Abstract:
The gene responsible for systemic carnitine deficiency was found to be the OCTN2 gene involved in the transportation of organic cations. This invention enables tests for this disease by detecting whether or not the OCTN2 gene has a mutation. Furthermore, systemic carnitine deficiency can be treated using the normal OCTN2 gene and its protein.

Description:
[0001]    This application is a continuation of PCT/JP99/04853, filed Sep. 7, 1999, and claims priority from Japanese Patent Application No. 10/252683, filed Sep. 7, 1998. 
     
    
     
       TECHNICAL FIELD  
         [0002]    This invention relates to molecules used in the testing and treatment of systemic carnitine deficiency, as well as methods for testing the disease.  
         BACKGROUND OF THE INVENTION  
         [0003]    Systemic Carnitine Deficiency (SCD) is a human genetic disease inherited through autosomal recessive inheritance, the main symptoms being skeletal or cardiac muscle disorders (NIM 212140) (Roe, C. R. and Coates, P. M., Mitochondrial fatty acid oxidation disorder, The metabolic and molecular bases of inherited diseases 7th ed., edited by Scriver, C. R., Beaudet, A. L., Sly, W. S. and Valle, D., McGraw-Hill, New York, 1995, 1508-1509; Karpati, G. et al., The syndrome of systemic carnitine deficiency: clinical, morphologic, biochemical, and pathophysiologic features, Neurology 1975, 25:16-24). Serum carnitine levels and intra-tissue carnitine levels are known to be extremely low in these patients compared to healthy individuals. Carnitine is an indispensable co-factor in the long-chain fatty acid metabolism. A carnitine-mediated mechanism enables intracellular fatty acids to permeate mitochondrial outer and inner membranes, and energy is produced when these fatty acids undergo β-oxidation within the mitochondria (Walter, J. H., L-Carnitine, Arch Dis Child, 1996, 74:475-478; Bremer, J., Carnitine metabolism and functions, Physiol Rev, 1983, 1420-1480). The abnormal decrease of carnitine concentration in systemic carnitine deficiency patients is thought to be the direct cause of diseases in tissues such as muscles that require a large amount of energy. Membrane physiological studies done using fibroblasts from systemic carnitine deficiency patients have shown that these cells lack the mechanism to transport carnitine from the outside of the cell to the inside. A gene that encodes a protein involved in this mechanism is presumed to be the gene responsible for this disease (Tein, I. et al., Impaired skin fibroblast carnitine uptake in primary systemic carnitine deficiency manifested by childhood carnitine-responsive cardiomyopathy, Pediatr Res, 1990, 28:247-255). However, the gene responsible for systemic carnitine deficiency is yet to be isolated.  
         SUMMARY OF THE INVENTION  
         [0004]    An objective of the present invention is to provide the gene responsible for systemic carnitine deficiency. Moreover, this invention aims to provide a molecule used in the testing and treatment of systemic carnitine deficiency, as well as a method for testing the disease.  
           [0005]    The Inventors isolated several genes encoding proteins involved in the transport of organic cations. Among these, the Inventors discovered the human gene (human OCTN2 gene) having an activity to transport carnitine in a sodium ion dependent manner, and the corresponding mouse gene (mouse OCTN2 gene) (Japanese Patent Application Hei 9-260972, Japanese Patent Application Hei 10-156660). The Inventors thought that the isolated OCTN2 gene might be the gene responsible for systemic carnitine deficiency, and evaluated this possibility.  
           [0006]    Specifically, the nucleotide sequence of the OCTN2 gene of the systemic carnitine deficiency mouse model and systemic carnitine deficiency patients were analyzed. As a result, the Inventors discovered the presence of various mutations in the OCTN2 gene of both the mouse model and systemic carnitine deficiency patients. In other words, for the first time in the world, the Inventors succeeded in revealing that systemic carnitine deficiency is caused by mutations in the OCTN2 gene.  
           [0007]    Moreover, due to the close relationship of OCTN2 gene mutation and systemic carnitine deficiency, the Inventors found that this disease can be tested by examining whether or not there is a mutation in the OCTN2 gene of a patient.  
           [0008]    It was also found that systemic carnitine deficiency could be treated by using the normal OCTN2 gene and its protein, to complete the invention.  
           [0009]    Therefore, this invention relates to molecules used in the testing and treatment of systemic carnitine deficiency, as well as methods for testing the disease. More specifically, the present invention relates to:  
           [0010]    (1) a DNA for testing systemic carnitine deficiency, wherein the DNA hybridizes to a DNA comprising the nucleotide sequence of SEQ ID NO:5, or the transcription regulatory region thereof, and comprises at least 15 nucleotides;  
           [0011]    (2) a molecule as in any one of (a) to (c) below, which is used for the treatment of systemic carnitine deficiency,  
           [0012]    (a) a protein comprising the amino acid sequence of SEQ ID NO:1,  
           [0013]    (b) a compound that promotes the activity of the protein comprising the amino acid sequence of SEQ ID NO:1, or,  
           [0014]    (c) a DNA encoding the protein comprising the amino acid sequence of SEQ ID NO:1;  
           [0015]    (3) a pharmaceutical composition for treating systemic carnitine deficiency, comprising a molecule of (2) as the active ingredient;  
           [0016]    (4) a pharmaceutical composition for treating systemic carnitine deficiency, comprising an antibody binding to the protein comprising the amino acid sequence of SEQ ID NO:1 as the active ingredient;  
           [0017]    (5) a test method for systemic carnitine deficiency comprising the detection of a mutation in the DNA encoding the protein comprising the amino acid sequence of SEQ ID NO:1, or the transcription regulatory region of said DNA;  
           [0018]    (6) the test method for systemic carnitine deficiency of (5) comprising the steps of,  
           [0019]    (a) preparing a DNA sample from a patient,  
           [0020]    (b) amplifying patient-derived DNA using the DNA of (1) as a primer,  
           [0021]    (c) cleaving the amplified DNA,  
           [0022]    (d) separating the DNA fragments by their size,  
           [0023]    (e) hybridizing the DNA of (1) labeled by a detectable label as a probe to the DNA fragments separated, and,  
           [0024]    (f) comparing the size of the DNA fragment detected with a control from a healthy individual, (7) the test method for systemic carnitine deficiency of (5) comprising the steps of,  
           [0025]    (a) preparing an RNA sample from a patient,  
           [0026]    (b) separating the prepared RNA by size,  
           [0027]    (c) hybridizing the DNA of (1) labeled by a detectable label as a probe to the RNA fragments separated, and,  
           [0028]    (d) comparing the size of the RNA fragment detected with a control from a healthy individual,  
           [0029]    (8) the test method for systemic carnitine deficiency of (5) comprising the steps of,  
           [0030]    (a) preparing a DNA sample from a patient,  
           [0031]    (b) amplifying patient-derived DNA using the DNA of (1) as a primer,  
           [0032]    (c) dissociating the amplified DNA to single-stranded DNA,  
           [0033]    (d) separating the dissociated single-stranded DNA on a non-denaturing gel, and,  
           [0034]    (e) comparing the mobility of separated single stranded DNA on the gel with a control from a healthy individual,  
           [0035]    (9) the test method for systemic carnitine deficiency of (5) comprising the steps of,  
           [0036]    (a) preparing a DNA sample from a patient,  
           [0037]    (b) amplifying patient-derived DNA using the DNA of (1) as a primer,  
           [0038]    (c) separating the amplified DNA on a gel in which the concentration of the DNA denaturant gradually increases, and,  
           [0039]    (d) comparing the mobility of separated DNA on the gel with a control from a healthy individual.  
           [0040]    The present invention is based on the finding by the present inventors that systemic carnitine deficiency is caused by a mutation in the gene named “OCTN2”. First and foremost, this invention relates to a molecule used in the testing and treatment of systemic carnitine deficiency, as well as a method for testing the disease.  
           [0041]    In the present invention, the genomic DNA region (for example, SEQ ID NO:5) containing OCTN2, or an oligonucleotide (probe and primer) that hybridizes to the nucleotide sequence of the regulatory region (comprising the intron, promoter, and enhancer sequences as well) of OCTN2 is used.  
           [0042]    This oligonucleotide preferably hybridizes specifically to the genomic DNA region containing OCTN2, or the regulatory region of OCTN2. Herein, “hybridizes specifically” indicates that cross-hybridization does not significantly occur with DNA encoding other proteins, under normal hybridizing conditions, preferably under stringent conditions (for example, the conditions in Sambrook et al., Molecular Cloning second edition, Cold Spring Harbor Laboratory Press, New York, USA, 1989).  
           [0043]    When using as a primer, the oligonucleotide is usually, 15 to 100 bp, preferably, 17 to 30 bp. The primer may be any, as long as it can amplify at least a part of the OCTN2 gene or the region regulating its expression. Such regions comprise, for example, the exon region of OCTN2, the intron region, the promoter region, and enhancer region.  
           [0044]    On the other hand, the oligonucleotide used as a probe usually comprises at least 15 bp or more if it is a synthetic oligonucleotide. It is also possible to use a double stranded DNA obtained from a clone incorporated into a vector such as plasmid DNA. The probe may be any, as long as it specifically hybridizes to at least a part of the OCTN2 gene or the region regulating the expression of the gene. Regions to which the probe hybridizes include, for example, the exon region, intron region, promoter region, and enhancer region of the OCTN2 gene. When using as the probe, oligonucleotide or double stranded DNA is suitably labeled. Examples of labeling methods are, phosphorylating the 5′ end of the oligonucleotide by  32 P using T4 polynucleotide kinase, and incorporating a substrate nucleotide labeled by an isotope such as  32 P, a florescent dye, or biotin, using the random hexamer oligonucleotide as a probe and using DNA polymerase such as the Klenow enzyme (random priming technique).  
           [0045]    In the present invention, “a test method for systemic carnitine deficiency” includes not only a test for patients showing symptoms of systemic carnitine deficiency caused by a mutation of the OCTN2 gene, but also a test for detecting a mutation of the OCTN2 gene for determining whether or not the person tested is likely to develop systemic carnitine deficiency arising from a OCTN2 gene mutation. In other words, the risk of developing systemic carnitine deficiency may greatly increase in cases where one of the OCTN2 alleles develops a mutation, even when no symptoms are visible on the outside. Therefore, tests for specifying patients (carriers) having a mutation in an OCTN2 allele are also included in the invention.  
           [0046]    In the present invention, a test method for systemic carnitine deficiency using the above oligonucleotides comprises the detection of a mutation in the OCTN2 gene or its transcription regulatory region. One embodiment of this method of testing is the direct determination of the nucleotide sequence of the patient&#39;s OCTN2 gene. For example, using the above oligonucleotide as the primer, the whole OCTN2 gene or a part of it is amplified by the Polymerase Chain Reaction (PCR) using as the template a DNA isolated from a patient suspected of having a disease caused by an OCTN2 mutation. By comparing this sequence with that of a healthy individual, it is possible to conduct a test for a disease arising from an OCTN2 gene mutation.  
           [0047]    As the testing method of the invention, other than determining the nucleotide sequence of DNA derived directly from the patient, several other methods are also used. One such embodiment comprises the following steps of: (a) preparing a DNA sample from a patient; (b) amplifying the patient-derived DNA using the primer of this invention; (c) dissociating amplified DNA into single-stranded DNA; (d) separating the dissociated single-stranded DNA on a non-denaturing gel; and, (e) comparing the mobility of separated single stranded DNA on the gel with a control from a healthy individual.  
           [0048]    An example of such a method is the PCR-single-strand conformation polymorphism (PCR-SSCP) method (Cloning and polymerase chain reaction-single-strand conformation polymorphism analysis of anonymous Alu repeats on chromosome 11, Genomics, Jan. 1, 1992 12(1):139-146; Detection of p53 gene mutations in human brain tumors by single-strand conformation polymorphism analysis of polymerase chain reaction products, Oncogene, Aug. 1, 1991 6(8):1313-1318; Multiple fluorescence-based PCR-SSCP analysis with postlabeling, PCR Methods Appl. Apr 1, 1995 4(5):275-282). This method is comparatively easy to handle, and has various advantages such as requiring only a small amount of a sample, and therefore, is suitable for screening a large number of DNA samples. The principle of this method is as follows. When a double stranded DNA fragment is disassociated into single strands, each strand forms an original high-order structure depending on its nucleotide sequence. When these dissociated DNA strands are electrophoresed within a polyacrylamide gel free of denaturants, the single stranded DNAs that are complementary and have the same length, migrate to different positions according to the difference in their high-order structure. This high order structure of the single strands change even by a single nucleotide substitution showing different mobilities in polyacrylamide gel electrophoresis. Therefore, the presence of a mutation in a DNA fragment due to point mutation, deletion, or insertion can be detected by the change in mobility.  
           [0049]    Specifically, first, the whole OCTN2 gene or a part of it is amplified by PCR, and such. A length of 200 to 400 bp is usually preferred amplified range. Regions amplified include all the exons and all the introns of the OCTN2 gene, as well as the promoter and enhancer of the OCTN2 gene. PCR can be done, for example, according to conditions described in Example 1. When amplifying the gene fragment by PCR, a primer labeled by an isotope such as  32 P, a fluorescent dye, or biotin is used, or the DNA fragment synthesized by PCR after adding a substrate nucleotide labeled by an isotope such as  32 P, a fluorescent dye, or biotin, is labeled. Labeling can also be done by adding to the synthesized DNA fragment a substrate nucleotide labeled by an isotope such as 32P, a fluorescent dye, or biotin, using the Klenow enzyme and such after the PCR reaction. The labeled DNA fragment thus obtained is denatured by heating and such, and electrophoresed in a polyacrylamide gel free of denaturants such as urea. Conditions for separating the DNA fragment can be improved by adding a suitable amount (about 5 to 10%) of glycerol to the polyacrylamide gel. Conditions of electrophoresis vary depending on the properties of the DNA fragment, but room temperature (from 20 to 25° C.) is usually used. When a preferable separation cannot be accomplished, the temperature that gives the optimum mobility at 4 to 30° C. is evaluated. Following electrophoresis, the mobility of the DNA fragment is detected by an autoradiography using X-ray films, a scanner that detects fluorescence, and so on, and analyzed. When a band having a difference in mobility is detected, this band is directly excised from the gel, re-amplified by PCR, and is directly sequenced to verify the presence of a mutation. Even when labeled DNA is not used, the band can be detected by staining the gel after electrophoresis with ethidium bromide, silver, and such.  
           [0050]    Another embodiment of the test method of the present invention comprises the following steps of: (a) preparing a DNA sample from a patient; (b) amplifying patient-derived DNA using the primer of this invention; (c) cleaving the amplified DNA; (d) separating the DNA fragments according to their size; (e) hybridizing the probe DNA of the invention labeled with a detectable label to the DNA fragments separated; and (f) comparing the size of the detected DNA fragment with a control from a healthy individual.  
           [0051]    Such methods include those using Restriction Fragment Length Polymorphism (RFLP), PCR-RFLP method, and so on. Restriction enzymes are usually used to cleave DNA. Specifically, compared to a DNA fragment of a healthy individual, the size of one obtained following restriction enzyme treatment changes when a mutation exists at the recognition site of the restriction enzyme, or when nucleotides have been inserted or deleted in the DNA fragment resulting from restriction enzyme treatment. The portion containing the mutation is amplified by PCR, the amplified products are treated with each restriction enzyme and electrophoresed to detect the mutation as the difference of mobility. Alternatively, chromosomal DNA is cleaved with these restriction enzymes, and after electrophoresis, the presence or absence of a mutation can be detected by southern-blotting using the probe DNA of the invention. The restriction enzymes used can be suitably selected according to each mutation. This method can use not only genomic DNA, but also cDNA made by treating RNA prepared from patients with reverse transcriptase, cleaving this cDNA as-it-is with restriction enzymes, and then conducting southern blotting. It is also possible to examine the changes in mobility after amplifying the whole OCTN2 gene, or a part of it, by PCR using the above cDNA as the template, and cleaving the amplified products by restriction enzymes.  
           [0052]    A similar detection is also possible using RNA prepared from patients instead of DNA. This method includes the steps of: (a) preparing an RNA sample from a patient; (b) separating the prepared RNA according to their size; (c) hybridizing the probe DNA of the invention labeled by a detectable label to the separated RNA; and (d) comparing the size of the detected RNA with a control from a healthy individual. In a specific example of this method, RNA prepared from a patient is electrophoresed, northern blotting is done using the probe of the invention to detect the mobility change.  
           [0053]    Another embodiment of the method of the invention comprises the steps of: (a) preparing a DNA sample from a patient; (b) amplifying patient-derived DNA using the primer of this invention; (c) separating the amplified DNA on a gel in which the concentration of the DNA denaturant gradually increases; and, (d) comparing mobility of the DNA separated upon the gel with a control from a healthy individual.  
           [0054]    An example of such a method is denaturant gradient gel electrophoresis (DGGE). The whole OCTN2 gene or a part of it is amplified by a method such as PCR using the primer of the invention, and the amplified product is electrophoresed in a gel in which the concentration of the DNA denaturant gradually increases, and compared with a control from a healthy individual. In the case of a DNA having a mutation, the DNA fragment will become single stranded at a low denaturant concentration and the moving speed will become extremely slow. The presence or absence of a mutation can be detected by detecting the change in mobility.  
           [0055]    Allele Specific Oligonucleotide (ASO) hybridization can be used alternatively when the aim is to detect a mutation at a specific site. When an oligonucleotide comprising a nucleotide sequence thought to have a mutation is prepared and this is hybridized with sample DNA, the hybrid formation efficiency will decrease when there is a mutation. This can be detected by southern blotting and by a method using the property of special fluorescent reagents that quench when intercalated into a hybrid gap. The detection by ribonuclease A mismatch cleavage method can also be used. Specifically, the whole OCTN2 gene, or a part of it, is amplified by a method such as PCR, and the amplified product is hybridized to labeled RNA prepared from OCTN2 cDNA and such incorporated into a plasmid vector, etc. The hybrids will be single stranded in the portion where a mutation exists. This portion is cleaved by ribonuclease A and the existence of a mutation can be detected by autoradiography, and such.  
           [0056]    The present invention also relates to a test drug for systemic carnitine deficiency that comprises an antibody binding to the OCTN2 protein as the active ingredient. An antibody binding to the OCTN2 protein can be prepared using methods well known to those skilled in the art. Polyclonal antibodies can be made by, obtaining the serum of small animals such as rabbits immunized with the OCTN2 protein (apart from the natural protein, recombinant OCTN2 proteins expressed in suitable host cells ( E. coli , yeasts, mammals, and such), such as recombinant OCTN2 protein expressed in  E. coli  as a fusion protein with GST) of the present invention, or a partial peptide. The serum is then purified by, for example, ammonium sulfate precipitation, protein A or protein G column chromatography, DEAE ion exchange chromatography, or an affinity chromatography using a column to which the protein of the present invention or synthetic peptide is coupled. Monoclonal antibodies can be made by immunizing small animals such as mice with the OCTN2 protein or a partial peptide thereof, excising the spleen from the mouse, homogenizing it and separating cells, fusing the cells with mouse myeloma cells using a reagent such as polyethylene glycol, and selecting clones that produce an antibody binding to the OCTN2 protein from the fused cells (hybridomas) produced. Next, the obtained hybridomas are transplanted into the abdominal cavity of a mouse, and ascites are extracted from the mouse. The obtained monoclonal antibodies can be purified by, for example, ammonium sulfate precipitation, protein A or protein G column chromatography, DEAE ion exchange chromatography, or an affinity chromatography using a column to which the OCTN2 protein or synthesized peptide is coupled. When using the antibody as a test drug, it is mixed with sterile water, physiological saline, plant oils, surfactants, lipids, solubilizers, stabilizers (BSA, gelatin, etc.), preservatives, and such, according to needs. An example of a test for systemic carnitine deficiency features the staining of tissues collected or cells isolated from a patient by the enzyme-labeled antibody method, fluorescence-labeled antibody method, and test for a deficiency, abnormal accumulation, or abnormal intracellular distribution of the OCTN2 protein. Testing can also be done by preparing a cell-extract of tissues collected or cells isolated from a systemic carnitine deficiency patient, separating the cell-extract by methods such as SDS-PAGE, transferring onto a nitrocellulose membrane, PVDF membrane, and such, and then staining this by a method (western blotting, immunoblotting, etc) using the above-described enzyme-labeled antibody method, etc.  
           [0057]    The present invention also relates to a therapeutic drug for systemic carnitine deficiency. One such embodiment has the OCTN2 gene as the active ingredient. When using the OCTN2 gene as a therapeutic drug, it is given to the patient by oral, intravenous, topical administration and such, as the full length OCTN2 chromosomal DNA, a part of it, or by incorporating the OCTN2 DNA into a suitable vector, for example, adenovirus vector, adeno associated virus vector, retro virus vector, or plasmid DNA. The ex vivo method can also be used for administration apart from the in vivo method. The transition and absorption into tissues can be enhanced by enclosing the gene in a liposome prepared by micellization of phospholipids, or by adding a cationic lipid and forming a complex with genomic DNA. Therefore, the method of the invention can replace a patient&#39;s mutated OCTN2 gene by a normal gene, and also additionally administer the normal gene, thereby enabling the treatment of systemic carnitine deficiency.  
           [0058]    Another embodiment of the invention relating to a therapeutic drug of systemic carnitine deficiency comprises the OCTN2 protein as the active ingredient. The amino acid sequences of human and mouse OCTN2 proteins are shown in SEQ ID NOs:1 and 3, respectively. The OCTN2 protein can be prepared as a natural protein and also as a recombinant protein. The natural protein can be prepared by a method well known to one skilled in the art, for example, by isolating the OCTN2 protein from tissues or cells that show a high level expression of the protein (e.g. fetal kidney) by affinity chromatography using an antibody against a partial peptide of the OCTN2 protein. On the other hand, a recombinant protein can be prepared by culturing cells transformed by DNA (for example, SEQ ID NO:2) encoding the OCTN2 protein. Cells used for the production of recombinant proteins include mammalian cells such as, COS cells, CHO cells, and NIH3T3 cells, insect cells such as sf9 cells, yeast cells, and  E coli  cells. Vectors for expressing the recombinant proteins within cells vary according to the host used, and normally, pcDNA3 (Invitrogen), pEF-BOS (Nucleic Acids Res. 1990, 18(17), 5322) and such are used as vectors for mammalian cells, the “BAC-to-BAC baculovirus expression system” (GIBCO BRL) and such are used for insect cells, “Pichia Expression Kit” (Invitrogen) and such are used for yeast cells, pGEX-5X-1 (Pharmacia), “QIAexpress system” (Qiagen) and such are used for  E. coli  cells. Vectors are introduced to hosts using, for example, the calcium phosphate method, DEAE dextran method, method using cationic liposome DOTAP (Boehringer Mannheim), and Superfect (Qiagen), electroporation method, calcium chloride method, and such. The recombinant protein can be purified from the transformant obtained usually using methods described in “The Qiaexpressionist handbook, Qiagen, Hilden, Germany”.  
           [0059]    When using the obtained OCTN2 protein as a therapeutic drug for treating systemic carnitine deficiency, the OCTN2 protein can be directly administered, or can be given after being formulated into a pharmaceutical composition by a well-known pharmaceutical manufacturing method. For example, the drug can be given after suitably combining with a generally used carrier or medium such as, sterilized water, physiological saline, plant oils, surfactants, lipids, solubilizers, stabilizers, preservatives, and such.  
           [0060]    The dosage varies depending on factors such as the patient&#39;s body weight, age, healthiness, and method of administration, but a skilled artisan can suitably select the dosage. Usually, it is within the range from 0.01 to 1000 mg/kg. The administration can be done orally, intravenously, intramuscularly, or percutaneously. A skilled artisan can easily replace, add, or delete amino acid(s) in the amino acid sequence of the OCTN2 protein using a well-known method such as the site-specific mutation induction system using PCR (GIBCO-BRL, Gaithersburg, Md.), site-specific mutagenesis using oligonucleotides (Kramer, W. and Fritz, H J, 1987, Methods in Enzymol, 154:350-367), the Kunkel method (Methods Enzymol., 1988, 85:2763-2766), and such.  
           [0061]    Another embodiment of the therapeutic drug for systemic carnitine deficiency uses a compound that enhances the activity of the OCTN2 protein as the active ingredient. Such a compound can be screened as follows. For example, a plasmid expressing the OCTN2 protein is constructed, and this is introduced into HEK293 cells by the calcium phosphate method. Radiolabeled carnitine and a test compound are added to this transformant and the carnitine transporting activity into the cells is determined. A compound that can enhance the carnitine transporting activity is selected by comparing with the activity of the OCTN2 protein in the absence of the test compound. See Japanese Patent Application Hei 9-260972 and Hei 10-156660 for the detailed method.  
           [0062]    Similar to the above-mentioned use of the OCTN2 protein as a therapeutic drug, the isolated compound can also be formulated into a pharmaceutical composition using well-known pharmaceutical manufacturing methods. The dose range is usually within 0.01 to 1000 mg/kg.  
           [0063]    It is also conceivable to utilize the region regulating OCTN2 gene expression or a factor that binds to this region for the treatment of systemic carnitine deficiency.  
           [0064]    The OCTN2 gene comprising the region that regulates OCTN2 gene expression is useful in the above-mentioned gene therapy as it can express the OCTN2 gene under normal expression regulation in vivo by introducing it into patients who lack the OCTN2 gene, or who have a defect in OCTN2 gene expression.  
           [0065]    Moreover, if the promoter site is determined from the upstream region of the OCTN2 gene, a compound that regulates OCTN2 gene expression amount can be simply screened by using a reporter gene expression vector having the above promoter site through examining the influence of various compounds on the production of reporter gene products. Such a screening method comprises the following steps of, (a) constructing a vector in which a reporter gene is ligated to the downstream of the promoter site, (b) introducing the vector into a suitable cell, and, (c) detecting the reporter gene activity by contacting or introducing a test compound to the above cell. Examples of the test compound include, proteins, peptides, synthetic compounds, natural compounds, genes, gene products, and such.  
           [0066]    A compound regulating OCTN2 gene expression can also be screened by contacting a test sample with the promoter site, and selecting a compound (such as a protein) that binds to the promoter site. For example, a synthetic oligo DNA and such having the nucleotide sequence of the promoter site is prepared, this is bound to a suitable support such as Sepharose, and contacted with a cell-extract, and such. Then, a transcription factor and such that binds to this promoter site and regulates OCTN2 gene expression can be purified by, for example, affinity chromatography.  
       
