central core of the PI-3 kinase-like domain contains two subdomains with highly conserved residues present in nearly all kinases, including protein and PI-3 kinases. The residues Asp and Asn (at positions 2870 and 2875 in ATM), and the triplet Asp-Phe-Gly (at positions 2889-2891), which represents the most highly conserved short stretch in the protein kinase catalytic domain, have been implicated in the binding of ATP and phosphotransferase activity. Mutations in the genes encoding these proteins result in a variety of phenotypes that share features with A-T, such as radiosensitivity, chromosomal instability, telomere shortening, and defective cell cycle checkpoints (reviewed by Savitsky et al., 1995a and b; Zakian, 1995). 
     A possible working model for the ATM protein&#39;s function is DNA-PK, a serine/threonine protein kinase that is activated in vitro by DNA double-strand breaks and responds by phosphorylating several regulatory proteins (Gottlieb and Jackson, 1994). The ATM protein may be responsible for conveying a signal evoked by a specific DNA damage to various checkpoint systems, possibly via lipid or protein phosphorylation. 
     The present invention further includes a recombinant protein encoded by SEQ ID No:3. This recombinant protein is isolated and purified by techniques known to those skilled in the art. 
     An analog will be generally at least 70% homologous over any portion that is functionally relevant. In more preferred embodiments, the homology will be at least 80% and can approach 95% homology to the ATM protein. The amino acid sequence of an analog may differ from that of the ATM protein when at least one residue is deleted, inserted or substituted but the protein remains functional and does not cause A-T. Differences in glycosylation can provide analogs. 
     The present invention provides an antibody, either polyclonal or monoclonal, which specifically binds to a polypeptide/protein encoded by the ATM gene and/or mutant epitopes on the protein. Examples of such antibodies are set forth in Example 5. In preparing the antibody, the protein (with and without mutations) encoded by the ATM gene and polymorphisms thereof is used as a source of the immunogen. Peptide amino acid sequences isolated from the amino acid sequence as set forth in SEQ ID No:3 or mutant peptide sequences can also be used as an immunogen. 
     The antibodies may be either monoclonal or polyclonal. Conveniently, the antibodies may be prepared against a synthetic peptide based on the sequence, or prepared recombinantly by cloning techniques or the natural gene product and/or portions thereof may be isolated and used as the immunogen. Such proteins or peptides can be used to produce antibodies by standard antibody production technology well known to those skilled in the art as described generally in Harlow and Lane,  Antibodies: A Laboratory Manual,  Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1988. 
     For producing polyclonal antibodies a host, such as a rabbit or goat, is immunized with the protein or peptide, generally with an adjuvant and, if necessary, coupled to a carrier; antibodies to the protein are collected from the sera. 
     For producing monoclonal antibodies, the technique involves hyperimmunization of an appropriate donor, generally a mouse, with the protein or peptide fragment and isolation of splenic antibody producing cells. These cells are fused to a cell having immortality, such as a myeloma cell, to provide a fused cell hybrid which has immortality and secretes the required antibody. The cells are then cultured, in bulk, and the monoclonal antibodies harvested from the culture media for use. 
     The antibody can be bound to a solid support substrate or conjugated with a detectable moiety or be both bound and conjugated as is well known in the art. (For a general discussion of conjugation of fluorescent or enzymatic moieties see Johnstone and Thorpe,  Immunochemistry in Practice,  Blackwell Scientific Publications, Oxford, 1982.) The binding of antibodies to a solid support substrate is also well known in the art. (see for a general discussion Harlow and Lane  Antibodies: A Laboratory Manual,  Cold Spring Harbor Laboratory Publications, New York, 1988) The detectable moieties contemplated with the present invention can include, but are not limited to, fluorescent, metallic, enzymatic and radioactive markers such as biotin, gold, ferritin, alkaline phosphatase, β-galactosidase, peroxidase, urease, fluorescein, rhodamine, tritium,  14 C and iodination. 
     The present invention provides vectors comprising an expression control sequence operatively linked to the nucleic acid sequence of the ATM gene, SEQ ID No:2 and portions thereof as well as mutant sequences which lead to the expression of A-T. The present invention further provides host cells, selected from suitable eucaryotic and procaryotic cells, which are transformed with these vectors. 
     Using the present invention, it is possible to transform host cells, including  E. coli , using the appropriate vectors so that they carry recombinant DNA sequences derived from the ATM transcript or containing the entire ATM transcript in its normal form or a mutated sequence containing point mutations, deletions, insertions, or rearrangements of DNA which lead to the expression of A-T. Such transformed cells allow the study of the function and the regulation of the A-T gene. Use of recombinantly transformed host cells allows for the study of the mechanisms of A-T and, in particular it will allow for the study of gene function interrupted by the mutations in the A-T gene region. 
     Vectors are known or can be constructed by those skilled in the art and should contain all expression elements necessary to achieve the desired transcription of the sequences. Other beneficial characteristics can also be contained within the vectors such as mechanisms for recovery of the nucleic acids in a different form. Phagemids are a specific example of such beneficial vectors because they can be used either as plasmids or as bacteriophage vectors. Examples of other vectors include viruses such as bacteriophages, baculoviruses and retroviruses, DNA viruses, cosmids, plasmids and other recombination vectors. The vectors can also contain elements for use in either procaryotic or eucaryotic host systems. One of ordinary skill in the art will know which host systems are compatible with a particular vector. 
     The vectors can be introduced into cells or tissues by any one of a variety of known methods within the art. Such methods can be found generally described in Sambrook et al.,  Molecular Cloning: A Laboratory Manual,  Cold Springs Harbor Laboratory, New York (1992), in Ausubel et al.,  Current Protocols in Molecular Biology,  John Wiley and Sons, Baltimore, Md. (1989), Chang et al.,  Somatic Gene Therapy,  CRC Press, Ann Arbor, Mich. (1995), Vega et al.,  Gene Targeting,  CRC Press, Ann Arbor, Mich. (1995) and Gilboa et al (1986) and include, for example, stable or transient transfection, lipofection, electroporation and infection with recombinant viral vectors. Introduction of nucleic acids by infection offers several advantages over the other listed methods. Higher efficiency can be obtained due to their infectious nature. See also U.S. Pat. Nos. 5,487,992 and 5,464,764. Moreover, viruses are very specialized and typically infect and propagate in specific cell types. Thus, their natural specificity can be used to target the vectors to specific cell types in vivo or within a tissue or mixed culture of cells. Viral vectors can also be modified with specific receptors or ligands to alter target specificity through receptor mediated events. 
     Recombinant methods known in the art can also be used to achieve the sense, antisense or triplex inhibition of a target nucleic acid. For example, vectors containing antisense nucleic acids can be employed to express protein or antisense message to reduce the expression of the target nucleic acid and therefore its activity. 
     A specific example of DNA viral vector for introducing and expressing antisense nucleic acids is the adenovirus derived vector Adenop53TK. This vector expresses a herpes virus thymidine kinase (TK) gene for either positive or negative selection and an expression cassette for desired recombinant sequences such as antisense sequences. This vector can be used to infect cells that have an adenovirus receptor which includes most cancers of epithelial origin as well as others. This vector as well as others that exhibit similar desired functions can be used to treat a mixed population of cells include, for example, an in vitro or ex vivo culture of cells, a tissue or a human subject. 
     Additional features can be added to the vector to ensure its safety and/or enhance its therapeutic efficacy. Such features include, for example, markers that can be used to negatively select against cells infected with the recombinant virus. An example of such a negative selection marker is the TK gene described above that confers sensitivity to the anti-viral gancyclovir. Negative selection is therefore a means by which infection can be controlled because it provides inducible suicide through the addition of antibiotic. Such protection ensures that if, for example, mutations arise that produce altered forms of the viral vector or sequence, cellular transformation will not occur. Features that limit expression to particular cell types can also be included. Such features include, for example, promoter and regulatory elements that are specific for the desired cell type. 
     Recombinant viral vectors are another example of vectors useful for in vivo expression of a desired nucleic acid because they offer advantages such as lateral infection and targeting specificity. Lateral infection is inherent in the life cycle of, for example, retrovirus and is the process by which a single infected cell produces many progeny virions that bud off and infect neighboring cells. The result is that a large area becomes rapidly infected, most of which was not initially infected by the original viral particles. This is in contrast to vertical-type of infection in which the infectious agent spreads only through daughter progeny. Viral vectors can also be produced that are unable to spread laterally. This characteristic can be useful if the desired purpose is to introduce a specified gene into only a localized number of targeted cells. 
     As described above, viruses are very specialized infectious agents that have evolved, in many cases, to elude host defense mechanisms. Typically, viruses infect and propagate in specific cell types. The targeting specificity of viral vectors utilizes its natural specificity to specifically target predetermined cell types and thereby introduce a recombinant gene into the infected cell. The vector to be used in the methods of the invention will depend on desired cell type to be targeted. For example, if breast cancer is to be treated, then a vector specific for such epithelial cells should be used. Likewise, if diseases or pathological conditions of the hematopoietic system are to be treated, then a viral vector that is specific for blood cells and their precursors, preferably for the specific type of hematopoietic cell, should be used. 
     Retroviral vectors can be constructed to function either as infectious particles or to undergo only a single initial round of infection. In the former case, the genome of the virus is modified so that it maintains all the necessary genes, regulatory sequences and packaging signals to synthesize new viral proteins and RNA. Once these molecules are synthesized, the host cell packages the RNA into new viral particles which are capable of undergoing further rounds of infection. The vector&#39;s genome is also engineered to encode and express the desired recombinant gene. In the case of non-infectious viral vectors, the vector genome is usually mutated to destroy the viral packaging signal that is required to encapsulate the RNA into viral particles. Without such a signal, any particles that are formed will not contain a genome and therefore cannot proceed through subsequent rounds of infection. The specific type of vector will depend upon the intended application. The actual vectors are also known and readily available within the art or can be constructed by one skilled in the art using well-known methodology. 
     If viral vectors are used, for example, the procedure can take advantage of their target specificity and consequently, do not have to be administered locally at the diseased site. However, local administration may provide a quicker and more effective treatment, administration can also be performed by, for example, intravenous or subcutaneous injection into the subject. Injection of the viral vectors into a spinal fluid can also be used as a mode of administration, especially in the case of neuro-degenerative diseases. Following injection, the viral vectors will circulate until they recognize host cells with the appropriate target specificity for infection. 
     Transfection vehicles such as liposomes can also be used to introduce the non-viral vectors described above into recipient cells within the inoculated area. Such transfection vehicles are known by one skilled within the art. 
     The present invention includes the construction of transgenic and knockout organisms that exhibit the phenotypic manifestations of A-T. The present invention provides for transgenic ATM gene and mutant ATM gene animal and cellular (cell lines) models as well as for knockout ATM models. The transgenic models include those carrying the sequence set forth SEQ ID Nos:2,8,9 (or 10). These models are constructed using standard methods known in the art and as set forth in U.S. Pat. Nos. 5,487,992, 5,464,764, 5,387,742, 5,360,735, 5,347,075, 5,298,422, 5,288,846, 5,221,778, 5,175,385, 5,175,384, 5,175,383, 4,736,866 as well as Burke and Olson, (1991), Capecchi, (1989), Davies et al., (1992), Dickinson et al., (1993), Huxley et al., (1991), Jakobovits et al., (1993), Lamb et al., (1993), Rothstein, (1991), Schedl et al., (1993), Strauss et al., (1993). Further, patent applications WO 94/23049, WO 93/14200, WO 94/06908, WO 94/28123 also provide information. See also in general Hogan et al “Manipulating the Mouse Embryo” Cold Spring Harbor Laboratory Press, 2nd Edition (1994). 
     Further, the mouse homolog of the A-T gene, designated Atm, has been identified as set forth in detail in Example 4, hereinbelow. The coding sequence of Atm (SEQ ID No:11), the mouse homolog of the human gene ATM defective in A-T, was cloned and found to contain an open reading frame encoding a protein of 3,066 amino acids (SEQ ID No:12) with 84% overall identity and 91% similarity to the human ATM protein (SEQ ID No:3). Variable levels of expression of Atm were observed in different tissues. Fluorescence in situ hybridization and linkage analysis located the Atm gene on mouse chromosome 9, band 9C, in a region homologous to the ATM region on human chromosome 11q22-23. The present invention includes the -construction of mice in which the mouse homolog of the A-T gene has been knocked out. 
     According to the present invention, there is provided a method for diagnosing and detecting carriers of the defective gene responsible for causing A-T. The present invention further provides methods for detecting normal copies of the ATM gene and its gene product. Carrier detection is especially important since A-T mutations underlie certain cases of cancer predisposition in the general population. Identifying the carriers either by their defective gene or by their missing or defective protein(s) encoded thereby, leads to earlier and more consistent diagnosis of A-T gene carriers. Thus, since carriers of the disease are more likely to be cancer-prone and/or sensitive to therapeutic applications of radiation, better surveillance and treatment protocols can be initiated for them. Conversely, exclusion of A-T heterozygotes from patients undergoing radiotherapy can allow for establishing routinely higher dose schedules for other cancer patients thereby improving the efficacy of their treatment. 
     Briefly, the methods comprise the steps of obtaining a sample from a test subject, isolating the appropriate test material from the sample and assaying for the target nucleic acid sequence or gene product. The sample can be tissue or bodily fluids from which genetic material and/or proteins are isolated using methods standard in the art. For example, DNA can be isolated from lymphocytes, cells in amniotic fluid and chorionic villi (Llerena et al., 1989). 
     More specifically, the method of carrier detection is carried out by first obtaining a sample of either cells or bodily fluid from a subject. Convenient methods for obtaining a cellular sample can include collection of either mouth wash fluids or hair roots. A cell sample could be amniotic or placental cells or tissue in the case of a prenatal diagnosis. A crude DNA could be made from the cells (or alternatively proteins isolated) by techniques well known in the art. This isolated target DNA is then used for PCR analysis (or alternatively, Western blot analysis for proteins from a cell line established from the subject) with appropriate primers derived from the gene sequence by techniques well known in the art. The PCR product would then be tested for the presence of appropriate sequence variations in order to assess genotypic A-T status of the subject. 
     The specimen can be assayed for polypeptides/proteins by immunohistochemical and immunocytochemical staining (see generally Stites and Terr,  Basic and Clinical Immunology,  Appleton and Lange, 1994), ELISA, RIA, immunoblots, Western blotting, immunoprecipitation, functional assays and protein truncation test. In preferred embodiments, Western blotting, functional assays and protein truncation test (Hogervorst et al., 1995) will be used. mRNA complementary to the target nucleic acid sequence can be assayed by in situ hybridization, Northern blotting and reverse transcriptase-polymerase chain reaction. Nucleic acid sequences can be identified by in situ hybridization, Southern blotting, single strand conformational polymorphism, PCR amplification and DNA-chip analysis using specific primers. (Kawasaki, 1990; Sambrook, 1992; Lichter et al, 1990; Orita et al, 1989; Fodor et al., 1993; Pease et al., 1994) 
     ELISA assays are well known to those skilled in the art. Both polyclonal and monoclonal antibodies can be used in the assays. Where appropriate other immunoassays, such as radioimmunoassays (RIA) can be used as are known to those in the art. Available immunoassays are extensively described in the patent and scientific literature. See, for example, U.S. Pat. Nos. 3,791,932; 3,839,153; 3,850,752; 3,850,578; 3,853,987; 3,867,517; 3,879,262; 3,901,654; 3,935,074; 3,984,533; 3,996,345; 4,034,074; 4,098,876; 4,879,219; 5,011,771 and 5,281,521 as well as Sambrook et al, 1992. 
     Current mutation data (as shown in Tables 1 and 2) indicate that A-T is a disease characterized by considerable allelic heterogenicity. It is not surprising that there are hundreds (or even thousands) of ATM mutations (as is the case for cystic fibrosis and BRCAI) as shown in Table 2. Thus, it will be important for a successful mutation screen to be able to detect all possible nucleotide alterations in the ATM gene, rather than being focused on a limited subset. Methods including direct sequencing of PCR amplified DNA or RNA or DNA chip hybridization (Fodor et al., 1993; Pease et al., 1994) can be applied along with other suitable methods known to those skilled in the art. 
     In order to use the method of the present invention for diagnostic applications, it is advantageous to include a mechanism for identifying the presence or absence of target polynucleotide sequence (or alternatively proteins). In many hybridization based diagnostic or experimental procedures, a label or tag is used to detect or visualize for the presence or absence of a particular polynucleotide sequence. Typically, oligomer probes are labelled with radioisotopes such as  32 P or  35 S (Sambrook, 1992) which can be detected by methods well known in the art such as autoradiography. Oligomer probes can also be labelled by non-radioactive methods such as chemiluminescent materials which can be detected by autoradiography (Sambrook, 1992). Also, enzyme-substrate based labelling and detection methods can be used. Labelling can be accomplished by mechanisms well known in the art such as end labelling (Sambrook, 1992), chemical labelling, or by hybridization with another labelled oligonucleotide. These methods of labelling and detection are provided merely as examples and are not meant to provide a complete and exhaustive list of all the methods known in the art. 
     The introduction of a label for detection purposes can be accomplished by attaching the label to the probe prior to hybridization. 
     An alternative method for practicing the method of the present invention includes the step of binding the target DNA to a solid support prior to the application of the probe. The solid support can be any material capable of binding the target DNA, such as beads or a membranous material such as nitrocellulose or nylon. After the target DNA is bound to the solid support, the probe oligomers is applied. 
     Functional assays can be used for detection of A-T carriers or affected individuals. For example, if the ATM protein product is shown to have PI 3-kinase biochemical activity which can be assayed in an accessible biological material, such as serum, peripheral leukocytes, etc., then homozygous normal individuals would have approximately normal biological activity and serve as the positive control. A-T carriers would have substantially less than normal biological activity, and affected (i.e. homozygous) individuals would have even less biological activity and serve as a negative control. Such a biochemical assay currently serves as the basis for Tay-Sachs carrier detection. 
     The present invention also provides a kit for diagnosis and detection of the defective A-T gene in populations. The kit includes a molecular probe complementary to genetic sequences of the defective gene which causes ataxia-telangiectasia (A-T) and suitable labels for detecting hybridization of the molecular probe and the defective gene thereby indicating the presence of the defective gene. The molecular probe has a DNA sequence complementary to mutant sequences in the population. Alternatively, the kit can contain reagents and antibodies for detection of mutant proteins. 
     The above discussion provides a factual basis for the use and identification of the ataxia-telangiectasia gene and gene products and identification of carriers as well as construction of transgenic organisms. The methods used in the present invention can be shown by the following non-limiting example and accompanying figures. 
     EXAMPLES 
     Materials and Methods 
     General methods in molecular biology: 
     Standard molecular biology techniques known in the art and not specifically described were generally followed as in Sambrook et al.,  Molecular Cloning: A Laboratory Manual,  Cold Springs Harbor Laboratory, New York (1989, 1992), and in Ausubel et al.,  Current Protocols in Molecular Biology,  John Wiley and Sons, Baltimore, Md. (1989) and methodology as set forth in U.S. Pat. Nos. 4,666,828; 4,683,202; 4,801,531; 5,192,659 and 5,272,057. Polymerase chain reaction (PCR) was carried out generally as in  PCR Protocols: A Guide To Methods And Applications,  Academic Press, San Diego, Calif. (1990). Protein analysis techniques were as described in Coligan et al.,  Current Protocols in Immunology,  John Wiley and Sons, Baltimore, Md. (1992, 1994). 
     Patient and family resources: 
     A cell line repository was established containing 230 patient cell lines and 143 cell lines from healthy members of Moroccan Jewish, Palestinian Arab and Druze families. Some of these pedigrees are highly inbred and unusually large (Ziv et al., 1991; Ziv, 1992). In view of the large number of meiotic events required for high-resolution linkage analysis, applicants collaborated with Dr. Carmel McConville (University of Birmingham, UK) and Dr. Richard Gatti (UCLA, Los Angeles, Calif.), who have also established extensive repositories of A-T families. Linkage analysis was conducted on a pool of 176 families. 
     EXAMPLE 1 
     Definition of the A-T Interval by Genetic Analysis 
     Studies based only on analysis of Israeli A-T families enabled localization of the A-T(C) gene at 11q22-23 (Ziv, 1991), and confirmed the localization of A-T(A) mutation in Palestinians to the same region (Ziv et al., 1992). Studies with the Birmingham group further narrowed the major A-T interval to 4 centimorgans, between D11S611 and D11S1897 (McConville et al., 1993), and subsequently to 3 centimorgans, between GRIA4 and D11S1897 (Ambrose et al., 1994; McConville et al., 1994; Shiloh, 1995, and FIG.  1 ). 
     All these studies were conducted with biallelic markers, whose power is limited by their low polymorphic information content (PIC). The recently discovered microsatellite markers based on variable numbers of tandem simple repeats (Litt and Luty, 1989; Weber and May, 1989) are much more powerful due to their high degree of polymorphism. Microsatellite markers were used to saturate the A-T region using two approaches. The first, was based on physical mapping of microsatellite markers generated by others which were loosely linked to chromosome 11q. 
     Mapping experiments were conducted using YAC and cosmid contigs which allowed precise, high-resolution localization of DNA sequences in this region of chromosome 11. Twelve microsatellites were localized at the A-T region (Vanagaite et al., 1994a; Vanagaite et al., 1995). 
     The second approach was based on generating new microsatellites within the YAC contig. A rapid method for the identification of polymorphic CA-repeats in YAC clones was set up (Rotman, 1995) resulting in the generation of twelve new markers within the A-T locus (Vanagaite et al., 1995; Rotman et al., 1995; Rotman et al., 1994b). Hence, the high-density microsatellite map constructed in this manner contained a total of 24 new microsatellite markers and spans the A-T locus and flanking sequences, over a total of six megabases (Vanagaite et al., 1995). 
     Repeated linkage analysis on the entire cohort of A-T families indicated that the A-T(A) locus was definitely located within a 1.5 megabase region between D11S1819 and D11S1818 (Gatti et al., 1994) as shown in FIG.  1  and in Shiloh (1995), with a clear peak of the cumulative lod score under D11S535 (Lange et al., 1994). 
     Concomitant with these studies, linkage disequilibrium (LD) analysis of Moroccan-Jewish A-T patients was conducted. LD refers to the non-random association between alleles at two or more polymorphic loci (Chakravarti et al., 1984). LD between disease loci and linked markers is a useful tool for the fine localization of disease genes (Chakravarti et al., 1984; Kerem et al. 1989; Ozelius et al., 1992; Sirugo et al., 1992; Hastbacka et al., 1992; Mitchison et al., 1993). LD is particularly powerful in isolated ethnic groups, where the number of different mutations at a disease locus is likely to be low (Hastbacka et al., 1992; Lehesjoki et al., 1993; Aksentijevitch et al., 1993). Early on, applicants observed very significant LD (p&lt;0.02-p&lt;0.001) between A-T and markers along the D11S1817-D11S927 region in the patients of the sixteen Moroccan-Jewish A-T families identified in Israel (Oskato et al., 1993). Further analysis with the new markers narrowed the peak of linkage disequilibrium to the D11S384-D11S1818 region as shown in FIG.  1 . 
     Haplotype analysis indicated that all of the mutant chromosomes carry the same D11S384-D11S1818 haplotype, suggesting a founder effect for A-T in this community, with one mutation predominating. 
     EXAMPLE 2 
     SEQUENCING THE ATM GENE 
     Cloning the disease locus in a contig (set of overlapping clones) was essential in isolating the. A-T disease gene. The entire A-T locus and flanking region in a contig of yeast artificial chromosomes (YACs) was cloned by methods well known in the art (Rotman et al. 1994c; Rotman et al., 1994d). This contig was instrumental in the construction of the microsatellite map of the region (Vanagaite et al., 1995) and subsequently enabled construction of cosmid contigs extending over most of the interval D11S384-D11S1818. Cosmids corresponding to the YAC clones were identified in a chromosome 11-specific cosmid library supplied by Dr. L. Deaven (Los Alamos National Laboratory) and were ordered into contigs by identifying overlaps as shown in FIG.  1 . 
     Isolation of the A-T gene: 
     Transcribed sequences were systematically identified based on two complementary methods: 
     1. Use of an improved direct selection method based on magnetic bead capture (MBC) of cDNAs corresponding to genomic clones (Morgan et al., 1992; Tagle et al., 1993). In several, large-scale experiments YAC or cosmid DNA was biotinylated and hybridized to PCR-amplified cDNA from thymus, brain and placenta. Genomic DNA-cDNA complexes were captured using streptavidin-coated magnetic beads which was followed with subsequent elution, amplification, and cloning of captured cDNAs. The cDNA inserts were excised from a gel, self-ligated to form concatamers and sonicated to obtain random fragments. These fragments were size fractionated by gel electrophoresis, and the 1.0-1.5 Kb fraction was extracted from the gel and subcloned in a plasmid vector. The end portions of individual clones were sequenced using vector-specific primers, in an automated sequencer (Model 373A, Applied Biosystems), and the sequences were aligned using the AutoAssembler program (Applied Biosystems Division, Perkin-Elmer Corporation). In the final sequence each nucleotide position represents at least 3 independent overlapping readings. 
     YACs were also used and were no less efficient than cosmids as starting material for MBC, with more than 50% of the products mapping back to the genomic clones. However, when a small panel of radiation hybrids spanning the A-T region was used to test the cDNA fragments, it was found that some clones that hybridized back to the. YACs and cosmids were not derived from this region. This pitfall probably stems from limited homology between certain portions of different genes, and points up the necessity to use radiation hybrid mapping when testing the authenticity of the captured sequences, and not to rely solely on cloned DNA for this purpose. 
     Homology searches in sequence databases showed that only one of the first 105 cDNA fragments mapped to the A-T region was homologous to a sequence previously deposited in one of the databases, as an expressed sequence tag (EST). 
     2. Exon amplification, also termed “exon trapping” (Duyk et al., 1990; Buckler et al., 1991), is based on cloning genomic fragments into a vector in which exon splice sites are flagged by splicing to their counterpart sites in the vector. This method of gene identification was expected to complement the MBC strategy, since it does not depend on the constitution of cDNA libraries or on the relative abundance of transcripts, and is not affected by the presence of repetitive sequences in the genomic clones. An improved version of this system (Church et al., 1993) that eliminated problems identified in an earlier version, including a high percentage of false positives and the effect of cryptic splice sites was utilized. Each experiment ran a pool of three to five cosmids with an average of two to five exons identified per cosmid. A total of forty five exons were identified. 
     Sequence analysis and physical mapping indicated that MBC and exon amplification were complementary in identifying transcribed sequences. 
     The availability of a deep cosmid contig enabled rapid and precise physical localization of the cDNA fragments and captured exons, leading to a detailed transcriptional map of the A-T region. 
     Both MBC and exon amplification yielded short (100-1000 bp) transcribed sequences. Those sequences were used as anchor points in isolating full-length clones from twenty eight cDNA libraries currently at applicants disposal and which represented a variety of tissues and cell lines. 
     Initial screening of the cDNA libraries by polymerase chain reaction (PCR) using primer sets derived from individual cDNA fragments or exons aided in the identification of the libraries most likely to yield corresponding cDNA clones. 
     Large scale screening experiments were carried out in which most of the cDNA fragments and exons were used in large pools. In addition to the mass screening by hybridization, PCR-based screening methods and RACE (rapid amplification of cDNA ends) (Frohman et al., 1988; Frohman et al., 1994) was employed to identify full-length cDNAs. 
     The above experiments resulted in the initial identification and isolation of a cDNA clone designated 7-9 (Savitsky et al, 1995a), the complete sequence of which is set forth in SEQ ID No:1 and which is derived from a gene located under the peak of cumulative location score obtained by linkage analysis as shown in FIG.  1 . The gene extends over some 300 kilobases (kb) of genomic DNA and codes for two major mRNA species of 12 kb and 10.5 kb in length. The 7-9 clone is 5.9 kb in length and, therefore, is not a full length clone. 
     An open reading frame of 5124 bp within this cDNA encodes a protein with signature motifs typical of a group of signal transduction proteins known as phosphatidylinositol 3-kinases (PI 3-kinases). PI 3-kinases take part in the complex system responsible for transmitting signals from the outer environment of a cell into the cell. It is not clear yet whether the protein product of the corresponding gene encodes a lipid kinase or a protein kinase. 
     The gene encoding the 7-9 cDNA clone was considered a strong A-T candidate and mutations were sought in patients. Southern blotting analysis revealed a homozygous deletion in this gene in affected members of Family N., an extended Palestinian Arab A-T family which has not been assigned to a specific complementation group. All the patients in this family are expected to be homozygous by descent for a single A-T mutation. The deletion includes almost the entire genomic region spanned by transcript 7-9, and was found to segregate in the family together with the disease. This finding led to a systematic search for mutations in the 7-9 transcript in additional patients, especially those previously assigned to specific complementation groups. 
     The restriction endonuclease fingerprinting (REF) method (Liu and Sommer 1995) was applied to reverse-transcribed and PCR-amplified RNA (RT-PCR) from A-T cell lines. Observation of abnormal REF patterns was followed by direct sequencing of the relevant portion of the transcript and repeated analysis of another independent RT product. In compound heterozygotes, the two alleles were separated by subcloning of RT-PCR products and individually sequenced. Genomic sequencing was conducted in some cases to confirm the sequence alteration at the genomic level. Additional family members were studied when available. 
     Ten sequence alterations (Table 1) were identified in the 7-9 transcript in 13 A-T patients including two sibling pairs. Most of these sequence changes are expected to lead to premature truncation of the protein product, while the rest are expected to create in-frame deletions of 1-3 amino acid residues in this protein. While the consequences of the in-frame deletions remain to be investigated, it is reasonable to assume that they result in impairment of protein function. In one patient, AT3NG, the loss of a serine residue at position 1512 occurs within the PI3-kinase signature sequence. This well conserved domain is distantly related to the catalytic site of protein kinases, hence this mutation is likely to functionally affect the 7-9 protein. 