    
    
     DESCRIPTION OF DRAWINGS  
       [0067]    [0067]FIG. 1 shows the direct sequencing of the mouse OCTN2 gene amplified by RT-PCR. wt/wt shows wild-type homologous mouse, and jvs/jvs shows the jvs homologous mouse. OCTN2 gene of the jvs mouse has a mutation at the nucleotide shown by the arrow.  
         [0068]    [0068]FIG. 2 is electrophoretic images showing the mutation in the OCTN2 gene of the jvs mouse, which was detected using the PCR-RFLP method (Cfr 131 cleavage). The fragment shown by the arrow head derives from the normal gene, and the fragments shown by the arrows were due to the mutated gene.  
         [0069]    [0069]FIG. 3 shows results of the carnitine transporting activity assay of wild-type mouse OCTN2 and the mutant mouse OCTN2. A sodium-dependent carnitine transporting activity is seen for the wild type, whereas the mutant (Jvs) shows absolutely no activity. “Mock” is when a cDNA-non-containing vector was used as the control.  
         [0070]    [0070]FIG. 4 is an electrophoretic image showing the results of western blot analysis using anti myc antibody. It can be seen that the wild-type OCTN2 protein (wild) and the mutant OCTN2 protein (Jvs) is produced in similar amounts. “Mock” is when a cDNA-non-containing vector was used as the control.  
         [0071]    [0071]FIG. 5 shows the results of OCTN2 gene analysis in the KR family. The pedigree chart of this family is shown on top. Squares indicate males, circles females, filled ones individuals having systemic carnitine deficiency, and crossed squares indicate deceased individuals. An electrophoretic image showing the PCR results is given below. “N” shows the results of the normal gene used as the control. The fragments shown by the arrowhead are PCR products derived from the normal gene, and the fragments shown by the arrow derived from the gene where the defect exits.  
         [0072]    [0072]FIG. 6 shows the results of sequencing exon 1 of the OCTN2 gene. Compared to the normal OCTN2 gene (upper panel; wild-type), the OCTN2 of systemic carnitine deficiency patients (lower panel) belonging to the AK family, show an insertion of a cytosine residue at the position indicated by the arrow.  
         [0073]    [0073]FIG. 7 shows the results of sequencing exon 2 of the OCTN2 gene. Compared to the normal OCTN2 gene (upper panel; wild-type), the OCTN2 of systemic carnitine deficiency patients (lower panel) belonging to the AK family, show a single nucleotide substitution (A has substituted G) as indicated by the arrow.  
         [0074]    [0074]FIG. 8 is electrophoretic images showing the results of the analysis of two-types of mutations seen in the OCTN2 gene of a systemic carnitine deficiency patient belonging to the AK family using a PCR-RFLP method utilizing BcnI and NlaIV, respectively. The pedigree chart of this family is shown on top. Square indicates a male, circles females, and the filled circle indicates a systemic carnitine deficiency patient. “N” shows the results of the normal gene used as the control. The fragments shown by the arrows derived from the mutant gene.  
         [0075]    [0075]FIG. 9 shows the results of the sequencing analysis of the intron 8/exon 9 of the OCTN2 gene. Compared to the normal gene (normal), the gene deriving from the patient belonging to the TH family (patient) has a splicing site mutation (AG to AA) in the 3′ end of intron 8. The pedigree chart of this family is shown on top. Squares indicate males, the circle a female, and filled square indicates a systemic carnitine deficiency patient. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0076]    The invention shall be described in detail below, but it is not to be construed as being limited thereto.  
       EXAMPLE 1  
     Proof in Mouse and Human Showing That the Gene Responsible for Systemic Carnitine Deficiency (SCD) is OCTN2  
       [0077]    The Inventors have previously isolated human cDNA encoding a protein having an activity to transport carnitine in a sodium-ion dependent manner, and also the corresponding mouse cDNA (Japanese Patent Application No. Hei 9-260972, Japanese Patent Application No. Hei 10-156660). The nucleotide sequences of the human and mouse OCTN2 cDNA isolated by the Inventors are shown in SEQ ID NO:2 and 4, respectively, and the amino acid sequences of the proteins encoded by these cDNAs are shown in SEQ ID NO:1 and 3, respectively.  
         [0078]    The Inventors drew up a working hypothesis that OCTN2 might be the gene responsible for systemic carnitine deficiency, and conducted experiments to prove this.  
         [0079]    (1) OCTN2 Gene Analysis in Juvenile Visceral Steatosis (JVS) Mouse  
         [0080]    The juvenile visceral steatosis (jvs) mouse was generated due to a mutation in the C3H.OH mouse. This jvs mouse shows symptoms similar to systemic carnitine deficiency patients, and shows an extremely low carnitine concentration within its blood and tissues. This phenotype is inherited by autosomal inheritance. From the above facts, the jvs mouse is considered to be a mouse model for systemic carnitine deficiency (Hashimoto, N. et al., Gene-dose effect on carnitine transport activity in embryonic fibroblasts of JVS mice as a model of human carnitine transporter deficiency, Biochem Pharmacol, 1998, 55:1729-1732). The Inventors examined the OCTN2 gene arrangement of the jvs mouse. Specifically, whole RNA was extracted from the kidney of a jvs homologous mouse, cDNA was synthesized, jvs mouse OCTN2 cDNA was amplified using this synthesized cDNA as the template by RT-PCR, and the sequence was examined by direct sequencing.  
         [0081]    The amplification reaction by PCR was conducted as follows. For the 5′ side fragment, the primers MONB 31 (5′-gataagcttacggtgtccccttattcccatacg-3′/SEQ ID NO:22) and MONB 20 (5′-cccatgccaacaaggacaaaaagc-3′/SEQ ID NO:23) were prepared. Then, amplification was done within a reaction solution (50 μl ) containing, cDNA, 5 μl of 10×KOD buffer (Toyobo), 5 μl of 2 mM dNTPs, 2 μl of 25 mM MgCl 2 , 0.5 μl of KOD DNA polymerase (Toyobo), 1 μl of 20 μM MONB 31 primer, and 1 μl of 20 μM MONB 20 primer at 94° C. for 3 min, 30 cycles of “94° C. for 30 sec, 50° C. for 30 sec, and 74° C. for 1 min”, and 72° C. for 10 min. As for the 3′ side fragment, the primers MONB 6 (5′-tgtttttcgtgggtgtgctgatgg-3′/SEQ ID NO:24) and MONB 26 (5′-acagaacagaaaagccctcagtca-3′/SEQ ID NO:25) were prepared, and amplification was done within a reaction solution (50 μl) containing cDNA, 5 μl of 10×ExTaq buffer (TaKaRa), 4 μl of 2.5 mM dNTPs, 1 μl of a mixture of ExTaq DNA polymerase (TaKaRa) and anti Taq antibody (TaqStart antibody™, CLONTECH), 1 μl of 20 μM MONB 6 primer, and 1 μl of 20 μM MONB 26 primer, at 94° C. for 2 min, 30 cycles of “94° C. for 30 sec, 60° C. for 30 sec, and 74° C. for 2 min”, and 72° C. for 10 min.  
         [0082]    Sequencing revealed that the codon encoding the 352 nd  leucine (CTG) was mutated to a codon encoding arginine (CGG) (FIG. 1). This mutation can be detected by Restriction Fragment Length Polymorphism (PCR-RFLP) due to the presence of the Cfr13I restriction enzyme site. This method revealed that the jvs homologous mouse (jvs/jvs) had this mutation in both alleles, and that the heterologous mouse (wt/jvs) has both the mutated and wild type alleles (FIG. 2 left). This mutation was also found in the C57BL jvs mouse in which the genetic background has been replaced with that of the C57BL/6 mouse by backcrossing 12 times or more (FIG. 2 right). Since the C57BL jvs mouse was constructed after a series of selections using the jvs phenotype as an index, the jvs phenotype and OCTN2 mutations are considered to be very closely associated.  
         [0083]    Next, the effect this mutation has on the carnitine transporting activity was examined. Plasmid DNA expressing wild-type mouse OCTN2, and those expressing mutated OCTN2 were separately introduced into HEK293 cells, and then, carnitine transporting ability was measured similar to the assay of human OCTN2 described in Japanese Patent Application Hei 10-156660 (FIG. 3). This revealed that although wild-type mouse OCTN2 shows a carnitine transporting activity similar to human OCTN2, the mutated OCTN2 has absolutely no activity. However, both proteins were confirmed to be expressed at a similar amount by a western blotting using an antibody against the c-myc epitope sequence (NH 2 —EQKLISEEDL—COOH) added to the C terminus (FIG. 4).  
         [0084]    Thus, the jvs mouse is thought to have developed the disease due to a functional deletion mutation of the OCTN2 gene.  
         [0085]    (2) OCTN2 Gene Analysis in Human Systemic Carnitine Deficiency Patients  
         [0086]    A database search using human OCTN2 cDNA sequence revealed that the human OCTN2 genomic DNA sequence has been decoded by Lawrence Berkeley National Laboratory (LBNL) of the United States as a part of the human genome project. However, it was only recorded as several cosmid clone sequences, therefore, the inventors determined a complete human OCTN2 genomic DNA sequence (SEQ ID NO:5) by comparing with human OCTN2 cDNA sequence and suitably combining the clone sequences. The human OCTN2 gene is an about 26 kb gene comprising ten exons and nine introns. The eight pairs of primers shown below, which can amplify all the exons as eight fragments, were prepared from this gene arrangement.  
         [0087]    Specifically, OCN2 43 (5′-GCAGGACCAAGGCGGCGGTGTCAG-3′, SEQ ID NO:6) and OCN2 44 (5′-AGACTAGAGGAAAAACGGGATAGC-3′, SEQ ID NO:7) for exon one; OCN2 25 (5′-AGATTTTTAGGAGCAAGCGTTAGA-3′ SEQ ID NO:8) and OCN2 26 (5′-GAGGCAGACACCGTGGCACTACTA-3′, SEQ ID NO:9) for exon two; OCN2 27 (5′-TTCACACCCACTTACTGGATGGAT-3′ SEQ ID NO:10) and OCN2 50 (5′-ATTCTGTTTTGTTTTGGCTCTTTT-3′, SEQ ID NO:11) for exons three and four; OCN2 31 (5′-AGCAGGGCCTGGGCTGACATAGAC-3′, SEQ ID NO:12) and OCN2 32 (5′-AAAGGACCTGACTCCAAGATGATA-3′, SEQ ID NO:13) for exon five; OCN2 33 (5′-TCTGACCACCTCTTCTTCCCATAC-3′, SEQ ID NO:14) and OCN2 34 (5′-GCCTCCTCAGCCACTGTCGGTAAC-3′, SEQ ID NO:15) for exon six; OCN2 35 (5′-ATGTTGTTCCTTTTGTTATCTTAT-3′, SEQ ID NO:16) and OCN2 36 (5′-CTTGTTTTCTTGTGTATCGTTATC-3′, SEQ ID NO:17) for exon seven; OCN2 37 (5′-TATGTTTGTTTTGCTCTCAATAGC-3′, SEQ ID NO:18) and OCN2 40 (5′-TCTGTGAGAGGGAGTTTGCGAGTA-3′, SEQ ID NO:19) for exon eight and nine; and, OCN2 41 (5′-TACGACCGCTTCCTGCCCTACATT-3′, SEQ ID NO:20) and OCN2 42 (5′-TCATTCTGCTCCATCTTCATTACC-3′, SEQ ID NO:21) for exon 10.  
         [0088]    Next, human OCTN2 gene mutations in three families that have systemic carnitine deficiency patients, but no blood relationships were examined. The analysis is done by amplifying all the exons using the above primers and genomic DNA prepared from blood cells as the template, and subjecting the amplified products into direct sequencing.  
         [0089]    The amplification reaction by PCR was done within a reaction solution (50 μl) containing 100 ng of genomic DNA, 5 μl of 10×ExTaq buffer (TaKaRa), 4 μl of 2.5 mM dNTPs, 1 μl of a mixture of ExTaq DNA polymerase (TaKaRa) and anti Taq antibody (TaqStart antibody™, CLONTECH), and 1 μl of each of the 20 μM primers. The reaction conditions were, 94° C. for 2 min, 36 cycles of “94° C. for 30 sec, 60° C. for 30 sec, and 74° C. for 2 min”, and 72° C. for 10 min. However, in the case of exon one and exon five amplification, a reaction solution (50 μl) containing 100 ng genomic DNA, 25 μl of 2×GC buffer 1 (TaKaRa), 8 μl of 2.5 mM dNTPs, 0.5 μl of LA Taq DNA polymerase (TaKaRa), and 1 μl of each of the 20 μM primers, was used.  
         [0090]    In the first family (KR family), a 113 bp deletion was found in first exon of the OCTN2 gene of a systemic carnitine deficiency patient (FIG. 5). This deletion affects the initiation codon and thus, a complete protein will not be produced. The next usable ATG codon present in the correct frame is at nucleotide no. 177, and in this case, it is thought that at least two transmembrane regions will be deleted. The two systemic carnitine deficiency patients in this family were found to contain this mutated OCTN2 gene in both alleles. On the other hand, the parents and the two brothers of the patient, who have not developed the disease, carry the mutation on just one allele.  
         [0091]    In the second family (AK family), the systemic carnitine patients were found to contain two types of mutated OCTN2 genes. One mutation was a cytosine insertion just after the initiation codon, which is thought to cause a frame shift and prevent the proper protein from being produced (FIG. 6). The other mutation is a single base substitution (G to A) in the codon encoding the 132 nd  tryptophan (TGG). This mutation had altered the codon into a stop codon (TGA) (FIG. 7). These mutations are thought to prevent the production of active OCTN2 proteins in patients. These mutations can be detected by PCR-RFLP analysis using BcnI, NlaIV restriction enzymes, respectively, which revealed that the patient&#39;s parents who have not developed the disease, had one of each of the mutations, and the patient&#39;s sisters who have not developed the disease, do not have any mutated genes (FIG. 8).  
         [0092]    In the third family (TH family), a mutation (AG to AA) was found in the splicing site in the 3′ end of the intron eight of the OCTN2 gene (FIG. 9). This mutation prevents the gene from undergoing normal splicing, and thus, it is expected that the normal protein would not be produced. Sequencing analysis showed that the systemic carnitine deficiency patient belonging to this family had this mutation in both alleles. On the other hand, the patient&#39;s parents and one of the brothers who have not developed the disease had one mutated allele.  
         [0093]    The above results revealed that systemic carnitine deficiency is a genetic disease caused by mutations in the OCTN2 gene. Thus, the present invention enables definitive diagnosis, prenatal diagnosis and such, of systemic carnitine deficiency by examining mutations in the OCTN2 gene using analyses described herein, as well as other methods. The present invention also enables treatment of systemic carnitine deficiency by treatments such as gene therapy using the OCTN2 gene.  
       Industrial Applicability  
       [0094]    The present invention revealed that the OCTN2 gene is the gene responsible for systemic carnitine deficiency, thus enabling tests for the disease by detecting mutations in the OCTN2 gene and its protein. Moreover, the present invention facilitates treatment of systemic carnitine deficiency by utilizing the OCTN2 gene and its protein.  
 
     
       
       
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                                                SEQUENCE LISTING  
               
               
                   
               
               
                   
               
               
                 &lt;160&gt; NUMBER OF SEQ ID NOS: 31  
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 1  
               
               
                 &lt;211&gt; LENGTH: 557  
               
               
                 &lt;212&gt; TYPE: PRT  
               
               
                 &lt;213&gt; ORGANISM: Homo sapiens  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 1  
               
               
                   
               
               
                 Met Arg Asp Tyr Asp Glu Val Thr Ala Phe Leu Gly Glu Trp Gly Pro  
               
               
                   1               5                  10                  15  
               
               
                   
               
               
                 Phe Gln Arg Leu Ile Phe Phe Leu Leu Ser Ala Ser Ile Ile Pro Asn  
               
               
                              20                  25                  30  
               
               
                   
               
               
                 Gly Phe Thr Gly Leu Ser Ser Val Phe Leu Ile Ala Thr Pro Glu His  
               
               
                          35                  40                  45  
               
               
                   
               
               
                 Arg Cys Arg Val Pro Asp Ala Ala Asn Leu Ser Ser Ala Trp Arg Asn  
               
               
                      50                  55                  60  
               
               
                   
               
               
                 His Thr Val Pro Leu Arg Leu Arg Asp Gly Arg Glu Val Pro His Ser  
               
               
                  65                  70                  75                  80  
               
               
                   
               
               
                 Cys Arg Arg Tyr Arg Leu Ala Thr Ile Ala Asn Phe Ser Ala Leu Gly  
               
               
                                  85                  90                  95  
               
               
                   
               
               
                 Leu Glu Pro Gly Arg Asp Val Asp Leu Gly Gln Leu Glu Gln Glu Ser  
               
               
                             100                 105                 110  
               
               
                   
               
               
                 Cys Leu Asp Gly Trp Glu Phe Ser Gln Asp Val Tyr Leu Ser Thr Ile  
               
               
                         115                 120                 125  
               
               
                   
               
               
                 Val Thr Glu Trp Asn Leu Val Cys Glu Asp Asp Trp Lys Ala Pro Leu  
               
               
                     130                 135                 140  
               
               
                   
               
               
                 Thr Ile Ser Leu Phe Phe Val Gly Val Leu Leu Gly Ser Phe Ile Ser  
               
               
                 145                 150                 155                 160  
               
               
                   
               
               
                 Gly Gln Leu Ser Asp Arg Phe Gly Arg Lys Asn Val Leu Phe Val Thr  
               
               
                                 165                 170                 175  
               
               
                   
               
               
                 Met Gly Met Gln Thr Gly Phe Ser Phe Leu Gln Ile Phe Ser Lys Asn  
               
               
                             180                 185                 190  
               
               
                   
               
               
                 Phe Glu Met Phe Val Val Leu Phe Val Leu Val Gly Met Gly Gln Ile  
               
               
                         195                 200                 205  
               
               
                   
               
               
                 Ser Asn Tyr Val Ala Ala Phe Val Leu Gly Thr Glu Ile Leu Gly Lys  
               
               
                     210                 215                 220  
               
               
                   
               
               
                 Ser Val Arg Ile Ile Phe Ser Thr Leu Gly Val Cys Ile Phe Tyr Ala  
               
               
                 225                 230                 235                 240  
               
               
                   
               
               
                 Phe Gly Tyr Met Val Leu Pro Leu Phe Ala Tyr Phe Ile Arg Asp Trp  
               
               
                                 245                 250                 255  
               
               
                   
               
               
                 Arg Met Leu Leu Val Ala Leu Thr Met Pro Gly Val Leu Cys Val Ala  
               
               
                             260                 265                 270  
               
               
                   
               
               
                 Leu Trp Trp Phe Ile Pro Glu Ser Pro Arg Trp Leu Ile Ser Gln Gly  
               
               
                         275                 280                 285  
               
               
                   
               
               
                 Arg Phe Glu Glu Ala Glu Val Ile Ile Arg Lys Ala Ala Lys Ala Asn  
               
               
                     290                 295                 300  
               
               
                   
               
               
                 Gly Ile Val Val Pro Ser Thr Ile Phe Asp Pro Ser Glu Leu Gln Asp  
               
               
                 305                 310                 315                 320  
               
               
                   
               
               
                 Leu Ser Ser Lys Lys Gln Gln Ser His Asn Ile Leu Asp Leu Leu Arg  
               
               
                                 325                 330                 335  
               
               
                   
               
               
                 Thr Trp Asn Ile Arg Met Val Thr Ile Met Ser Ile Met Leu Trp Met  
               
               
                             340                 345                 350  
               
               
                   
               
               
                 Thr Ile Ser Val Gly Tyr Phe Gly Leu Ser Leu Asp Thr Pro Asn Leu  
               
               
                         355                 360                 365  
               
               
                   
               
               
                 His Gly Asp Ile Phe Val Asn Cys Phe Leu Ser Ala Met Val Glu Val  
               
               
                     370                 375                 380  
               
               
                   
               
               
                 Pro Ala Tyr Val Leu Ala Trp Leu Leu Leu Gln Tyr Leu Pro Arg Arg  
               
               
                 385                 390                 395                 400  
               
               
                   
               
               
                 Tyr Ser Met Ala Thr Ala Leu Phe Leu Gly Gly Ser Val Leu Leu Phe  
               
               
                                 405                 410                 415  
               
               
                   
               
               
                 Met Gln Leu Val Pro Pro Asp Leu Tyr Tyr Leu Ala Thr Val Leu Val  
               
               
                             420                 425                 430  
               
               
                   
               
               
                 Met Val Gly Lys Phe Gly Val Thr Ala Ala Phe Ser Met Val Tyr Val  
               
               
                         435                 440                 445  
               
               
                   
               
               
                 Tyr Thr Ala Glu Leu Tyr Pro Thr Val Val Arg Asn Met Gly Val Gly  
               
               
                     450                 455                 460  
               
               
                   
               
               
                 Val Ser Ser Thr Ala Ser Arg Leu Gly Ser Ile Leu Ser Pro Tyr Phe  
               
               
                 465                 470                 475                 480  
               
               
                   
               
               
                 Val Tyr Leu Gly Ala Tyr Asp Arg Phe Leu Pro Tyr Ile Leu Met Gly  
               
               
                                 485                 490                 495  
               
               
                   
               
               
                 Ser Leu Thr Ile Leu Thr Ala Ile Leu Thr Leu Phe Leu Pro Glu Ser  
               
               
                             500                 505                 510  
               
               
                   
               
               
                 Phe Gly Thr Pro Leu Pro Asp Thr Ile Asp Gln Met Leu Arg Val Lys  
               
               
                         515                 520                 525  
               
               
                   
               
               
                 Gly Met Lys His Arg Lys Thr Pro Ser His Thr Arg Met Leu Lys Asp  
               
               
                     530                 535                 540  
               
               
                   
               
               
                 Gly Gln Glu Arg Pro Thr Ile Leu Lys Ser Thr Ala Phe  
               
               
                 545                 550                 555  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 2  
               
               
                 &lt;211&gt; LENGTH: 1831  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Homo sapiens  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;221&gt; NAME/KEY: CDS  
               
               
                 &lt;222&gt; LOCATION: (124)..(1794)  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 2  
               
               
                   
               
               
                 cggacggtct tgggtcgcct gctgcctggc ttgcctggtc ggcggcgggt gccccgcgcg     60  
               
               
                   
               
               
                 cacgcgcaaa gcccgccgcg ttcccagacc ccaggccgcg ctctgtgggc ctctgagggc    120  
               
               
                   
               
               
                 ggc atg cgg gac tac gac gag gtg acc gcc ttc ctg ggc gag tgg ggg      168  
               
               
                     Met Arg Asp Tyr Asp Glu Val Thr Ala Phe Leu Gly Glu Trp Gly  
               
               
                       1               5                  10                  15  
               
               
                   
               
               
                 ccc ttc cag cgc ctc atc ttc ttc ctg ctc agc gcc agc atc atc ccc      216  
               
               
                 Pro Phe Gln Arg Leu Ile Phe Phe Leu Leu Ser Ala Ser Ile Ile Pro  
               
               
                                  20                  25                  30  
               
               
                   
               
               
                 aat ggc ttc acc ggc ctg tcc tcc gtg ttc ctg ata gcg acc ccg gag      264  
               
               
                 Asn Gly Phe Thr Gly Leu Ser Ser Val Phe Leu Ile Ala Thr Pro Glu  
               
               
                              35                  40                  45  
               
               
                   
               
               
                 cac cgc tgc cgg gtg ccg gac gcc gcg aac ctg agc agc gcc tgg cgc      312  
               
               
                 His Arg Cys Arg Val Pro Asp Ala Ala Asn Leu Ser Ser Ala Trp Arg  
               
               
                          50                  55                  60  
               
               
                   
               
               
                 aac cac act gtc cca ctg cgg ctg cgg gac ggc cgc gag gtg ccc cac      360  
               
               
                 Asn His Thr Val Pro Leu Arg Leu Arg Asp Gly Arg Glu Val Pro His  
               
               
                      65                  70                  75  
               
               
                   
               
               
                 agc tgc cgc cgc tac cgg ctc gcc acc atc gcc aac ttc tcg gcg ctc      408  
               
               
                 Ser Cys Arg Arg Tyr Arg Leu Ala Thr Ile Ala Asn Phe Ser Ala Leu  
               
               
                  80                  85                  90                  95  
               
               
                   
               
               
                 ggg ctg gag ccg ggg cgc gac gtg gac ctg ggg cag ctg gag cag gag      456  
               
               
                 Gly Leu Glu Pro Gly Arg Asp Val Asp Leu Gly Gln Leu Glu Gln Glu  
               
               
                                 100                 105                 110  
               
               
                   
               
               
                 agc tgt ctg gat ggc tgg gag ttc agt cag gac gtc tac ctg tcc acc      504  
               
               
                 Ser Cys Leu Asp Gly Trp Glu Phe Ser Gln Asp Val Tyr Leu Ser Thr  
               
               
                             115                 120                 125  
               
               
                   