     In view of the strong evidence that mutations in this gene are responsible for A-T, it was designated ATM (A-T, Mutated). Since these patients represent all complementation groups of the disease and considerable ethnic variability, these results indicate that the ATM gene alone is responsible for all A-T cases. 
     In order to complete the cloning of the entire ATM open reading frame, fetal brain and colon random-primed libraries obtained from Stratagene (San Diego, Calif.) and an endothelial cell random-primed library (a gift of Dr. David Ginsburg, University of Michigan) were screened. A total of 1×10 6  pfu were screened at a density of 40,000 pfu per 140 mm plate, and replicas were made on Qiabrane filters (Qiagen), as recommended by the manufacturer. Filters were prehybridized in a solution containing 6×SSC, 5×Denhardt&#39;s, 1% N-laurylsarcosyl, 10% dextran sulfate and 100 μg/ml salmon sperm DNA for 2 hours at 65° C. Hybridization was performed for 16 hrs under the same conditions with 1×10 6  cpm/ml of  32 P-labelled probe, followed by final washes of 30 minutes in 0.25×SSC, 0.1%SDS at 60° C. Positive clones were plaque-purified using standard techniques and sequenced. DNA sequencing was performed using an automated DNA sequencer (Applied Biosystems, model 373A), and the sequence was assembled using the AutoAssembler program (Applied Biosystems Division, Perkin-Elmer Corporation). In the final sequence, each nucleotide represents at least four independent readings in both directions. 
     Database searches for sequence similarities were performed using the BLAST network service. Alignment of protein sequences and pairwise comparisons were done using the MACAW program, and the PILEUP and BESTFIT programs in the sequence analysis software package developed by the Genetics Computer Group at the University of Wisconsin. 
     EXAMPLE 3 
     DETECTION OF MUTATIONS 
     Determination of mutations: 
     The recently discovered ATM gene is probably involved in a novel signal transduction system that links DNA damage surveillance to cell cycle control. A-T mutations affect a variety of tissues and lead to cancer predisposition. This striking phenotype together with the existence of “partial A-T phenotypes” endow the study of ATM mutations with special significance. 
     MATERIALS AND METHODS 
     RT-PCR: 
     Total RNA was extracted from cultured fibroblast or lymphoblast cells using the Tri-Reagent system (Molecular research Center, Cincinnati, Ohio). Reverse transcription was performed on 2.5 ug of total RNA in a final volume of 10 ul, using the Superscript II Reverse Transcriptase (Gibco BRL, Gaithersburg, Md.) in the buffer recommended by the supplier, and in the presence of 125 U/ml of RNAsin (Promega) and 1 mM dNTPs (Pharmacia). Primers were either oligo(dT) (Pharmacia) or a specifically designed primer. The reaction products were used as templates for PCR performed with specific primers. These reactions were carried out in 50 μl containing 2 units of Taq DNA Polymerase (Boehringer Mannheim, Mannheim, Germany), 200 μM dNTPs, 0.5 μM of each primer, and one tenth of the RT-PCR products. The products were purified using the QIA-quick spin system (Qiagen, Hilden, Germany). 
     Restriction endonuclease fingerprinting: 
     The protocol of Liu and Sommer (1995) was followed with slight modifications. RT-PCR was performed as described above, using primers defining PCR products of 1.0-1.6 kb. One hundred ng of amplified DNA was digested separately with 5 or 6 restriction endonucleases in the presence of 0.2 units of shrimp alkaline phosphatase (United States Biochemicals, Cleveland, Ohio). Following heat inactivation at 65° C. for 10 minutes, the digestion products corresponding to the same PCR product were pooled, denatured at 96° C. for 5 minutes and immediately chilled on ice. Ten ng of this fragment mixture was labeled in the presence of 6 μCi of [γ- 33 P]ATP and 1 unit of T4 polynucleotide kinase (New England Biolabs, Beverly, Mass.) at 37° C. for 45 minutes. Twenty μl of stop solution containing 95% formamide, 20 mM EDTA, 0.05% bromophenol blue, 0.05% xylene cyanol, and 10 mM NaOH were added, and the samples were boiled for 3 minutes and quick-chilled on ice. Electrophoresis was performed in 5.6% polyacrylamide gels in 50 mM Tris-borate, pH 8.3, 1 mM EDTA at constant power of 12 W for 3 hours at room temperature, with a fan directed to the glass plates, keeping them at 22-24° C. The gels were dried and subjected to autoradiography. 
     Direct sequencing of PCR products: 
     Five hundred ng of PCR products was dried under vacuum, resuspended in reaction buffer containing the sequencing primer, and the mixture was boiled and snap-frozen in liquid nitrogen. The Sequenase II system (Unites States Biochemicals) was used to carry out the sequencing reaction in the presence of 0.5 μg of single-strand binding protein (T4 gene 32 protein, United States Biochemicals). The reaction products were treated with 0.1 μg of proteinase K at 65° C. for 15 minutes, separated on a 6% polyacrylamide gel, and visualized by autoradiography. 
     Using the methods described herein above the ATM transcript was scanned for mutations in fibroblast and lymphoblast cell lines derived from an extended series of A-T patients from 13 countries, all of whom were characterized by the classical A-T phenotype. The analysis was based on RT-PCR followed by restriction endonuclease fingerprinting (REF). REF is a modification of the single-strand conformation polymorphism (SSCP) method, and enables efficient detection of sequence alterations in DNA fragments up to 2 kb in length (Liu and Sommer, 1995). 
     Briefly, after PCR amplification of the target region, multiple restriction endonuclease digestions are performed prior to SSCP analysis, in order to increase the sensitivity of the method and enable precise localization of a sequence alteration within the analyzed fragment. The coding sequence of the ATM transcript, which spans 9168 nucleotides (SEQ ID No:2) (Savitsky et al., 1995b), was thus divided into 8 partly overlapping portions of 1.0-1.6 Kb, and each one was analyzed separately. Sequence alterations causing. abnormal REF patterns were located and disclosed by direct sequencing. Mutations identified in this way were reconfirmed by repeating the RT-PCR and sequencing, or by testing the presence of the same mutations in genomic DNA. 
     In compound heterozygotes, the two alleles were separated by subcloning and individually sequenced. In some cases, agarose gel electrophoresis showed large deletions in the ATM transcript manifested as RT-PCR products of reduced sizes. The breakpoints of such deletions were delineated by direct sequencing of these products. 
     The 44 mutations identified to date in our patient cohort (Table 2) include 34 new ones and 10 previously published ones (Table 1). (Mutations in Table 2 are presented according to the nomenclature proposed by Beaudet &amp; Tsui (1993); nucleotide numbers refer to their positions in the sequence of the ATM transcript (accession number U33841); the first nucleotide of the open reading frame was designated +1.) These mutations were found amongst 55 A-T families: many are unique to a single family, while others are shared by several families, most notably the 4 nt deletion, 7517del4, which is common to 6 A-T families from South-Central Italy (Table 2). According to this sample, there is a considerable heterogeneity of mutations in A-T, and most of them are “private”. The proportion of homozygotes in this sample is relatively high due to a high degree of consanguinity the populations studied. It should be noted, however, that apparently homozygous patients from non-consanguineous families may in fact be compound heterozygotes with one allele not expressed. 
     This series of 44 A-T mutations is dominated by deletions and insertions. The smaller ones, of less than 12 nt, reflect identical sequence alterations in genomic DNA. Deletions spanning larger segments of the ATM transcript were found to reflect exon skipping, not corresponding genomic deletions. This phenomenon usually results from sequence alterations at splice junctions or within introns, or mutations within the skipped exons, mainly of the nonsense type (Cooper and Krawczak, 1993; Sommer, 1995; Steingrimsdottir et al., 1992; Gibson et al., 1993; Dietz and Kendzior, 1994). One large deletion spans about 7.5 Kb of the transcript and represents a genomic deletion of about 85 Kb within the ATM gene. Of these deletions and insertions, 25 are expected to result in frameshifts. Together with the 4 nonsense mutations, truncation mutations account for 66% of the total number of mutations in this sample. Seven in-frame deletions span long segments (30-124 aa) of the protein, and similarly to the truncation mutations, are expected to have a severe effect on the protein&#39;s structure. It should be noted that two base substitutions abolish the translation initiation and termination codons. The latter is expected to result in an extension of the ATM protein by an additional 29 amino acids. This mutation may affect the conformation of the nearby PI 3-kinase-like domain. 
     While the effect of the 4 small (1-3 aa) in-frame deletions and insertions on the ATM protein remains to be studied, it should be noted that one such deletion (8578del3) leads to a loss of a serine residue at position 2860. This amino acid is part of a conserved motif within the PI 3-kinase-like domain typical of the protein family to which ATM is related, and is present in 7 of 9 members of this family. The single missense mutation identified in this study, which leads to a Glu2904Gly substitution, results in a nonconservative alteration of another extremely conserved residue within this domain, which is shared by all of these proteins. The patient homozygous for this mutation, AT41RM, shows the typical clinical A-T phenotype. Measurement of radioresistant DNA synthesis in the patient&#39;s cell line revealed a typical A-T response, demonstrating that this patient has the classical A-T cellular phenotype. 
     As discussed herein above, the ATM gene of the present invention is probably involved in a novel signal transduction system that links DNA damage surveillance to cell cycle control. A-T mutations affect a variety of tissues and lead to cancer predisposition. This striking phenotype together with the existence of “partial A-T phenotypes” endow the study of ATM mutations with special significance. 
     The ATM gene leaves a great deal of room for mutations: it encodes a large transcript. The variety of mutations identified in this study indeed indicates a rich mutation repertoire. Despite this wealth of mutations, their structural characteristics point to a definite bias towards those that inactivate or eliminate the ATM protein. The nature or distribution of the genomic deletions among these mutations do not suggest a special preponderance of the ATM gene for such mutations, such as that of the dystrophin (Anderson and Kunkel, 1992) or steroid sulfatase (Ballabio et al., 1989) genes which are particularly prone to such deletions. Thus, one would have expected also a strong representation of missense mutations, which usually constitute a significant portion of the molecular lesions in many disease genes (Cooper and Krawczak, 1993; Sommer, 1995). However, only one such mutation was identified in the present study. Other point mutations reflected in this series are those that probably underlie the exon skipping deletions observed in many patients, again, exerting a severe structural effect on the ATM protein. 
     A technical explanation for this bias towards deletions and insertions could be a greater ability of the REF method to detect such lesions versus its ability to detect base substitution. Liu and Sommer (1995) have shown, however, that the detection rate of this method in a sample of 42 point mutations in the factor IX gene ranged between 88% and 100%, depending on the electrophoresis conditions. The 7 base substitutions detected directly by the REP method in the present study (Table 2), indicate that such sequence alterations are detected in our hands as well. 
     Since the expected result of most of these mutations is complete inactivation of the protein, this skewed mutation profile might represent a functional bias related to the studied phenotype, rather than a structural feature of the ATM gene that lends itself to a particular mutation mechanism. The classical A-T phenotype appears to be caused by homozygosity or compound heterozygosity for null alleles, and hence is probably the most severe expression of defects in the ATM gene. The plethora of missense mutations expected in the large coding region of this gene is probably rarely represented in patients with classical A-T, unless such a mutation results in complete functional inactivation of the protein. By inference, the only missense identified in this study, Glu2940Gly, which substitutes a conserved amino acid at the PI 3-kinase domain and clearly gives rise to a classical A-T phenotype, points to the importance of this domain for the biological activity of the ATM protein. Mutations in this domain abolish the telomere-preserving function of the TEL1 protein in  S. cerevisiae  (Greenwell et al., 1995), a protein which shows a particularly high sequence similarity to ATM (Savitsky et al., 1995b; Zakian, 1995). Another member of the family of PI 3-kinase-related proteins that includes ATM is the mammalian FRAP. Mutations in the PI 3-kinase domain abolish its autophosphorylation ability and biological activity (Brown et al., 1995). These observations, together with the mutation shown here, suggest that this domain in ATM is also likely to include the catalytic site, which may function as a protein kinase. 
     Genotype-phenotype relationships associated with the ATM gene appear therefore to extend beyond classical A-T. There are several examples of genes in which different mutations lead to related but clinically different phenotypes. For example, different combinations of defective alleles of the ERCC2 gene may result in xeroderma pigmentosum (group D), Cockayne&#39;s syndrome or trichothiodystrophy—three diseases with different clinical features involving UV sensitivity (Broughton et al., 1994, 1995). 
     Different mutations in the CFTR gene may lead to full-fledged cystic fibrosis, or only to congenital bilateral absence of the vas deferens which is one feature of this disease (Chillon et al., 1995; Jarvi et al., 1995). A particularly interesting example is the X-linked WASP gene responsible for Wiskott Aldrich syndrome (WAS), characterized by immunodeficiency, eczema and thrombocytopenia. Most of the mutations responsible for this phenotype cause protein truncations; however, certain missense mutations may result in X-linked thrombocytopenia, which represents a partial WAS phenotype, while compound heterozygosity for a severe and mild mutation results in females in an intermediate phenotype (Kolluri et al., 1995; Derry et al., 1995). 
     In a similar manner, genotypic combinations of mutations with different severities create a continuous spectrum of phenotypic variation in many metabolic diseases. 
     Which phenotypes are most likely to be associated with milder ATM mutations? Since cerebellar damage is the early and severe manifestation of A-T, it is reasonable to assume that the cerebellum might also be affected to some extent in phenotypes associated with milder ATM mutations. Such phenotypes may include cerebellar ataxia, either isolated (Harding, 1993) or coupled with various degrees of immunodeficiency. The latter combination has indeed been described, sometimes with chromosomal instability, and is often designated “ataxia without telangiectasia” (Ying and Decoteau, 1983; Byrne et al., 1984; Aicardi et al., 1988; Maserati, 1988; Friedman and Weitberg, 1993). Friedman and Weitberg (1993) recently suggested a new clinical category of “ataxia with immune deficiency” that would include A-T as well as other cases of cerebellar degeneration with immune deficits. Evaluation of patients with cerebellar disorders with the present invention may reveal a higher frequency of such cases than previously estimated. However, in view of the pleiotropic nature of the ATM gene, the range of phenotypes associated with various ATM genotypes may be even broader, and include mild progressive conditions not always defined as clear clinical entities. Screening for mutations in this gene in such cases may reveal wider boundaries for the molecular pathology associated with the ATM gene. 
     EXAMPLE 4 
     Identification of the Mouse Atm Gene 
     MATERIALS AND METHODS 
     Library screening: 
     An oligo(dT)-primed mouse brain cDNA library in a Uni-Zap XR vector, a mouse 129Sv genomic library (Stratagene, San Diego, Calif.) and a randomly primed mouse brain cDNA library in lambda-gt10 (Clontech, Palo Alto, Calif.) were used. 10 6  pfu were screened with each probe. The libraries were plated at a density of 5×10 4  pfu per 140 mm plate, and two sets of replica filters were made using Qiabrane nylon membranes (Qiagen, Hilden, Germany) according to the manufacturer&#39;s instructions. Filters were prehybridized for 2 hours at 65° C. in 6×SSC, 5×Denhardt&#39;s, 1% N-laurylsarcosyl, 10% dextran sulfate and 100 μg/ml sheared salmon sperm DNA. Hybridization was performed at 65° C. for 16-18 hours in the same solution containing 10 6  cpm/ml of probe labeled with  32 P-dCTP by random priming. Final washes were made for 30 minutes in 0.5×SSC, 0.1% SDS at 50° C. Positive clones were plaque-purified using standard techniques. 
     RT-PCR: 
     First strand synthesis was performed using 2 μg of total RNA from mouse 3T3 cells with an oligo(dT) primer and Superscript II (Gibco-BRL, Gaithersburg, Md.). The reaction products served as templates for PCR with gene-specific primers. 
     Sequence analysis: 
     The insert of cDNA clone 15-1 (see below) was excised from a gel, self-ligated to form concatamers, and sonicated to obtain random fragments. These fragments were size-fractionated by gel electrophoresis, and the 1.0- to 1.5-kb fraction was extracted from the gel and subcloned in a pBluescript vector (Stratagene). The end portions of individual clones were sequenced with vector-specific primers in an automated sequencer (Model 373A, Applied Biosystems Division, Perkin Elmer), and the sequences were aligned with the AutoAssembler program (Applied Biosystems). In the final sequence, each nucleotide position represents at least three independent overlapping readings. In smaller cDNA inserts, sequencing was initiated with vector-specific primers, and additional sequencing primers were designed for both strands as sequencing progressed. Sequencing of RT-PCR products was performed with the PCR primers. 
     Fluorescence in-situ hybridization (FISH): 
     Preliminary chromosomal localization of the Atm gene was determined by FISH analysis. Mouse metaphase chromosomes were prepared from concanavalin A (conA) stimulated lymphocytes obtained after splenectomy as described by Boyle at al. (1992), with slight modifications. Briefly, homogenized spleen tissue was cultured for 48 hours in RPMI 1640 medium supplemented with 20% fetal bovine serum, 6 μg/ml concanavalin A, and 86.4 μM β-mercaptoethanol. The cell cycle was synchronized by incubation with methotrexate (17 hours, 4.5 mM). The S-phase block was released with BrdU (30 μM) and FUdR (0.15 μg/ml) for 5 hours. Colcemid was added for 10 minutes; the cells were incubated in KCl (0.55%) and fixed with methanol/acetic acid (3:1). The mouse Atm genomic clone used for FISH analysis was obtained by screening the mouse 129Sv genomic library with a human 236 bp PCR probe corresponding to nt 5381-5617 of the human ATM cDNA. Sequence analysis confirmed that this clone contains a 177 bp exon corresponding to nt 5705-5881 of the mouse Atm cDNA. 
     The mouse Atm genomic clone was labeled by nick-translation with digoxigenin-11dUTP (Boehringer Mannheim, Indianapolis, Ind.). To facilitate chromosome identification, a biotinylated mouse chromosome 9-specific painting probe (Vector Laboratories, Burlingame, Calif.) was used for cohybridization. The probe sequences and metaphase chromosomes were heat denatured separately. Hybridization was performed for 15 hours at 37° C. in a solution containing 50% formamide, 2×SSC, and 10% dextran sulfate. Post-hybridization washes were performed as described by Ried et al. (1992). The biotinylated probe sequences were detected by incubation with avidin conjugated to FITC (Vector Laboratories), and the digoxigenin labeled sequences by incubation with mouse anti-digoxin and goat anti-mouse conjugated to TRITC (Sigma Chemicals, St. Louis, Mo.). Chromosomes were counterstained with DAPI. The fluorescent signals were sequentially acquired using a cooled CCD camera (Photometrics, Tucson, Ariz.) coupled to a Leica DMRBE microscope. Gray scale images were converted to tintscale using Gene Join (Ried et al., 1992). 
     Linkage analysis: 
     Interspecific backcross progeny were generated by mating (C57BL/6J× M. spretus )F1 females and C57BL/6J males, as described by Copeland and Jenkins (1991). A total of 205 N 2  mice were used to map the Atm locus as described herein below. Southern blot analysis was performed (Jenkins et al., 1982). All blots were prepared with Hybond-N +  membrane (Amersham). The Atm probe, REF3, a PCR-amplified fragment from the Atm mouse cDNA representing nt 6000-7264 was labeled with [α 32 P]dCTP using a random priming labeling kit (Stratagene); washing was done to a final stringency of 0.5×SSCP, 0.1% SDS, 65° C. Fragments of 4.9, 3.6, and 1.4 kb were detected in HindIII-digested C57BL/6J DNA and fragments of 5.6 and 4.3 kb were detected in HindIII-digested  M. spretus  DNA. The presence or absence of the 5.6 and 4.3 kb  M. spretus -specific fragments, which cosegregated, were followed in the backcross mice. 
     A description of the probes and RFLPs for the loci linked to Atm, including glutamate receptor, ionotropic, kainate 4 (Grik4); thymus cell antigen-1 theta (Thy1); Casitas B-lineage lymphoma (Cbl); CD3 antigen, gamma polypeptide (Cd3g); and dopamine receptor 2 (Drd2), has been reported previously (Kingsley at al., 1989; Regnier et al., 1989; Szpirer et al., 1994). The mouse chromosomal locations of mitochondrial acetoacetyl-CoA thiolase (Acat1) and src-kinase (Csk) were determined for the first time, herein. Recombination distances were calculated as described (Green, 1981), using the computer program SPRETUS MADNESS. Gene order was determined by minimizing the number of recombination events required to explain the allele distribution patterns. 
     The Csk probe, a 2.2 kb EcoRI/XhoI fragment derived from the mouse cDNA (Thomas et al., 1991), was labeled with [α 32 P]dCTP using a nick] translation labeling kit (Boehringer Mannhein); washing was done to a final stringency of 0.1×SSPE, 0.1% SDS, 65° C. A fragment of 9.4 kb was detected in HindIII-digested C57BL/6J DNA and a fragment of 5.8 kb was detected in HindIII-digested  M. spretus  DNA. The presence or absence of the 5.8 kb  M. spretus -specific fragment was followed in the backcross mice. The Acat1 probe, a 1.4 kb fragment from the Acat rat cDNA (Fukao et al., 1990), was labeled by nick translation and washed from the blots to a final stringency of 0.8×SSCP, 0.1% SDS, 65° C. A fragment of 23 kb was detected in EcoRI-digested C57BL/6J DNA, and fragments of 22 and 5.4 kb were detected in EcoRI-digested  M. spretus  DNA. The presence or absence of the 22 and 5.4 kb  M. spretus -specific fragments, which cosegregated, were followed in the backcross mice. 
     RESULTS 
     Molecular cloning of the coding sequence of Atm gene: 
     In search of a cDNA clone derived from a murine gene corresponding to the human ATM, 10 6  pfu from a mouse brain cDNA library were screened with a PCR product corresponding to nt 4021-8043 of the human ATM cDNA (Savistky et al., 1995b; the first nucleotide of the open reading frame was numbered 1). Fifteen positive clones were identified, and the longest one, of 8.5 kb (designated 15-1; FIG.  3 ), was further analyzed. High-stringency hybridization of this clone to panels of radiation hybrids, YAC and cosmid clones representing the human ATM locus (Rotman et al.,1994; Shiloh, 1994; Savitsky et al., 1995a,b) showed strongly hybridizing sequences within the ATM locus. Northern blotting analysis and subsequent sequencing and alignment with the human ATM transcript confirmed that 15-1 corresponded throughout its length to the human gene but was missing the 5′ end of the corresponding mouse transcript. 
     Screening of a randomly primed mouse brain cDNA library with a probe corresponding to the 5′ region of the human ATM transcript (nt 1-2456) identified 2 clones, MRP1 and MRP2, of 1.3 and 0.6 kb, respectively (FIG.  3 ). The gap between clones 15-1 and MRP1 was subsequently bridged using RT-PCR with primers derived from these clones, which produced the fragment m4m5 of 840 bp. Finally, a primer derived from the MRP1 sequence was designed and used with vector-specific primers to obtain two PCR products, 23m9 and 24m9, from the randomly primed brain cDNA library. All these clones and PCR products hybridized exclusively to the ATM locus in the human genome. Their sequences were assembled and formed a contig of 9620 nucleotides (FIG. 3; GenBank accession no. U43678). 
     Sequence comparisons: 
     The sequence of the contig shown in FIG. 3 shows an open reading frame (ORF) of 9201 nt, and includes a 41 nt 5′ UTR and a 378 nt 3′ UTR. These UTRs are probably not complete, in view of the length of the UTRs of the ATM transcript and the lack of a poly(A) tail in 15-1. The ORF encodes a putative protein of 3,066 amino acids with a molecular weight of 349.5 kDa (SEQ ID No:3). When the nucleotide and amino acid sequences corresponding to the coding regions of the mouse and human ATM transcripts were aligned, there was an overall identity of 85% at the nucleotide sequence level, and an 84% identity and 91% similarity at the amino acid level. The difference of 10 amino acids between the human and mouse proteins is the net sum of several insertions and deletions in both proteins, when compared to each other. The PI 3-kinase domain found in ATM and other related proteins was identified in the mouse sequence (SEQ ID No:12, aa residues 2750-3055), as was the leucine zipper (SEQ ID No:12, aa residues 1211 to 1243) present in the human ATM protein (SEQ ID No:3, aa residues 2855-2875 and 1217-1238 respectively). 
     These results indicated that applicants had obtained the entire coding sequence of Atm, the murine homolog of the human ATM gene. It is noteworthy that the human and mouse proteins were most similar within the PI 3-kinase domain at the carboxy terminus (94% identity, 97% similarity), while the other portions of these proteins show variable identity and similarity reaching a minimum of 70% and 82%, respectively, in some regions (FIG.  4 ). 
     Expression pattern: 
     A Northern blot representing several mouse tissues (Clontech) was probed with a fragment representing nt 2297-5311 of the Atm transcript. This probe identified a message of about 13 kb in brain, skeletal muscle and testis, which was barely detectable in heart, spleen, lung and kidney. In the testis, another band of about 10.5 kb was observed at about 50% intensity compared to the 13 kb band. This pattern seems to represent greater differences in expression levels between tissues, compared to the more uniform pattern observed in human tissues (Savitsky et al., 1995a). In addition, the 10.5 kb band, which may represent mRNA species with alternative polyadenylation, was not detected in any of 16 human tissues tested previously, but was clearly observed in cultured human fibroblasts (Savitsky et al., 1995a). 
     Chromosomal localization of the Atm gene by FISH: 
     Initial chromosomal localization of the mouse Atm gene was determined by dual-color FISH. A digoxigenin-labeled probe was cohybridized with a chromosome painting probe specific for mouse chromosome 9, that confirms the identification of DAPI-stained mouse chromosomes. Mouse chromosome 9 contains homologous regions of human chromosomes 11q, including 11q22-23, the region to which the human ATM gene was assigned. Twelve randomly selected metaphases were analyzed. Signals were observed in 90% of the cells on mouse chromosome 9C. Other chromosomal positions were not observed. 
     Genetic mapping of the Atm gene: 
     The Atm gene was further localized on the genetic map of mouse chromosome 9 using interspecific backcross analysis using progeny derived from matings of [(C57BL/6J× M. spretus ) F 1 ×C57BL/6J] mice. This interspecific backcross mapping panel has been typed for over 2000 loci which are well distributed among all the autosomes as well as the X chromosome (Copeland and Jenkins, 1991). C57BL/6J and  M. spretus  DNAs were digested with several enzymes and analyzed by Southern blot hybridization for informative restriction fragment length polymorphisms (RFLPs), using a probe representing nt 6000-7264 of the Atm transcript. 
     The results indicated that Atm is located in the proximal region of mouse chromosome 9 linked to Grik4, Thy1, Cbl, C3g, Drd2, Acat1 and Csk (FIG.  5 B). Ninety-one mice were analyzed for every marker and are shown in the segregation analysis (FIG.  5 A), however up to 203 mice were typed for some pairs of markers. Each locus was analyzed in pairwise combinations for recombination frequencies using the additional data. The ratios of the total number of mice analyzed for each pair of loci and the recombination frequencies between the loci are shown in FIG.  5 B. 
     Two mapping methods were used to assign the Atm gene to chromosome 9, band 9C. Comparative gene mapping in mouse and human has revealed numerous regions of homology between the two species (Copeland et al., 1993). (References for the human map positions of loci cited in this study can be obtained from GDB (Genome Database), a computerized database of human linkage information maintained by The William H. Welch Medical Library of The Johns Hopkins University (Baltimore, Md.).) This is clearly demonstrated between this portion of mouse chromosome 9 and human chromosome 11q22-23. The human homologs of Grik4, Thy1, Cbl, Cd3g, Drd2, Acat1 and Atm map to 11q22-23. It is noteworthy that, similarly to the close map locations of Atm and Acat1 in the mouse, ATM and ACAT1 lie about 200 kb apart in the human genome. The mapping of Atm refines the distal end of the human 11q22-23 homology unit. Csk, 1.1 cM distal to Acat and Atm, maps to human chromosome 15q23-q25. The average length of a conserved autosomal segment in mice was estimated at 8.1 cM (Nadeau and Taylor, 1984). The conserved segment on mouse chromosome 9 which corresponds to 11q22-23 in humans, extends centromeric to Grik4 and spans approximately 19 cM. 
     The high degree of conservation between the human and mouse proteins suggests similar roles; however, the difference in expression patterns between mice and humans suggested by these northern results may lead to differences between the phenotypes associated with these proteins in the two organisms. To date, no phenotype identical to A-T has been reported in the mouse. 
     The derived chromosome 9 interspecific map of the present invention was compared with a composite mouse linkage map from Mouse Genome Database (The Jackson Laboratory, Bar Harbor, Me.), that reports location of many uncloned mouse mutations. Only one uncloned mouse mutation, luxoid (lu), lies in the vicinity of Atm, but this skeletal abnormality is highly unlikely to represent a mouse disorder corresponding to A-T. The mouse phenotype closest to A-T is severe combined immune deficiency (SCID) on mouse chromosome 16. It is characterized by a deficiency in mature B and T lymphocytes, radiation sensitivity, chromosomal instability, defective rejoining of DNA double-strand breaks and defective V(D)J recombination (Bosma and Carroll, 1991). This phenotype is caused by defects in one of the proteins with a PI 3-kinase domain, the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) (Blunt et al., 1995; Hartley et al., 1995). The reason for lack of a mouse phenotype associated with the Atm gene may be that, unlike in humans, such a phenotype is either embryonic lethal, or considerably milder than in humans. As described herein below, a knockout mouse for the Atm gene in mice has been generated and the phenotype appears in young mice to be somwhat milder than in humans. 
     Using a 200 bp PCR product from the human ATM sequence, mouse genomic clones were screened and isolated. The sequence of the 200 bp PCR product corresponds approximately to ATM exons 40 and 41 as set forth in SEQ ID No:24. The targeted disruption of the homologous mouse gene (Atm) involves insertion of a neomycin cassette in the targeted exon and homologous recombination in 129/Sv-ES cells. Generation and analysis of knockout mice were done in collaboration with Dr. Anthony Wynshaw-Boris at the NIH. Neomycin resistant clones were analyzed by PCR and Southern, and injected into blastocysts. Targeted ES cells showed moderate radiosensitivity. No outward phenotypic differences were observed in the heterozygous progenies thus far. Heterozygous matings resulted in homozygote nulls whose preliminary analysis are shown to be infertile, are radiosensitive and show stunted growth. Techniques used are as described in Hogan et al.,  Manipulating the Mouse Embryo: A Laboratory Manual,  Cold Spring Harbor Laboratory, New York, (1994). 
     EXAMPLE 5 
     Generation of Antibodies Against the ATM Protein 
     Antibodies, both polyclonal and monoclonal, were generated against peptide sequences based on the human ATM sequence as set forth in SEQ ID Nos:4-7,13-15: 
     HEPANSSASQSTDLC (SEQ ID No:4), 
     CKRNLSDIDQSFDKV (SEQ ID No:5), 
     PEDETELHPTLNADDQEC (SEQ ID No:6), 
     CKSLASFIKKPFDRGEVESMEDDTNG (SEQ ID No:7), 
     CRQLEHDRATERRKKEVEKFK (SEQ ID No:13) 
     CLRIAKPNVSASTQASRQKK (SEQ ID No:14) 
     CARQEKSSSGLNHILAA (SEQ ID No:15) 
     Two rabbits each and six mice each were immunized with each of the antigens. 
     Additional peptide sequences based on the mouse atm sequence to which polyclonal antibodies were raised includes: 
     CRQLEHDRATERKKEVDKF (SEQ ID No:16) 
     CFKHSSQASRSATPANSD (SEQ ID No:17) 
     RPEDESDLHSTPNADDQEC (SEQ ID No:18) 
     Glutathione S-transferase recombinant fusions with the ATM fragments from which polyclonals and monoclonals have been raised are set forth in SEQ ID Nos:19-23. 
     Antibodies raised against the ATM protein detect mono-specifically a high molecular weight of the expected size of 350 kDa on Western blots of protein lysates derived from fibroblast and lymphoblastoid cell lines. Because of the high frequency of truncation mutations in the ATM gene, mutated ATM protein can be identified if such proteins are stable. Indirect immunofluorescence showed the ATM protein to be predominantly nuclear. Cell-fractionation studies of normal fibroblast cells identified the presence of the ATM protein in both the nuclear and microsomal fractions. 
     Throughout this application various publications and patents are referenced by citation or number, respectively. Full citations for the publications referenced are listed below. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. 
     The invention has been described in an illustrative manner, and it is to be understood that the terminology which has been used is intended to be in the nature of words of description rather than of limitation. 
     Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 illustrates several mutations found in A—T patients 
               