               
               
                 att gtg acc gag tgg aac ctg gtg tgt gag gac gac tgg aag gcc cca      552  
               
               
                 Ile Val Thr Glu Trp Asn Leu Val Cys Glu Asp Asp Trp Lys Ala Pro  
               
               
                         130                 135                 140  
               
               
                   
               
               
                 ctc aca atc tcc ttg ttc ttc gtg ggt gtg ctg ttg ggc tcc ttc att      600  
               
               
                 Leu Thr Ile Ser Leu Phe Phe Val Gly Val Leu Leu Gly Ser Phe Ile  
               
               
                     145                 150                 155  
               
               
                   
               
               
                 tca ggg cag ctg tca gac agg ttt ggc cgg aag aat gtg ctg ttc gtg      648  
               
               
                 Ser Gly Gln Leu Ser Asp Arg Phe Gly Arg Lys Asn Val Leu Phe Val  
               
               
                 160                 165                 170                 175  
               
               
                   
               
               
                 acc atg ggc atg cag aca ggc ttc agc ttc ctg cag atc ttc tcg aag      696  
               
               
                 Thr Met Gly Met Gln Thr Gly Phe Ser Phe Leu Gln Ile Phe Ser Lys  
               
               
                                 180                 185                 190  
               
               
                   
               
               
                 aat ttt gag atg ttt gtc gtg ctg ttt gtc ctt gta ggc atg ggc cag      744  
               
               
                 Asn Phe Glu Met Phe Val Val Leu Phe Val Leu Val Gly Met Gly Gln  
               
               
                             195                 200                 205  
               
               
                   
               
               
                 atc tcc aac tat gtg gca gca ttt gtc ctg ggg aca gaa att ctt ggc      792  
               
               
                 Ile Ser Asn Tyr Val Ala Ala Phe Val Leu Gly Thr Glu Ile Leu Gly  
               
               
                         210                 215                 220  
               
               
                   
               
               
                 aag tca gtt cgt ata ata ttc tct acg tta gga gtg tgc ata ttt tat      840  
               
               
                 Lys Ser Val Arg Ile Ile Phe Ser Thr Leu Gly Val Cys Ile Phe Tyr  
               
               
                     225                 230                 235  
               
               
                   
               
               
                 gca ttt ggc tac atg gtg ctg cca ctg ttt gct tac ttc atc cga gac      888  
               
               
                 Ala Phe Gly Tyr Met Val Leu Pro Leu Phe Ala Tyr Phe Ile Arg Asp  
               
               
                 240                 245                 250                 255  
               
               
                   
               
               
                 tgg cgg atg ctg ctg gtg gcg ctg acg atg ccg ggg gtg ctg tgc gtg      936  
               
               
                 Trp Arg Met Leu Leu Val Ala Leu Thr Met Pro Gly Val Leu Cys Val  
               
               
                                 260                 265                 270  
               
               
                   
               
               
                 gca ctc tgg tgg ttc atc cct gag tcc ccc cga tgg ctc atc tct cag      984  
               
               
                 Ala Leu Trp Trp Phe Ile Pro Glu Ser Pro Arg Trp Leu Ile Ser Gln  
               
               
                             275                 280                 285  
               
               
                   
               
               
                 gga cga ttt gaa gag gca gag gtg atc atc cgc aag gct gcc aaa gcc     1032  
               
               
                 Gly Arg Phe Glu Glu Ala Glu Val Ile Ile Arg Lys Ala Ala Lys Ala  
               
               
                         290                 295                 300  
               
               
                   
               
               
                 aat ggg att gtt gtg cct tcc act atc ttt gac ccg agt gag tta caa     1080  
               
               
                 Asn Gly Ile Val Val Pro Ser Thr Ile Phe Asp Pro Ser Glu Leu Gln  
               
               
                     305                 310                 315  
               
               
                   
               
               
                 gac cta agt tcc aag aag cag cag tcc cac aac att ctg gat ctg ctt     1128  
               
               
                 Asp Leu Ser Ser Lys Lys Gln Gln Ser His Asn Ile Leu Asp Leu Leu  
               
               
                 320                 325                 330                 335  
               
               
                   
               
               
                 cga acc tgg aat atc cgg atg gtc acc atc atg tcc ata atg ctg tgg     1176  
               
               
                 Arg Thr Trp Asn Ile Arg Met Val Thr Ile Met Ser Ile Met Leu Trp  
               
               
                                 340                 345                 350  
               
               
                   
               
               
                 atg acc ata tca gtg ggc tat ttt ggg ctt tcg ctt gat act cct aac     1224  
               
               
                 Met Thr Ile Ser Val Gly Tyr Phe Gly Leu Ser Leu Asp Thr Pro Asn  
               
               
                             355                 360                 365  
               
               
                   
               
               
                 ttg cat ggg gac atc ttt gtg aac tgc ttc ctt tca gcg atg gtt gaa     1272  
               
               
                 Leu His Gly Asp Ile Phe Val Asn Cys Phe Leu Ser Ala Met Val Glu  
               
               
                         370                 375                 380  
               
               
                   
               
               
                 gtc cca gca tat gtg ttg gcc tgg ctg ctg ctg caa tat ttg ccc cgg     1320  
               
               
                 Val Pro Ala Tyr Val Leu Ala Trp Leu Leu Leu Gln Tyr Leu Pro Arg  
               
               
                     385                 390                 395  
               
               
                   
               
               
                 cgc tat tcc atg gcc act gcc ctc ttc ctg ggt ggc agt gtc ctt ctc     1368  
               
               
                 Arg Tyr Ser Met Ala Thr Ala Leu Phe Leu Gly Gly Ser Val Leu Leu  
               
               
                 400                 405                 410                 415  
               
               
                   
               
               
                 ttc atg cag ctg gta ccc cca gac ttg tat tat ttg gct aca gtc ctg     1416  
               
               
                 Phe Met Gln Leu Val Pro Pro Asp Leu Tyr Tyr Leu Ala Thr Val Leu  
               
               
                                 420                 425                 430  
               
               
                   
               
               
                 gtg atg gtg ggc aag ttt gga gtc acg gct gcc ttt tcc atg gtc tac     1464  
               
               
                 Val Met Val Gly Lys Phe Gly Val Thr Ala Ala Phe Ser Met Val Tyr  
               
               
                             435                 440                 445  
               
               
                   
               
               
                 gtg tac aca gcc gag ctg tat ccc aca gtg gtg aga aac atg ggt gtg     1512  
               
               
                 Val Tyr Thr Ala Glu Leu Tyr Pro Thr Val Val Arg Asn Met Gly Val  
               
               
                         450                 455                 460  
               
               
                   
               
               
                 gga gtc agc tcc aca gca tcc cgc ctg ggc agc atc ctg tct ccc tac     1560  
               
               
                 Gly Val Ser Ser Thr Ala Ser Arg Leu Gly Ser Ile Leu Ser Pro Tyr  
               
               
                     465                 470                 475  
               
               
                   
               
               
                 ttc gtt tac ctt ggt gcc tac gac cgc ttc ctg ccc tac att ctc atg     1608  
               
               
                 Phe Val Tyr Leu Gly Ala Tyr Asp Arg Phe Leu Pro Tyr Ile Leu Met  
               
               
                 480                 485                 490                 495  
               
               
                   
               
               
                 gga agt ctg acc atc ctg aca gcc atc ctc acc ttg ttt ctc cca gag     1656  
               
               
                 Gly Ser Leu Thr Ile Leu Thr Ala Ile Leu Thr Leu Phe Leu Pro Glu  
               
               
                                 500                 505                 510  
               
               
                   
               
               
                 agc ttc ggt acc cca ctc cca gac acc att gac cag atg cta aga gtc     1704  
               
               
                 Ser Phe Gly Thr Pro Leu Pro Asp Thr Ile Asp Gln Met Leu Arg Val  
               
               
                             515                 520                 525  
               
               
                   
               
               
                 aaa gga atg aaa cac aga aaa act cca agt cac aca agg atg tta aaa     1752  
               
               
                 Lys Gly Met Lys His Arg Lys Thr Pro Ser His Thr Arg Met Leu Lys  
               
               
                         530                 535                 540  
               
               
                   
               
               
                 gat ggt caa gaa agg ccc aca atc ctt aaa agc aca gcc ttc             1794  
               
               
                 Asp Gly Gln Glu Arg Pro Thr Ile Leu Lys Ser Thr Ala Phe  
               
               
                     545                 550                 555  
               
               
                   
               
               
                 taacatcgct tccagtaagg gagaaactga agaggaa                            1831  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 3  
               
               
                 &lt;211&gt; LENGTH: 557  
               
               
                 &lt;212&gt; TYPE: PRT  
               
               
                 &lt;213&gt; ORGANISM: Mus musculus  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 3  
               
               
                   
               
               
                 Met Arg Asp Tyr Asp Glu Val Thr Ala Phe Leu Gly Glu Trp Gly Pro  
               
               
                   1               5                  10                  15  
               
               
                   
               
               
                 Phe Gln Arg Leu Ile Phe Phe Leu Leu Ser Ala Ser Ile Ile Pro Asn  
               
               
                              20                  25                  30  
               
               
                   
               
               
                 Gly Phe Asn Gly Met Ser Ile Val Phe Leu Ala Gly Thr Pro Glu His  
               
               
                          35                  40                  45  
               
               
                   
               
               
                 Arg Cys Leu Val Pro His Thr Val Asn Leu Ser Ser Ala Trp Arg Asn  
               
               
                      50                  55                  60  
               
               
                   
               
               
                 His Ser Ile Pro Leu Glu Thr Lys Asp Gly Arg Gln Val Pro Gln Lys  
               
               
                  65                  70                  75                  80  
               
               
                   
               
               
                 Cys Arg Arg Tyr Arg Leu Ala Thr Ile Ala Asn Phe Ser Glu Leu Gly  
               
               
                                  85                  90                  95  
               
               
                   
               
               
                 Leu Glu Pro Gly Arg Asp Val Asp Leu Glu Gln Leu Glu Gln Glu Ser  
               
               
                             100                 105                 110  
               
               
                   
               
               
                 Cys Leu Asp Gly Trp Glu Tyr Asp Lys Asp Val Phe Leu Ser Thr Ile  
               
               
                         115                 120                 125  
               
               
                   
               
               
                 Val Thr Glu Trp Asp Leu Val Cys Lys Asp Asp Trp Lys Ala Pro Leu  
               
               
                     130                 135                 140  
               
               
                   
               
               
                 Thr Thr Ser Leu Phe Phe Val Gly Val Leu Met Gly Ser Phe Ile Ser  
               
               
                 145                 150                 155                 160  
               
               
                   
               
               
                 Gly Gln Leu Ser Asp Arg Phe Gly Arg Lys Asn Val Leu Phe Leu Thr  
               
               
                                 165                 170                 175  
               
               
                   
               
               
                 Met Gly Met Gln Thr Gly Phe Ser Phe Leu Gln Val Phe Ser Val Asn  
               
               
                             180                 185                 190  
               
               
                   
               
               
                 Phe Glu Met Phe Thr Val Leu Phe Val Leu Val Gly Met Gly Gln Ile  
               
               
                         195                 200                 205  
               
               
                   
               
               
                 Ser Asn Tyr Val Ala Ala Phe Val Leu Gly Thr Glu Ile Leu Ser Lys  
               
               
                     210                 215                 220  
               
               
                   
               
               
                 Ser Ile Arg Ile Ile Phe Ala Thr Leu Gly Val Cys Ile Phe Tyr Ala  
               
               
                 225                 230                 235                 240  
               
               
                   
               
               
                 Phe Gly Phe Met Val Leu Pro Leu Phe Ala Tyr Phe Ile Arg Asp Trp  
               
               
                                 245                 250                 255  
               
               
                   
               
               
                 Arg Met Leu Leu Leu Ala Leu Thr Val Pro Gly Val Leu Cys Gly Ala  
               
               
                             260                 265                 270  
               
               
                   
               
               
                 Leu Trp Trp Phe Ile Pro Glu Ser Pro Arg Trp Leu Ile Ser Gln Gly  
               
               
                         275                 280                 285  
               
               
                   
               
               
                 Arg Ile Lys Glu Ala Glu Val Ile Ile Arg Lys Ala Ala Lys Ile Asn  
               
               
                     290                 295                 300  
               
               
                   
               
               
                 Gly Ile Val Ala Pro Ser Thr Ile Phe Asp Pro Ser Glu Leu Gln Asp  
               
               
                 305                 310                 315                 320  
               
               
                   
               
               
                 Leu Asn Ser Thr Lys Pro Gln Leu His His Ile Tyr Asp Leu Ile Arg  
               
               
                                 325                 330                 335  
               
               
                   
               
               
                 Thr Arg Asn Ile Arg Val Ile Thr Ile Met Ser Ile Ile Leu Trp Leu  
               
               
                             340                 345                 350  
               
               
                   
               
               
                 Thr Ile Ser Val Gly Tyr Phe Gly Leu Ser Leu Asp Thr Pro Asn Leu  
               
               
                         355                 360                 365  
               
               
                   
               
               
                 His Gly Asp Ile Tyr Val Asn Cys Phe Leu Leu Ala Ala Val Glu Val  
               
               
                     370                 375                 380  
               
               
                   
               
               
                 Pro Ala Tyr Val Leu Ala Trp Leu Leu Leu Gln Tyr Leu Pro Arg Arg  
               
               
                 385                 390                 395                 400  
               
               
                   
               
               
                 Tyr Ser Ile Ser Ala Ala Leu Phe Leu Gly Gly Ser Val Leu Leu Phe  
               
               
                                 405                 410                 415  
               
               
                   
               
               
                 Met Gln Leu Val Pro Ser Glu Leu Phe Tyr Leu Ser Thr Ala Leu Val  
               
               
                             420                 425                 430  
               
               
                   
               
               
                 Met Val Gly Lys Phe Gly Ile Thr Ser Ala Tyr Ser Met Val Tyr Val  
               
               
                         435                 440                 445  
               
               
                   
               
               
                 Tyr Thr Ala Glu Leu Tyr Pro Thr Val Val Arg Asn Met Gly Val Gly  
               
               
                     450                 455                 460  
               
               
                   
               
               
                 Val Ser Ser Thr Ala Ser Arg Leu Gly Ser Ile Leu Ser Pro Tyr Phe  
               
               
                 465                 470                 475                 480  
               
               
                   
               
               
                 Val Tyr Leu Gly Ala Tyr Asp Arg Phe Leu Pro Tyr Ile Leu Met Gly  
               
               
                                 485                 490                 495  
               
               
                   
               
               
                 Ser Leu Thr Ile Leu Thr Ala Ile Leu Thr Leu Phe Phe Pro Glu Ser  
               
               
                             500                 505                 510  
               
               
                   
               
               
                 Phe Gly Val Pro Leu Pro Asp Thr Ile Asp Gln Met Leu Arg Val Lys  
               
               
                         515                 520                 525  
               
               
                   
               
               
                 Gly Ile Lys Gln Trp Gln Ile Gln Ser Gln Thr Arg Met Gln Lys Asp  
               
               
                     530                 535                 540  
               
               
                   
               
               
                 Gly Glu Glu Ser Pro Thr Val Leu Lys Ser Thr Ala Phe  
               
               
                 545                 550                 555  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 4  
               
               
                 &lt;211&gt; LENGTH: 1888  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Mus musculus  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;221&gt; NAME/KEY: CDS  
               
               
                 &lt;222&gt; LOCATION: (60)..(1730)  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 4  
               
               
                   
               
               
                 ctcccgcgcc acggtgtccc cttattccca tacgggcgct gtgggaggct gaggacggc      59  
               
               
                   
               
               
                 atg cgg gac tac gac gag gtg acc gcc ttc cta ggc gag tgg ggg ccc      107  
               
               
                 Met Arg Asp Tyr Asp Glu Val Thr Ala Phe Leu Gly Glu Trp Gly Pro  
               
               
                   1               5                  10                  15  
               
               
                   
               
               
                 ttc cag cgc ctc atc ttc ttc ctg ctc agc gcc agc atc atc ccc aat      155  
               
               
                 Phe Gln Arg Leu Ile Phe Phe Leu Leu Ser Ala Ser Ile Ile Pro Asn  
               
               
                              20                  25                  30  
               
               
                   
               
               
                 ggc ttc aat ggt atg tcc atc gtg ttc ctg gcg ggg acc ccg gag cac      203  
               
               
                 Gly Phe Asn Gly Met Ser Ile Val Phe Leu Ala Gly Thr Pro Glu His  
               
               
                          35                  40                  45  
               
               
                   
               
               
                 cgt tgc ctt gtg cct cac acc gtg aac ctg agc agc gcg tgg cgc aac      251  
               
               
                 Arg Cys Leu Val Pro His Thr Val Asn Leu Ser Ser Ala Trp Arg Asn  
               
               
                      50                  55                  60  
               
               
                   
               
               
                 cac agt atc ccg ttg gag acg aag gac gga cga cag gtg cct cag aaa      299  
               
               
                 His Ser Ile Pro Leu Glu Thr Lys Asp Gly Arg Gln Val Pro Gln Lys  
               
               
                  65                  70                  75                  80  
               
               
                   