            
           
           
               
               
               
               
            
               
                   
                 Ethnic/ 
                 Complemen- 
                 Mutation 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 geographic 
                 tation 
                   
                   
                   
                 Patient&#39;s 
               
               
                 Patient 1   
                 origin 
                 group 4   
                 mBNA sequence change 
                 Protein alteration 
                 Codon 9   
                 genotype 10   
               
               
                   
               
               
                 AT2RO 
                 Arab 
                 A 
                 Deletion of 11 nt 5   
                 Frameshift, truncation 
                  499 
                 Homozygote 
               
               
                 AT3NG 
                 Dutch 
                 A 
                 Deletion of 3 nt 
                 Deletion, 1 residue 8   
                 1512 
                 Compound 
               
               
                   
                   
                   
                   
                   
                   
                 heterozygote 
               
               
                 AT15LA 
                 Phillipine 
                 A 
                 Insertion, +A 
                 Frameshift, truncation 
                  557 
                 Compound 
               
               
                   
                   
                   
                   
                   
                   
                 heterozygote 
               
               
                 AT3LA 2   
                 African-American 
                 C 
                 Deletion of 139 nt 6 / 
                 Frameshift, truncation 
                 1196 
                 Compound 
               
               
                 AT4LA 2   
                   
                   
                 Deletion of 298 nt 6   
                   
                   
                 heterozygote 
               
               
                 AT2BR 
                 Celtic/Irish 
                 C 
                 Deletion, 9 nt 
                 Deletion, 3 residues 
                 1198- 
                 Homozygote 
               
               
                   
                   
                   
                   
                   
                 1200 
               
               
                 AT1ABR 
                 Australian 
                 E 
                 Deletion, 9 nt 
                 Deletion, 3 residues 
                 1198- 
                 Homozygote 
               
               
                 AT2ABR 
                 (Irish/British) 
                   
                   
                   
                 1200 
               
               
                 AT5BI 2   
                 Indian/English 
                 D 
                 Deletion, 6 nt 
                 Deletion, 2 residues 
                 1079- 
                 Compound 
               
               
                 AT6BI 2   
                   
                   
                   
                   
                 1080 
                 heterozygote 
               
               
                 F-2079 3   
                 Turkish 
                 ND 
                 Insertion, +C 5   
                 Frameshift, truncation 
                  504 
                 Homozygote 
               
               
                 AT29RM 
                 Italian 
                 ND 
                 Deletion of 175 nt 
                 Frameshift, truncation 
                  132 
                 Homozygote 
               
               
                 AT103LO 
                 Canadian 
                 ND 
                 Insertion, +A 
                 Frameshift, truncation 
                 1635 
                 Homozygote 
               
               
                 F-596 3   
                 Palestinian Arab 
                 ND 
                 Deletion 7   
                 Truncation 
                 Most 
                 Homozygote 
               
               
                   
                   
                   
                   
                   
                 of ORF 
               
               
                   
               
               
                   1 Cell line designation.  
               
               
                   2 Sibling patients in both of whom the same mutation was identified.  
               
               
                   3 Patient expected to be homozygous by descent for an A—T mutation.  
               
               
                   4 According to the methods of Jaspers et al. (1988) ND: not determined.  
               
               
                   5 An identical sequence change was observed in genomic DNA  
               
               
                   6 No evidence for deletion was observed in genomic DNA. In both siblings, a normal mRNA was observed in addition to the two deleted species. The two deleted mRNAs may represent abnormal splicing events caused by a splice site mutation.  
               
               
                   7 Reflects a genomic deletion segregating with the disease in Family N.  
               
               
                   8 The deleted serine residue is located within the PI3-kinase signature sequence (1507-1527 of SEQ ID No:2).  
               
               
                   9 Numbers refer to residue positions in SEQ ID No:2.  
               
               
                   10 In all the compound heterozygotes, the second mutation is still unidentified.  
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Mutations in the ATM gene in patients with classical A—T. 
               
            
           
           
               
               
               
               
               
               
            
               
                 mRNA 
                 Predicted 
                   
                   
                 Ethnic/ 
                   
               
               
                 sequence 
                 protein 
                   
                   
                 geographical 
               
               
                 change 1   
                 alteration 
                 Codon 6   
                 Patient 
                 origin 
                 Genotype 11   
               
               
                   
               
               
                 Truncations and exon 
                   
                   
                   
                   
                   
               
               
                 skipping deletions: 
               
               
                 9001delAG 
                 Truncation 
                 3001 
                 91RD90 9   
                 Turkish 
                 Hmz 
               
               
                 8946insA 
                 Truncation 
                 2983 
                 AP1O3LO 
                 American 
                 Hmz 
               
               
                 8370G−&gt;A 
                 Trp−&gt;ter; truncation 
                 2769 
                 AT2SF 
                 American 
                 Compd Htz 
               
               
                 8283delTC 
                 Truncation 
                 2762 
                 AT28RM 
                 Italian 
                 Compd Htz 
               
               
                 8269del403 3   
                 Truncation 
                 2758 
                 AT12RM 
                 Italian 
                 Hmz 
               
               
                 8269del1503 
                 Del, 50 aa 
                 2758 
                 F-2086 
                 Turkish 
                 Compd Htz 
               
               
                   
                   
                   
                 GM9587 
                 American 
                 Compd Htz 
               
               
                 8140C−&gt;T 
                 Gln−&gt;ter; truncation 
                 2714 
                 IARC12/AT3 
                 French 
                 Hmz 
               
               
                 7883del5 
                 Truncation 
                 2628 
                 ATF104 
                 Japanese 
                 Hmz 
               
               
                   
                   
                   
                 JCRB316 
                 Japanese 
                 Compd Htz 
               
               
                 7789del139/7630del298 4,5   
                 Truncation 
                 2544 
                 AT4LA 
                 Carribean Black 
                 Comp Htz 
               
               
                 7630del159 3   
                 Del, 53 aa 
                 2544 
                 F-2086 
                 Turkish 
                 Compd Htz 
               
               
                   
                   
                   
                 AT13BER 
                   
                 Compd Htz 
               
               
                 7517del4 
                 Truncation 
                 2506 
                 AT43RM 10   
                 Italian 
                 Hmz 
               
               
                   
                   
                   
                 AT59RM 10   
                 Italian 
                 Hmz 
               
               
                   
                   
                   
                 AT22RM 10   
                 Italian 
                 Hmz 
               
               
                   
                   
                   
                 AT57RM 10   
                 Italian 
                 Compd Htz 
               
               
                   
                   
                   
                 AT7RM 10   
                 Italian 
                 Compd Htz 
               
               
                   
                   
                   
                 AT8RM 10   
                 Italian 
                 Compd Htz 
               
               
                 6573del5 
                 Truncation 
                 2192 
                 AT12ABR 
                 Australian 
                 Compd Htz 
               
               
                 6348del105 3   
                 Del, 35 aa 
                 2116 
                 IARC15/AT4 
                 French 
                 Hmz 
               
               
                 6199del149 3   
                 Truncation 
                 2067 
                 WG1101 
                 Canadian 
                 Hmz 
               
               
                 5979del5 
                 Truncation 
                 1994 
                 AT5RM 
                 Italian 
                 Compd Htz 
               
               
                 5712insA 
                 Truncation 
                 1905 
                 AT15LA 
                 Philippino 
                 Compd Htz 
               
               
                 5554insC 
                 Truncation 
                 1852 
                 F-2079 9   
                 Turkish 
                 Hmz 
               
               
                 5539del11 
                 Truncation 
                 1847 
                 AT2RO 9   
                 Arab 
                 Hmz 
               
               
                 5320del355 6   
                 Truncation 
                 1774 
                 AT7RM 
                 Italian 
                 Compd Htz 
               
               
                 5320del7 
                 Truncation 
                 1774 
                 AT2SF 
                 American 
                 Compd Htz 
               
               
                 5178del142 3   
                 Truncation 
                 1727 
                 AT50RM 
                 Italian 
                 Compd Htz 
               
               
                 4612del165 3   
                 Del, 55 aa 
                 1538 
                 ATL105 
                 Japanese 
                 Hmz 
               
               
                 44437del175 3   
                 Truncation 
                 1480 
                 AT29RM 
                 Italian 
                 Hmz 
               
               
                 4110del127 3   
                 Truncation 
                 1371 
                 AT2TAN 9   
                 Turkish 
                 Hmz 
               
               
                 3403del174 3   
                 Del, 58 aa 
                 1135 
                 F-2095 
                 Turkish 
                 Compd Htz 
               
               
                 2839del83 3   
                 Truncation 
                  947 
                 F-2080 9   
                 Turkish 
                 Hmz 
               
               
                   
                   
                   
                 AT10TAN 9   
                 Turkish 
                 Hmz 
               
               
                 2467del372 3,5   
                 Del, 124 aa 
                  823 
                 AT6LA 
                 English/Irish 
                 Hmz 
               
               
                 2377del90 3   
                 Del, 30 aa 
                  793 
                 AT21RM 9   
                 Italian 
                 Hmz 
               
               
                 22284delCT 
                 Truncation 
                  762 
                 F-169 9   
                 Palestinian Arab 
                 Hmz 
               
               
                 2125del125 3   
                 Truncation 
                  709 
                 F-2078 9   
                 Turkish 
                 Hmz 
               
               
                 2113delT 
                 Truncation 
                  705 
                 AT5RM 
                 Italian 
                 Compd Htz 
               
               
                 1563delAG 5   
                 Truncation 
                  522 
                 AT8LA 9   
                 Swiss/German 
                 Hmz 
               
               
                 1339C−&gt;T 
                 Arg−&gt;ter; truncation 
                  447 
                 F-2005 9   
                 Druze 
                 Hmz 
               
               
                 1240C−&gt;T 
                 Gln−&gt;ter; truncation 
                  414 
                 AT26RM 
                 Italian 
                 Hmz 
               
               
                 755delGT 
                 Truncation 
                  252 
                 AT24RM 
                 Italian 
                 Hmz 
               
               
                 497del7514 7   
                 Truncation 
                  166 
                 F-596 9   
                 Palestinian-Arab 
                 Hmz 
               
               
                 −30del215 
                 Incorrect* 
                 5′ UTR 
                 F-303 
                 Bedouine 
                 Hmz 
               
               
                   
                 initiation 
               
               
                 In-frame genomic deletions 
               
               
                 and insertion: 
               
               
                 8578del3 
                 Del, 1 aa 
                 2860 
                 AT3NG 
                 Dutch 
                 Compd Htz 
               
               
                 7636del9 
                 Del, 3 aa 
                 2547 
                 AT2BR 
                 Celtic/Irish 
                 Hmz 
               
               
                   
                   
                   
                 AT1ABR 
                 Australian (Irish) 
                 Hmz 
               
               
                   
                   
                   
                 AT1SF 
                 American 
                 Compd Htz 
               
               
                 7278del6 5   
                 Del, 2 aa 
                 2427 
                 AT5BI 
                 Indian/English 
                 Compd Htz 
               
               
                   
                   
                   
                 GM5823 
                 English 
                 Compd Htz 
               
               
                 5319ins9 
                 Ins, 3 aa 
                 1774 
                 251075-008T 
                 Finnish 
                 Compd Htz 
               
               
                 Other base substitutions: 
               
               
                 9170G−&gt;C 
                 ter−&gt;Ser 
                 ter 
                 F-2089 9   
                 Turkish 
                 Hmz 
               
               
                   
                 Extension of protein 
               
               
                   
                 by 29 amino acids 
               
               
                 8711A−&gt;G 
                 Glu2904Gly 
                 2904 
                 AT41RM 
                 Italian 
                 Hmz 
               
               
                 2T−&gt;C 
                 Met−&gt;Thr 
                   1 
                 AT8BI 
                 British 
                 Compd Htz 
               
               
                   
                 Initiation codon 
               
               
                   
                 abolished 
               
               
                   
               
               
                   1 Presented according to the nomenclature proposed by Beaudet &amp; Tsui (1993). Nucleotide numbers refer to their positions in the sequence of the ATM transcript (accession number U33841). The first nucleotide of the open reading frame was designated +1.  
               
               
                   2 Three adjacent exons skipped.  
               
               
                   3 One exon skipped.  
               
               
                   4 This allele produces two transcripts, with one or two ajacent exons skipped.  
               
               
                   5 The same mutation was found in two affected siblings.  
               
               
                   6 Two exons skipped.  
               
               
                   7 This transcript is produced by an allele containing a large genomic deletion spanning approximately 85 Kb within the ATM gene in Family ISAT 9 (Savitsky, et al., 1995a).  
               
               
                   8 For deletions, the number of the first codon on the amino terminus side is indicated. Codon numbers are according to the ATM protein sequence published by Savitsky et al. (1995b). In each section of the table, the mutations are ordered according to the codon numbers in this column, beginning with the one closest to the carboxyl terminus.  
               
               
                   9 Consanguineous family.  
               
               
                   10 All patients are from the same region.  
               
               
                   11 Genotypic combinations in which the mutation was found. Hmz: homozygote, Compd Htz: compound heterozygote. Each patient represents one family.  
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Comparison of the ATM protein to related proteins in different species 
               
            
           
           
               
               
            
               
                   
                 % identity/similarity 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Size 
                   
                 Carboxy 
                   
               
               
                 Protein 
                 (aa) 
                 Species 
                 terminus* 
                 Rest of protein** 
               
               
                   
               
               
                 TEL1 
                 2789 
                 
                   S. cerevisiae 
                 
                 45/67 
                 19/44 
               
               
                 MEC1 
                 2368 
                 
                   S. cerevisiae 
                 
                 37/63 
                 20/46 
               
               
                 rad3 
                 2386 
                 
                   S. pombe 
                 
                 38/59 
                 21/46 
               
               
                 ME1-41 
                 2356 
                 
                   D. melanogaster 
                 
                 37/59 
                 22/47 
               
               
                 TOR1 
                 2470 
                 
                   S. cerevisiae 
                 
                 33/58 
                 19/45 
               
               
                 TOR2 
                 2473 
                 
                   S. cerevisiae 
                 
                 35/60 
                 20/45 
               
               
                 mTOR 
                 2549 
                 
                   R. norvegicus 
                 
                 32/59 
                 18/44 
               
               
                 DNA-PK cs   
                 4096 
                 
                   H. sapiens 
                 
                 28/51 
                 18/43 
               
               
                   
               
               
                 *350 aa of the carboxy terminus, containing the P1-3 kinase-like domain.  
               
               
                 **The entire protein excluding the carboxy terminal 350 aa. An average value is given, since the values obtained for different parts of the proteins vary only by 1-3%.  
               
            
           
         
       
     
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     Vanagaite et al., “Physical localization of microsatellite markers at the ataxia-telangiectasia locus at 11q22-23.  Genomics,  22:231-233 (1994a). 
     Vanagaite et al., “High-density microsatellite map of ataxia-telangiectasia locus”  Human Genetics  95:451-453 (1995). 
     Vetrie et al., “The gene involved in X-linked agammaglobulinemia is a member of the src family of protein-tyrosine kinases”  Nature,  361:226-233 (1993). 
     Weber and May, “Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction”  Am. J. Hum. Genet.,  44:388-396 (1989). 
     Weemaes et al., “Nijmegen breakage syndrome: A progress report”  Int. J. Radiat. Biol.  66:S185-S188 (1994). 
     Ying and Decoteau, “Cytogenetic anomalies in a patient with ataxia, immune deficiency, and high alpha-fetoprotein in the absence of telangiectasia”  Cancer Genet. Cytogenet.  4:311-317 (1983). 
     Zakian, “ATM-related genes: What do they tell us about functions of the human gene?”  Cell  82:685-687 (1995). 
     Ziv et al., “Ataxia-telangiectasia: linkage analysis in highly inbred Arab and Druze families and differentiation from an ataxia-microcephaly-cataract syndrome”  Hum. Genet.,  88:619-626 (1992). 
     Ziv et al., “The ATC (ataxia-telangiectasia complementation group C) locus localizes to 11q22-q23.  Genomics,  9:373-375 (1991). 
     Ziv et al., “Ataxia telangiectasia: a variant with altered in vitro phenotype of fibroblast cells”  Mutation Res.  210:211-219 (1989). 
     