               
               
                 tgc cgc cgc tac cga ctg gcc acc atc gcc aac ttc tct gag cta ggg      347  
               
               
                 Cys Arg Arg Tyr Arg Leu Ala Thr Ile Ala Asn Phe Ser Glu Leu Gly  
               
               
                                  85                  90                  95  
               
               
                   
               
               
                 ctg gag ccg ggg cgg gac gtg gac ctg gag cag ctg gag cag gag agc      395  
               
               
                 Leu Glu Pro Gly Arg Asp Val Asp Leu Glu Gln Leu Glu Gln Glu Ser  
               
               
                             100                 105                 110  
               
               
                   
               
               
                 tgc ctg gat ggc tgg gag tac gac aag gac gtc ttc ctg tcc acc atc      443  
               
               
                 Cys Leu Asp Gly Trp Glu Tyr Asp Lys Asp Val Phe Leu Ser Thr Ile  
               
               
                         115                 120                 125  
               
               
                   
               
               
                 gtg aca gag tgg gac ctg gtg tgt aag gat gac tgg aaa gcc cca ctc      491  
               
               
                 Val Thr Glu Trp Asp Leu Val Cys Lys Asp Asp Trp Lys Ala Pro Leu  
               
               
                     130                 135                 140  
               
               
                   
               
               
                 acc acc tcc ttg ttt ttc gtg ggt gtg ctg atg ggc tcc ttc att tca      539  
               
               
                 Thr Thr Ser Leu Phe Phe Val Gly Val Leu Met Gly Ser Phe Ile Ser  
               
               
                 145                 150                 155                 160  
               
               
                   
               
               
                 gga cag ctc tca gac agg ttt ggt cgc aag aat gtg ctg ttt ttg acc      587  
               
               
                 Gly Gln Leu Ser Asp Arg Phe Gly Arg Lys Asn Val Leu Phe Leu Thr  
               
               
                                 165                 170                 175  
               
               
                   
               
               
                 atg ggc atg cag act ggc ttc agc ttc ctg cag gtc ttc tct gtg aac      635  
               
               
                 Met Gly Met Gln Thr Gly Phe Ser Phe Leu Gln Val Phe Ser Val Asn  
               
               
                             180                 185                 190  
               
               
                   
               
               
                 ttc gag atg ttt aca gtg ctt ttt gtc ctt gtt ggc atg ggt cag atc      683  
               
               
                 Phe Glu Met Phe Thr Val Leu Phe Val Leu Val Gly Met Gly Gln Ile  
               
               
                         195                 200                 205  
               
               
                   
               
               
                 tcc aac tac gtg gca gca ttt gtc ctg gga aca gaa att ctt tcc aag      731  
               
               
                 Ser Asn Tyr Val Ala Ala Phe Val Leu Gly Thr Glu Ile Leu Ser Lys  
               
               
                     210                 215                 220  
               
               
                   
               
               
                 tca att cga att ata ttc gcc acc tta gga gtt tgc ata ttt tat gcg      779  
               
               
                 Ser Ile Arg Ile Ile Phe Ala Thr Leu Gly Val Cys Ile Phe Tyr Ala  
               
               
                 225                 230                 235                 240  
               
               
                   
               
               
                 ttt ggc ttc atg gtg ctg cca ctg ttt gca tac ttc atc aga gac tgg      827  
               
               
                 Phe Gly Phe Met Val Leu Pro Leu Phe Ala Tyr Phe Ile Arg Asp Trp  
               
               
                                 245                 250                 255  
               
               
                   
               
               
                 agg atg ctg ctg ctg gcg ctc act gtg cca ggg gtg cta tgt ggg gct      875  
               
               
                 Arg Met Leu Leu Leu Ala Leu Thr Val Pro Gly Val Leu Cys Gly Ala  
               
               
                             260                 265                 270  
               
               
                   
               
               
                 ctc tgg tgg ttc atc cct gag tcc cca cga tgg ctc atc tct caa ggc      923  
               
               
                 Leu Trp Trp Phe Ile Pro Glu Ser Pro Arg Trp Leu Ile Ser Gln Gly  
               
               
                         275                 280                 285  
               
               
                   
               
               
                 cga att aaa gag gca gag gtg atc atc cgc aaa gct gcc aaa atc aat      971  
               
               
                 Arg Ile Lys Glu Ala Glu Val Ile Ile Arg Lys Ala Ala Lys Ile Asn  
               
               
                     290                 295                 300  
               
               
                   
               
               
                 ggg att gtt gca cct tcc act atc ttc gat cca agt gag tta caa gac     1019  
               
               
                 Gly Ile Val Ala Pro Ser Thr Ile Phe Asp Pro Ser Glu Leu Gln Asp  
               
               
                 305                 310                 315                 320  
               
               
                   
               
               
                 tta aat tct acg aag cct cag ttg cac cac att tat gat ctg atc cga     1067  
               
               
                 Leu Asn Ser Thr Lys Pro Gln Leu His His Ile Tyr Asp Leu Ile Arg  
               
               
                                 325                 330                 335  
               
               
                   
               
               
                 aca cgg aat atc agg gtc atc acc atc atg tct ata atc ctg tgg ctg     1115  
               
               
                 Thr Arg Asn Ile Arg Val Ile Thr Ile Met Ser Ile Ile Leu Trp Leu  
               
               
                             340                 345                 350  
               
               
                   
               
               
                 acc ata tca gtg ggc tat ttt gga cta tct ctt gac act cct aac ttg     1163  
               
               
                 Thr Ile Ser Val Gly Tyr Phe Gly Leu Ser Leu Asp Thr Pro Asn Leu  
               
               
                         355                 360                 365  
               
               
                   
               
               
                 cat ggg gac atc tat gtg aac tgc ttc cta ctg gcg gct gtt gaa gtc     1211  
               
               
                 His Gly Asp Ile Tyr Val Asn Cys Phe Leu Leu Ala Ala Val Glu Val  
               
               
                     370                 375                 380  
               
               
                   
               
               
                 cca gcc tat gtg ctg gcc tgg ctg ttg ttg cag tac ttg ccc cgg cga     1259  
               
               
                 Pro Ala Tyr Val Leu Ala Trp Leu Leu Leu Gln Tyr Leu Pro Arg Arg  
               
               
                 385                 390                 395                 400  
               
               
                   
               
               
                 tat tct atc tcg gct gcc ctt ttc ctg ggt ggc agt gtc ctt ctc ttc     1307  
               
               
                 Tyr Ser Ile Ser Ala Ala Leu Phe Leu Gly Gly Ser Val Leu Leu Phe  
               
               
                                 405                 410                 415  
               
               
                   
               
               
                 atg cag ctg gtg cct tca gaa ttg ttt tac ttg tcc act gcc ctg gtg     1355  
               
               
                 Met Gln Leu Val Pro Ser Glu Leu Phe Tyr Leu Ser Thr Ala Leu Val  
               
               
                             420                 425                 430  
               
               
                   
               
               
                 atg gtg ggg aag ttt gga atc acc tct gcc tac tcc atg gtc tat gtg     1403  
               
               
                 Met Val Gly Lys Phe Gly Ile Thr Ser Ala Tyr Ser Met Val Tyr Val  
               
               
                         435                 440                 445  
               
               
                   
               
               
                 tac aca gct gag ctg tac ccc act gtg gtc aga aac atg ggt gtg ggg     1451  
               
               
                 Tyr Thr Ala Glu Leu Tyr Pro Thr Val Val Arg Asn Met Gly Val Gly  
               
               
                     450                 455                 460  
               
               
                   
               
               
                 gtc agc tcc aca gca tcc cgc ctt ggc agc atc ctg tct ccc tac ttt     1499  
               
               
                 Val Ser Ser Thr Ala Ser Arg Leu Gly Ser Ile Leu Ser Pro Tyr Phe  
               
               
                 465                 470                 475                 480  
               
               
                   
               
               
                 gtt tac cta ggt gcc tat gat cgc ttc ctg cct tat att ctc atg gga     1547  
               
               
                 Val Tyr Leu Gly Ala Tyr Asp Arg Phe Leu Pro Tyr Ile Leu Met Gly  
               
               
                                 485                 490                 495  
               
               
                   
               
               
                 agt ctg acc atc ctg aca gct atc ctc acc ttg ttc ttc cct gag agc     1595  
               
               
                 Ser Leu Thr Ile Leu Thr Ala Ile Leu Thr Leu Phe Phe Pro Glu Ser  
               
               
                             500                 505                 510  
               
               
                   
               
               
                 ttt ggt gtc cct ctc cca gat acc att gac cag atg cta agg gtc aaa     1643  
               
               
                 Phe Gly Val Pro Leu Pro Asp Thr Ile Asp Gln Met Leu Arg Val Lys  
               
               
                         515                 520                 525  
               
               
                   
               
               
                 gga ata aaa cag tgg caa atc caa agc cag aca aga atg caa aaa gat     1691  
               
               
                 Gly Ile Lys Gln Trp Gln Ile Gln Ser Gln Thr Arg Met Gln Lys Asp  
               
               
                     530                 535                 540  
               
               
                   
               
               
                 ggt gaa gaa agc cca aca gtc cta aag agc aca gcc ttc taacaccctg      1740  
               
               
                 Gly Glu Glu Ser Pro Thr Val Leu Lys Ser Thr Ala Phe  
               
               
                 545                 550                 555  
               
               
                   
               
               
                 tccagaaggc aaaaaactga ttggaaacct tcatgttgtc agaaatgctc tccatgactg   1800  
               
               
                   
               
               
                 agggcttttc tgttctgtta accttgtgtc taacatgctc atggattggg gcatctgtcc   1860  
               
               
                   
               
               
                 tggagagtca ccttcctcta gggacacc                                      1888  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 5  
               
               
                 &lt;211&gt; LENGTH: 25871  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Homo sapiens  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;221&gt; NAME/KEY: exon  
               
               
                 &lt;222&gt; LOCATION: (1)..(614)  
               
               
                 &lt;221&gt; NAME/KEY: intron  
               
               
                 &lt;222&gt; LOCATION: (615)..(8636)  
               
               
                 &lt;221&gt; NAME/KEY: exon  
               
               
                 &lt;222&gt; LOCATION: (8637)..(8740)  
               
               
                 &lt;221&gt; NAME/KEY: intron  
               
               
                 &lt;222&gt; LOCATION: (8741)..(14409)  
               
               
                 &lt;221&gt; NAME/KEY: exon  
               
               
                 &lt;222&gt; LOCATION: (14410)..(14564)  
               
               
                 &lt;221&gt; NAME/KEY: intron  
               
               
                 &lt;222&gt; LOCATION: (14565)..(15590)  
               
               
                 &lt;221&gt; NAME/KEY: exon  
               
               
                 &lt;222&gt; LOCATION: (15591)..(15762)  
               
               
                 &lt;221&gt; NAME/KEY: intron  
               
               
                 &lt;222&gt; LOCATION: (15763)..(17282)  
               
               
                 &lt;221&gt; NAME/KEY: exon  
               
               
                 &lt;222&gt; LOCATION: (17283)..(17409)  
               
               
                 &lt;221&gt; NAME/KEY: intron  
               
               
                 &lt;222&gt; LOCATION: (17410)..(19178)  
               
               
                 &lt;221&gt; NAME/KEY: exon  
               
               
                 &lt;222&gt; LOCATION: (19179)..(19279)  
               
               
                 &lt;221&gt; NAME/KEY: intron  
               
               
                 &lt;222&gt; LOCATION: (19280)..(20947)  
               
               
                 &lt;221&gt; NAME/KEY: exon  
               
               
                 &lt;222&gt; LOCATION: (20948)..(21162)  
               
               
                 &lt;221&gt; NAME/KEY: intron  
               
               
                 &lt;222&gt; LOCATION: (21163)..(22690)  
               
               
                 &lt;221&gt; NAME/KEY: exon  
               
               
                 &lt;222&gt; LOCATION: (22691)..(22873)  
               
               
                 &lt;221&gt; NAME/KEY: intron  
               
               
                 &lt;222&gt; LOCATION: (22874)..(23934)  
               
               
                 &lt;221&gt; NAME/KEY: exon  
               
               
                 &lt;222&gt; LOCATION: (23935)..(24070)  
               
               
                 &lt;221&gt; NAME/KEY: intron  
               
               
                 &lt;222&gt; LOCATION: (24071)..(24443)  
               
               
                 &lt;221&gt; NAME/KEY: exon  
               
               
                 &lt;222&gt; LOCATION: (24444)..(25871)  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 5  
               
               
                   
               
               
                 gcggcccagg cccggaacct tccctggtcg tgcgccatat gtaaggccag ccgcggcagg     60  
               
               
                   
               
               
                 accaaggcgg cggtgtcagc tcgcgagcct accctccgcg gacggtcttg ggtcgcctgc    120  
               
               
                   
               
               
                 tgcctggctt gcctggtcgg cggcgggtgc cccgcgcgca cgcgcaaagc ccgccgcgtt    180  
               
               
                   
               
               
                 cccagacccc aggccgcgct ctgtgggcct ctgagggcgg catgcgggac tacgacgagg    240  
               
               
                   
               
               
                 tgaccgcctt cctgggcgag tgggggccct tccagcgcct catcttcttc ctgctcagcg    300  
               
               
                   
               
               
                 ccagcatcat ccccaatggc ttcaccggcc tgtcctccgt gttcctgata gcgaccccgg    360  
               
               
                   
               
               
                 agcaccgctg ccgggtgccg gacgccgcga acctgagcag cgcctggcgc aaccacactg    420  
               
               
                   
               
               
                 tcccactgcg gctgcgggac ggccgcgagg tgccccacag ctgccgccgc taccggctcg    480  
               
               
                   
               
               
                 ccaccatcgc caacttctcg gcgctcgggc tggagccggg gcgcgacgtg gacctggggc    540  
               
               
                   
               
               
                 agctggagca ggagagctgt ctggatggct gggagttcag tcaggacgtc tacctgtcca    600  
               
               
                   
               
               
                 ccattgtgac cgaggtgggt gccggcccct gctggggctg agaccagggc tcggaggacc    660  
               
               
                   
               
               
                 tgtcgcggtc cttgaacccg agctcctctc tcccagatgc gcactggacg ctgtcactcc    720  
               
               
                   
               
               
                 ccctccccca acggtcaaca ccctagcgat ggagaccctc cagccaggtg gcttgggaac    780  
               
               
                   
               
               
                 gcttcacgag gtgacctcca gccacagtgt gctcctccct gcacaggtgg tcagtctggc    840  
               
               
                   
               
               
                 ctcccgtcct gatggccact ttgaagaggg taccaggaag gtcctggcgg tccctgggcg    900  
               
               
                   
               
               
                 atgctctatg gccctgtgtg tccaggactt actctagttg gggttggggg tggtaagtag    960  
               
               
                   
               
               
                 cagagccagg acttgggcca ggggctatcc cgtttttcct ctagtctctt gatttctttt   1020  
               
               
                   
               
               
                 tagaagagaa gaaatacttc tctttcctga acttttaaaa gttaaataaa gcatgtgtat   1080  
               
               
                   
               
               
                 acaactgcct cttccctttt tcctctagtt actccttccc ctaccgtcca caacccaaaa   1140  
               
               
                   
               
               
                 acgacaatct ggtcatgccc tgtaagtaat tgtttgcctt ttcccatggt cagttgtcag   1200  
               
               
                   
               
               
                 tctttttttt tttttttttt ttttgagaca gagtctccct ctgtcaccag gctggagcgc   1260  
               
               
                   
               
               
                 agtcgtgtgt tcttggctca ctgcaacctt cgcagtcgtg cgttcttggc tcactgcaat   1320  
               
               
                   
               
               
                 cttcgccttc cgggctcaag tgattctcct gcctcagcct ccgagtagct gtgagccacg   1380  
               
               
                   
               
               
                 acgcccagct aatttttgtg tttttagtag agacggggtt tcaccgtgtt ggccaggatg   1440  
               
               
                   
               
               
                 gtctcgatct cttgacctcg tgatctgcct gcttctgcct gcaaagctgg gattacaacc   1500  
               
               
                   
               
               
                 gtgagccacc acgccaggcc gtcagttgtc actctttaag atccattcat ctgaagatgg   1560  
               
               
                   
               
               
                 gttcagggtg acttgttgac ctggaatatt ttctcaggta ttatgaggca aggctgtcgg   1620  
               
               
                   
               
               
                 ccagatttag ttaaagcata cagccttagg tcatagggtg tgggggagcc tttctcattt   1680  
               
               
                   
               
               
                 ctcatcccct tggattttcc ctctgggtgg ttttgtctgt cccctccgaa cctgttggag   1740  
               
               
                   
               
               
                 cagttgttgg agctggatgt aggaacatga tgttaatgat gtatgtgttt tgtgtctttt   1800  
               
               
                   
               
               
                 ttagacactg gcactctagc tccctgaagt ttcagcagca ttgagtaagt agccagtgag   1860  
               
               
                   
               
               
                 tagccctcat tgatagatag gctcactaaa tgtgcagatg accaattcgc aggttagaga   1920  
               
               
                   
               
               
                 aggcttccca gaagaggagg cctctcagtg agcctagggt gttcagctca gcataatagt   1980  
               
               
                   
               
               
                 gagctgaagg ccccaatgca gcagcaagaa accacccagc aggacggcgg agttcacaga   2040  
               
               
                   