       
         
           
             24 
           
           
             
               5912 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               cDNA 
             
             
               unknown 
             
             
               7-9 
             
             1
CATACTTTTT CCTCTTAGTC TACAGGTTGG CTGCATAGAA GAAAAAGGTA GAGTTATTTA     60
TAATCTTGTA AATCTTGGAC TTTGAGTCAT CTATTTTCTT TTACAGTCAT CGAATACTTT    120
TGGAAATAAG GTAATATATG CCTTTTGAGC TGTCTTGACG TTCACAGATA TAAAATATTA    180
AATATATTTT AATTTTGTGC CCTTGCAGAT TGATCACTTA TTCATTAGTA ATTTACCAGA    240
GATTGTGGTG GAGTTATTGA TGACGTTACA TGAGCCAGCA AATTCTAGTG CCAGTCAGAG    300
CACTGACCTC TGTGACTTTT CAGGGGATTT GGATCCTGCT CCTAATCCAC CTCATTTTCC    360
ATCGCATGTG ATTAAAGCAA CATTTGCCTA TATCAGCAAT TGTCATAAAA CCAAGTTAAA    420
AAGCATTTTA GAAATTCTTT CCAAAAGCCC TGATTCCTAT CAGAAAATTC TTCTTGCCAT    480
ATGTGAGCAA GCAGCTGAAA CAAATAATGT TTATAAGAAG CACAGAATTC TTAAAATATA    540
TCACCTGTTT GTTAGTTTAT TACTGAAAGA TATAAAAAGT GGCTTAGGAG GAGCTTGGGC    600
CTTTGTTCTT CGAGACGTTA TTTATACTTT GATTCACTAT ATCAACCAAA GGCCTTCTTG    660
TATCATGGAT GTGTCATTAC GTAGCTTCTC CCTTTGTTGT GACTTATTAA GTCAGGTTTG    720
CCAGACAGCC GTGACTTACT GTAAGGATGC TCTAGAAAAC CATCTTCATG TTATTGTTGG    780
TACACTTATA CCCCTTGTGT ATGAGCAGGT GGAGGTTCAG AAACAGGTAT TGGACTTGTT    840
GAAATACTTA GTGATAGATA ACAAGGATAA TGAAAACCTC TATATCACGA TTAAGCTTTT    900
AGATCCTTTT CCTGACCATG TTGTTTTTAA GGATTTGCGT ATTACTCAGC AAAAAATCAA    960
ATACAGTAGA GGACCCTTTT CACTCTTGGA GGAAATTAAC CATTTTCTCT CAGTAAGTGT   1020
TTATGATGCA CTTCCATTGA CAAGACTTGA AGGACTAAAG GATCTTCGAA GACAACTGGA   1080
ACTACATAAA GATCAGATGG TGGACATTAT GAGAGCTTCT CAGGATAATC CGCAAGATGG   1140
GATTATGGTG AAACTAGTTG TCAATTTGTT GCAGTTATCC AAGATGGCAA TAAACCACAC   1200
TGGTGAAAAA GAAGTTCTAG AGGCTGTTGG AAGCTGCTTG GGAGAAGTGG GTCCTATAGA   1260
TTTCTCTACC ATAGCTATAC AACATAGTAA AGATGCATCT TATACCAAGG CCCTTAAGTT   1320
ATTTGAAGAT AAAGAACTTC AGTGGACCTT CATAATGCTG ACCTACCTGA ATAACACACT   1380
GGTAGAAGAT TGTGTCAAAG TTCGATCAGC AGCTGTTACC TGTTTGAAAA ACATTTTAGC   1440
CACAAAGACT GGACATAGTT TCTGGGAGAT TTATAAGATG ACAACAGATC CAATGCTGGC   1500
CTATCTACAG CCTTTTAGAA CATCAAGAAA AAAGTTTTTA GAAGTACCCA GATTTGACAA   1560
AGAAAACCCT TTTGAAGGCC TGGATGATAT AAATCTGTGG ATTCCTCTAA GTGAAAATCA   1620
TGACATTTGG ATAAAGACAC TGACTTGTGC TTTTTTGGAC AGTGGAGGCA CAAAATGTGA   1680
AATTCTTCAA TTATTAAAGC CAATGTGTGA AGTGAAAACT GACTTTTGTC AGACTGTACT   1740
TCCATACTTG ATTCATGATA TTTTACTCCA AGATACAAAT GAATCATGGA GAAATCTGCT   1800
TTCTACACAT GTTCAGGGAT TTTTCACCAG CTGTCTTCGA CACTTCTCGC AAACGAGCCG   1860
ATCCACAACC CCTGCAAACT TGGATTCAGA GTCAGAGCAC TTTTTCCGAT GCTGTTTGGA   1920
TAAAAAATCA CAAAGAACAA TGCTTGCTGT TGTGGACTAC ATGAGAAGAC AAAAGAGACC   1980
TTCTTCAGGA ACAATTTTTA ATGATGCTTT CTGGCTGGAT TTAAATTATC TAGAAGTTGC   2040
CAAGGTAGCT CAGTCTTGTG CTGCTCACTT TACAGCTTTA CTCTATGCAG AAATCTATGC   2100
AGATAAGAAA AGTATGGATG ATCAAGAGAA AAGAAGTCTT GCATTTGAAG AAGGAAGCCA   2160
GAGTACAACT ATTTCTAGCT TGAGTGAAAA AAGTAAAGAA GAAACTGGAA TAAGTTTACA   2220
GGATCTTCTC TTAGAAATCT ACAGAAGTAT AGGGGAGCCA GATAGTTTGT ATGGCTGTGG   2280
TGGAGGGAAG ATGTTACAAC CCATTACTAG ACTACGAACA TATGAACACG AAGCAATGTG   2340
GGGCAAAGCC CTAGTAACAT ATGACCTCGA AACAGCAATC CCCTCATCAA CACGCCAGGC   2400
AGGAATCATT CAGGCCTTGC AGAATTTGGG ACTCTGCCAT ATTCTTTCCG TCTATTTAAA   2460
AGGATTGGAT TATGAAAATA AAGACTGGTG TCCTGAACTA GAAGAACTTC ATTACCAAGC   2520
AGCATGGAGG AATATGCAGT GGGACCATTG CACTTCCGTC AGCAAAGAAG TAGAAGGAAC   2580
CAGTTACCAT GAATCATTGT ACAATGCTCT ACAATCTCTA AGAGACAGAG AATTCTCTAC   2640
ATTTTATGAA AGTCTCAAAT ATGCCAGAGT AAAAGAAGTG GAAGAGATGT GTAAGCGCAG   2700
CCTTGAGTCT GTGTATTCGC TCTATCCCAC ACTTAGCAGG TTGCAGGCCA TTGGAGAGCT   2760
GGAAAGCATT GGGGAGCTTT TCTCAAGATC AGTCACACAT AGACAACTCT CTGAAGTATA   2820
TATTAAGTGG CAGAAACACT CCCAGCTTCT CAAGGACAGT GATTTTAGTT TTCAGGAGCC   2880
TATCATGGCT CTACGCACAG TCATTTTGGA GATCCTGATG GAAAAGGAAA TGGACAACTC   2940
ACAAAGAGAA TGTATTAAGG ACATTCTCAC CAAACACCTT GTAGAACTCT CTATACTGGC   3000
CAGAACTTTC AAGAACACTC AGCTCCCTGA AAGGGCAATA TTTCAAATTA AACAGTACAA   3060
TTCAGTTAGC TGTGGAGTCT CTGAGTGGCA GCTGGAAGAA GCACAAGTAT TCTGGGCAAA   3120
AAAGGAGCAG AGTCTTGCCC TGAGTATTCT CAAGCAAATG ATCAAGAAGT TGGATGCCAG   3180
CTGTGCAGCG AACAATCCCA GCCTAAAACT TACATACACA GAATGTCTGA GGGTTTGTGG   3240
CAACTGGTTA GCAGAAACGT GCTTAGAAAA TCCTGCGGTC ATCATGCAGA CCTATCTAGA   3300
AAAGGCAGTA GAAGTTGCTG GAAATTATGA TGGAGAAAGT AGTGATGAGC TAAGAAATGG   3360
AAAAATGAAG GCATTTCTCT CATTAGCCCG GTTTTCAGAT ACTCAATACC AAAGAATTGA   3420
AAACTACATG AAATCATCGG AATTTGAAAA CAAGCAAGCT CTCCTGAAAA GAGCCAAAGA   3480
GGAAGTAGGT CTCCTTAGGG AACATAAAAT TCAGACAAAC AGATACACAG TAAAGGTTCA   3540
GCGAGAGCTG GAGTTGGATG AATTAGCCCT GCGTGCACTG AAAGAGGATC GTAAACGCTT   3600
CTTATGTAAA GCAGTTGAAA ATTATATCAA CTGCTTATTA AGTGGAGAAG AACATGATAT   3660
GTGGGTATTC CGACTTTGTT CCCTCTGGCT TGAAAATTCT GGAGTTTCTG AAGTCAATGG   3720
CATGATGAAG AGAGACGGAA TGAAGATTCC AACATATAAA TTTTTGCCTC TTATGTACCA   3780
ATTGGCTGCT AGAATGGGGA CCAAGATGAT GGGAGGCCTA GGATTTCATG AAGTCCTCAA   3840
TAATCTAATC TCTAGAATTT CAATGGATCA CCCCCATCAC ACTTTGTTTA TTATACTGGC   3900
CTTAGCAAAT GCAAACAGAG ATGAATTTCT GACTAAACCA GAGGTAGCCA GAAGAAGCAG   3960
AATAACTAAA AATGTGCCTA AACAAAGCTC TCAGCTTGAT GAGGATCGAA CAGAGGCTGC   4020
AAATAGAATA ATATGTACTA TCAGAAGTAG GAGACCTCAG ATGGTCAGAA GTGTTGAGGC   4080
ACTTTGTGAT GCTTATATTA TATTAGCAAA CTTAGATGCC ACTCAGTGGA AGACTCAGAG   4140
AAAAGGCATA AATATTCCAG CAGACCAGCC AATTACTAAA CTTAAGAATT TAGAAGATGT   4200
TGTTGTCCCT ACTATGGAAA TTAAGGTGGA CCACACAGGA GAATATGGAA ATCTGGTGAC   4260
TATACAGTCA TTTAAAGCAG AATTTCGCTT AGCAGGAGGT GTAAATTTAC CAAAAATAAT   4320
AGATTGTGTA GGTTCCGATG GCAAGGAGAG GAGACAGCTT GTTAAGGGCC GTGATGACCT   4380
GAGACAAGAT GCTGTCATGC AACAGGTCTT CCAGATGTGT AATACATTAC TGCAGAGAAA   4440
CACGGAAACT AGGAAGAGGA AATTAACTAT CTGTACTTAT AAGGTGGTTC CCCTCTCTCA   4500
GCGAAGTGGT GTTCTTGAAT GGTGCACAGG AACTGTCCCC ATTGGTGAAT TTCTTGTTAA   4560
CAATGAAGAT GGTGCTCATA AAAGATACAG GCCAAATGAT TTCAGTGCCT TTCAGTGCCA   4620
AAAGAAAATG ATGGAGGTGC AAAAAAAGTC TTTTGAAGAG AAATATGAAG TCTTCATGGA   4680
TGTTTGCCAA AATTTTCAAC CAGTTTTCCG TTACTTCTGC ATGGAAAAAT TCTTGGATCC   4740
AGCTATTTGG TTTGAGAAGC GATTGGCTTA TACGCGCAGT GTAGCTACTT CTTCTATTGT   4800
TGGTTACATA CTTGGACTTG GTGATAGACA TGTACAGAAT ATCTTGATAA ATGAGCAGTC   4860
AGCAGAACTT GTACATATAG ATCTAGGTGT TGCTTTTGAA CAGGGCAAAA TCCTTCCTAC   4920
TCCTGAGACA GTTCCTTTTA GACTCACCAG AGATATTGTG GATGGCATGG GCATTACGGG   4980
TGTTGAAGGT GTCTTCAGAA GATGCTGTGA GAAAACCATG GAAGTGATGA GAAACTCTCA   5040
GGAAACTCTG TTAACCATTG TAGAGGTCCT TCTATATGAT CCACTCTTTG ACTGGACCAT   5100
GAATCCTTTG AAAGCTTTGT ATTTACAGCA GAGGCCGGAA GATGAAACTG AGCTTCACCC   5160
TACTCTGAAT GCAGATGACC AAGAATGCAA ACGAAATCTC AGTGATATTG ACCAGAGTTT   5220
CGACAAAGTA GCTGAACGTG TCTTAATGAG ACTACAAGAG AAACTGAAAG GAGTGGAAGA   5280
AGGCACTGTG CTCAGTGTTG GTGGACAGGT GAATTTGCTC ATACAGCAGG CCATAGACCC   5340
CAAAAATCTC AGCCGACTTT TCCCAGGATG GAAAGCTTGG GTGTGATCTT CAGTATATGA   5400
ATTACCCTTT CATTCAGCCT TTAGAAATTA TATTTTAGCC TTTATTTTTA ACCTGCCAAC   5460
ATACTTTAAG TAGGGATTAA TATTTAAGTG AACTATTGTG GGTTTTTTTG AATGTTGGTT   5520
TTAATACTTG ATTTAATCAC CACTCAAAAA TGTTTTGATG GTCTTAAGGA ACATCTCTGC   5580
TTTCACTCTT TAGAAATAAT GGTCATTCGG GCTGGGCGCA GCGGCTCACG CCTGTAATCC   5640
CAGCACTTTG GGAGGCCGAG GTGAGCGGAT CACAAGGTCA GGAGTTCGAG ACCAGCCTGG   5700
CCAAGAGACC AGCCTGGCCA GTATGGTGAA ACCCTGTCTC TACTAAAAAT ACAAAAATTA   5760
GCCGAGCATG GTGGCGGGCA CCTGTAGTCC CAGCTACTCG AGAGGCTGAG GCAGGAGAAT   5820
CTCTTGAACC TGGGAGGTGA AGGTTGCTGT GGGCCAAAAT CATGCCATTG CACTCCAGCC   5880
TGGGTGACAA GAGCGAAACT CCATCTCAAA AA                                 5912 
           
           
             
               9171 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               cDNA 
             
             
               Homo sapiens 
             
             
               11q22-23 
             
             2
ATGAGTCTAG TACTTAATGA TCTGCTTATC TGCTGCCGTC AACTAGAACA TGATAGAGCT     60
ACAGAACGAA AGAAAGAAGT TGAGAAATTT AAGCGCCTGA TTCGAGATCC TGAAACAATT    120
AAACATCTAG ATCGGCATTC AGATTCCAAA CAAGGAAAAT ATTTGAATTG GGATGCTGTT    180
TTTAGATTTT TACAGAAATA TATTCAGAAA GAAACAGAAT GTCTGAGAAT AGCAAAACCA    240
AATGTATCAG CCTCAACACA AGCCTCCAGG CAGAAAAAGA TGCAGGAAAT CAGTAGTTTG    300
GTCAAATACT TCATCAAATG TGCAAACAGA AGAGCACCTA GGCTAAAATG TCAAGAACTC    360
TTAAATTATA TCATGGATAC AGTGAAAGAT TCATCTAATG GTGCTATTTA CGGAGCTGAT    420
TGTAGCAACA TACTACTCAA AGACATTCTT TCTGTGAGAA AATACTGGTG TGAAATATCT    480
CAGCAACAGT GGTTAGAATT GTTCTCTGTG TACTTCAGGC TCTATCTGAA ACCTTCACAA    540
GATGTTCATA GAGTTTTAGT GGCTAGAATA ATTCATGCTG TTACCAAAGG ATGCTGTTCT    600
CAGACTGACG GATTAAATTC CAAATTTTTG GACTTTTTTT CCAAGGCTAT TCAGTGTGCG    660
AGACAAGAAA AGAGCTCTTC AGGTCTAAAT CATATCTTAG CAGCTCTTAC TATCTTCCTC    720
AAGACTTTGG CTGTCAACTT TCGAATTCGA GTGTGTGAAT TAGGAGATGA AATTCTTCCC    780
ACTTTGCTTT ATATTTGGAC TCAACATAGG CTTAATGATT CTTTAAAAGA AGTCATTATT    840
GAATTATTTC AACTGCAAAT TTATATCCAT CATCCGAAAG GAGCCAAAAC CCAAGAAAAA    900
GGTGCTTATG AATCAACAAA ATGGAGAAGT ATTTTATACA ACTTATATGA TCTGCTAGTG    960
AATGAGATAA GTCATATAGG AAGTAGAGGA AAGTATTCTT CAGGATTTCG TAATATTGCC   1020
GTCAAAGAAA ATTTGATTGA ATTGATGGCA GATATCTGTC ACCAGGTTTT TAATGAAGAT   1080
ACCAGATCCT TGGAGATTTC TCAATCTTAC ACTACTACAC AAAGAGAATC TAGTGATTAC   1140
AGTGTCCCTT GCAAAAGGAA GAAAATAGAA CTAGGCTGGG AAGTAATAAA AGATCACCTT   1200
CAGAAGTCAC AGAATGATTT TGATCTTGTG CCTTGGCTAC AGATTGCAAC CCAATTAATA   1260
TCAAAGTATC CTGCAAGTTT ACCTAACTGT GAGCTGTCTC CATTACTGAT GATACTATCT   1320
CAGCTTCTAC CCCAACAGCG ACATGGGGAA CGTACACCAT ATGTGTTACG ATGCCTTACG   1380
GAAGTTGCAT TGTGTCAAGA CAAGAGGTCA AACCTAGAAA GCTCACAAAA GTCAGATTTA   1440
TTAAAACTCT GGAATAAAAT TTGGTGTATT ACCTTTCGTG GTATAAGTTC TGAGCAAATA   1500
CAAGCTGAAA ACTTTGGCTT ACTTGGAGCC ATAATTCAGG GTAGTTTAGT TGAGGTTGAC   1560
AGAGAATTCT GGAAGTTATT TACTGGGTCA GCCTGCAGAC CTTCATGTCC TGCAGTATGC   1620
TGTTTGACTT TGGCACTGAC CACCAGTATA GTTCCAGGAA CGGTAAAAAT GGGAATAGAG   1680
CAAAATATGT GTGAAGTAAA TAGAAGCTTT TCTTTAAAGG AATCAATAAT GAAATGGCTC   1740
TTATTCTATC AGTTAGAGGG TGACTTAGAA AATAGCACAG AAGTGCCTCC AATTCTTCAC   1800
AGTAATTTTC CTCATCTTGT ACTGGAGAAA ATTCTTGTGA GTCTCACTAT GAAAAACTGT   1860
AAAGCTGCAA TGAATTTTTT CCAAAGCGTG CCAGAATGTG AACACCACCA AAAAGATAAA   1920
GAAGAACTTT CATTCTCAGA AGTAGAAGAA CTATTTCTTC AGACAACTTT TGACAAGATG   1980
GACTTTTTAA CCATTGTGAG AGAATGTGGT ATAGAAAAGC ACCAGTCCAG TATTGGCTTC   2040
TCTGTCCACC AGAATCTCAA GGAATCACTG GATCGCTGTC TTCTGGGATT ATCAGAACAG   2100
CTTCTGAATA ATTACTCATC TGAGATTACA AATTCAGAAA CTCTTGTCCG GTGTTCACGT   2160
CTTTTGGTGG GTGTCCTTGG CTGCTACTGT TACATGGGTG TAATAGCTGA AGAGGAAGCA   2220
TATAAGTCAG AATTATTCCA GAAAGCCAAG TCTCTAATGC AATGTGCAGG AGAAAGTATC   2280
ACTCTGTTTA AAAATAAGAC AAATGAGGAA TTCAGAATTG GTTCCTTGAG AAATATGATG   2340
CAGCTATGTA CACGTTGCTT GAGCAACTGT ACCAAGAAGA GTCCAAATAA GATTGCATCT   2400
GGCTTTTTCC TGCGATTGTT AACATCAAAG CTAATGAATG ACATTGCAGA TATTTGTAAA   2460
AGTTTAGCAT CCTTCATCAA AAAGCCATTT GACCGTGGAG AAGTAGAATC AATGGAAGAT   2520
GATACTAATG GAAATCTAAT GGAGGTGGAG GATCAGTCAT CCATGAATCT ATTTAACGAT   2580
TACCCTGATA GTAGTGTTAG TGATGCAAAC GAACCTGGAG AGAGCCAAAG TACCATAGGT   2640
GCCATTAATC CTTTAGCTGA AGAATATCTG TCAAAGCAAG ATCTACTTTT CTTAGACATG   2700
CTCAAGTTCT TGTGTTTGTG TGTAACTACT GCTCAGACCA ATACTGTGTC CTTTAGGGCA   2760
GCTGATATTC GGAGGAAATT GTTAATGTTA ATTGATTCTA GCACGCTAGA ACCTACCAAA   2820
TCCCTCCACC TGCATATGTA TCTAATGCTT TTAAAGGAGC TTCCTGGAGA AGAGTACCCC   2880
TTGCCAATGG AAGATGTTCT TGAACTTCTG AAACCACTAT CCAATGTGTG TTCTTTGTAT   2940
CGTCGTGACC AAGATGTTTG TAAAACTATT TTAAACCATG TCCTTCATGT AGTGAAAAAC   3000
CTAGGTCAAA GCAATATGGA CTCTGAGAAC ACAAGGGATG CTCAAGGACA GTTTCTTACA   3060
GTAATTGGAG CATTTTGGCA TCTAACAAAG GAGAGGAAAT ATATATTCTC TGTAAGAATG   3120
GCCCTAGTAA ATTGCCTTAA AACTTTGCTT GAGGCTGATC CTTATTCAAA ATGGGCCATT   3180
CTTAATGTAA TGGGAAAAGA CTTTCCTGTA AATGAAGTAT TTACACAATT TCTTGCTGAC   3240
AATCATCACC AAGTTCGCAT GTTGGCTGCA GAGTCAATCA ATAGATTGTT CCAGGACACG   3300
AAGGGAGATT CTTCCAGGTT ACTGAAAGCA CTTCCTTTGA AGCTTCAGCA AACAGCTTTT   3360
GAAAATGCAT ACTTGAAAGC TCAGGAAGGA ATGAGAGAAA TGTCCCATAG TGCTGAGAAC   3420
CCTGAAACTT TGGATGAAAT TTATAATAGA AAATCTGTTT TACTGACGTT GATAGCTGTG   3480
GTTTTATCCT GTAGCCCTAT CTGCGAAAAA CAGGCTTTGT TTGCCCTGTG TAAATCTGTG   3540
AAAGAGAATG GATTAGAACC TCACCTTGTG AAAAAGGTTT TAGAGAAAGT TTCTGAAACT   3600
TTTGGATATA GACGTTTAGA AGACTTTATG GCATCTCATT TAGATTATCT GGTTTTGGAA   3660
TGGCTAAATC TTCAAGATAC TGAATACAAC TTATCTTCTT TTCCTTTTAT TTTATTAAAC   3720
TACACAAATA TTGAGGATTT CTATAGATCT TGTTATAAGG TTTTGATTCC ACATCTGGTG   3780
ATTAGAAGTC ATTTTGATGA GGTGAAGTCC ATTGCTAATC AGATTCAAGA GGACTGGAAA   3840
AGTCTTCTAA CAGACTGCTT TCCAAAGATT CTTGTAAATA TTCTTCCTTA TTTTGCCTAT   3900
GAGGGTACCA GAGACAGTGG GATGGCACAG CAAAGAGAGA CTGCTACCAA GGTCTATGAT   3960
ATGCTTAAAA GTGAAAACTT ATTGGGAAAA CAGATTGATC ACTTATTCAT TAGTAATTTA   4020
CCAGAGATTG TGGTGGAGTT ATTGATGACG TTACATGAGC CAGCAAATTC TAGTGCCAGT   4080
CAGAGCACTG ACCTCTGTGA CTTTTCAGGG GATTTGGATC CTGCTCCTAA TCCACCTCAT   4140
TTTCCATCGC ATGTGATTAA AGCAACATTT GCCTATATCA GCAATTGTCA TAAAACCAAG   4200
TTAAAAAGCA TTTTAGAAAT TCTTTCCAAA AGCCCTGATT CCTATCAGAA AATTCTTCTT   4260
GCCATATGTG AGCAAGCAGC TGAAACAAAT AATGTTTATA AGAAGCACAG AATTCTTAAA   4320
ATATATCACC TGTTTGTTAG TTTATTACTG AAAGATATAA AAAGTGGCTT AGGAGGAGCT   4380
TGGGCCTTTG TTCTTCGAGA CGTTATTTAT ACTTTGATTC ACTATATCAA CCAAAGGCCT   4440
TCTTGTATCA TGGATGTGTC ATTACGTAGC TTCTCCCTTT GTTGTGACTT ATTAAGTCAG   4500
GTTTGCCAGA CAGCCGTGAC TTACTGTAAG GATGCTCTAG AAAACCATCT TCATGTTATT   4560
GTTGGTACAC TTATACCCCT TGTGTATGAG CAGGTGGAGG TTCAGAAACA GGTATTGGAC   4620
TTGTTGAAAT ACTTAGTGAT AGATAACAAG GATAATGAAA ACCTCTATAT CACGATTAAG   4680
CTTTTAGATC CTTTTCCTGA CCATGTTGTT TTTAAGGATT TGCGTATTAC TCAGCAAAAA   4740
ATCAAATACA GTAGAGGACC CTTTTCACTC TTGGAGGAAA TTAACCATTT TCTCTCAGTA   4800
AGTGTTTATG ATGCACTTCC ATTGACAAGA CTTGAAGGAC TAAAGGATCT TCGAAGACAA   4860
CTGGAACTAC ATAAAGATCA GATGGTGGAC ATTATGAGAG CTTCTCAGGA TAATCCGCAA   4920
GATGGGATTA TGGTGAAACT AGTTGTCAAT TTGTTGCAGT TATCCAAGAT GGCAATAAAC   4980
CACACTGGTG AAAAAGAAGT TCTAGAGGCT GTTGGAAGCT GCTTGGGAGA AGTGGGTCCT   5040
ATAGATTTCT CTACCATAGC TATACAACAT AGTAAAGATG CATCTTATAC CAAGGCCCTT   5100
AAGTTATTTG AAGATAAAGA ACTTCAGTGG ACCTTCATAA TGCTGACCTA CCTGAATAAC   5160
ACACTGGTAG AAGATTGTGT CAAAGTTCGA TCAGCAGCTG TTACCTGTTT GAAAAACATT   5220
TTAGCCACAA AGACTGGACA TAGTTTCTGG GAGATTTATA AGATGACAAC AGATCCAATG   5280
CTGGCCTATC TACAGCCTTT TAGAACATCA AGAAAAAAGT TTTTAGAAGT ACCCAGATTT   5340
GACAAAGAAA ACCCTTTTGA AGGCCTGGAT GATATAAATC TGTGGATTCC TCTAAGTGAA   5400
AATCATGACA TTTGGATAAA GACACTGACT TGTGCTTTTT TGGACAGTGG AGGCACAAAA   5460
TGTGAAATTC TTCAATTATT AAAGCCAATG TGTGAAGTGA AAACTGACTT TTGTCAGACT   5520
GTACTTCCAT ACTTGATTCA TGATATTTTA CTCCAAGATA CAAATGAATC ATGGAGAAAT   5580
CTGCTTTCTA CACATGTTCA GGGATTTTTC ACCAGCTGTC TTCGACACTT CTCGCAAACG   5640
AGCCGATCCA CAACCCCTGC AAACTTGGAT TCAGAGTCAG AGCACTTTTT CCGATGCTGT   5700
TTGGATAAAA AATCACAAAG AACAATGCTT GCTGTTGTGG ACTACATGAG AAGACAAAAG   5760
AGACCTTCTT CAGGAACAAT TTTTAATGAT GCTTTCTGGC TGGATTTAAA TTATCTAGAA   5820
GTTGCCAAGG TAGCTCAGTC TTGTGCTGCT CACTTTACAG CTTTACTCTA TGCAGAAATC   5880
TATGCAGATA AGAAAAGTAT GGATGATCAA GAGAAAAGAA GTCTTGCATT TGAAGAAGGA   5940
AGCCAGAGTA CAACTATTTC TAGCTTGAGT GAAAAAAGTA AAGAAGAAAC TGGAATAAGT   6000
TTACAGGATC TTCTCTTAGA AATCTACAGA AGTATAGGGG AGCCAGATAG TTTGTATGGC   6060
TGTGGTGGAG GGAAGATGTT ACAACCCATT ACTAGACTAC GAACATATGA ACACGAAGCA   6120
ATGTGGGGCA AAGCCCTAGT AACATATGAC CTCGAAACAG CAATCCCCTC ATCAACACGC   6180
CAGGCAGGAA TCATTCAGGC CTTGCAGAAT TTGGGACTCT GCCATATTCT TTCCGTCTAT   6240
TTAAAAGGAT TGGATTATGA AAATAAAGAC TGGTGTCCTG AACTAGAAGA ACTTCATTAC   6300
CAAGCAGCAT GGAGGAATAT GCAGTGGGAC CATTGCACTT CCGTCAGCAA AGAAGTAGAA   6360
GGAACCAGTT ACCATGAATC ATTGTACAAT GCTCTACAAT CTCTAAGAGA CAGAGAATTC   6420
TCTACATTTT ATGAAAGTCT CAAATATGCC AGAGTAAAAG AAGTGGAAGA GATGTGTAAG   6480
CGCAGCCTTG AGTCTGTGTA TTCGCTCTAT CCCACACTTA GCAGGTTGCA GGCCATTGGA   6540
GAGCTGGAAA GCATTGGGGA GCTTTTCTCA AGATCAGTCA CACATAGACA ACTCTCTGAA   6600
GTATATATTA AGTGGCAGAA ACACTCCCAG CTTCTCAAGG ACAGTGATTT TAGTTTTCAG   6660
GAGCCTATCA TGGCTCTACG CACAGTCATT TTGGAGATCC TGATGGAAAA GGAAATGGAC   6720
AACTCACAAA GAGAATGTAT TAAGGACATT CTCACCAAAC ACCTTGTAGA ACTCTCTATA   6780
CTGGCCAGAA CTTTCAAGAA CACTCAGCTC CCTGAAAGGG CAATATTTCA AATTAAACAG   6840
TACAATTCAG TTAGCTGTGG AGTCTCTGAG TGGCAGCTGG AAGAAGCACA AGTATTCTGG   6900
GCAAAAAAGG AGCAGAGTCT TGCCCTGAGT ATTCTCAAGC AAATGATCAA GAAGTTGGAT   6960
GCCAGCTGTG CAGCGAACAA TCCCAGCCTA AAACTTACAT ACACAGAATG TCTGAGGGTT   7020
TGTGGCAACT GGTTAGCAGA AACGTGCTTA GAAAATCCTG CGGTCATCAT GCAGACCTAT   7080
CTAGAAAAGG CAGTAGAAGT TGCTGGAAAT TATGATGGAG AAAGTAGTGA TGAGCTAAGA   7140
AATGGAAAAA TGAAGGCATT TCTCTCATTA GCCCGGTTTT CAGATACTCA ATACCAAAGA   7200
ATTGAAAACT ACATGAAATC ATCGGAATTT GAAAACAAGC AAGCTCTCCT GAAAAGAGCC   7260
AAAGAGGAAG TAGGTCTCCT TAGGGAACAT AAAATTCAGA CAAACAGATA CACAGTAAAG   7320
GTTCAGCGAG AGCTGGAGTT GGATGAATTA GCCCTGCGTG CACTGAAAGA GGATCGTAAA   7380
CGCTTCTTAT GTAAAGCAGT TGAAAATTAT ATCAACTGCT TATTAAGTGG AGAAGAACAT   7440
GATATGTGGG TATTCCGACT TTGTTCCCTC TGGCTTGAAA ATTCTGGAGT TTCTGAAGTC   7500
AATGGCATGA TGAAGAGAGA CGGAATGAAG ATTCCAACAT ATAAATTTTT GCCTCTTATG   7560
TACCAATTGG CTGCTAGAAT GGGGACCAAG ATGATGGGAG GCCTAGGATT TCATGAAGTC   7620
CTCAATAATC TAATCTCTAG AATTTCAATG GATCACCCCC ATCACACTTT GTTTATTATA   7680
CTGGCCTTAG CAAATGCAAA CAGAGATGAA TTTCTGACTA AACCAGAGGT AGCCAGAAGA   7740
AGCAGAATAA CTAAAAATGT GCCTAAACAA AGCTCTCAGC TTGATGAGGA TCGAACAGAG   7800
GCTGCAAATA GAATAATATG TACTATCAGA AGTAGGAGAC CTCAGATGGT CAGAAGTGTT   7860
GAGGCACTTT GTGATGCTTA TATTATATTA GCAAACTTAG ATGCCACTCA GTGGAAGACT   7920
CAGAGAAAAG GCATAAATAT TCCAGCAGAC CAGCCAATTA CTAAACTTAA GAATTTAGAA   7980
GATGTTGTTG TCCCTACTAT GGAAATTAAG GTGGACCACA CAGGAGAATA TGGAAATCTG   8040
GTGACTATAC AGTCATTTAA AGCAGAATTT CGCTTAGCAG GAGGTGTAAA TTTACCAAAA   8100
ATAATAGATT GTGTAGGTTC CGATGGCAAG GAGAGGAGAC AGCTTGTTAA GGGCCGTGAT   8160
GACCTGAGAC AAGATGCTGT CATGCAACAG GTCTTCCAGA TGTGTAATAC ATTACTGCAG   8220
AGAAACACGG AAACTAGGAA GAGGAAATTA ACTATCTGTA CTTATAAGGT GGTTCCCCTC   8280
TCTCAGCGAA GTGGTGTTCT TGAATGGTGC ACAGGAACTG TCCCCATTGG TGAATTTCTT   8340
GTTAACAATG AAGATGGTGC TCATAAAAGA TACAGGCCAA ATGATTTCAG TGCCTTTCAG   8400
TGCCAAAAGA AAATGATGGA GGTGCAAAAA AAGTCTTTTG AAGAGAAATA TGAAGTCTTC   8460
ATGGATGTTT GCCAAAATTT TCAACCAGTT TTCCGTTACT TCTGCATGGA AAAATTCTTG   8520
GATCCAGCTA TTTGGTTTGA GAAGCGATTG GCTTATACGC GCAGTGTAGC TACTTCTTCT   8580
ATTGTTGGTT ACATACTTGG ACTTGGTGAT AGACATGTAC AGAATATCTT GATAAATGAG   8640
CAGTCAGCAG AACTTGTACA TATAGATCTA GGTGTTGCTT TTGAACAGGG CAAAATCCTT   8700
CCTACTCCTG AGACAGTTCC TTTTAGACTC ACCAGAGATA TTGTGGATGG CATGGGCATT   8760
ACGGGTGTTG AAGGTGTCTT CAGAAGATGC TGTGAGAAAA CCATGGAAGT GATGAGAAAC   8820
TCTCAGGAAA CTCTGTTAAC CATTGTAGAG GTCCTTCTAT ATGATCCACT CTTTGACTGG   8880
ACCATGAATC CTTTGAAAGC TTTGTATTTA CAGCAGAGGC CGGAAGATGA AACTGAGCTT   8940
CACCCTACTC TGAATGCAGA TGACCAAGAA TGCAAACGAA ATCTCAGTGA TATTGACCAG   9000
AGTTTCAACA AAGTAGCTGA ACGTGTCTTA ATGAGACTAC AAGAGAAACT GAAAGGAGTG   9060
GAAGAAGGCA CTGTGCTCAG TGTTGGTGGA CAAGTGAATT TGCTCATACA GCAGGCCATA   9120
GACCCCAAAA ATCTCAGCCG ACTTTTCCCA GGATGGAAAG CTTGGGTGTG A            9171 
           
           
             
               3056 amino acids 
               amino acid 
               single 
               linear 
             
             
               protein 
             
             
               Homo sapiens 
             
             3
Met Ser Leu Val Leu Asn Asp Leu Leu Ile Cys Cys Arg Gln Leu Glu
1               5                   10                  15
His Asp Arg Ala Thr Glu Arg Lys Lys Glu Val Glu Lys Phe Lys Arg
            20                  25                  30
Leu Ile Arg Asp Pro Glu Thr Ile Lys His Leu Asp Arg His Ser Asp
        35                  40                  45
Ser Lys Gln Gly Lys Tyr Leu Asn Trp Asp Ala Val Phe Arg Phe Leu
    50                  55                  60
Gln Lys Tyr Ile Gln Lys Glu Thr Glu Cys Leu Arg Ile Ala Lys Pro
65                  70                  75                  80
Asn Val Ser Ala Ser Thr Gln Ala Ser Arg Gln Lys Lys Met Gln Glu
                85                  90                  95
Ile Ser Ser Leu Val Lys Tyr Phe Ile Lys Cys Ala Asn Arg Arg Ala
            100                 105                 110
Pro Arg Leu Lys Cys Gln Glu Leu Leu Asn Tyr Ile Met Asp Thr Val
        115                 120                 125
Lys Asp Ser Ser Asn Gly Ala Ile Tyr Gly Ala Asp Cys Ser Asn Ile
    130                 135                 140
Leu Leu Lys Asp Ile Leu Ser Val Arg Lys Tyr Trp Cys Glu Ile Ser
145                 150                 155                 160
Gln Gln Gln Trp Leu Glu Leu Phe Ser Val Tyr Phe Arg Leu Tyr Leu
                165                 170                 175
Lys Pro Ser Gln Asp Val His Arg Val Leu Val Ala Arg Ile Ile His
            180                 185                 190
Ala Val Thr Lys Gly Cys Cys Ser Gln Thr Asp Gly Leu Asn Ser Lys
        195                 200                 205
Phe Leu Asp Phe Phe Ser Lys Ala Ile Gln Cys Ala Arg Gln Glu Lys
    210                 215                 220
Ser Ser Ser Gly Leu Asn His Ile Leu Ala Ala Leu Thr Ile Phe Leu
225                 230                 235                 240
Lys Thr Leu Ala Val Asn Phe Arg Ile Arg Val Cys Glu Leu Gly Asp
                245                 250                 255
Glu Ile Leu Pro Thr Leu Val Tyr Ile Trp Thr Gln His Arg Leu Asn
            260                 265                 270
Asp Ser Leu Lys Glu Val Ile Ile Glu Leu Phe Gln Leu Gln Ile Tyr
        275                 280                 285
Ile His His Pro Lys Gly Ala Lys Thr Gln Glu Lys Gly Ala Tyr Glu
    290                 295                 300
Ser Thr Lys Trp Arg Ser Ile Leu Tyr Asn Leu Tyr Asp Leu Leu Val
305                 310                 315                 320
Asn Glu Ile Ser His Ile Gly Ser Arg Gly Lys Tyr Ser Ser Gly Phe
                325                 330                 335
Arg Asn Ile Ala Val Lys Glu Asn Leu Ile Glu Leu Met Ala Asp Ile
            340                 345                 350
Cys His Gln Val Phe Asn Glu Asp Thr Arg Ser Leu Glu Ile Ser Gln
        355                 360                 365
Ser Tyr Thr Thr Thr Gln Arg Glu Ser Ser Asp Tyr Ser Val Pro Cys
    370                 375                 380
Lys Arg Lys Lys Ile Glu Leu Gly Trp Glu Val Ile Lys Asp His Leu
385                 390                 395                 400
Gln Lys Ser Gln Asn Asp Phe Asp Leu Val Pro Trp Leu Gln Ile Ala
                405                 410                 415
Thr Gln Leu Ile Ser Lys Tyr Pro Ala Ser Leu Pro Asn Cys Glu Leu
            420                 425                 430
Ser Pro Leu Leu Met Ile Leu Ser Gln Leu Leu Pro Gln Gln Arg His
        435                 440                 445
Gly Glu Arg Thr Pro Tyr Val Leu Arg Cys Leu Thr Glu Val Ala Leu
    450                 455                 460
Cys Gln Asp Lys Arg Ser Asn Leu Glu Ser Ser Gln Lys Ser Asp Leu
465                 470                 475                 480
Leu Lys Leu Trp Asn Lys Ile Trp Cys Ile Thr Phe Arg Gly Ile Ser
                485                 490                 495
Ser Glu Gln Lys Gln Ala Glu Asn Phe Gly Leu Leu Gly Ala Ile Ile
            500                 505                 510
Gln Gly Ser Leu Val Glu Val Asp Arg Glu Phe Trp Lys Leu Phe Thr
        515                 520                 525
Gly Ser Ala Cys Arg Pro Ser Cys Pro Ala Val Cys Cys Leu Thr Leu
    530                 535                 540
Ala Leu Thr Thr Ser Ile Val Pro Gly Ala Val Lys Met Gly Ile Glu
545                 550                 555                 560
Gln Asn Met Cys Glu Val Asn Arg Ser Phe Ser Leu Lys Glu Ser Ile
                565                 570                 575
Met Lys Trp Leu Leu Phe Tyr Gln Leu Glu Gly Asp Leu Glu Asn Ser
            580                 585                 590
Thr Glu Val Pro Pro Ile Leu His Ser Asn Phe Pro His Leu Val Leu
        595                 600                 605
Glu Lys Ile Leu Val Ser Leu Thr Met Lys Asn Cys Lys Ala Ala Met
    610                 615                 620
Asn Phe Phe Gln Ser Val Pro Glu Cys Glu His His His Lys Asp Lys
625                 630                 635                 640
Glu Glu Leu Ser Phe Ser Glu Val Glu Glu Leu Phe Leu Gln Thr Thr
                645                 650                 655
Phe Asp Lys Met Asp Phe Leu Thr Ile Val Arg Glu Cys Gly Ile Glu
            660                 665                 670
Lys His Gln Ser Ser Ile Gly Phe Ser Val His Gln Asn Leu Lys Glu
        675                 680                 685
Ser Leu Asp Arg Cys Leu Leu Gly Leu Ser Glu Gln Leu Leu Asn Asn
    690                 695                 700
Tyr Ser Ser Glu Ile Thr Asn Ser Glu Thr Leu Val Arg Cys Ser Arg
705                 710                 715                 720
Leu Leu Val Gly Val Leu Gly Cys Tyr Cys Tyr Met Gly Val Ile Ala
                725                 730                 735
Glu Glu Glu Ala Tyr Lys Ser Glu Leu Phe Gln Lys Ala Asn Ser Leu
            740                 745                 750
Met Gln Cys Ala Gly Glu Ser Ile Thr Leu Phe Lys Asn Lys Thr Asn
        755                 760                 765
Glu Glu Phe Arg Ile Gly Ser Leu Arg Asn Met Met Gln Leu Cys Thr
    770                 775                 780
Arg Cys Leu Ser Asn Cys Thr Lys Lys Ser Pro Asn Lys Ile Ala Ser
785                 790                 795                 800
Gly Phe Phe Leu Arg Leu Leu Thr Ser Lys Leu Met Asn Asp Ile Ala
                805                 810                 815
Asp Ile Cys Lys Ser Leu Ala Ser Phe Ile Lys Lys Pro Phe Asp Arg
            820                 825                 830
Gly Glu Val Glu Ser Met Glu Asp Asp Thr Asn Gly Asn Leu Met Glu
        835                 840                 845
Val Glu Asp Gln Ser Ser Met Asn Leu Phe Asn Asp Tyr Pro Asp Ser
    850                 855                 860
Ser Val Ser Asp Ala Asn Glu Pro Gly Glu Ser Gln Ser Thr Ile Gly
865                 870                 875                 880
Ala Ile Asn Pro Leu Ala Glu Glu Tyr Leu Ser Lys Gln Asp Leu Leu
                885                 890                 895
Phe Leu Asp Met Leu Lys Phe Leu Cys Leu Cys Val Thr Thr Ala Gln
            900                 905                 910
Thr Asn Thr Val Ser Phe Arg Ala Ala Asp Ile Arg Arg Lys Leu Leu
        915                 920                 925
Met Leu Ile Asp Ser Ser Thr Leu Glu Pro Thr Lys Ser Leu His Leu
    930                 935                 940
His Met Tyr Leu Met Leu Leu Lys Glu Leu Pro Gly Glu Glu Tyr Pro
945                 950                 955                 960
Leu Pro Met Glu Asp Val Leu Glu Leu Leu Lys Pro Leu Ser Asn Val
                965                 970                 975
Cys Ser Leu Tyr Arg Arg Asp Gln Asp Val Cys Lys Thr Ile Leu Asn
            980                 985                 990
His Val Leu His Val Val Lys Asn Leu Gly Gln Ser Asn Met Asp Ser
        995                 1000                1005
Glu Asn Thr Arg Asp Ala Gln Gly Gln Phe Leu Thr Val Ile Gly Ala
    1010                1015                1020
Phe Trp His Leu Thr Lys Glu Arg Lys Tyr Ile Phe Ser Val Arg Met
1025                1030                1035                1040
Ala Leu Val Asn Cys Leu Lys Thr Leu Leu Glu Ala Asp Pro Tyr Ser
                1045                1050                1055
Lys Trp Ala Ile Leu Asn Val Met Gly Lys Asp Phe Pro Val Asn Glu
            1060                1065                1070
Val Phe Thr Gln Phe Leu Ala Asp Asn His His Gln Val Arg Met Leu
        1075                1080                1085
Ala Ala Glu Ser Ile Asn Arg Leu Phe Gln Asp Thr Lys Gly Asp Ser
    1090                1095                1100
Ser Arg Leu Leu Lys Ala Leu Pro Leu Lys Leu Gln Gln Thr Ala Phe
1105                1110                1115                1120
Glu Asn Ala Tyr Leu Lys Ala Gln Glu Gly Met Arg Glu Met Ser His
                1125                1130                1135
Ser Ala Glu Asn Pro Glu Thr Leu Asp Glu Ile Tyr Asn Arg Lys Ser
            1140                1145                1150
Val Leu Leu Thr Leu Ile Ala Val Val Leu Ser Cys Ser Pro Ile Cys
        1155                1160                1165
Glu Lys Gln Ala Leu Phe Ala Leu Cys Lys Ser Val Lys Glu Asn Gly
    1170                1175                1180
Leu Glu Pro His Leu Val Lys Lys Val Leu Glu Lys Val Ser Glu Thr
1185                1190                1195                1200
Phe Gly Tyr Arg Arg Leu Glu Asp Phe Met Ala Ser His Leu Asp Tyr
                1205                1210                1215
Leu Val Leu Glu Trp Leu Asn Leu Gln Asp Thr Glu Tyr Asn Leu Ser
            1220                1225                1230
Ser Phe Pro Phe Ile Leu Leu Asn Tyr Thr Asn Ile Glu Asp Phe Tyr
        1235                1240                1245
Arg Ser Cys Tyr Lys Val Leu Ile Pro His Leu Val Ile Arg Ser His
    1250                1255                1260
Phe Asp Glu Val Lys Ser Ile Ala Asn Gln Ile Gln Glu Asp Trp Lys
1265                1270                1275                1280
Ser Leu Leu Thr Asp Cys Phe Pro Lys Ile Leu Val Asn Ile Leu Pro
                1285                1290                1295
Tyr Phe Ala Tyr Glu Gly Thr Arg Asp Ser Gly Met Ala Gln Gln Arg
            1300                1305                1310
Glu Thr Ala Thr Lys Val Tyr Asp Met Leu Lys Ser Glu Asn Leu Leu
        1315                1320                1325
Gly Lys Gln Ile Asp His Leu Phe Ile Ser Asn Leu Pro Glu Ile Val
    1330                1335                1340
Val Glu Leu Leu Met Thr Leu His Glu Pro Ala Asn Ser Ser Ala Ser
1345                1350                1355                1360
Gln Ser Thr Asp Leu Cys Asp Phe Ser Gly Asp Leu Asp Pro Ala Pro
                1365                1370                1375
Asn Pro Pro His Phe Pro Ser His Val Ile Lys Ala Thr Phe Ala Tyr
            1380                1385                1390
Ile Ser Asn Cys His Lys Thr Lys Leu Lys Ser Ile Leu Glu Ile Leu
        1395                1400                1405
Ser Lys Ser Pro Asp Ser Tyr Gln Lys Ile Leu Leu Ala Ile Cys Glu
    1410                1415                1420
Gln Ala Ala Glu Thr Asn Asn Val Tyr Lys Lys His Arg Ile Leu Lys
1425                1430                1435                1440
Ile Tyr His Leu Phe Val Ser Leu Leu Leu Lys Asp Ile Lys Ser Gly
                1445                1450                1455
Leu Gly Gly Ala Trp Ala Phe Val Leu Arg Asp Val Ile Tyr Thr Leu
            1460                1465                1470
Ile His Tyr Ile Asn Gln Arg Pro Ser Cys Ile Met Asp Val Ser Leu
        1475                1480                1485
Arg Ser Phe Ser Leu Cys Cys Asp Leu Leu Ser Gln Val Cys Gln Thr
    1490                1495                1500
Ala Val Thr Tyr Cys Lys Asp Ala Leu Glu Asn His Leu His Val Ile
1505                1510                1515                1520
Val Gly Thr Leu Ile Pro Leu Val Tyr Glu Gln Val Glu Val Gln Lys
                1525                1530                1535
Gln Val Leu Asp Leu Leu Lys Tyr Leu Val Ile Asp Asn Lys Asp Asn
            1540                1545                1550
Glu Asn Leu Tyr Ile Thr Ile Lys Leu Leu Asp Pro Phe Pro Asp His
        1555                1560                1565
Val Val Phe Lys Asp Leu Arg Ile Thr Gln Gln Lys Ile Lys Tyr Ser
    1570                1575                1580
Arg Gly Pro Phe Ser Leu Leu Glu Glu Ile Asn His Phe Leu Ser Val
1585                1590                1595                1600
Ser Val Tyr Asp Ala Leu Pro Leu Thr Arg Leu Glu Gly Leu Lys Asp
                1605                1610                1615
Leu Arg Arg Gln Leu Glu Leu His Lys Asp Gln Met Val Asp Ile Met
            1620                1625                1630
Arg Ala Ser Gln Asp Asn Pro Gln Asp Gly Ile Met Val Lys Leu Val
        1635                1640                1645
Val Asn Leu Leu Gln Leu Ser Lys Met Ala Ile Asn His Thr Gly Glu
    1650                1655                1660
Lys Glu Val Leu Glu Ala Val Gly Ser Cys Leu Gly Glu Val Gly Pro
1665                1670                1675                1680
Ile Asp Phe Ser Thr Ile Ala Ile Gln His Ser Lys Asp Ala Ser Tyr
                1685                1690                1695
Thr Lys Ala Leu Lys Leu Phe Glu Asp Lys Glu Leu Gln Trp Thr Phe
            1700                1705                1710
Ile Met Leu Thr Tyr Leu Asn Asn Thr Leu Val Glu Asp Cys Val Lys
        1715                1720                1725
Val Arg Ser Ala Ala Val Thr Cys Leu Lys Asn Ile Leu Ala Thr Lys
    1730                1735                1740
Thr Gly His Ser Phe Trp Glu Ile Tyr Lys Met Thr Thr Asp Pro Met
1745                1750                1755                1760
Leu Ala Tyr Leu Gln Pro Phe Arg Thr Ser Arg Lys Lys Phe Leu Glu
                1765                1770                1775
Val Pro Arg Phe Asp Lys Glu Asn Pro Phe Glu Gly Leu Asp Asp Ile
            1780                1785                1790
Asn Leu Trp Ile Pro Leu Ser Glu Asn His Asp Ile Trp Ile Lys Thr
        1795                1800                1805
Leu Thr Cys Ala Phe Leu Asp Ser Gly Gly Thr Lys Cys Glu Ile Leu
    1810                1815                1820
Gln Leu Leu Lys Pro Met Cys Glu Val Lys Thr Asp Phe Cys Gln Thr
1825                1830                1835                1840
Val Leu Pro Tyr Leu Ile His Asp Ile Leu Leu Gln Asp Thr Asn Glu
                1845                1850                1855
Ser Trp Arg Asn Leu Leu Ser Thr His Val Gln Gly Phe Phe Thr Ser
            1860                1865                1870
Cys Leu Arg His Phe Ser Gln Thr Ser Arg Ser Thr Thr Pro Ala Asn
        1875                1880                1885
Leu Asp Ser Glu Ser Glu His Phe Phe Arg Cys Cys Leu Asp Lys Lys
    1890                1895                1900
Ser Gln Arg Thr Met Leu Ala Val Val Asp Tyr Met Arg Arg Gln Lys
1905                1910                1915                1920
Arg Pro Ser Ser Gly Thr Ile Phe Asn Asp Ala Phe Trp Leu Asp Leu
                1925                1930                1935
Asn Tyr Leu Glu Val Ala Lys Val Ala Gln Ser Cys Ala Ala His Phe
            1940                1945                1950
Thr Ala Leu Leu Tyr Ala Glu Ile Tyr Ala Asp Lys Lys Ser Met Asp
        1955                1960                1965
Asp Gln Glu Lys Arg Ser Leu Ala Phe Glu Glu Gly Ser Gln Ser Thr
    1970                1975                1980
Thr Ile Ser Ser Leu Ser Glu Lys Ser Lys Glu Glu Thr Gly Ile Ser
1985                1990                1995                2000
Leu Gln Asp Leu Leu Leu Glu Ile Tyr Arg Ser Ile Gly Glu Pro Asp
                2005                2010                2015
Ser Leu Tyr Gly Cys Gly Gly Gly Lys Met Leu Gln Pro Ile Thr Arg
            2020                2025                2030
Leu Arg Thr Tyr Glu His Glu Ala Met Trp Gly Lys Ala Leu Val Thr
        2035                2040                2045
Tyr Asp Leu Glu Thr Ala Ile Pro Ser Ser Thr Arg Gln Ala Gly Ile
    2050                2055                2060
Ile Gln Ala Leu Gln Asn Leu Gly Leu Cys His Ile Leu Ser Val Tyr
2065                2070                2075                2080
Leu Lys Gly Leu Asp Tyr Glu Asn Lys Asp Trp Cys Pro Glu Leu Glu
                2085                2090                2095
Glu Leu His Tyr Gln Ala Ala Trp Arg Asn Met Gln Trp Asp His Cys
            2100                2105                2110
Thr Ser Val Ser Lys Glu Val Glu Gly Thr Ser Tyr His Glu Ser Leu
        2115                2120                2125
Tyr Asn Ala Leu Gln Ser Leu Arg Asp Arg Glu Phe Ser Thr Phe Tyr
    2130                2135                2140
Glu Ser Leu Lys Tyr Ala Arg Val Lys Glu Val Glu Glu Met Cys Lys
2145                2150                2155                2160
Arg Ser Leu Glu Ser Val Tyr Ser Leu Tyr Pro Thr Leu Ser Arg Leu
                2165                2170                2175
Gln Ala Ile Gly Glu Leu Glu Ser Ile Gly Glu Leu Phe Ser Arg Ser
            2180                2185                2190
Val Thr His Arg Gln Leu Ser Glu Val Tyr Ile Lys Trp Gln Lys His
        2195                2200                2205
Ser Gln Leu Leu Lys Asp Ser Asp Phe Ser Phe Gln Glu Pro Ile Met
    2210                2215                2220
Ala Leu Arg Thr Val Ile Leu Glu Ile Leu Met Glu Lys Glu Met Asp
2225                2230                2235                2240
Asn Ser Gln Arg Glu Cys Ile Lys Asp Ile Leu Thr Lys His Leu Val
                2245                2250                2255
Glu Leu Ser Ile Leu Ala Arg Thr Phe Lys Asn Thr Gln Leu Pro Glu
            2260                2265                2270
Arg Ala Ile Phe Gln Ile Lys Gln Tyr Asn Ser Val Ser Cys Gly Val
        2275                2280                2285
Ser Glu Trp Gln Leu Glu Glu Ala Gln Val Phe Trp Ala Lys Lys Glu
    2290                2295                2300
Gln Ser Leu Ala Leu Ser Ile Leu Lys Gln Met Ile Lys Lys Leu Asp
2305                2310                2315                2320
Ala Ser Cys Ala Ala Asn Asn Pro Ser Leu Lys Leu Thr Tyr Thr Glu
                2325                2330                2335
Cys Leu Arg Val Cys Gly Asn Trp Leu Ala Glu Thr Cys Leu Glu Asn
            2340                2345                2350
Pro Ala Val Ile Met Gln Thr Tyr Leu Glu Lys Ala Val Glu Val Ala
        2355                2360                2365
Gly Asn Tyr Asp Gly Glu Ser Ser Asp Glu Leu Arg Asn Gly Lys Met
    2370                2375                2380
Lys Ala Phe Leu Ser Leu Ala Arg Phe Ser Asp Thr Gln Tyr Gln Arg
2385                2390                2395                2400
Ile Glu Asn Tyr Met Lys Ser Ser Glu Phe Glu Asn Lys Gln Ala Leu
                2405                2410                2415
Leu Lys Arg Ala Lys Glu Glu Val Gly Leu Leu Arg Glu His Lys Ile
            2420                2425                2430
Gln Thr Asn Arg Tyr Thr Val Lys Val Gln Arg Glu Leu Glu Leu Asp
        2435                2440                2445
Glu Leu Ala Leu Arg Ala Leu Lys Glu Asp Arg Lys Arg Phe Leu Cys
    2450                2455                2460
Lys Ala Val Glu Asn Tyr Ile Asn Cys Leu Leu Ser Gly Glu Glu His
2465                2470                2475                2480
Asp Met Trp Val Phe Arg Leu Cys Ser Leu Trp Leu Glu Asn Ser Gly
                2485                2490                2495
Val Ser Glu Val Asn Gly Met Met Lys Arg Asp Gly Met Lys Ile Pro
            2500                2505                2510
Thr Tyr Lys Phe Leu Pro Leu Met Tyr Gln Leu Ala Ala Arg Met Gly
        2515                2520                2525
Thr Lys Met Met Gly Gly Leu Gly Phe His Glu Val Leu Asn Asn Leu
    2530                2535                2540
Ile Ser Arg Ile Ser Met Asp His Pro His His Thr Leu Phe Ile Ile
2545                2550                2555                2560
Leu Ala Leu Ala Asn Ala Asn Arg Asp Glu Phe Leu Thr Lys Pro Glu
                2565                2570                2575
Val Ala Arg Arg Ser Arg Ile Thr Lys Asn Val Pro Lys Gln Ser Ser
            2580                2585                2590
Gln Leu Asp Glu Asp Arg Thr Glu Ala Ala Asn Arg Ile Ile Cys Thr
        2595                2600                2605
Ile Arg Ser Arg Arg Pro Gln Met Val Arg Ser Val Glu Ala Leu Cys
    2610                2615                2620
Asp Ala Tyr Ile Ile Leu Ala Asn Leu Asp Ala Thr Gln Trp Lys Thr
2625                2630                2635                2640
Gln Arg Lys Gly Ile Asn Ile Pro Ala Asp Gln Pro Ile Thr Lys Leu
                2645                2650                2655
Lys Asn Leu Glu Asp Val Val Val Pro Thr Met Glu Ile Lys Val Asp
            2660                2665                2670
His Thr Gly Glu Tyr Gly Asn Leu Val Thr Ile Gln Ser Phe Lys Ala
        2675                2680                2685
Glu Phe Arg Leu Ala Gly Gly Val Asn Leu Pro Lys Ile Ile Asp Cys
    2690                2695                2700
Val Gly Ser Asp Gly Lys Glu Arg Arg Gln Leu Val Lys Gly Arg Asp
2705                2710                2715                2720
Asp Leu Arg Gln Asp Ala Val Met Gln Gln Val Phe Gln Met Cys Asn
                2725                2730                2735
Thr Leu Leu Gln Arg Asn Thr Glu Thr Arg Lys Arg Lys Leu Thr Ile
            2740                2745                2750
Cys Thr Tyr Lys Val Val Pro Leu Ser Gln Arg Ser Gly Val Leu Glu
        2755                2760                2765
Trp Cys Thr Gly Thr Val Pro Ile Gly Glu Phe Leu Val Asn Asn Glu
    2770                2775                2780
Asp Gly Ala His Lys Arg Tyr Arg Pro Asn Asp Phe Ser Ala Phe Gln
2785                2790                2795                2800
Cys Gln Lys Lys Met Met Glu Val Gln Lys Lys Ser Phe Glu Glu Lys
                2805                2810                2815
Tyr Glu Val Phe Met Asp Val Cys Gln Asn Phe Gln Pro Val Phe Arg
            2820                2825                2830
Tyr Phe Cys Met Glu Lys Phe Leu Asp Pro Ala Ile Trp Phe Glu Lys
        2835                2840                2845
Arg Leu Ala Tyr Thr Arg Ser Val Ala Thr Ser Ser Ile Val Gly Tyr
    2850                2855                2860
Ile Leu Gly Leu Gly Asp Arg His Val Gln Asn Ile Leu Ile Asn Glu
2865                2870                2875                2880
Gln Ser Ala Glu Leu Val His Ile Asp Leu Gly Val Ala Phe Glu Gln
                2885                2890                2895
Gly Lys Ile Leu Pro Thr Pro Glu Thr Val Pro Phe Arg Leu Thr Arg
            2900                2905                2910
Asp Ile Val Asp Gly Met Gly Ile Thr Gly Val Glu Gly Val Phe Arg
        2915                2920                2925
Arg Cys Cys Glu Lys Thr Met Glu Val Met Arg Asn Ser Gln Glu Thr
    2930                2935                2940
Leu Leu Thr Ile Val Glu Val Leu Leu Tyr Asp Pro Leu Phe Asp Trp
2945                2950                2955                2960
Thr Met Asn Pro Leu Lys Ala Leu Tyr Leu Gln Gln Arg Pro Glu Asp
                2965                2970                2975
Glu Thr Glu Leu His Pro Thr Leu Asn Ala Asp Asp Gln Glu Cys Lys
            2980                2985                2990
Arg Asn Leu Ser Asp Ile Asp Gln Ser Phe Asp Lys Val Ala Glu Arg
        2995                3000                3005
Val Leu Met Arg Leu Gln Glu Lys Leu Lys Gly Val Glu Glu Gly Thr
    3010                3015                3020
Val Leu Ser Val Gly Gly Gln Val Asn Leu Leu Ile Gln Gln Ala Ile
3025                3030                3035                3040
Asp Pro Lys Asn Leu Ser Arg Leu Phe Pro Gly Trp Lys Ala Trp Val
                3045                3050                3055 
           