               
               
                 gaggggagag ttcatagaga gggagagtgc cacaggccct ggcacagctt caagccctgc   2100  
               
               
                   
               
               
                 tggatgttgg tgctgagcct cccctcctgg agcctcagag gggcttacag gggctctgga   2160  
               
               
                   
               
               
                 gatcccaact gtgttgcttc ttggcgtcat cacccttcaa tggagtctga gagctaccct   2220  
               
               
                   
               
               
                 gggagatcca agtgtgtgtg catgtgtgtg ttttttcttt ttggaaattt gatgtcccca   2280  
               
               
                   
               
               
                 gcatttggac ctgctttctc cacatatatg tagtgggagt gtgaccggag ccccactggg   2340  
               
               
                   
               
               
                 atttcttagc tagtgacata gcttcagtgt ccagaggcat catggcttga caaaagaggc   2400  
               
               
                   
               
               
                 actccttgga ggtagccaac tgtgctttct ggcccatgaa tccacaggaa attggaactt   2460  
               
               
                   
               
               
                 tcagttgcca caaatcctgg gtcctagcct cacaggtggg tgtgttacct tcccggaagc   2520  
               
               
                   
               
               
                 cagtgagtac tatgaaagca gaggctgtcc ctgaggttgc aggcagaggc cacagagggg   2580  
               
               
                   
               
               
                 aacatgacac aggaatccct acaaattcta cttggggctg cctaaagaag agggaagtag   2640  
               
               
                   
               
               
                 tgaagcaaga agaagcacat ggcatctctt ggagttttac attgacccct gagggttccc   2700  
               
               
                   
               
               
                 cggcttactc tagtcacttg ttcctgcttt gctgcctcca tcccacattg ggctgagtga   2760  
               
               
                   
               
               
                 tggtggcatt gatgagctcc caaaggccag ctgtgccagg gggtctgacc ttatcttgct   2820  
               
               
                   
               
               
                 gccaatgtca gccttttgtt ttttaatatt tagactattt atttagctgt cttagcagtt   2880  
               
               
                   
               
               
                 tcaaaggagt tatgtgccct ttcacctact tatatgttgt cagtctttgc agggaggcca   2940  
               
               
                   
               
               
                 gattaatgct tagatctttg ttttgggcta ctggaatgct tgacttgaag ttcagagctg   3000  
               
               
                   
               
               
                 cttgttccca ggtgaacagc tactgctgga agttgctgca tcaacattct aatggctttt   3060  
               
               
                   
               
               
                 tctatggcct gttgtctttc aacccaaacc tggcctgctg aacactgcat ctagtcccat   3120  
               
               
                   
               
               
                 gcctgctaaa tgtctctaag cctgccctct gccccaaatc atacataaag gtgtttgtaa   3180  
               
               
                   
               
               
                 gtacactggt attgaattac tagtcatatt ttttccactg aagactggaa cctcaggtgt   3240  
               
               
                   
               
               
                 cctgtttgga tttttttaat ttgttcaagt taaagtacat acatgtagta ccaaactttg   3300  
               
               
                   
               
               
                 tggtggattt agatctttgc gtcttcctca atttctgaca caattctgga tgcagaggga   3360  
               
               
                   
               
               
                 ggttctcagg aaaattttta ttgaatgagt taatgaataa tttaagaaat catctctaaa   3420  
               
               
                   
               
               
                 gtttgagaac taaagaaaaa tagttcagtt cttagaaggg aaacttgagg gtggctgaaa   3480  
               
               
                   
               
               
                 aggattgact ggaatttttt aaaggaaatg tgactccccc tgcccactga ctggggcttt   3540  
               
               
                   
               
               
                 gatgccacat ggatgtggaa tgaggtgttg ggattggcag agggaatctg ctagcaatta   3600  
               
               
                   
               
               
                 ataaataaat aaatattggc agggcgtggt ggctcacgcc tgtaatccca gcactttggg   3660  
               
               
                   
               
               
                 aagccaaggc agcaggtcac ttgaggtcgg gagttcaaga ccagtctggc caacatggtg   3720  
               
               
                   
               
               
                 aaactccatc tctactaaaa atacaaaaat tagctgggtg tggtggcaca tgcctgtatt   3780  
               
               
                   
               
               
                 cccagctact tgggagactg aagcaggaga atcgcttgaa cccaggaggc gggctttgca   3840  
               
               
                   
               
               
                 gtgaaccgag atcgagcctc tgcactctag cctgggcgac aaagcgagac tccatctcaa   3900  
               
               
                   
               
               
                 aagaataata ataatattaa taaataaaaa tgatttatga ggtaaaagag ttttatgccc   3960  
               
               
                   
               
               
                 ccatgttcca ggaatagttt ggtggtccac atggttctcg gctggcctct cctctggccc   4020  
               
               
                   
               
               
                 ctcagtcatc cctggggtac tggggaatta gccaacccat catgcagtgc ttcttggcca   4080  
               
               
                   
               
               
                 tggactgccc catctgctgg aaacctgggt tgtttctgag gttgtctggg ctgtccgctc   4140  
               
               
                   
               
               
                 tttggtttca ccatagctct gtccagccta tggacagaca ggttccttga gaaacttccg   4200  
               
               
                   
               
               
                 gctgggtgtg gtggctcatg cctgtaaacc cagcactttg ggaggctgag gcaggtggat   4260  
               
               
                   
               
               
                 cacaaggcag gagttcgaga ccagcctggc caacatggtg aaacctcgtc tccgctaaaa   4320  
               
               
                   
               
               
                 atacaaaaat tagccctgcg tggtggcggg tgcctgtaat cccagctact cgggagggag   4380  
               
               
                   
               
               
                 gctgaggcag gagaatttct tgaacctggg aagtgggggt tgcagtagcc aagatcgcac   4440  
               
               
                   
               
               
                 cattgcatgc cagcctgggt gacaagagca agactccgtc tcaaaaaaaa aaaaagaaaa   4500  
               
               
                   
               
               
                 agaaaagaaa cttccaagct gctctgcatc gccttgctct ccacctgtct gcttctaaga   4560  
               
               
                   
               
               
                 agccctcggc ccagtcctgg gtgggactcc cactccctcc ccattgtcct ggactagctt   4620  
               
               
                   
               
               
                 ttctatcagc cttatcttgt gtagagacag atagtcttag aagatgagag agccctcact   4680  
               
               
                   
               
               
                 gttatcccca aagctgcctg gaggaaaagc cagagcaacc tgggagctgg gaccggggct   4740  
               
               
                   
               
               
                 gactctgggc agcagagacc cgagagacct ggaacttgaa cctcactgtt acgcctttgt   4800  
               
               
                   
               
               
                 tgatttctct cactcagggg acacacagac cctcatccag ccttttgcag ctatatggca   4860  
               
               
                   
               
               
                 aggcagagaa gccacttgcg gggtcccgtg gcccactatg cacgtacata gtagacacat   4920  
               
               
                   
               
               
                 ctggccatga gtggtcagat tgagccactc tctagctagc tgacacctgt catcctgggt   4980  
               
               
                   
               
               
                 caaatttctg acagttgaca caaagcaggg ggtcagggag ccaaaaaaaa aaatggccag   5040  
               
               
                   
               
               
                 gtgtggtggc tcttgcctgt aatcccaggg ctttgggagg ccaaggtggg cagataacct   5100  
               
               
                   
               
               
                 gaggtcagag ttcaagacca gcctggtcaa catggcaaaa ccccgtctct actaaaaata   5160  
               
               
                   
               
               
                 caaaaattag ccaggctggt ggtgcatccc tgtagtccca gccactcagg aggctgaggc   5220  
               
               
                   
               
               
                 atgagaatca cttgaacccg ggaggtggag gttgcagtga gccgagattg tgccactgca   5280  
               
               
                   
               
               
                 ctccagcctg ggagacagag caagactctg tttcaaaaga aaaaaaagag tattctggag   5340  
               
               
                   
               
               
                 attgaagttc aggagttcag ggttcatctc gactttgggc agccaagcaa gaactaaagt   5400  
               
               
                   
               
               
                 ataccaagat gttgaaggtt gatacctttt tatttatcga ttcattcact cacctatgta   5460  
               
               
                   
               
               
                 ccaaagagct cctgagcctc tcttcgatac agggggcact gccaggagtt gtagaggatg   5520  
               
               
                   
               
               
                 tgatagcaaa gataggaaat accttttctc tttgctctga caacggtggg gcaaggattc   5580  
               
               
                   
               
               
                 atcattgatt tcagcaggag gcaggataaa atgtgtgtag gaatatagga atacatggca   5640  
               
               
                   
               
               
                 atcagtaaca tgtggtacct agcagcatgt ctgactgttg atacggtcag gctaggtaca   5700  
               
               
                   
               
               
                 tcccctcagg gaagaacttc tgtcttaggg gcacacaccc tatctttttt cccttcctgc   5760  
               
               
                   
               
               
                 caattcacag gtaagaacat ttagtcccag ggaactatgt catctctcta cttctcataa   5820  
               
               
                   
               
               
                 ctgaaaaagc agtgccaatt atgtatgagg tataggagac acaattctcc ctctttttaa   5880  
               
               
                   
               
               
                 aaatgtttaa tagctttatt aaggtgtaaa tgacataaaa actgcatgta gctaaagcat   5940  
               
               
                   
               
               
                 gcaatttggc acacatgtat ctctacaccc ttgaaaccat caccactaga aaggtgcatt   6000  
               
               
                   
               
               
                 tctccccagg aagaggggca agtctaggcc ctttgccaga gttgctccca gattgttttc   6060  
               
               
                   
               
               
                 aggttgggcc tgcattcaca gctcagccag ctgaagggtg acagcattag actcgtgacc   6120  
               
               
                   
               
               
                 caaatcttaa acccacacat tccattttaa cattgatacc tgtgatcatc agccagtata   6180  
               
               
                   
               
               
                 gcccatccca tgtgccaggc ggaggcatca ataagctggt ctgtagcagc tttaatcaca   6240  
               
               
                   
               
               
                 gctggggagc caggagctaa ggaatgctag actcctttgt aaacaattta agtagggggt   6300  
               
               
                   
               
               
                 acttagcctg gactctatgt gcttctcatc cacctcttct cagggagatt ctggccaagt   6360  
               
               
                   
               
               
                 cctggaacct actgcagtcc atctggtggt tgacagatat gtggacggat tggcaggctg   6420  
               
               
                   
               
               
                 ggacccaatc tatgtttgcc cttgtgttca gttttgagac ctagcacctt tcctgatcct   6480  
               
               
                   
               
               
                 gctcacagac cccctgcggc caataggaaa gaagtgttaa tgcatatttg cttttggagg   6540  
               
               
                   
               
               
                 gcccaaagcc aggcccagag agttgtcaag ggcggtcagt ggtgggtgga tggcagagtt   6600  
               
               
                   
               
               
                 aaccaaggag ttacacacct gcctagacta aggacaggct ggaccaagta gagagggtgg   6660  
               
               
                   
               
               
                 ggctaaggga gcctgagaga tgctctgggg cctgtctcaa aatgagcact atagtcaccc   6720  
               
               
                   
               
               
                 tgtcccctgc agagattgtc tgacctggtt ttaggtcaca cccaaccttg ccagccaagg   6780  
               
               
                   
               
               
                 agtctttaga agcctgatat tgggagacct gtcctggggt ctacaacccc agaactcact   6840  
               
               
                   
               
               
                 gcagaagccc acgtggattg ctagtctagc tcagccatat gggtccccaa ccctcacctc   6900  
               
               
                   
               
               
                 atgatagtcc tgtgagaaac cgctgctgac cctttgttca tgttttcatc ttttccacta   6960  
               
               
                   
               
               
                 taaaagacat gctagctggg aaatagagcc catcatactc aagagtggca ggagccaggt   7020  
               
               
                   
               
               
                 cctggcccct gaagcttggc ctcacacaca gaggccggca ccctgtcatc aattccctca   7080  
               
               
                   
               
               
                 gctttttctc cgcctccact cccagtccta gatttagcag ccatgtgtgg gtgggggcca   7140  
               
               
                   
               
               
                 ctgcagggat acttacccac ctaccagaga gatggcctgt gggtgctggc ccttctgagg   7200  
               
               
                   
               
               
                 ctgtggaggt tggaggctgt ggcagcctgg gcagtcaggc tgtggtcctc ccatgttctt   7260  
               
               
                   
               
               
                 gactcctgct agtctgggct gcctcctgat taggggttgg atgctccagt tcttccctgg   7320  
               
               
                   
               
               
                 gttggggatt gccaccctac tcccagccca tccaggttca cgcttattcc aaagcggagc   7380  
               
               
                   
               
               
                 accagcagtg tgcctgctgc gggagttctc cgtgtccagc ctgagggttg cctgccaacc   7440  
               
               
                   
               
               
                 cctctgagag gtgcccggag gctgtgcgcc cacactgccc agcagtgcgg agaagcaggc   7500  
               
               
                   
               
               
                 ttgtttttcc ctgtcactgg cttggaagag atgctttgtt ctagggagcc gcatgtcccc   7560  
               
               
                   
               
               
                 ttgcctgcgt tgttggtgag gagccagcag gctccgtgga gggcaggcta gcagcctggc   7620  
               
               
                   
               
               
                 accagggagg caagggtctg agttcctagg agggtggttg ctcatgtgag aagtctgcaa   7680  
               
               
                   
               
               
                 aggttactac tgagcaccat ctctctgtct gaaaaacatt tttcattttt ctgtgaacca   7740  
               
               
                   
               
               
                 ctaagtttcc cgtttgggct ttcttcctgc ttttggctct tgtttaggca ggcgtagcca   7800  
               
               
                   
               
               
                 gatccaagcg tctggctgct tccccatgtc ttcagacctc tttttctgtt catggtaact   7860  
               
               
                   
               
               
                 atagatggaa ccacacattg gaagctggaa actcaagcgg tgcagcctat tccttacccc   7920  
               
               
                   
               
               
                 aatccctgtt ttacaaatgg ggaaatcaag gcacagcatg gggtgatgct tatctgaggt   7980  
               
               
                   
               
               
                 tggaagagtt aatagtagag tgggagctaa aacccagttt cttacctcca agctcagggc   8040  
               
               
                   
               
               
                 tttcagctgt aattgagcct agtatagttg gtgtgcagca tcagggattc cagctctaaa   8100  
               
               
                   
               
               
                 ggtcacaaaa aggacccggg ggtcattggc ccagggtggg aacctgagca gagcaggtcc   8160  
               
               
                   
               
               
                 agatggtgca ctctgtgccc tggccttagt ttcttgctgg atgctttggc ccgtagagcc   8220  
               
               
                   
               
               
                 ccagagccct gcttccagaa ccactccagt gacgttcatg ccaatggcct gaaccccact   8280  
               
               
                   
               
               
                 gagcgagggt gccctgcctc ttccacagcc ctgggctccg ctcagatttt taggagcaag   8340  
               
               
                   
               
               
                 cgttagaggc cttgctttct ccagggtcag catgtggaca gaacacttac tctctgcctg   8400  
               
               
                   
               
               
                 tctctcctcc tcaaaatgga agcaagacag tggggcctac aatgctatga aaaacaggat   8460  
               
               
                   
               
               
                 gggaaagaag cctgctctct gccttcctgc ccaggtgagc catcacctga ctaagtgagt   8520  
               
               
                   
               
               
                 tcacactcag agcgtgtggg gatggcagga tgttctgact tcattttcca ggatgccttt   8580  
               
               
                   
               
               
                 gctttaaaac cttttaaaaa gaagtgaatg atacaccccc tttgctcatc ttgcagtgga   8640  
               
               
                   
               
               
                 acctggtgtg tgaggacgac tggaaggccc cactcacaat ctccttgttc ttcgtgggtg   8700  
               
               
                   
               
               
                 tgctgttggg ctccttcatt tcagggcagc tgtcagacag gtaaggtgtc tgtcttctgg   8760  
               
               
                   
               
               
                 agcaccaggg gacctcagca ctgaggaaga agcgtgtgcc tggcccttga tttcagttgg   8820  
               
               
                   
               
               
                 tagtattctt tcagcgcagg gccctgtatt ttaaagaaga ggaagctatg tctgtgatat   8880  
               
               
                   
               
               
                 agactccatg cctagtaaga agagccaaca aatcatctga ctccgtaatt cttgctaagt   8940  
               
               
                   
               
               
                 aaagaaacct gagctgtcta agctgaatgt atctgtgatc cggttgacta ggtaatatgc   9000  
               
               
                   
               
               
                 catgattcac ttctgcagta gcctggcttg cctcccctgg gtcactgtga ctctgtcatg   9060  
               
               
                   
               
               
                 cccctgagca tgggagaggt tgacatcatg cacacatgca catgtgctag attgtagatc   9120  
               
               
                   
               
               
                 tgtagtagtg ccacggtgtc tgcctctgta gtcccaagaa gaccagcatt ctctctgcaa   9180  
               
               
                   
               
               
                 agtgaaagga gctctcacca gccactagtg gtatgaaaag cagaactctt ttgtccacaa   9240  
               
               
                   