           
             
               15 amino acids 
               amino acid 
               single 
               linear 
             
             
               peptide 
             
             
               unknown 
             
             4
His Glu Pro Ala Asn Ser Ser Ala Ser Gln Ser Thr Asp Leu Cys
1               5                   10                  15 
           
           
             
               15 amino acids 
               amino acid 
               single 
               linear 
             
             
               peptide 
             
             
               unknown 
             
             5
Cys Lys Arg Asn Leu Ser Asp Ile Asp Gln Ser Phe Asp Lys Val
1               5                   10                  15 
           
           
             
               18 amino acids 
               amino acid 
               single 
               linear 
             
             
               peptide 
             
             
               unknown 
             
             6
Pro Glu Asp Glu Thr Glu Leu His Pro Thr Leu Asn Ala Asp Asp Gln
1               5                   10                  15
Glu Cys 
           
           
             
               26 amino acids 
               amino acid 
               single 
               linear 
             
             
               peptide 
             
             
               unknown 
             
             7
Cys Lys Ser Leu Ala Ser Phe Ile Lys Lys Pro Phe Asp Arg Gly Glu
1               5                   10                  15
Val Glu Ser Met Glu Asp Asp Thr Asn Gly
            20                  25 
           
           
             
               3607 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               cDNA 
             
             
               Homo sapiens 
             
             
               3′UTR 
                1..3607 
             
             8
TCTTCAGTAT ATGAATTACC CTTTCATTCA GCCTTTAGAA ATTATATTTT AGCCTTTATT     60
TTTAACCTGC CAACATACTT TAAGTAGGGA TTAATATTTA AGTGAACTAT TGTGGGTTTT    120
TTTGAATGTT GGTTTTAATA CTTGATTTAA TCACCACTCA AAAATGTTTT GATGGTCTTA    180
AGGAACATCT CTGCTTTCAC TCTTTAGAAA TAATGGTCAT TCGGGCTGGG CGCAGCGGCT    240
CACGCCTGTA ATCCCAGCAC TTTGGGAGGC CGAGGTGAGC GGATCACAAG GTCAGGAGTT    300
CGAGACCAGC CTGGCCAAGA GACCAGCCTG GCCAGTATGG TGAAACCCTG TCTCTACTAA    360
AAATACAAAA ATTAGCCGAG CATGGTGGCG GGCACCTGTA ATCCCAGCTA CTCGAGAGGC    420
TGAGGCAGGA GAATCTCTTG AACCTGGGAG GTGAAGGTTG CTGTGGGCCA AAATCATGCC    480
ATTGCACTCC AGCCTGGGTG ACAAGAGCGA AACTCCATCT CAAAAAAAAA AAAAAAAAAC    540
AGAAACTTAT TTGGATTTTT CCTAGTAAGA TCACTCAGTG TTACTAAATA ATGAAGTTGT    600
TATGGAGAAC AAATTTCAAA GACACAGTTA GTGTAGTTAC TATTTTTTTA AGTGTGTATT    660
AAAACTTCTC ATTCTATTCT CTTTATCTTT TAAGCCCTTC TGTACTGTCC ATGTATGTTA    720
TCTTTCTGTG ATAACTTCAT AGATTGCCTT CTAGTTCATG AATTCTCTTG TCAGATGTAT    780
ATAATCTCTT TTACCCTATC CATTGGGCTT CTTCTTTCAG AAATTGTTTT TCATTTCTAA    840
TTATGCATCA TTTTTCAGAT CTCTGTTTCT TGATGTCATT TTTAATGTTT TTTTAATGTT    900
TTTTATGTCA CTAATTATTT TAAATGTCTG TACCTGATAG ACACTGTAAT AGTTCTATTA    960
AATTTAGTTC CTGCTGTTTA TATCTGTTGA TTTTTGTATT TGATAGGCTG TTCATCCAGT   1020
TTTGTCTTTT TGAAAAGTGA GTTTATTTTC AGCAAGGCTT TATCTATGGG AATCTTGAGT   1080
GTCTGTTTAT GTCATATTCC CAGGGCTGTT GCTGCACACA AGCCCATTCT TATTTTAATT   1140
TCTTGGCTTT AGGGTTTCCA TACCTGAAGT GTAGCATAAA TACTGATAGG AGATTTCCCA   1200
GGCCAAGGCA AACACACTTC CTCCTCATCT CCTTGTGCTA GTGGGCAGAA TATTTGATTG   1260
ATGCCTTTTT CACTGAGAGT ATAAGCTTCC ATGTGTCCCA CCTTTATGGC AGGGGTGGAA   1320
GGAGGTACAT TTAATTCCCA CTGCCTGCCT TTGGCAAGCC CTGGGTTCTT TGCTCCCCAT   1380
ATAGATGTCT AAGCTAAAAG CCGTGGGTTA ATGAGACTGG CAAATTGTTC CAGGACAGCT   1440
ACAGCATCAG CTCACATATT CACCTCTCTG GTTTTTCATT CCCCTCATTT TTTTCTGAGA   1500
CAGAGTCTTG CTCTGTCACC CAGGCTGGAG TGCAGTGGCA TGATCTCAGC TCACTGAAAC   1560
CTCTGCCTCC TGGGTTCAAG CAATTCTCCT GCCTCAGCCT CCCGAGTAGC TGGGACTACA   1620
GGCGTGTGCC AACACGCCCG GCTAATTTTT TGTATTTTTA TTAGAGACGG AGTTTCACCG   1680
TGTTAGCCAG GATGGTCTCG ATCGCTTGAC CTCGTGATCC ACCCTCCTCG GCCTCCCAAA   1740
GTGCTGGGAT TACAGGTGTG AGCCACCGCG CCCGGCCTCA TTCCCCTCAT TTTTGACCGT   1800
AAGGATTTCC CCTTTCTTGT AAGTTCTGCT ATGTATTTAA AAGAATGTTT TCTACATTTT   1860
ATCCAGCATT TCTCTGTGTT CTGTTGGAAG GGAAGGGCTT AGGTATCTAG TTTGATACAT   1920
AGGTAGAAGT GGAACATTTC TCTGTCCCCC AGCTGTCATC ATATAAGATA AACATCAGAT   1980
AAAAAGCCAC CTGAAAGTAA AACTACTGAC TCGTGTATTA GTGAGTATAA TCTCTTCTCC   2040
ATCCTTAGGA AAATGTTCAT CCCAGCTGCG GAGATTAACA AATGGGTGAT TGAGCTTTCT   2100
CCTCGTATTT GGACCTTGAA GGTTATATAA ATTTTTTTCT TATGAAGAGT TGGCATTTCT   2160
TTTTATTGCC AATGGCAGGC ACTCATTCAT ATTTGATCTC CTCACCTTCC CCTCCCCTAA   2220
AACCAATCTC CAGAACTTTT TGGACTATAA ATTTCTTGGT TTGACTTCTG GAGAACTGTT   2280
CAGAATATTA CTTTGCATTT CAAATTACAA ACTTACCTTG GTGTATCTTT TTCTTACAAG   2340
CTGCCTAAAT GAATATTTGG TATATATTGG TAGTTTTATT ACTATAGTAA ATCAAGGAAA   2400
TGCAGTAAAC TTAAAATGTC TTTAAGAAAG CCCTGAAATC TTCATGGGTG AAATTAGAAA   2460
TTATCAACTA GATAATAGTA TAGATAAATG AATTTGTAGC TAATTCTTGC TAGTTGTTGC   2520
ATCCAGAGAG CTTTGAATAA CATCATTAAT CTACTCTTTA GCCTTGCATG GTATGCTATG   2580
AGGCTCCTGT TCTGTTCAAG TATTCTAATC AATGGCTTTG AAAAGTTTAT CAAATTTACA   2640
TACAGATCAC AAGCCTAGGA GAAATAACTA ATTCACAGAT GACAGAATTA AGATTATAAA   2700
AGATTTTTTT TTGGTAATTT TAGTAGAGAC AGGGTTGCCA TTGTATTCCA GCCTTGGCGA   2760
CAGAGCAAGA CTCTGCCTCA AAAAAAAAAA AAAAAAGGTT TTGCCAAGCT GGAACTCTTT   2820
CTGCAAATGA CTAAGATAGA AAACTGCCAA GGACAAATGA GGAGTAGTTA GATTTTGAAA   2880
ATATTAATCA TAGAATAGTT GTTGTATGCT AAGTCACTGA CCCATATTAT GTACAGCATT   2940
TCTGATCTTT ACTTTGCAAG ATTAGTGATA CTATGCCAAT ACACTGCTGG AGAAATCAGA   3000
ATTTGGAGAA ATAAGTTGTC CAAGGCAAGA AGATAGTAAA TTATAAGTAC AAGTGTAATA   3060
TGGACAGTAT CTAACTTGAA AAGATTTCAG GCGAAAAGAA TCTGGGGTTT GCCAGTCAGT   3120
TGCTCAAAAG GTCAATGAAA ACCAAATAGT GAAGCTATCA GAGAAGCTAA TAAATTATAG   3180
ACTGCTTGAA CAGTTGTGTC CAGATTAAGG GAGATAATAG CTTTCCCACC CTACTTTGTG   3240
CAGGTCATAC CTCCCCAAAG TGTTTACCTA ATCAGTAGGT TCACAAACTC TTGGTCATTA   3300
TAGTATATGC CTAAAATGTA TGCACTTAGG AATGCTAAAA ATTTAAATAT GGTCTAAAGC   3360
AAATAAAAGC AAAGAGGAAA AACTTTGGAC ATCGTAAAGA CTAGAATAGT CTTTTAAAAA   3420
GAAAGCCAGT ATATTGGTTT GAAATATAGA GATGTGTCCC AATTTCAAGT ATTTTAATTG   3480
CACCTTAATG AAATTATCTA TTTTCTATAG ATTTTAGTAC TATTGAATGT ATTACTTTAC   3540
TGTTACCTGA ATTTATTATA AAGTGTTTTT GAATAAATAA TTCTAAAAGC AAAAAAAAAA   3600
AAAAAAA                                                             3607 
           
           
             
               884 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               cDNA 
             
             
               Homo sapiens 
             
             
               5′UTR 
                1..884 
             
             9
TCCTCCTTTT AAACGCCCTG AATTGAACCC TGCCTCCTGC GCATCCTCTT TTTGTGTCAC     60
CTTAGGGTTC AGATTTAACT ACGCGACTTG ACTAGTCATC TTTTGATCTC TCTCTCGTAT    120
TTAGTACTTT TAGTCAGCGA GCATTTATTG ATATTTCAAC TTCAGCCTCG CGGTTAAGAG    180
CTTGGGCTCT GGAATCATAC GGCTGGAATT GGAATTCTGT CAGTCGTGTG GCCGCTCTCT    240
ACTGTCTTGT GAAGATAAGT GAGATAATCT TGACCTGTGG TGAGCACTCG TGAGCGTTAG    300
CTGCTGTATT TACCAGGTAC AGATAAGACA ACTACAGTGG ATGATAATGT ATGTGGTGAT    360
AGGGGAGTAC TCTGATGGTA GAGGAGTGAC TTTGGTTCTC TGCAAACTCA GCCTGAGACT    420
ATCAATTCAG TTTGTGGTGA GACCTCGCAG TGTTACCTTG GCAGATGGTA GAAGCCTTCC    480
AGATGGAAGG AAAAATGCGT GTAAAGGCAC AAAGTGTAGA AGGACCCTGA AGCTCCAGCG    540
TGAGGCCTGG CATTGAATGA AATATATTTT GTGGGTTTTC AGCTGCTGAA GTCATAGGAA    600
TGGATGAGAC CAAGAAAACA AAGCTGTTTT TGAGGTATGA GCGGAAGAAG AGATATCAGG    660
AGACTTTCGA AACAGTCATA ACGGAAGTTA ATATGATCAT TGCTAACATT TGCTGTGTTT    720
CAGGCACTGT AAGCATGTAT ATGGGTCCTT AAAGGGACTC ATAGAGAGGC ATACATCACA    780
ATTTGGAATT ATGCATTGGT TTATCAATTT ACTTGTTTAT TGTCACCCTG CTGCCCAGAT    840
ATGACTTCAT GAGGACAGTG ATGTGTGTTC TGAAATTGTG AACC                     884 
           
           
             
               120 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               cDNA 
             
             
               unknown 
             
             10
AGGTAGCTGC GTGGCTAACG GAGAAAAGAA GCCGTGGCCA CGGGAGGAGG CGAGAGGAGT     60
CGGGATCTGC GCTGCAGCCA CCGCCGCGGT TGATACTACT TTGACCTTCC GAGTGCAGTG    120 
           
           
             
               9620 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               cDNA 
             
             
               Mus musculus 
             
             
               Chromosome 9, Band 9C 
             
             11
AGAATGCAGC GGTGAGGATG CATGTTCTGA AATCTTAAAC CATGAGTCTA GCACTCAATG     60
ATCTGCTCAT TTGCTGCCGG CAGTTAGAGC ATGACAGAGC TACAGAAAGA AGGAAAGAAG    120
TGGATAAATT TAAGCGCCTG ATTCAGGATC CTGAAACAGT TCAACATTTA GATAGGCATT    180
CTGATTCCAA ACAAGGAAAA TATCTGAATT GGGATGCTGT TTTCAGGTTT TTACAGAAGT    240
ACATTCAAAA AGAAATGGAA AGTCTGAGAA CAGCAAAATC AAATGTATCA GCCACCACAC    300
AGAGCTCCAG ACAGAAGAAG ATGCAAGAGA TCAGCAGTTT GGTCAGATAC TTCATCAAAT    360
GTGCAAACAA AAGAGCACCC AGGCTAAAAT GTCAAGACCT CTTGAATTAT GTCATGGATA    420
CAGTGAAAGA CTCATCTAAT GGTCTAACGT ATGGAGCTGA CTGTAGCAAC ATACTACTCA    480
AAGACATTCT TTCTGTGAGA AAATACTGGT GTGAAGTATC TCAGCAACAG TGGCTAGAAT    540
TGTTTTCACT GTACTTCAGG CTGTATCTCA AGCCATCACA GGACATTAAT AGAGTTTTAG    600
TGGCTAGAAT AATTCATGCT GTCACCAGAG GATGCTGTTC ACAGACTGAT GGATTACCTT    660
CAAAGTTTTT AGATCTTTTT TCCAAGGCTA TTCAGTATGC CAGACAAGAA AAGAGCTCTC    720
CTGGCTTAAG TCACATCTTA GCAGCCCTTA ACATTTTCCT CAAGTCTCTG GCTGTCAACT    780
TCCGAAAACG GGTGTGTGAA GCAGGAGATG AAATTCTTCC TACCTTACTA TATATTTGGA    840
CTCAACATAG ACTTAATGAT TCTTTAAAAG AAGTAATTAT TGAACTAATT CAACTGCAGA    900
TTTATATCCA TCATCCACAA GGAGCCAGAG CTCCTGAAGA AGGTGCTTAT GAATCCATGA    960
AATGGAAAAG TATCTTGTAC AACTTATATG ACTTGCTAGT GAATGAGATA AGTCATATAG   1020
GAAGCCGAGG GAAATATTCC TCAGGATCTC GTAATATTGC TGTCAAGGAA AATCTGATTG   1080
ACCTGATGGC AGATATCTGT TACCAGCTTT TTGATGCAGA TACCAGATCC GTGGAGATTT   1140
CTCAATCTTA TGTGACACAA AGGGAATCCA CTGATTACAG TGTACCTTGC AAAAGAAGGA   1200
AAATAGACGT AGGCTGGGAA GTGATAAAAG ATTATCTTCA GAAGTCACAG AGTGATTTTG   1260
ATCTCGTGCC TTGGCTACAG ATTACAACCC GATTAATATC AAAATATCCT TCCAGTTTAC   1320
CTAACTGTGA GCTGTCTCCA TTAATACTGA TACTGTACCA GCTTCTGCCT CAACAGCGAC   1380
GTGGAGAACG CATCCCATAT GTGTTACGAT GCCTTAAGGA AGTTGCCTTA TGTCAAGGCA   1440
AGAAATCAAA CCTGGAAAGC TCTCAGAAGT CAGATTTATT GAAACTATGG ATCAAAATTT   1500
GGTCTATTAC CTTTCGTGGT ATAAGTTCTG GACAAACACA AACTGAAAAC TTTGGTTTAC   1560
TTGAGGCCAT CATTCAAGGT AGTTTAGTTG AACTTGACAG AGAATTCTGG AAGTTATTTA   1620
CTGGCTCAGC CTGTAAACCT TCTAGTCCTT CAGTATGCTG CTTGACTTTG GCACTTAGCA   1680
TCTGTGTAGT TCCAGATGCA ATAAAAATGG GAACAGAACA AAGTGTGTGT GAAGCAAATA   1740
GAAGTTTTTC TGTAAAGGAG TCAATAATGA GGTGGCTCTT ATTCTACCAG TTAGAGGATG   1800
ACTTAGAAGA CAGCACAGAG CTGCCTCCAA TTCTTCAGCG TAATTTTCCT CATCTTGTAG   1860
TCGAAAAAAT TCTTGTAAGT CTCACTATGA AAAACTCAAA AGCTGCAATG AAGTTTTTTC   1920
AAAGTGTGCC AGAATGTGAA CAACACTGCG AAGATAAAGA AGAGCCTTCA TTTTCAGAAG   1980
TAGAAGAACT GTTTCTTCAG ACTACTTTTG ACAAGATGGA TTTTTTAACT ACTGTCAAAG   2040
AGTATGCTGT AGAAAAATTT CAGTCTAGTG TTGGCTTCTC TGTCCAGCAA AATCTCAAGG   2100
AATCATTGGA TCACTATCTT CTGGGATTAT CAGAACAGCT TTTAAGTAAT TACTCTTCTG   2160
AGATTACAAG TTCTGAAACC CTTGTCCGGT GTTCAAGTCT TTTGGTGGGT GTTCTTGGCT   2220
GCTATTGTTA CATGGGTATA ATAACTGAAG ACGAAGCCCA TAAATCAGAA TTATTCCAGA   2280
AAGCCAAGTC TCTGATGCAA TGTGCAGGAG AAAGTATCTC TCTGTTTAAA AATAAAACAA   2340
ATGAGGAATC AAGAATTGGT TCATTGAGAA ATGTGATGCA TCTGTGTACA AGTTGCTTGT   2400
GTATACATAC CAAGCATACG CCAAACAAGA TTGCCTCTGG CTTTTTCCTA CGATTATTAA   2460
CATCAAAGCT TATGAATGAC ATTGCAGATA TTTGTAAAAG TTTAGCATCC TGTACGAAAA   2520
AGCCATTGGA TCACGGAGTA CATCCAGGGG AAGATGATGA AGATGGTGGT GGTTGTGACA   2580
GTCTGATGGA GGCAGAGGGT CCATCGTCCA CTGGTCTTTC TACTGCTTAC CCCGCTAGTT   2640
CTGTGAGCGA TGCAAATGAT TATGGAGAGA ACCAGAATGC TGTTGGTGCC ATGAGTCCTT   2700
TAGCTGCCGA CTACCTGTCC AAACAAGATC ATCTTCTCTT AGACATGCTC AGGTTCTTAG   2760
GCCGATCTGT AACTGCATCT CAGAGCCATA CTGTGTCGTT TAGAGGAGCT GACATTAGAA   2820
GAAAATTGTT ACTGTTGCTT GATTCTAGCA TACTCGATCT CATGAAGCCC CTCCACCTGC   2880
ATATGTACTT AGTGCTCCTG AAGGATCTCC CTGGAAACGA GCACTCATTG CCAATGGAAG   2940
ATGTTGTTGA ACTTCTGCAA CCATTATCCC TTGTGTGTTC TCTGCACCGA CGTGACCAAG   3000
ATGTCTGTAA AACGATTCTA AGCAATGTCC TTCATATAGT GACAAACCTA GGCCAGGGCA   3060
GTGTGGACAT GGAGAGCACA CGGATTGCTC AAGGACACTT CCTGACAGTG ATGGGAGCAT   3120
TTTGGCATTT GACAAAGGAA AAGAAATGTG TATTCTCTGT AAGAATGGCA TTAGTAAAGT   3180
GTCTTCAAAC ATTGCTTGAG GCTGATCCAT ATTCCGAATG GGCAATTCTT AATGTAAAAG   3240
GACAAGACTT TCCTGTAAAT GAAGCTTTTT CACAATTTCT TGCTGACGAT CATCATCAAG   3300
TTCGGATGTT GGCTGCAGGG TCAGTCAACA GATTATTTCA GGATATGAGA CAAGGCGATT   3360
TCTCCAGAAG CTTGAAAGCA CTCCCTCTGA AGTTTCAGCA GACATCTTTT AACAATGCAT   3420
ACACGACAGC AGAGGCGGGG ATCAGAGGAC TGTTATGTGA TTCTCAGAAC CCTGATCTGC   3480
TGGATGAGAT CTATAACAGA AAATCTGTAC TACTGATGAT GATAGCTGTG GTCTTGCACT   3540
GTAGCCCAGT CTGTGAAAAG CAGGCTTTGT TTGCTTTATG CAAGTCTGTG AAGGAAAACA   3600
GACTAGAACC TCATCTTGTG AAAAAGGTTT TAGAGAAAGT CTCCGAATCG TTTGGATGTA   3660
GAAGTTTAGA AGACTTCATG ATTTCTCACC TAGACTACCT GGTTTTGGAA TGGCTGAACC   3720
TTCAAGATAC TGAATATAGC TTATCTTCTT TTCCTTTTAT GTTATTAAAC TACACAAGCA   3780
TTGAGGATTT CTATCGGTCT TGTTACAAGA TTTTGATCCC ACATTTGGTA ATCAGAAGCC   3840
ATTTTGATGA GGTGAAGTCC ATTGCTAATC AGATTCAAAA GTGCTGGAAA AGCCTGTTGG   3900
TAGATTGCTT TCCGAAGATT CTTGTGCACA TCCTTCCTTA CTTTGCCTAC GAGGGCACGA   3960
GAGACAGCTA CGTGTCACAG AAAAGAGAGA CTGCTACCAA GGTCTACGAT ACTCTTAAAG   4020
GGGAAGACTT CCTAGGAAAA CAGATTGACC AAGTATTCAT TAGTAATTTG CCAGAGATTG   4080
TGGTGGAGTT GCTGATGACA TTGCATGAGA CAGCTGACTC GGCTGACTCG GACGCCAGTC   4140
AAAGCGCCAC CGCCTTGTGT GATTTTTCAG GGGATTTGGA TCCTGCCCCC AACCCGCCAT   4200
ATTTCCCCTC ACATGTCATT CAGGCAACGT TTGCTTACAT CAGCAACTGT CATAAAACCA   4260
AGTTTAAAAG CATTCTAGAA ATTCTTTCTA AAATCCCCGA TTCCTATCAG AAAATACTTC   4320
TGGCCATTTG TGAACAAGCA GCTGAGACAA ATAATGTCTT TAAAAAGCAC AGAATTCTTA   4380
AAATATATCA CCTGTTTGTT AGTTTATTAC TGAAAGATAT ACAGAGTGGC CTGGGAGGGG   4440
CTTGGGCCTT TGTCCTTCGC GATGTTATTT ATACTCTGAT TCACTACATC AACAAAAGGT   4500
CTTCTCATTT CACAGATGTG TCGTTGCGTA GCTTTTCCCT TTGCTGTGAC CTATTAAGTC   4560
GAGTTTGTCA TACAGCTGTA ACTCAATGTA AGGATGCTCT AGAAAGCCAT CTTCACGTTA   4620
TCGTTGGCAC ACTTATTCCC CTTGTGGATT ATCAGGAAGT TCAAGAACAG GTATTGGACC   4680
TGTTGAAGTA CTTAGTGATA GATAACAAAG ACAATAAAAA CCTCTCTGTC ACAATTAAGC   4740
TTTTGGATCC CTTTCCTGAC CATGTTATTT TTAAGGACTT GCGTCTTACT CAACAGAAAA   4800
TCAAATATAG TGGAGGACCT TTTTCACTCT TAGAGGAAAT AAACCATTTT CTCTCAGTAA   4860
GTGCTTACAA TCCACTTCCG CTGACCAGGC TTGAAGGACT GAAGGATCTT CGAAGACAAC   4920
TGGAGCAACA TAAAGATCAG ATGCTAGATC TTCTGAGAGC GTCTCAAGAT AACCCACAAG   4980
ATGGCATTGT GGTGAAGCTA GTTGTCAGCT TGTTGCAGTT ATCCAAGATG GCAGTGAACC   5040
AGACTGGTGA AAGAGAAGTT TTAGAGGCTG TCGGAAGGTG TTTGGGAGAA ATAGGTCCTC   5100
TGGATTTCTC CACCATAGCT GTCCAGCATA ACAAAGATGT GTCCTATACC AAAGCCTACG   5160
GGTTACCTGA AGACAGAGAA CTTCAGTGGA CCTTGATAAT GCTGACTGCC CTCAACAATA   5220
CCCTGGTAGA GGACAGTGTC AAAATTCGAT CTGCTGCTGC TACCTGTTTG AAAAACATTT   5280
TGGCTACAAA GATTGGACAT ATTTTCTGGG AGAATTATAA GACATCAGCG GATCCAATGC   5340
TGACCTATCT ACAACCTTTT AGAACATCGA GGAAAAAGTT TTTAGAAGTG CCCCGATCTG   5400
TTAAAGAAGA TGTTTTAGAA GGCCTGGATG CTGTGAATCT GTGGGTTCCT CAAAGTGAAA   5460
GTCATGACAT TTGGATAAAG ACACTGACGT GTGCCTTTCT GGACAGTGGA GGCATAAACA   5520
GTGAAATTCT CCAGTTATTA AAGCCAATGT GTGAAGTGAA AACCGACTTC TGTCAGATGT   5580
TGCTGCCATA CTTGATCCAT GATGTTTTAC TGCAAGATAC ACATGAATCG TGGAGAACTC   5640
TGCTGTCTGC GCACGTCCGA GGATTTTTCA CTAGTTGTTT TAAGCATTCC TCCCAAGCAA   5700
GCCGCTCAGC AACTCCTGCA AATTCGGATT CAGAGTCAGA GAACTTTCTC CGATGCTGTT   5760
TGGATAAAAA GTCACAAAGA ACCATGCTTG CTGTTGTCGA CTATCTGAGA AGGCAAAAGA   5820
GACCTTCCTC GGGAACAGCT TTTGATGACG CTTTCTGGCT GGATTTGAAT TATCTTGAGG   5880
TTGCGAAGGT GGCTCAGTCC TGCTCTGCTC ACTTCACGGC CTTGCTCTAC GCAGAGATCT   5940
ATTCAGATAA GAAAAGCACA GACGAGCAAG AGAAAAGAAG TCCAACATTT GAAGAAGGAA   6000
GTCAAGGAAC AACTATTTCT AGTTTGAGTG AAAAAAGTAA AGAAGAAACT GGAATAAGCT   6060
TACAGGATCT TCTCTTAGAG ATCTACAGAA GTATAGGAGA GCCGGACAGC CTGTATGGCT   6120
GTGGAGGAGG GAAAATGTTA CAACCCCTTA CTAGAATACG GACATATGAA CATGAAGCTA   6180
CGTGGGAGAA AGCCTTAGTA ACTTACGACC TGGAGACCAG CATCTCCTCC TCCACCCGCC   6240
AGTCAGGAAT CATCCAGGCC CTGCAGAATT TGGGGCTCTC CCATATCCTG TCTGTCTATC   6300
TGAAAGGATT AGACTATGAA AGACGAGAGT GGTGCGCTGA GCTGCAGGAG CTGCGTTACC   6360
AGGCGGCGTG GAGGAACATG CAGTGGGGCC TCTGCGCTTC TGCCGGCCAA GAAGTAGAAG   6420
GAACCAGTTA CCATGAATCG TTGTATAATG CTCTGCAGTG TCTAAGAAAC AGAGAATTCT   6480
CCACATTTTA TGAAAGTCTC CGATATGCCA GTCTTTTCAG GGTGAAAGAA GTTGAAGAGT   6540
TGAGTAAGGG CAGCCTTGAG TCTGTATATT CGCTGTATCC CACACTTAGT AGATTGCAGG   6600
CAATTGGAGA ACTGGAAAAC AGTGGCGAGC TTTTCTCAAG GTCAGTCACA GACAGAGAGC   6660
GCTCTGAAGC ATACTGGAAG TGGCAGAAGC ACTCCCAGCT TCTGAAAGAC AGCGACTTCA   6720
GCTTTCAGGA GCCTCTCATG GCTCTGCGCA CAGTCATTCT GGAGACCCTG GTACAGAAGG   6780
AAATGGAGCG CTCTCAAGGA GCATGCTCTA AGGACATTCT CACCAAACAC CTCGTTGAAT   6840
TCTCTGTTCT GGCTCGAACC TTCAAGAACA CACAGCTCCC TGAAAGAGCA ATATTCAAAA   6900
TTAAGCAATA TAATTCAGCT ATTTGTGGAA TTTCTGAGTG GCATTTGGAA GAAGCACAAG   6960
TATTCTGGGC AAAAAAGGAG CAGAGTCTTG CTCTGAGTAT TCTCAAGCAG ATGATCAAGA   7020
AGTTGGACTC CAGCTTTAAA GATAAAGAGA ATGATGCAGG TCTCAAAGTC ATATACGCAG   7080
AGTGTCTGAG GGTTTGTGGC AGCTGGCTGG CAGAAACTTG CTTAGAAAAC CCTGCAGTCA   7140
TCATGCAGAC CTATCTAGAA AAGGCGGTGA AGGTTGCTGG AAGTTACGAT GGCAACAGCA   7200
GAGAGCTCAG AAATGGACAG ATGAAGGCCT TTCTCTCGTT GGCAAGGTTC TCTGATACTC   7260
AGTACCAGAG AATTGAAAAC TACATGAAGT CATCAGAATT TGAAAACAAG CAAACTCTCT   7320
TAAAAAGAGC CAAAGAGGAA GTGGGCCTTC TAAGGGAACA TAAAATTCAG ACCAACAGAT   7380
ACACAGTAAA GGTTCAGCGA GAACTGGAGC TGGACGAATG TGCTCTCCGT GCACTGAGAG   7440
AGGATCGCAA GCGCTTCCTG TGTAAAGCAG TGGAGAACTA CATCAACTGC TTACTAAGCG   7500
GGGAAGAACA TGATCTGTGG GTGTTCCGGC TTTGCTCCCT CTGGCTTGAA AATTCTGGAG   7560
TTTCTGAAGT CAATGGCATG ATGAAGAAAG ATGGAATGAA GATTTCATCC TATAAGTTTT   7620
TGCCTCTCAT GTATCAATTG GCTGCTCGAA TGGGGACCAA AATGACGGGA GGCCTAGGAT   7680
TTCACGAAGT CCTCAATAAT CTAATCTCTA GGATTTCACT GGATCACCCC CATCATACTT   7740
TGTTCATTAT ACTGGCCTTA GCAAATGCGA ACAAAGATGA ATTTTTGAGC AAACCAGAGA   7800
CAACAAGAAG GAGTCGAATA ACCAAAAGTA CATCTAAAGA AAACTCTCAC CTTGATGAGG   7860
ATCGAACAGA GGCTGCAACC AGAATCATCC ACTCCATCAG AAGTAAGCGA TGTAAGATGG   7920
TGAAGGACAT GGAGGCGCTC TGCGATGCCT ACATCATCTT GGCAAACATG GACGCCTCTC   7980
AGTGGAGGGC TCAGAGAAAA GGCATCAATA TTCCAGCCAA CCAGCCAATC ACTAAACTGA   8040
AGAATTTAGA AGATGTTGTT GTTCCCACTA TGGAAATTAA GGTTGATCCC ACAGGAGAGT   8100
ATGAAAATCT GGTGACTATA AAATCATTTA AAACAGAATT TCGCTTAGCT GGAGGCTTAA   8160
ATTTACCCAA AATAATAGAT TGTGTGGGTT CTGATGGCAA GGAAAGGAGA CAGCTTGTGA   8220
AGGGCCGTGA TGACCTGAGG CAAGATGCTG TCATGCAGCA GGTCTTCCAG ATGTGCAATA   8280
CACTACTGCA GAGAAACACT GAGACTAGAA AGAGGAAACT GACTATCTGC ACATACAAGG   8340
TGGTTCCCCT TTCTCAGCGA AGCGGTGTTC TCGAGTGGTG CACAGGAACC GTTCCTATTG   8400
GTGAATATCT TGTTAACAGC GAAGACGGTG CACATAGAAG ATACAGGCCA AATGATTTCA   8460
GTGCCAATCA GTGCCAAAAG AAAATGATGG AAGTGCAGAA GAAGTCTTTT GAAGAGAAAT   8520
ATGATACCTT CATGACGATT TGCCAAAACT TTGAACCAGT TTTCCGTTAC TTCTGCATGG   8580
AAAAATTCTT GGACCCAGCT GTTTGGTTTG AGAAACGATT GGCATATACA CGCAGTGTGG   8640
CCACATCTTC TATCGTCGGT TACATCCTTG GACTTGGCGA CAGGCACGTA CAGAATATCT   8700
TGATAAACGA GCAGTCGGCA GAGCTTGTGC ACATAGACCT GGGAGTGGCT TTTGAACAGG   8760
GGAAGATCCT TCCCACTCCA GAAACAGTTC CTTTTAGACT CAGCAGAGAT ATTGTGGACG   8820
GGATGGGCAT CACCGGTGTG GAAGGTGTCT TCAGAAGGTG CTGTGAAAAA ACGATGGAAG   8880
TTATGCGGAG TTCTCAGGAA ACCCTGCTGA CCATTGTAGA GGTTCTTTTG TACGATCCAC   8940
TCTTTGATTG GACTATGAAT CCTTTAAAAG CTCTGTATCT ACAGCAGAGA CCAGAAGATG   9000
AGTCCGACCT CCATTCCACC CCCAATGCAG ATGATCAAGA ATGCAAACAA AGTCTTAGTG   9060
ATACTGACCA GAGTTTCAAC AAAGTAGCTG AGCGTGTCTT GATGAGACTG CAAGAGAAAC   9120
TGAAAGGCGT GGAGGAAGGC ACTGTGCTCA GTGTGGGTGG ACAGGTGAAC TTGCTTATCC   9180
AGCAGGCCAT GGATCCCAAA AATCTCAGCC GACTCTTCCC AGGATGGAAA GCTTGGGTGT   9240
GACCTTCACC CTTAAACTCG AACTTCAGAA ATGACATCTC ACCCACCATA TTTGGACAGG   9300
AATTACTTAA GTGAATAACT GCTTTTGATC CAATTTTCTA CTTGACTGAT CACCACCTAA   9360
ATATTAGTAT TTCTACTCTC TTCTGTTAGA GGTAATGGTC ACTCAAGATC CATTCGTAGG   9420
ATACGTGCTG ACTCTTAGGT CATGCTTGTG CTACTGCAGC AAGACCGCCG CATACACACT   9480
GAACTGCAAA TGGTGGGGGC AGCAGAGTGA GCTTTACTGC TGGTGTACAT GAAGACAAGT   9540
TCGTAACTTC TGCTCTAAAA CAACCTTTAA TTAAAGCATG TTTTCCAGAC TGTGTGTGTG   9600
TGTGTGTGTG TGTGTGTGTG                                               9620 
           
           
             
               3066 amino acids 
               amino acid 
               single 
               linear 
             
             
               protein 
             
             
               Mus musculus 
             
             12
Met Ser Leu Ala Leu Asn Asp Leu Leu Ile Cys Cys Arg Gln Leu Glu
1               5                   10                  15
His Asp Arg Ala Thr Glu Arg Arg Lys Glu Val Asp Lys Phe Lys Arg
            20                  25                  30
Leu Ile Gln Asp Pro Glu Thr Val Gln His Leu Asp Arg His Ser Asp
        35                  40                  45
Ser Lys Gln Gly Lys Tyr Leu Asn Trp Asp Ala Val Phe Arg Phe Leu
    50                  55                  60
Gln Lys Tyr Ile Gln Lys Glu Met Glu Ser Leu Arg Thr Ala Lys Ser
65                  70                  75                  80
Asn Val Ser Ala Thr Thr Gln Ser Ser Arg Gln Lys Lys Met Gln Glu
                85                  90                  95
Ile Ser Ser Leu Val Arg Tyr Phe Ile Lys Cys Ala Asn Lys Arg Ala
            100                 105                 110
Pro Arg Leu Lys Cys Gln Asp Leu Leu Asn Tyr Val Met Asp Thr Val
        115                 120                 125
Lys Asp Ser Ser Asn Gly Leu Thr Tyr Gly Ala Asp Cys Ser Asn Ile
    130                 135                 140
Leu Leu Lys Asp Ile Leu Ser Val Arg Lys Tyr Trp Cys Glu Val Ser
145                 150                 155                 160
Gln Gln Gln Trp Leu Glu Leu Phe Ser Leu Tyr Phe Arg Leu Tyr Leu
                165                 170                 175
Lys Pro Ser Gln Asp Ile Asn Arg Val Leu Val Ala Arg Ile Ile His
            180                 185                 190
Ala Val Thr Arg Gly Cys Cys Ser Gln Thr Asp Gly Leu Pro Ser Lys
        195                 200                 205
Phe Leu Asp Leu Phe Ser Lys Ala Ile Gln Tyr Ala Arg Gln Glu Lys
    210                 215                 220
Ser Ser Pro Gly Leu Ser His Ile Leu Ala Ala Leu Asn Ile Phe Leu
225                 230                 235                 240
Lys Ser Leu Ala Val Asn Phe Arg Lys Arg Val Cys Glu Ala Gly Asp
                245                 250                 255
Glu Ile Leu Pro Thr Leu Leu Tyr Ile Trp Thr Gln His Arg Leu Asn
            260                 265                 270
Asp Ser Leu Lys Glu Val Ile Ile Glu Leu Ile Gln Leu Gln Ile Tyr
        275                 280                 285
Ile His His Pro Gln Gly Ala Arg Ala Pro Glu Glu Gly Ala Tyr Glu
    290                 295                 300
Ser Met Lys Trp Lys Ser Ile Leu Tyr Asn Leu Tyr Asp Leu Leu Val
305                 310                 315                 320
Asn Glu Ile Ser His Ile Gly Ser Arg Gly Lys Tyr Ser Ser Gly Ser
                325                 330                 335
Arg Asn Ile Ala Val Lys Glu Asn Leu Ile Asp Leu Met Ala Asp Ile
            340                 345                 350
Cys Tyr Gln Leu Phe Asp Ala Asp Thr Arg Ser Val Glu Ile Ser Gln
        355                 360                 365
Ser Tyr Val Thr Gln Arg Glu Ser Thr Asp Tyr Ser Val Pro Cys Lys
    370                 375                 380
Arg Arg Lys Ile Asp Val Gly Trp Glu Val Ile Lys Asp Tyr Leu Gln
385                 390                 395                 400
Lys Ser Gln Ser Asp Phe Asp Leu Val Pro Trp Leu Gln Ile Thr Thr
                405                 410                 415
Arg Leu Ile Ser Lys Tyr Pro Ser Ser Leu Pro Asn Cys Glu Leu Ser
            420                 425                 430
Pro Leu Ile Leu Ile Leu Tyr Gln Leu Leu Pro Gln Gln Arg Arg Gly
        435                 440                 445
Glu Arg Ile Pro Tyr Val Leu Arg Cys Leu Lys Glu Val Ala Leu Cys
    450                 455                 460
Gln Gly Lys Lys Ser Asn Leu Glu Ser Ser Gln Lys Ser Asp Leu Leu
465                 470                 475                 480
Lys Leu Trp Ile Lys Ile Trp Ser Ile Thr Phe Arg Gly Ile Ser Ser
                485                 490                 495
Gly Gln Thr Gln Thr Glu Asn Phe Gly Leu Leu Glu Ala Ile Ile Gln
            500                 505                 510
Gly Ser Leu Val Glu Leu Asp Arg Glu Phe Trp Lys Leu Phe Thr Gly
        515                 520                 525
Ser Ala Cys Lys Pro Ser Ser Pro Ser Val Cys Cys Leu Thr Leu Ala
    530                 535                 540
Leu Ser Ile Cys Val Val Pro Asp Ala Ile Lys Met Gly Thr Glu Gln
545                 550                 555                 560
Ser Val Cys Glu Ala Asn Arg Ser Phe Ser Val Lys Glu Ser Ile Met
                565                 570                 575
Arg Trp Leu Leu Phe Tyr Gln Leu Glu Asp Asp Leu Glu Asp Ser Thr
            580                 585                 590
Glu Leu Pro Pro Ile Leu Gln Arg Asn Phe Pro His Leu Val Val Glu
        595                 600                 605
Lys Ile Leu Val Ser Leu Thr Met Lys Asn Ser Lys Ala Ala Met Lys
    610                 615                 620
Phe Phe Gln Ser Val Pro Glu Cys Glu Gln His Cys Glu Asp Lys Glu
625                 630                 635                 640
Glu Pro Ser Phe Ser Glu Val Glu Glu Leu Phe Leu Gln Thr Thr Phe
                645                 650                 655
Asp Lys Met Asp Phe Leu Thr Thr Val Lys Glu Tyr Ala Val Glu Lys
            660                 665                 670
Phe Gln Ser Ser Val Gly Phe Ser Val Gln Gln Asn Leu Lys Glu Ser
        675                 680                 685
Leu Asp His Tyr Leu Leu Gly Leu Ser Glu Gln Leu Leu Ser Asn Tyr
    690                 695                 700
Ser Ser Glu Ile Thr Ser Ser Glu Thr Leu Val Arg Cys Ser Ser Leu
705                 710                 715                 720
Leu Val Gly Val Leu Gly Cys Tyr Cys Tyr Met Gly Ile Ile Thr Glu
                725                 730                 735
Asp Glu Ala His Lys Ser Glu Leu Phe Gln Lys Ala Lys Ser Leu Met
            740                 745                 750
Gln Cys Ala Gly Glu Ser Ile Ser Leu Phe Lys Asn Lys Thr Asn Glu
        755                 760                 765
Glu Ser Arg Ile Gly Ser Leu Arg Asn Val Met His Leu Cys Thr Ser
    770                 775                 780
Cys Leu Cys Ile His Thr Lys His Thr Pro Asn Lys Ile Ala Ser Gly
785                 790                 795                 800
Phe Phe Leu Arg Leu Leu Thr Ser Lys Leu Met Asn Asp Ile Ala Asp
                805                 810                 815
Ile Cys Lys Ser Leu Ala Ser Cys Thr Lys Lys Pro Leu Asp His Gly
            820                 825                 830
Val His Pro Gly Glu Asp Asp Glu Asp Gly Gly Gly Cys Asp Ser Leu
        835                 840                 845
Met Glu Ala Glu Gly Pro Ser Ser Thr Gly Leu Ser Thr Ala Tyr Pro
    850                 855                 860
Ala Ser Ser Val Ser Asp Ala Asn Asp Tyr Gly Glu Asn Gln Asn Ala
865                 870                 875                 880
Val Gly Ala Met Ser Pro Leu Ala Ala Asp Tyr Leu Ser Lys Gln Asp
                885                 890                 895
His Leu Leu Leu Asp Met Leu Arg Phe Leu Gly Arg Ser Val Thr Ala
            900                 905                 910
Ser Gln Ser His Thr Val Ser Phe Arg Gly Ala Asp Ile Arg Arg Lys
        915                 920                 925
Leu Leu Leu Leu Leu Asp Ser Ser Ile Leu Asp Leu Met Lys Pro Leu
    930                 935                 940
His Leu His Met Tyr Leu Val Leu Leu Lys Asp Leu Pro Gly Asn Glu
945                 950                 955                 960
His Ser Leu Pro Met Glu Asp Val Val Glu Leu Leu Gln Pro Leu Ser
                965                 970                 975
Leu Val Cys Ser Leu His Arg Arg Asp Gln Asp Val Cys Lys Thr Ile
            980                 985                 990
Leu Ser Asn Val Leu His Ile Val Thr Asn Leu Gly Gln Gly Ser Val
        995                 1000                1005
Asp Met Glu Ser Thr Arg Ile Ala Gln Gly His Phe Leu Thr Val Met
    1010                1015                1020
Gly Ala Phe Trp His Leu Thr Lys Glu Lys Lys Cys Val Phe Ser Val
1025                1030                1035                1040
Arg Met Ala Leu Val Lys Cys Leu Gln Thr Leu Leu Glu Ala Asp Pro
                1045                1050                1055
Tyr Ser Glu Trp Ala Ile Leu Asn Val Lys Gly Gln Asp Phe Pro Val
            1060                1065                1070
Asn Glu Ala Phe Ser Gln Phe Leu Ala Asp Asp His His Gln Val Arg
        1075                1080                1085
Met Leu Ala Ala Gly Ser Val Asn Arg Leu Phe Gln Asp Met Arg Gln
    1090                1095                1100
Gly Asp Phe Ser Arg Ser Leu Lys Ala Leu Pro Leu Lys Phe Gln Gln
1105                1110                1115                1120
Thr Ser Phe Asn Asn Ala Tyr Thr Thr Ala Glu Ala Gly Ile Arg Gly
                1125                1130                1135
Leu Leu Cys Asp Ser Gln Asn Pro Asp Leu Leu Asp Glu Ile Tyr Asn
            1140                1145                1150
Arg Lys Ser Val Leu Leu Met Met Ile Ala Val Val Leu His Cys Ser
        1155                1160                1165
Pro Val Cys Glu Lys Gln Ala Leu Phe Ala Leu Cys Lys Ser Val Lys
    1170                1175                1180
Glu Asn Arg Leu Glu Pro His Leu Val Lys Lys Val Leu Glu Lys Val
1185                1190                1195                1200
Ser Glu Ser Phe Gly Cys Arg Ser Leu Glu Asp Phe Met Ile Ser His
                1205                1210                1215
Leu Asp Tyr Leu Val Leu Glu Trp Leu Asn Leu Gln Asp Thr Glu Tyr
            1220                1225                1230
Ser Leu Ser Ser Phe Pro Phe Met Leu Leu Asn Tyr Thr Ser Ile Glu
        1235                1240                1245
Asp Phe Tyr Arg Ser Cys Tyr Lys Ile Leu Ile Pro His Leu Val Ile
    1250                1255                1260
Arg Ser His Phe Asp Glu Val Lys Ser Ile Ala Asn Gln Ile Gln Lys
1265                1270                1275                1280
Cys Trp Lys Ser Leu Leu Val Asp Cys Phe Pro Lys Ile Leu Val His
                1285                1290                1295
Ile Leu Pro Tyr Phe Ala Tyr Glu Gly Thr Arg Asp Ser Tyr Val Ser
            1300                1305                1310
Gln Lys Arg Glu Thr Ala Thr Lys Val Tyr Asp Thr Leu Lys Gly Glu
        1315                1320                1325
Asp Phe Leu Gly Lys Gln Ile Asp Gln Val Phe Ile Ser Asn Leu Pro
    1330                1335                1340
Glu Ile Val Val Glu Leu Leu Met Thr Leu His Glu Thr Ala Asp Ser
1345                1350                1355                1360
Ala Asp Ser Asp Ala Ser Gln Ser Ala Thr Ala Leu Cys Asp Phe Ser
                1365                1370                1375
Gly Asp Leu Asp Pro Ala Pro Asn Pro Pro Tyr Phe Pro Ser His Val
            1380                1385                1390
Ile Gln Ala Thr Phe Ala Tyr Ile Ser Asn Cys His Lys Thr Lys Phe
        1395                1400                1405
Lys Ser Ile Leu Glu Ile Leu Ser Lys Ile Pro Asp Ser Tyr Gln Lys
    1410                1415                1420
Ile Leu Leu Ala Ile Cys Glu Gln Ala Ala Glu Thr Asn Asn Val Phe
1425                1430                1435                1440
Lys Lys His Arg Ile Leu Lys Ile Tyr His Leu Phe Val Ser Leu Leu
                1445                1450                1455
Leu Lys Asp Ile Gln Ser Gly Leu Gly Gly Ala Trp Ala Phe Val Leu
            1460                1465                1470
Arg Asp Val Ile Tyr Thr Leu Ile His Tyr Ile Asn Lys Arg Ser Ser
        1475                1480                1485
His Phe Thr Asp Val Ser Leu Arg Ser Phe Ser Leu Cys Cys Asp Leu
    1490                1495                1500
Leu Ser Arg Val Cys His Thr Ala Val Thr Gln Cys Lys Asp Ala Leu
1505                1510                1515                1520
Glu Ser His Leu His Val Ile Val Gly Thr Leu Ile Pro Leu Val Asp
                1525                1530                1535
Tyr Gln Glu Val Gln Glu Gln Val Leu Asp Leu Leu Lys Tyr Leu Val
            1540                1545                1550
Ile Asp Asn Lys Asp Asn Lys Asn Leu Ser Val Thr Ile Lys Leu Leu
        1555                1560                1565
Asp Pro Phe Pro Asp His Val Ile Phe Lys Asp Leu Arg Leu Thr Gln
    1570                1575                1580
Gln Lys Ile Lys Tyr Ser Gly Gly Pro Phe Ser Leu Leu Glu Glu Ile
1585                1590                1595                1600
Asn His Phe Leu Ser Val Ser Ala Tyr Asn Pro Leu Pro Leu Thr Arg
                1605                1610                1615
Leu Glu Gly Leu Lys Asp Leu Arg Arg Gln Leu Glu Gln His Lys Asp
            1620                1625                1630
Gln Met Leu Asp Leu Leu Arg Ala Ser Gln Asp Asn Pro Gln Asp Gly
        1635                1640                1645
Ile Val Val Lys Leu Val Val Ser Leu Leu Gln Leu Ser Lys Met Ala
    1650                1655                1660
Val Asn Gln Thr Gly Glu Arg Glu Val Leu Glu Ala Val Gly Arg Cys
1665                1670                1675                1680
Leu Gly Glu Ile Gly Pro Leu Asp Phe Ser Thr Ile Ala Val Gln His
                1685                1690                1695
Asn Lys Asp Val Ser Tyr Thr Lys Ala Tyr Gly Leu Pro Glu Asp Arg
            1700                1705                1710
Glu Leu Gln Trp Thr Leu Ile Met Leu Thr Ala Leu Asn Asn Thr Leu
        1715                1720                1725
Val Glu Asp Ser Val Lys Ile Arg Ser Ala Ala Ala Thr Cys Leu Lys
    1730                1735                1740
Asn Ile Leu Ala Thr Lys Ile Gly His Ile Phe Trp Glu Asn Tyr Lys
1745                1750                1755                1760
Thr Ser Ala Asp Pro Met Leu Thr Tyr Leu Gln Pro Phe Arg Thr Ser
                1765                1770                1775
Arg Lys Lys Phe Leu Glu Val Pro Arg Ser Val Lys Glu Asp Val Leu
            1780                1785                1790
Glu Gly Leu Asp Ala Val Asn Leu Trp Val Pro Gln Ser Glu Ser His
        1795                1800                1805
Asp Ile Trp Ile Lys Thr Leu Thr Cys Ala Phe Leu Asp Ser Gly Gly
    1810                1815                1820
Ile Asn Ser Glu Ile Leu Gln Leu Leu Lys Pro Met Cys Glu Val Lys
1825                1830                1835                1840
Thr Asp Phe Cys Gln Met Leu Leu Pro Tyr Leu Ile His Asp Val Leu
                1845                1850                1855
Leu Gln Asp Thr His Glu Ser Trp Arg Thr Leu Leu Ser Ala His Val
            1860                1865                1870
Arg Gly Phe Phe Thr Ser Cys Phe Lys His Ser Ser Gln Ala Ser Arg
        1875                1880                1885
Ser Ala Thr Pro Ala Asn Ser Asp Ser Glu Ser Glu Asn Phe Leu Arg
    1890                1895                1900
Cys Cys Leu Asp Lys Lys Ser Gln Arg Thr Met Leu Ala Val Val Asp
1905                1910                1915                1920
Tyr Leu Arg Arg Gln Lys Arg Pro Ser Ser Gly Thr Ala Phe Asp Asp
                1925                1930                1935
Ala Phe Trp Leu Asp Leu Asn Tyr Leu Glu Val Ala Lys Val Ala Gln
            1940                1945                1950
Ser Cys Ser Ala His Phe Thr Ala Leu Leu Tyr Ala Glu Ile Tyr Ser
        1955                1960                1965
Asp Lys Lys Ser Thr Asp Glu Gln Glu Lys Arg Ser Pro Thr Phe Glu
    1970                1975                1980
Glu Gly Ser Gln Gly Thr Thr Ile Ser Ser Leu Ser Glu Lys Ser Lys
1985                1990                1995                2000
Glu Glu Thr Gly Ile Ser Leu Gln Asp Leu Leu Leu Glu Ile Tyr Arg
                2005                2010                2015
Ser Ile Gly Glu Pro Asp Ser Leu Tyr Gly Cys Gly Gly Gly Lys Met
            2020                2025                2030
Leu Gln Pro Leu Thr Arg Ile Arg Thr Tyr Glu His Glu Ala Thr Trp
        2035                2040                2045
Glu Lys Ala Leu Val Thr Tyr Asp Leu Glu Thr Ser Ile Ser Ser Ser
    2050                2055                2060
Thr Arg Gln Ser Gly Ile Ile Gln Ala Leu Gln Asn Leu Gly Leu Ser
2065                2070                2075                2080
His Ile Leu Ser Val Tyr Leu Lys Gly Leu Asp Tyr Glu Arg Arg Glu
                2085                2090                2095
Trp Cys Ala Glu Leu Gln Glu Leu Arg Tyr Gln Ala Ala Trp Arg Asn
            2100                2105                2110
Met Gln Trp Gly Leu Cys Ala Ser Ala Gly Gln Glu Val Glu Gly Thr
        2115                2120                2125
Ser Tyr His Glu Ser Leu Tyr Asn Ala Leu Gln Cys Leu Arg Asn Arg
    2130                2135                2140
Glu Phe Ser Thr Phe Tyr Glu Ser Leu Arg Tyr Ala Ser Leu Phe Arg
2145                2150                2155                2160
Val Lys Glu Val Glu Glu Leu Ser Lys Gly Ser Leu Glu Ser Val Tyr
                2165                2170                2175
Ser Leu Tyr Pro Thr Leu Ser Arg Leu Gln Ala Ile Gly Glu Leu Glu
            2180                2185                2190
Asn Ser Gly Glu Leu Phe Ser Arg Ser Val Thr Asp Arg Glu Arg Ser
        2195                2200                2205
Glu Ala Tyr Trp Lys Trp Gln Lys His Ser Gln Leu Leu Lys Asp Ser
    2210                2215                2220
Asp Phe Ser Phe Gln Glu Pro Leu Met Ala Leu Arg Thr Val Ile Leu
2225                2230                2235                2240
Glu Thr Leu Val Gln Lys Glu Met Glu Arg Ser Gln Gly Ala Cys Ser
                2245                2250                2255
Lys Asp Ile Leu Thr Lys His Leu Val Glu Phe Ser Val Leu Ala Arg
            2260                2265                2270
Thr Phe Lys Asn Thr Gln Leu Pro Glu Arg Ala Ile Phe Lys Ile Lys
        2275                2280                2285
Gln Tyr Asn Ser Ala Ile Cys Gly Ile Ser Glu Trp His Leu Glu Glu
    2290                2295                2300
Ala Gln Val Phe Trp Ala Lys Lys Glu Gln Ser Leu Ala Leu Ser Ile
2305                2310                2315                2320
Leu Lys Gln Met Ile Lys Lys Leu Asp Ser Ser Phe Lys Asp Lys Glu
                2325                2330                2335
Asn Asp Ala Gly Leu Lys Val Ile Tyr Ala Glu Cys Leu Arg Val Cys
            2340                2345                2350
Gly Ser Trp Leu Ala Glu Thr Cys Leu Glu Asn Pro Ala Val Ile Met
        2355                2360                2365
Gln Thr Tyr Leu Glu Lys Ala Val Lys Val Ala Gly Ser Tyr Asp Gly
    2370                2375                2380
Asn Ser Arg Glu Leu Arg Asn Gly Gln Met Lys Ala Phe Leu Ser Leu
2385                2390                2395                2400
Ala Arg Phe Ser Asp Thr Gln Tyr Gln Arg Ile Glu Asn Tyr Met Lys
                2405                2410                2415
Ser Ser Glu Phe Glu Asn Lys Gln Thr Leu Leu Lys Arg Ala Lys Glu
            2420                2425                2430
Glu Val Gly Leu Leu Arg Glu His Lys Ile Gln Thr Asn Arg Tyr Thr
        2435                2440                2445
Val Lys Val Gln Arg Glu Leu Glu Leu Asp Glu Cys Ala Leu Arg Ala
    2450                2455                2460
Leu Arg Glu Asp Arg Lys Arg Phe Leu Cys Lys Ala Val Glu Asn Tyr
2465                2470                2475                2480
Ile Asn Cys Leu Leu Ser Gly Glu Glu His Asp Leu Trp Val Phe Arg
                2485                2490                2495
Leu Cys Ser Leu Trp Leu Glu Asn Ser Gly Val Ser Glu Val Asn Gly
            2500                2505                2510
Met Met Lys Lys Asp Gly Met Lys Ile Ser Ser Tyr Lys Phe Leu Pro
        2515                2520                2525
Leu Met Tyr Gln Leu Ala Ala Arg Met Gly Thr Lys Met Thr Gly Gly
    2530                2535                2540
Leu Gly Phe His Glu Val Leu Asn Asn Leu Ile Ser Arg Ile Ser Leu
2545                2550                2555                2560
Asp His Pro His His Thr Leu Phe Ile Ile Leu Ala Leu Ala Asn Ala
                2565                2570                2575
Asn Lys Asp Glu Phe Leu Ser Lys Pro Glu Thr Thr Arg Arg Ser Arg
            2580                2585                2590
Ile Thr Lys Ser Thr Ser Lys Glu Asn Ser His Leu Asp Glu Asp Arg
        2595                2600                2605
Thr Glu Ala Ala Thr Arg Ile Ile His Ser Ile Arg Ser Lys Arg Cys
    2610                2615                2620
Lys Met Val Lys Asp Met Glu Ala Leu Cys Asp Ala Tyr Ile Ile Leu
2625                2630                2635                2640
Ala Asn Met Asp Ala Ser Gln Trp Arg Ala Gln Arg Lys Gly Ile Asn
                2645                2650                2655
Ile Pro Ala Asn Gln Pro Ile Thr Lys Leu Lys Asn Leu Glu Asp Val
            2660                2665                2670
Val Val Pro Thr Met Glu Ile Lys Val Asp Pro Thr Gly Glu Tyr Glu
        2675                2680                2685
Asn Leu Val Thr Ile Lys Ser Phe Lys Thr Glu Phe Arg Leu Ala Gly
    2690                2695                2700
Gly Leu Asn Leu Pro Lys Ile Ile Asp Cys Val Gly Ser Asp Gly Lys
2705                2710                2715                2720
Glu Arg Arg Gln Leu Val Lys Gly Arg Asp Asp Leu Arg Gln Asp Ala
                2725                2730                2735
Val Met Gln Gln Val Phe Gln Met Cys Asn Thr Leu Leu Gln Arg Asn
            2740                2745                2750
Thr Glu Thr Arg Lys Arg Lys Leu Thr Ile Cys Thr Tyr Lys Val Val
        2755                2760                2765
Pro Leu Ser Gln Arg Ser Gly Val Leu Glu Trp Cys Thr Gly Thr Val
    2770                2775                2780
Pro Ile Gly Glu Tyr Leu Val Asn Ser Glu Asp Gly Ala His Arg Arg
2785                2790                2795                2800
Tyr Arg Pro Asn Asp Phe Ser Ala Asn Gln Cys Gln Lys Lys Met Met
                2805                2810                2815
Glu Val Gln Lys Lys Ser Phe Glu Glu Lys Tyr Asp Thr Phe Met Thr
            2820                2825                2830
Ile Cys Gln Asn Phe Glu Pro Val Phe Arg Tyr Phe Cys Met Glu Lys
        2835                2840                2845
Phe Leu Asp Pro Ala Val Trp Phe Glu Lys Arg Leu Ala Tyr Thr Arg
    2850                2855                2860
Ser Val Ala Thr Ser Ser Ile Val Gly Tyr Ile Leu Gly Leu Gly Asp
2865                2870                2875                2880
Arg His Val Gln Asn Ile Leu Ile Asn Glu Gln Ser Ala Glu Leu Val
                2885                2890                2895
His Ile Asp Leu Gly Val Ala Phe Glu Gln Gly Lys Ile Leu Pro Thr
            2900                2905                2910
Pro Glu Thr Val Pro Phe Arg Leu Ser Arg Asp Ile Val Asp Gly Met
        2915                2920                2925
Gly Ile Thr Gly Val Glu Gly Val Phe Arg Arg Cys Cys Glu Lys Thr
    2930                2935                2940
Met Glu Val Met Arg Ser Ser Gln Glu Thr Leu Leu Thr Ile Val Glu
2945                2950                2955                2960
Val Leu Leu Tyr Asp Pro Leu Phe Asp Trp Thr Met Asn Pro Leu Lys
                2965                2970                2975
Ala Leu Tyr Leu Gln Gln Arg Pro Glu Asp Glu Ser Asp Leu His Ser
            2980                2985                2990
Thr Pro Asn Ala Asp Asp Gln Glu Cys Lys Gln Ser Leu Ser Asp Thr
        2995                3000                3005
Asp Gln Ser Phe Asn Lys Val Ala Glu Arg Val Leu Met Arg Leu Gln
    3010                3015                3020
Glu Lys Leu Lys Gly Val Glu Glu Gly Thr Val Leu Ser Val Gly Gly
3025                3030                3035                3040
Gln Val Asn Leu Leu Ile Gln Gln Ala Met Asp Pro Lys Asn Leu Ser
                3045                3050                3055
Arg Leu Phe Pro Gly Trp Lys Ala Trp Val
            3060                3065 
           