               
               
                 ggctgatgcc ccttagctaa gtggcctgtg gttttggcat ttactttatg acaggaggga   9300  
               
               
                   
               
               
                 gaatagtgtt ttgatccatt tcttataagc aggttatttg tataattcta aagcttttaa   9360  
               
               
                   
               
               
                 ctcaaggaaa cattaacggc ttagagaatc ccaaacccct cgaaattata tgcacaatgt   9420  
               
               
                   
               
               
                 tagagactac atgtgagcat ttttttggag agaggtccgt agctttcatg aagttcttag   9480  
               
               
                   
               
               
                 aggggtccat tatgttgtgt cttctttccc tggagcttca gggtctgtca gagaagactg   9540  
               
               
                   
               
               
                 tgaagagagt agcagccttc agcaagtcct tggccacatg gcacatgtga gaacacccca   9600  
               
               
                   
               
               
                 caaatcggtg ggttagccgg tggaaaggag tcccagcatc ttccctggtt tttaattcct   9660  
               
               
                   
               
               
                 ggcctcaagc aatcctccct ccataacctc ccaaagtgct gggattacag gcgtgagaca   9720  
               
               
                   
               
               
                 ccatgcgcag ccagatattt tttattgttg ttgttttttt ttggaaaagg agtttcactc   9780  
               
               
                   
               
               
                 ttgttaccca ggctggagtg caatggcacg atctcggctc actgcaacct ctgcctccca   9840  
               
               
                   
               
               
                 ggttcaagag attctcctgt ctcagcctcc tgagttgctg ggattacagg catgcaccac   9900  
               
               
                   
               
               
                 catgcccagc taattttgta tttttaatag agacaaggtt tctccatgtt ggtcaggctg   9960  
               
               
                   
               
               
                 gtctcaaact cccgacctca ggtgatccac ccacctcggc ctcccaaagt gctgggatta  10020  
               
               
                   
               
               
                 caggcgcgag ccactgcacc tgcccagcca gatttttttt taaaaagcag gttaacctgt  10080  
               
               
                   
               
               
                 ttattattcc tactttacag atggagaaag tgagacagag ggattaaata acttccccaa  10140  
               
               
                   
               
               
                 ggtttcacag ctggcaagtg gcagagttag gatttggacc caggtagtct tgctcctcta  10200  
               
               
                   
               
               
                 ttgtgtatgg actactgttc taggtccctg ctgtcctaaa acttgctttc tagcaaggtg  10260  
               
               
                   
               
               
                 gaatgtatta aacaaccaag tgaggaagtc gttgttgtcc ttggccatgg taagagatac  10320  
               
               
                   
               
               
                 agagaagtgc agggtgccac aggagtgtct aacagaggag gtcaggggca gcatccctga  10380  
               
               
                   
               
               
                 gaaggtgaag catgagcgag agtgggaaga tgagtcgaaa gtagccagct gaggggtaga  10440  
               
               
                   
               
               
                 gaggagaaag aacatccagg cagggagaat agcaagtgct aaagccgggg ctcatgaaaa  10500  
               
               
                   
               
               
                 ggcatgggag caggacaaag tccgtgtggt agaggtgcgg agagtggtgt taagatgaag  10560  
               
               
                   
               
               
                 gggagaggca ggcagagccc tgggcagatg agcaaccagg gcttagtgga tcacagttag  10620  
               
               
                   
               
               
                 gactttgggc ttcagccaca gagcagcggt gggctactga gattttttaa agcaatagtg  10680  
               
               
                   
               
               
                 tgacaatcag atttgtcctt tttttttttt taaagatgct ttgacaacct tgtgaagaaa  10740  
               
               
                   
               
               
                 gaattgaagg gaagcaaaag gtgttgtaga gagaccaatt aaaaggttgt cacagtagtt  10800  
               
               
                   
               
               
                 catgccagag atgatggtgg catggcctag catgacggtg gtagaaatgg agggaagtgg  10860  
               
               
                   
               
               
                 taagaggtaa aatcaacaag acttgccgat gggctggatg tcggaattgg gggaagaaag  10920  
               
               
                   
               
               
                 ctttctggcc tgagtaactg ggtgaatgaa ggtacacttc tctaagacag agaatgctgg  10980  
               
               
                   
               
               
                 aaaagaacca cgttcatgga tattgagttc aatttgtgtg tactaaattt ggggtgacta  11040  
               
               
                   
               
               
                 tgagacccct aagtggagaa gtagagtgtg aagctggctg tatggatatg gtactgcatg  11100  
               
               
                   
               
               
                 agaggttttg gctagagaaa cacatgtagg atttgtcagc atatagaacc ctcagcagag  11160  
               
               
                   
               
               
                 ccccagatag ggatgaggtt gcctggggag aggggagtgg ggaggggagg ggggaactgg  11220  
               
               
                   
               
               
                 gggaggattg tgctatgctt agaggccacc tgagtggaca tgggagattc cttctcacgg  11280  
               
               
                   
               
               
                 agctaagtga cagctgcggc tcagaagaat gcccttgatg tgaaaaggag ataccccaag  11340  
               
               
                   
               
               
                 ttcagagtag aaatgcagtg tatttttctg ggtcagctgt gtcatgggtc agcttaagaa  11400  
               
               
                   
               
               
                 ccttcttgcc atgtgacaca atgattacct gaggaaagca tttaagttcc aaaaggtcta  11460  
               
               
                   
               
               
                 ttcccaggga aagtggaaac aaaatttgtg agtgtgttta ggaccacttt agtctacaga  11520  
               
               
                   
               
               
                 agggctaata tagtgttttt caaacctttc taaacatttt ggccacagaa ctttcattaa  11580  
               
               
                   
               
               
                 agtaggataa tttaagtcta gtaaatgaaa tacaccctaa gtggctaaaa gtatggctgt  11640  
               
               
                   
               
               
                 tctgcctgca gcccctgcct tcaattccca atgccctgcc tcaagcctgt ctgtgccccc  11700  
               
               
                   
               
               
                 ttggaaggcc cagggccctg tgggatggac agcttctgag tgcattactt ctgagtaaac  11760  
               
               
                   
               
               
                 cagttctaaa acctaagcta agtagattac ctgaaagcaa tcaattcatg ccctaacttg  11820  
               
               
                   
               
               
                 tctaggacat caatgtaact ttttatatag tataaaggtt tcaccttctt tctggcctat  11880  
               
               
                   
               
               
                 gaatatgtct gaaattcaag agcaattaaa gtactcctgg gttgtcaaag ccctttatgt  11940  
               
               
                   
               
               
                 aacactattg agttatcttt atgcgtctga cttgtaagag atgcacaact ctaggaagaa  12000  
               
               
                   
               
               
                 gtagactgct gtgtcctgtt tccaggtatg tgtgtgtttg ccattttgtt gacagacttt  12060  
               
               
                   
               
               
                 aaaagcaaac atttctggcc ccaaccctga actgccaagg actggtgcta tgtaaagggt  12120  
               
               
                   
               
               
                 tctctggatc tgtctcttcc ctaccatccc agggagctct taggaaggga aagggcatag  12180  
               
               
                   
               
               
                 agattatacc agcctgcctt gtggttagga accacccctt ggttggcata tagaacatgc  12240  
               
               
                   
               
               
                 ttgttaaaaa aaccatgcag gggaaagtag agtctactac caggcgagag tttctcaacc  12300  
               
               
                   
               
               
                 tcgaccctat taacattttg agccaaataa ttttgttcta gggcattttc ctgggcattt  12360  
               
               
                   
               
               
                 tagaatattt aacaacatat ctggcctcta ctcattagat gccagtgaac cccaagtgat  12420  
               
               
                   
               
               
                 ggaaaaaaaa aacaacaaca gaaaaaaacc tcttttattg aggaaaaaca ccaaactctt  12480  
               
               
                   
               
               
                 ccacatagtt gcaagacctt gtgcaatttg cctcctagcc accactgtac tcttgaattg  12540  
               
               
                   
               
               
                 cacgcctgat gccaaccaca ctggttcctc atgttcacca tgccccctcc agccatgggg  12600  
               
               
                   
               
               
                 gtgtgtggtc ttctcagagt ctgaagcatt ccccacccac cccaacccac cccctgtggc  12660  
               
               
                   
               
               
                 cttctttaac catgctggct aattcaggat ccctagttcc ttatgacttt cctttaaaac  12720  
               
               
                   
               
               
                 gtctaccaga aattggggga aaaaaagtgt tattatagga ttaatgttgg tcttccccac  12780  
               
               
                   
               
               
                 tatactgtga atatcattga gagcttggtc cctacacctt aaatccccca tcgtcaacta  12840  
               
               
                   
               
               
                 ttttttccca tctcagtgtc ccatgatcaa ggagaccctc cctgaatgtc cagttcccca  12900  
               
               
                   
               
               
                 acccttaccc ccagtccagg gtagcttcct tccttgtgcc tctcattaac ctgcatgccg  12960  
               
               
                   
               
               
                 atccttcagt gcacttgact cagtgtgtaa ttgtatattc agtagcgtgt tgttagatta  13020  
               
               
                   
               
               
                 aaatgtggtt aatatgtgtt tcaccagtta tactatgaca ctccttaagg gcagaaacag  13080  
               
               
                   
               
               
                 catctttttt aatttattga tatccaagtg ccctctataa tagatgctca ataaacattg  13140  
               
               
                   
               
               
                 aatgaaagtg ggtgtcagcc agtactggcc agactcaaac tgaacccact gcttcccact  13200  
               
               
                   
               
               
                 agcttgactt tttcctcctg tttgtggcac tctctttaaa acaaaccaaa ataaacccaa  13260  
               
               
                   
               
               
                 ttttaaaaac tttttaaaat gagcacggat acagaaaacc acacagaaca aatgtgtagc  13320  
               
               
                   
               
               
                 ttaatgaatt tttttcagag aaataacctt atgaccacca ccaagtcgag cagtagaact  13380  
               
               
                   
               
               
                 ttgctgtcca ctaagaagcc ctgtccatgt gccccatccc aattacagca tcctctctct  13440  
               
               
                   
               
               
                 ctccccatta agtaaccgct agcctgactc ctgtaataat cacttccttg tgagtttttt  13500  
               
               
                   
               
               
                 tagttttatt atcgaaatat gcatccttga cacaaattta gtgttgccca cttaatatat  13560  
               
               
                   
               
               
                 ttgatgtctt ttagtctact taatctatgg attctccttc tatcgccttc tatgccttac  13620  
               
               
                   
               
               
                 tgattatcta tgaagaacct gagctattcc acctatagaa tttcccagtc tggatttgtt  13680  
               
               
                   
               
               
                 gattgcacac tgatgatgca gttcagcaca ttcctctatg ctctgcattt cctcaaaatt  13740  
               
               
                   
               
               
                 ggcagttgga tccagagact tgagattcag gttctgattc aggttcagtc cttttggcaa  13800  
               
               
                   
               
               
                 gaccatagga agcatgcaat tcctgactgt ctctttatga tgttaacagt aattagtata  13860  
               
               
                   
               
               
                 taatgcatag atctattaat ccattggggg ctataaatgg tattattcta attttattac  13920  
               
               
                   
               
               
                 cttttcattt aaaagttaga atacttttgt acatgatact acctcttatc tattattggt  13980  
               
               
                   
               
               
                 tgctgttcac atagtttaca aaggaaaatc aggacaaatg cttctttctc tttatttgcc  14040  
               
               
                   
               
               
                 agttttcatt tataatgaat tgtttctctg ttattctcca aatttggcag attctttttt  14100  
               
               
                   
               
               
                 aaaaaaaata tcattatgaa tgtatggatt aaataattga tgtatttcag tctcttgcaa  14160  
               
               
                   
               
               
                 tcattatcat aattgtagca ttgcttttta ggcaaccctg gtacccaggc tgtacatttg  14220  
               
               
                   
               
               
                 tcatggggag tggggagggg gagaaatagc atgggcactg tgagaccgag actgtccctg  14280  
               
               
                   
               
               
                 gcagccagta ttctggcaac actgttcaca cccacttact ggatggatct tgagaaagcc  14340  
               
               
                   
               
               
                 ccacttggtg gagcccattc ctgctgccct tttccagctg gttatctgtc actctccttt  14400  
               
               
                   
               
               
                 tcttcccagg tttggccgga agaatgtgct gttcgtgacc atgggcatgc agacaggctt  14460  
               
               
                   
               
               
                 cagcttcctg cagatcttct cgaagaattt tgagatgttt gtcgtgctgt ttgtccttgt  14520  
               
               
                   
               
               
                 aggcatgggc cagatctcca actatgtggc agcatttgtc ctgggtatgg ccatcaggtt  14580  
               
               
                   
               
               
                 ggagttgagt acttgatcct gtatttcacc atcatcccat cacctacctt tctggagaca  14640  
               
               
                   
               
               
                 gctgtgatgt ccctcaaggg ggacagggtt tctaacaaaa ctagccagag cttcctggtg  14700  
               
               
                   
               
               
                 aaccttactt acaggcaggg aaactgagcc agacatgaga ccagcctggg gtccccagca  14760  
               
               
                   
               
               
                 gcacaatggc ctgacttctg atttccagtt cttttctggc ctctgggctg tggctccttg  14820  
               
               
                   
               
               
                 gtcttagtac ttggtagtca atttactagg actcaccaga gatcctccat ttacaaaaag  14880  
               
               
                   
               
               
                 ggcctgccac tgcacagggc tgagccagcc ccagaaagag ggcggcatgg ttggaggagg  14940  
               
               
                   
               
               
                 aggggctgtg actggcaagc ttgctaaggt agagaacccc ttgtctgcag agcactgtgg  15000  
               
               
                   
               
               
                 ctggtgatat ctacggacaa gaataaattg ataggaaggg gctttcgtca ccttcagggt  15060  
               
               
                   
               
               
                 tttaattcag agtgcacact gcagggcttt gtctcaaatg tgccagcctg ttgtcactga  15120  
               
               
                   
               
               
                 gaagctgcca ggccggcctg tgtttggagg aacctgactc tagctgataa ggcctttgag  15180  
               
               
                   
               
               
                 ttccttgggt tgtattgttg aaagggttgt tttttctttt tatatttaat attctttcct  15240  
               
               
                   
               
               
                 tgaggcttaa gtcagcatgt gctgacttag taatgacttc acttttaata aattcttcct  15300  
               
               
                   
               
               
                 catgtgagga ttaaaggggg cctaccatgg catctttagc acatggcttc agaacatggc  15360  
               
               
                   
               
               
                 gaaattttca agagagaact gttgcttggg ggcctgagag gccacaggga tgtaccccca  15420  
               
               
                   
               
               
                 ggagacagtc agacaggagg ggttcagaac gccatccgct ccctagcgcc atgaacttag  15480  
               
               
                   
               
               
                 agagagttct cgctgttttc ttgtctgtgt attcacaaag ataccataaa aaattaataa  15540  
               
               
                   
               
               
                 ggaaggaacc caaattaaac tgctaactcg acctcccttg ttttgaacag ggacagaaat  15600  
               
               
                   
               
               
                 tcttggcaag tcagttcgta taatattctc tacgttagga gtgtgcatat tttatgcatt  15660  
               
               
                   
               
               
                 tggctacatg gtgctgccac tgtttgctta cttcatccga gactggcgga tgctgctggt  15720  
               
               
                   
               
               
                 ggcgctgacg atgccggggg tgctgtgcgt ggcactctgg tggtgagtgt gaccctgtgc  15780  
               
               
                   
               
               
                 cccatgtgcc cactggcagg atgatttctg tctggccttc actagagggc agcaacaacc  15840  
               
               
                   
               
               
                 catgaatccc tattttgtct cccagagaca ggaagcatag attataaatt atttcagaat  15900  
               
               
                   
               
               
                 gttttctcca cactcaaaag agccaaaaca aaacagaatc ccatgacagc aacagacttg  15960  
               
               
                   
               
               
                 ctctcagccc tgtgctgggt tgccccaagt gtggggaaaa atagcagtag ctgtgagaag  16020  
               
               
                   
               
               
                 atggggtcca gcatgccctg taggaagttc ccaagcctca gggcaggaca gtgtaggccc  16080  
               
               
                   
               
               
                 tagttctggc tgtgtgctgc tgaagcctca tgccacaggc actggcacca aaagcaagag  16140  
               
               
                   
               
               
                 tcctcagggt agccacatgg aggaagccag gctccttctg caccaccaag gtagaggagt  16200  
               
               
                   
               
               
                 tgaacaggca gagaagaggc cattccagac caagagggga acactgcaga ggtgctaagg  16260  
               
               
                   
               
               
                 tgggaatcac cccttgcagg tggagaaggt gagatcacca gcccaagtgg agcagagagc  16320  
               
               
                   
               
               
                 atttcagggc atagtgggag agtaagccgc acatcatggg gcccagtcat gaccgagggt  16380  
               
               
                   
               
               
                 ggggggcggc tacctggtcc cagcaaggtg gaaaataata tccatagagc actcaagtgc  16440  
               
               
                   
               
               
                 cttgataaac atgctaattt ttttcctttt tttcttttct ttttcttttt ttttcttttt  16500  
               
               
                   
               
               
                 tttttctcag acaaagtctc tgttgcccag gctgtagtgc agtggcgtga tttccactta  16560  
               
               
                   