           
             
               21 amino acids 
               amino acid 
               single 
               linear 
             
             
               peptide 
             
             
               unknown 
             
             13
Cys Arg Gln Leu Glu His Asp Arg Ala Thr Glu Arg Arg Lys Lys Glu
1               5                   10                  15
Val Glu Lys Phe Lys
            20 
           
           
             
               20 amino acids 
               amino acid 
               single 
               linear 
             
             
               peptide 
             
             
               unknown 
             
             14
Cys Leu Arg Ile Ala Lys Pro Asn Val Ser Ala Ser Thr Gln Ala Ser
1               5                   10                  15
Arg Gln Lys Lys
            20 
           
           
             
               17 amino acids 
               amino acid 
               single 
               linear 
             
             
               peptide 
             
             
               unknown 
             
             15
Cys Ala Arg Gln Glu Lys Ser Ser Ser Gly Leu Asn His Ile Leu Ala
1               5                   10                  15
Ala 
           
           
             
               19 amino acids 
               amino acid 
               single 
               linear 
             
             
               peptide 
             
             
               unknown 
             
             16
Cys Arg Gln Leu Glu His Asp Arg Ala Thr Glu Arg Lys Lys Glu Val
1               5                   10                  15
Asp Lys Phe 
           
           
             
               18 amino acids 
               amino acid 
               single 
               linear 
             
             
               peptide 
             
             
               unknown 
             
             17
Cys Phe Lys His Ser Ser Gln Ala Ser Arg Ser Ala Thr Pro Ala Asn
1               5                   10                  15
Ser Asp 
           
           
             
               19 amino acids 
               amino acid 
               single 
               linear 
             
             
               peptide 
             
             
               unknown 
             
             18
Arg Pro Glu Asp Glu Ser Asp Leu His Ser Thr Pro Asn Ala Asp Asp
1               5                   10                  15
Gln Glu Cys 
           
           
             
               249 amino acids 
               amino acid 
               single 
               linear 
             
             
               peptide 
             
             
               unknown 
             
             19
Met Ser Leu Val Leu Asn Asp Leu Leu Ile Cys Cys Arg Gln Leu Glu
1               5                   10                  15
His Asp Arg Ala Thr Glu Arg Lys Lys Glu Val Glu Lys Phe Lys Arg
            20                  25                  30
Leu Ile Arg Asp Pro Glu Thr Ile Lys His Leu Asp Arg His Ser Asp
        35                  40                  45
Ser Lys Gln Gly Lys Tyr Leu Asn Trp Asp Ala Val Phe Arg Phe Leu
    50                  55                  60
Gln Lys Tyr Ile Gln Lys Glu Thr Glu Cys Leu Arg Ile Ala Lys Pro
65                  70                  75                  80
Asn Val Ser Ala Ser Thr Gln Ala Ser Arg Gln Lys Lys Met Gln Glu
                85                  90                  95
Ile Ser Ser Leu Val Lys Phe Tyr Ile Lys Cys Ala Asn Arg Arg Ala
            100                 105                 110
Pro Arg Leu Lys Cys Gln Glu Leu Leu Asn Tyr Ile Met Asp Thr Val
        115                 120                 125
Lys Asp Ser Ser Asn Gly Ala Ile Tyr Gly Ala Asp Cys Ser Asn Ile
    130                 135                 140
Leu Leu Lys Asp Ile Leu Ser Val Arg Lys Tyr Trp Cys Glu Ile Ser
145                 150                 155                 160
Gln Gln Gln Trp Leu Glu Leu Phe Ser Val Tyr Phe Arg Leu Tyr Leu
                165                 170                 175
Lys Pro Ser Gln Asp Val His Arg Val Leu Val Ala Ile Ile His His
            180                 185                 190
Ala Val Thr Lys Gly Cys Cys Ser Gln Thr Asp Gly Leu Asn Ser Lys
        195                 200                 205
Phe Leu Asp Phe Phe Ser Lys Ala Ile Gln Cys Ala Arg Gln Glu Lys
    210                 215                 220
Ser Ser Ser Gly Leu Asn His Ile Leu Ala Ala Leu Thr Ile Phe Leu
225                 230                 235                 240
Lys Thr Leu Ala Val Asn Phe Arg Ile
                245 
           
           
             
               210 amino acids 
               amino acid 
               single 
               linear 
             
             
               peptide 
             
             
               unknown 
             
             20
Gly Phe Ser Val His Gln Asn Leu Lys Glu Ser Leu Asp Arg Cys Leu
1               5                   10                  15
Leu Gly Leu Ser Glu Gln Leu Leu Asn Asn Tyr Ser Ser Glu Ile Thr
            20                  25                  30
Asn Ser Glu Thr Leu Val Arg Cys Ser Arg Leu Leu Val Gly Val Leu
        35                  40                  45
Gly Cys Tyr Cys Tyr Met Gly Val Ile Ala Glu Glu Glu Ala Tyr Lys
    50                  55                  60
Ser Glu Leu Phe Gln Lys Ala Asn Ser Leu Met Gln Cys Ala Gly Glu
65                  70                  75                  80
Ser Ile Thr Leu Phe Lys Asn Lys Thr Asn Glu Glu Phe Arg Ile Gly
                85                  90                  95
Ser Leu Arg Asn Met Met Gln Leu Cys Thr Arg Cys Leu Ser Asn Cys
            100                 105                 110
Thr Lys Lys Ser Pro Asn Lys Ile Ala Ser Gly Phe Phe Leu Arg Leu
        115                 120                 125
Leu Thr Ser Lys Leu Met Asn Asp Ile Ala Asp Ile Cys Lys Ser Leu
    130                 135                 140
Ala Ser Phe Ile Lys Lys Pro Phe Asp Arg Gly Glu Val Glu Ser Met
145                 150                 155                 160
Glu Asp Asp Thr Asn Gly Asn Leu Met Glu Val Glu Asp Gln Ser Ser
                165                 170                 175
Met Asn Leu Phe Asn Asp Tyr Pro Asp Ser Ser Val Ser Asp Ala Asn
            180                 185                 190
Glu Pro Gly Glu Ser Gln Ser Thr Ile Gly Ala Ile Asn Pro Leu Ala
        195                 200                 205
Glu Glu
    210 
           
           
             
               448 amino acids 
               amino acid 
               single 
               linear 
             
             
               peptide 
             
             
               unknown 
             
             21
Gly Phe Ser Val His Gln Asn Leu Lys Glu Ser Leu Asp Arg Cys Leu
1               5                   10                  15
Leu Gly Leu Ser Glu Gln Leu Leu Asn Asn Tyr Ser Ser Glu Ile Thr
            20                  25                  30
Asn Ser Glu Thr Leu Val Arg Cys Ser Arg Leu Leu Val Gly Val Leu
        35                  40                  45
Gly Cys Tyr Cys Tyr Met Gly Val Ile Ala Glu Glu Glu Ala Tyr Lys
    50                  55                  60
Ser Glu Leu Phe Gln Lys Ala Asn Ser Leu Met Gln Cys Ala Gly Glu
65                  70                  75                  80
Ser Ile Thr Leu Phe Lys Asn Lys Thr Asn Glu Glu Phe Arg Ile Gly
                85                  90                  95
Ser Leu Arg Asn Met Met Gln Leu Cys Thr Arg Cys Leu Ser Asn Cys
            100                 105                 110
Thr Lys Lys Ser Pro Asn Lys Ile Ala Ser Gly Phe Phe Leu Arg Leu
        115                 120                 125
Leu Thr Ser Lys Leu Met Asn Asp Ile Ala Asp Ile Cys Lys Ser Leu
    130                 135                 140
Ala Ser Phe Ile Lys Lys Pro Phe Asp Arg Gly Glu Val Glu Ser Met
145                 150                 155                 160
Glu Asp Asp Thr Asn Gly Asn Leu Met Glu Val Glu Asp Gln Ser Ser
                165                 170                 175
Met Asn Leu Phe Asn Asp Tyr Pro Asp Ser Ser Val Ser Asp Ala Asn
            180                 185                 190
Glu Pro Gly Glu Ser Gln Ser Thr Ile Gly Ala Ile Asn Pro Leu Ala
        195                 200                 205
Glu Glu Tyr Leu Ser Lys Gln Asp Leu Leu Phe Leu Asp Met Leu Lys
    210                 215                 220
Phe Leu Cys Leu Cys Val Thr Thr Ala Gln Thr Asn Thr Val Ser Phe
225                 230                 235                 240
Arg Ala Ala Asp Ile Arg Arg Lys Leu Leu Met Leu Ile Asp Ser Ser
                245                 250                 255
Thr Leu Glu Pro Thr Lys Ser Leu His Leu His Met Tyr Leu Met Leu
            260                 265                 270
Leu Lys Glu Leu Pro Gly Glu Glu Tyr Pro Leu Pro Met Glu Asp Val
        275                 280                 285
Leu Glu Leu Leu Lys Pro Leu Ser Asn Val Cys Ser Leu Tyr Arg Arg
    290                 295                 300
Asp Gln Asp Val Cys Lys Thr Ile Leu Asn His Val Leu His Val Val
305                 310                 315                 320
Lys Asn Leu Gly Gln Ser Asn Met Asp Ser Glu Asn Thr Arg Asp Ala
                325                 330                 335
Gln Gly Gln Phe Leu Thr Val Ile Gly Ala Phe Trp His Leu Thr Lys
            340                 345                 350
Glu Arg Lys Tyr Ile Phe Ser Val Arg Met Ala Leu Val Asn Cys Leu
        355                 360                 365
Lys Thr Leu Leu Glu Ala Asp Pro Tyr Ser Lys Trp Ala Ile Leu Asn
    370                 375                 380
Val Met Gly Lys Asp Phe Pro Val Asn Glu Val Phe Thr Gln Phe Leu
385                 390                 395                 400
Ala Asp Asn His His Gln Val Arg Met Leu Ala Ala Glu Ser Ile Asn
                405                 410                 415
Arg Leu Phe Gln Asp Thr Lys Gly Asp Ser Ser Arg Leu Leu Lys Ala
            420                 425                 430
Leu Pro Leu Lys Leu Gln Gln Thr Ala Phe Glu Asn Ala Tyr Leu Lys
        435                 440                 445 
           
           
             
               216 amino acids 
               amino acid 
               single 
               linear 
             
             
               peptide 
             
             
               unknown 
             
             22
Leu Gln Asp Thr Glu Tyr Asn Leu Ser Ser Phe Pro Phe Ile Leu Leu
1               5                   10                  15
Asn Tyr Thr Asn Ile Glu Asp Phe Tyr Arg Ser Cys Tyr Lys Val Leu
            20                  25                  30
Ile Pro His Leu Val Ile Arg Ser His Phe Asp Glu Val Lys Ser Ile
        35                  40                  45
Ala Asn Gln Ile Gln Glu Asp Trp Lys Ser Leu Leu Thr Asp Cys Phe
    50                  55                  60
Pro Lys Ile Leu Val Asn Ile Leu Pro Tyr Phe Ala Tyr Glu Gly Thr
65                  70                  75                  80
Arg Asp Ser Gly Met Ala Gln Gln Arg Glu Thr Ala Thr Lys Val Tyr
                85                  90                  95
Asp Met Leu Lys Ser Glu Asn Leu Leu Gly Lys Gln Ile Asp His Leu
            100                 105                 110
Phe Ile Ser Asn Leu Pro Glu Ile Val Val Glu Leu Leu Met Thr Leu
        115                 120                 125
His Glu Pro Ala Asn Ser Ser Ala Ser Gln Ser Thr Asp Leu Cys Asp
    130                 135                 140
Phe Ser Gly Asp Leu Asp Pro Ala Pro Asn Pro Pro His Phe Pro Ser
145                 150                 155                 160
His Val Ile Lys Ala Thr Phe Ala Tyr Ile Ser Asn Cys His Lys Thr
                165                 170                 175
Lys Leu Lys Ser Ile Leu Glu Ile Leu Ser Lys Ser Pro Asp Ser Tyr
            180                 185                 190
Gln Lys Ile Leu Leu Ala Ile Cys Glu Gln Ala Ala Glu Thr Asn Asn
        195                 200                 205
Val Tyr Lys Lys His Arg Ile Leu
    210                 215 
           
           
             
               286 amino acids 
               amino acid 
               single 
               linear 
             
             
               peptide 
             
             
               unknown 
             
             23
Gly Val Ser Glu Trp Gln Leu Glu Glu Ala Gln Val Phe Trp Ala Lys
1               5                   10                  15
Lys Glu Gln Ser Leu Ala Leu Ser Ile Leu Lys Gln Met Ile Lys Lys
            20                  25                  30
Leu Asp Ala Ser Cys Ala Ala Asn Asn Pro Ser Leu Lys Leu Thr Tyr
        35                  40                  45
Thr Glu Cys Leu Arg Val Cys Gly Asn Trp Leu Ala Glu Thr Cys Leu
    50                  55                  60
Glu Asn Pro Ala Val Ile Met Gln Thr Tyr Leu Glu Lys Ala Val Glu
65                  70                  75                  80
Val Ala Gly Asn Tyr Asp Gly Glu Ser Ser Asp Glu Leu Arg Asn Gly
                85                  90                  95
Lys Met Lys Ala Phe Leu Ser Leu Ala Arg Phe Ser Asp Thr Gln Tyr
            100                 105                 110
Gln Arg Ile Glu Asn Tyr Met Lys Ser Ser Glu Phe Glu Asn Lys Gln
        115                 120                 125
Ala Leu Leu Lys Arg Ala Lys Glu Glu Val Gly Leu Leu Arg Glu His
    130                 135                 140
Lys Ile Gln Thr Asn Arg Tyr Thr Val Lys Val Gln Arg Glu Leu Glu
145                 150                 155                 160
Leu Asp Glu Leu Ala Arg Leu Ala Leu Lys Glu Asp Arg Lys Arg Phe
                165                 170                 175
Leu Cys Lys Ala Val Glu Asn Tyr Ile Asn Cys Leu Leu Ser Gly Glu
            180                 185                 190
Glu His Asp Met Trp Val Phe Arg Leu Cys Ser Leu Trp Leu Glu Asn
        195                 200                 205
Ser Gly Val Ser Glu Val Asn Gly Met Met Lys Arg Asp Gly Met Lys
    210                 215                 220
Ile Pro Thr Tyr Lys Phe Leu Pro Leu Met Tyr Gln Leu Ala Ala Arg
225                 230                 235                 240
Met Gly Thr Lys Met Met Gly Gly Leu Gly Phe His Glu Val Leu Asn
                245                 250                 255
Asn Leu Ile Ser Arg Ile Ser Met Asp His Pro His His Thr Leu Phe
            260                 265                 270
Ile Ile Leu Ala Leu Ala Asn Ala Asn Arg Asp Glu Phe Leu
        275                 280                 285 
           
           
             
               236 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               unknown 
             
             24
TGCTTTTTTG GACAGTGGAG GCACAAAATG TGAAATTCTT CAATTATTAA AGCCAATGTG     60
TGAAGTGAAA ACTGACTTTT GTCAGACTGT ACTTCCATAC TTGATTCATG ATATTTTACT    120
CCAAGATACA AATGAATCAT GGAGAAATCT GCTTTCTACA CATGTTCAGG AATTTTTCAC    180
CAGCTGTCTT CGACACTTCT CGCAAACGAG CCGATCCACA ACCCCTGCAA ACTTGG        236