               
               
                 ctgcaacctc cgcctcccca gttcaagcga ttctcatgtc tcagcctccc gagtagctgg  16620  
               
               
                   
               
               
                 gactacaggt gcctgccacc gcacttggct aatttttttt gtatttcttt ggagagacgg  16680  
               
               
                   
               
               
                 gtttcactgc gttggccagg ctggtctgga actcctagcc tcaaatgatc caccggcctt  16740  
               
               
                   
               
               
                 ggcctcctaa agtgctggga ttataggagt gaaccactgc acctggccaa acatgctatt  16800  
               
               
                   
               
               
                 ttaggtagag tatctgacta atctgttgga taaatcaggg gtagggtgag gagagaagag  16860  
               
               
                   
               
               
                 aagctaaaag gccagtgcag aagcttctgt tggtgccggg gacagggagg agagtgtagc  16920  
               
               
                   
               
               
                 agggcctggg ctgacataga catgcacaga agccaggctt ccggagccca tcttgcaccc  16980  
               
               
                   
               
               
                 atctcctcag cccagcagat ggcaacactg ctcttcagaa atggaggtgg ccagccagca  17040  
               
               
                   
               
               
                 tggggatgcc gtcagggggt gcagggctct cccatttttg tgcggtgtgg ggtacacata  17100  
               
               
                   
               
               
                 agctcatcca ccccaggtta ttgctgcgtg tggatcagct ctttgcttct ggcttgtgat  17160  
               
               
                   
               
               
                 caccaaacat tccacaagct ctggttctgc aaccttattc ccacctatgg ctgtgctcta  17220  
               
               
                   
               
               
                 cctggtctgt gggtctgctg ttggcaggga ggcctcactg agattggacc ttgtactgcc  17280  
               
               
                   
               
               
                 aggttcatcc ctgagtcccc ccgatggctc atctctcagg gacgatttga agaggcagag  17340  
               
               
                   
               
               
                 gtgatcatcc gcaaggctgc caaagccaat gggattgttg tgccttccac tatctttgac  17400  
               
               
                   
               
               
                 ccgagtgagg taagcaccat gtgggtgtgg gtgagaggga cagactgacc gtgatttgag  17460  
               
               
                   
               
               
                 agcagcagca cccagccctg aagtcctccc tgctcacagc agcccagccc tctctctgcc  17520  
               
               
                   
               
               
                 caagccccaa ctgcccattc cccccatccc cccactcccc acccccacac gggccctgtt  17580  
               
               
                   
               
               
                 aacactcaga agttgaggaa taggttacag ctgcctcact cttttcacca cgggtttcag  17640  
               
               
                   
               
               
                 attttcattt tttacttcct ttctaggcaa tcatatattt taaccattac ttctaacaat  17700  
               
               
                   
               
               
                 aaatactctt tttgagtaat aggcctttca taaagtcagc atttgggaaa atcattgttt  17760  
               
               
                   
               
               
                 cttataccta aggtggcttg tcaccttaca aagctaaccc caaacgtaaa atgtaaagca  17820  
               
               
                   
               
               
                 caaatagatt tggagttaga agtatttcat ctcttgagta ttagcaatta ttcattaaaa  17880  
               
               
                   
               
               
                 agaaaaaaaa agtgtttagt ctctttctgc cctccaatgg ttaattattg catatcatct  17940  
               
               
                   
               
               
                 tggagtcagg tcctttttga tgtccacctc ttccccctac cccacccctc ccgtcagccc  18000  
               
               
                   
               
               
                 tgttctcaca caccatgact catttcttgg ctctacctag ttcctggttc ttgcttttcc  18060  
               
               
                   
               
               
                 ttcccgttcc ctctcctacc atctctgtag caggcagttt tccttggtct cgtgactatg  18120  
               
               
                   
               
               
                 agaggttaga agctgtaaat gctgcctggt ggggttctgg aatgtgtctg tggtctgact  18180  
               
               
                   
               
               
                 ggaagatgag gggttgggtg tgggaacagc cacaagcagc cctgctgaag tgtgagaggc  18240  
               
               
                   
               
               
                 aggcatggtt gggcttggaa aagagggaac agttattgta gacagcggag gccaatggcc  18300  
               
               
                   
               
               
                 actgccagcc ctgcagactt cccagtgagt ggtggcccag cagccactgt cagcatgcac  18360  
               
               
                   
               
               
                 cagaaagggg tcctgtgcgc aaaggtcagg caggagtgtg gcagagggct tttaagttag  18420  
               
               
                   
               
               
                 gtggttttgg gggcttttaa gtgaggggtc aatctgggtg aatgcataag ccccactggc  18480  
               
               
                   
               
               
                 atctttgagg aaatgaggct atttcagggg atactttcag tccaaagttg accttttgtt  18540  
               
               
                   
               
               
                 gaacttctaa ctctggaaaa acaagctcca aacctgggtt tgcttaagaa agcaacatca  18600  
               
               
                   
               
               
                 gtgtgtttag acgtgtggtt tattaatggc cttggctgtg ctgaatttca taggaagtca  18660  
               
               
                   
               
               
                 ctctgggtga agctcaggtc aattttcctg tttttctatt tgaattcttt ttccctggaa  18720  
               
               
                   
               
               
                 gcacaccagt aactacatag tataaggact caaaacatta acttttaaaa aatatcagac  18780  
               
               
                   
               
               
                 caataaacca cacagccagg tactctctct gacccagagg gcagggagcc aggcttcggg  18840  
               
               
                   
               
               
                 aggaatactt agaggcctcc ttggaatgtg gccaccgaca ggaatatgtg ggggtgcagt  18900  
               
               
                   
               
               
                 gaggaagctg tcagcctggg cctctgtctt cctgtaccct tgagggactg gtcacttact  18960  
               
               
                   
               
               
                 tttcctcatt ttcattcact ctgatttgtt actgacaagg cctagggaag ttttcacagc  19020  
               
               
                   
               
               
                 ctaaaacaca gtcagtatac ttactgttct tagaaacgta acactccccg acgctgagat  19080  
               
               
                   
               
               
                 gcagacagct aagatgccag ggattcaagt atgttattgt gtgctctgag tctctgacca  19140  
               
               
                   
               
               
                 cctcttcttc ccatacactt atgatgttgt tcctgcagtt acaagaccta agttccaaga  19200  
               
               
                   
               
               
                 agcagcagtc ccacaacatt ctggatctgc ttcgaacctg gaatatccgg atggtcacca  19260  
               
               
                   
               
               
                 tcatgtccat aatgctgtgg tatgtaaaag agacctgcct gaggcttcca gacaaagctt  19320  
               
               
                   
               
               
                 cttgaagtgg ccattgggcc tcttgtttac agacatgcct cagacaaaat tcaaagccta  19380  
               
               
                   
               
               
                 tgtcatcaga gagtgaaaag gatatgtctt gtgttagatg gaaaaaatgg gcatgtcaca  19440  
               
               
                   
               
               
                 attcttaatg ggatggaacc tcagaaaagg agaatgaaaa caattgtgga ggctgttgtg  19500  
               
               
                   
               
               
                 ggaaatatgg actctcgtgg ggaatctctc cagatcttaa gatgaatcct tgcccaattt  19560  
               
               
                   
               
               
                 gggtcattta gttcccgtct cctacccagt taccgacagt ggctgaggag gccaggtagg  19620  
               
               
                   
               
               
                 gcttttaaga aggatctgag tgaagacacc atgtcctgta ggctgcagag gctgccagtt  19680  
               
               
                   
               
               
                 actttctgga aatgtggaag tgggatgtgc tcctcctggg atgtccataa acggtcctgg  19740  
               
               
                   
               
               
                 agtcagggct atagcctaga tgtccttacc aggttcccac taatgaggca aagtatgtca  19800  
               
               
                   
               
               
                 gaaagggatt tgtgaattac cagggagagg aaacatgtcc aagtgcacat cgctagcttt  19860  
               
               
                   
               
               
                 tgctcagcgg ccgaaccctg ggattctagg cgacttctgg agcctggtgg gttagcggtg  19920  
               
               
                   
               
               
                 agaagatggg cgaggagggc ggacttcatc tcagagtcct tattactagt ctcatccagc  19980  
               
               
                   
               
               
                 tttgaggcag tcagccactg tgcctactga gggagtgcta tgagtcaccc gcttccaagg  20040  
               
               
                   
               
               
                 aatggcccag gatccctcca ggcagttcac cattccctga gttggcctca agacaggagc  20100  
               
               
                   
               
               
                 agcatgtagc ctgcaccaca gacatgcaag cctgtgatga gtcacccact tttgtgttca  20160  
               
               
                   
               
               
                 cccaggctct cctccctgct ctggatttcc tggggactca tgcacatact ctttttattg  20220  
               
               
                   
               
               
                 taccagctgt gtgttccacc tgcagatgag tcaaaacagt ctaatccata aaggtctggt  20280  
               
               
                   
               
               
                 ttgtcaaaga gtgtgggtca tcaacagaga gaatgcctac tggggatgcc caggtcaggg  20340  
               
               
                   
               
               
                 gtactgcagg gcatcctgat gagaggcagt gtggcccctc cattgggagc cacctctctg  20400  
               
               
                   
               
               
                 ctccacaagt accgcggggc tggtgtcagc tgtctctgac cagcctcttc ctgactggtc  20460  
               
               
                   
               
               
                 accacaggta gtgtgtgagg gtctctctcc aagtgtttga cctaatgttg ttccttttgt  20520  
               
               
                   
               
               
                 tatcttatcc cccaaatcct atcacacctc acttgatgtc tgcctcctga ctcattctct  20580  
               
               
                   
               
               
                 agctccttct gcagttgctg gatttgagga ggttcagctt aggattttta aagctgaaag  20640  
               
               
                   
               
               
                 gcaggttgga atttttcttt tcaatgaagt aaatctatct gaattataca agcttttttg  20700  
               
               
                   
               
               
                 ctgggacact gtctatatgg aaggctctga gagcgcactg gcgcagggtt tacactgtac  20760  
               
               
                   
               
               
                 cacttgggct ggggaaaatt atcttttgat ctatgaagta agacgcaggg ttacagttac  20820  
               
               
                   
               
               
                 tgctgcctta ctagtctctg cttaaagatg gtttggaatt tactgaaata attgcattgt  20880  
               
               
                   
               
               
                 aaaagttgta caggttggga aagatgtgga tactgctttt ccagctttct tctgcactct  20940  
               
               
                   
               
               
                 gtttcaggat gaccatatca gtgggctatt ttgggctttc gcttgatact cctaacttgc  21000  
               
               
                   
               
               
                 atggggacat ctttgtgaac tgcttccttt cagcgatggt tgaagtccca gcatatgtgt  21060  
               
               
                   
               
               
                 tggcctggct gctgctgcaa tatttgcccc ggcgctattc catggccact gccctcttcc  21120  
               
               
                   
               
               
                 tgggtggcag tgtccttctc ttcatgcagc tggtaccccc aggtagggac catgtgcatc  21180  
               
               
                   
               
               
                 tatggtttgg ggtcttcact gagtctctta ctgtctacca ggctgtctca attaataaag  21240  
               
               
                   
               
               
                 agaataaaat caagcccatc acagctccct tgcttatata cattcttggc ctaaaaatca  21300  
               
               
                   
               
               
                 atagaaagtg tcttctgaga ctagaacact tatggcctgg gctttgaggg agtgggaaaa  21360  
               
               
                   
               
               
                 agcagccatt ggggctgttg gttaatttta ctctgtaccc aagttaatgt gctcatactg  21420  
               
               
                   
               
               
                 ttttccactg cagaagaaga gggaagaaat agctatccca ttcctttttt tcctggccct  21480  
               
               
                   
               
               
                 gtcttcttta tttattcaac aaatagctat ggcatgccta ccatgggctg ggcactgtgc  21540  
               
               
                   
               
               
                 tcggtgataa cgatacacaa gaaaacaagc caggcagaac cccaggccct catggaacgt  21600  
               
               
                   
               
               
                 acaccctaga tgagaagaca gacaacaaac aagtaaataa aatgcttaat atagttcaga  21660  
               
               
                   
               
               
                 ctgtgttacc ttctaggaat acaaatgaag gacaatgccg agttagttta catagtcaca  21720  
               
               
                   
               
               
                 gatagtgtcc ctgaacaggg ggcagttcag tagaaatgta cataaagtga cagaaagccc  21780  
               
               
                   
               
               
                 tgaaaaagtc taggagaaca ttttaggaag aagaaatggc aaaggcagcg accctgagca  21840  
               
               
                   
               
               
                 ggggatgagc ctggcatgtt tgaggaggag ggagaagggg aggggccaga ccactgagag  21900  
               
               
                   
               
               
                 ggcctcacag acccttagca ggattttatt tctgaaacta tcttagtatc ccacagatgg  21960  
               
               
                   
               
               
                 gtgggaggta gccatttcca ataatttata gaacagttca tgggccctca tctctccctc  22020  
               
               
                   
               
               
                 tccatcactg tgcccagaga cttcagtgta cctgtagatt tgggagcctc tgatggtcac  22080  
               
               
                   
               
               
                 ttttgggccc atcaggctga gaacactgca cgggaacagc tccccatggg atgtggcagg  22140  
               
               
                   
               
               
                 aggagcccag aactgatgta gaggctcaca gctgagctca gagtgacctt caggtcacac  22200  
               
               
                   
               
               
                 atagctctcc catcagcaca gcacagagag attagaagat caactcgaga ttctgatggc  22260  
               
               
                   
               
               
                 ctatgatttt tttgaggtct gagtgggagg aaagcatgaa atgagttaga actgaattct  22320  
               
               
                   
               
               
                 ccattcatct aaacatcatg agttaattcc atagtgcctg cagtgtgagg ttctggggtg  22380  
               
               
                   
               
               
                 acagttaatc cctgacagac atgtctttaa tgacttatag actgggaagc aggttgattg  22440  
               
               
                   
               
               
                 gactattaag gagcttactc tggtggtctc caggttgagg aaagtgcatg tccttatagc  22500  
               
               
                   
               
               
                 tgcaggtccc agcctccttt cagcaatcaa tttggaggga aatcttggct atagcccctt  22560  
               
               
                   
               
               
                 cccccacaat aggaagtgat agaaactgac tccccaaaaa atttgggaag aaagtatgtt  22620  
               
               
                   
               
               
                 tgttttgctc tcaatagctg catgccatgg gttggtacct actcctaccc tctttccttt  22680  
               
               
                   
               
               
                 gcttctccag acttgtatta tttggctaca gtcctggtga tggtgggcaa gtttggagtc  22740  
               
               
                   
               
               
                 acggctgcct tttccatggt ctacgtgtac acagccgagc tgtatcccac agtggtgaga  22800  
               
               
                   
               
               
                 aacatgggtg tgggagtcag ctccacagca tcccgcctgg gcagcatcct gtctccctac  22860  
               
               
                   
               
               
                 ttcgtttacc ttggtaagtc ccatgagcca agggcacact agagcaacgg gatggaagta  22920  
               
               
                   
               
               
                 ctaactggct tgaatgtgag ctggaggttg cgtgttaaca ggaaaacaag ttcatacagt  22980  
               
               
                   
               
               
                 acatgggctc catccagtac tggatctttg gccgggaagg gttcttgtcc cagtgcactg  23040  
               
               
                   
               
               
                 gccctcactt tcaaatggaa aacaacctat agattaccta gaaattgatg agaatattag  23100  
               
               
                   
               
               
                 agggtttgtt tctgttttag ccatcccagg ccttccatca gagactacaa ttcctttatc  23160  
               
               
                   
               
               
                 ctaagaacct acagagtggt ttagggagcc agtgtgctta gttggagaaa tttcttggaa  23220  
               
               
                   
               
               
                 tcagagttta aaaggaacat gaggggaaag atgtccatgc aagaggtctg atgaacgtaa  23280  
               
               
                   
               
               
                 aattattata acctagagca ctatagagtg attttatctt gtgtgaagat ccaccccatg  23340  
               
               
                   
               
               
                 ccattttatg tagcaggtct ccagttttct cttctcagaa ttatgtcttc atagcacctg  23400  
               
               
                   
               
               
                 tggtttccct gcacatccct agccagtacc tctttaggga gggtggcacc cacctgagag  23460  
               
               
                   
               
               
                 tactcagagt gctttgtgaa catgctatgt agatctcaaa gcaagcaaaa gcaccctgcc  23520  
               
               
                   
               
               
                 taatctgaag gcagatcaca tgggctggga cacatctgca gaggtggaag agttatttcc  23580  
               
               
                   
               
               
                 atccctggac aagtacctca ggttccttgg aaacccaacc ttggtaaata agaataatca  23640  
               
               
                   
               
               
                 gcatggccca gaaataggaa taatcagcat ggcccagctc ttctcctgca accgcccctt  23700  
               
               
                   
               
               
                 tgtactcctc ccctgcatgg tggaacactg ctgggctctg ggcatgcctg tgccagctct  23760  
               
               
                   
               
               
                 gggttctgaa acctgtctag atgccagatt ctaatctgac tgctcagact gtgagagatg  23820  
               
               
                   
               
               
                 tgagaccaag aaggaaagtg atccccttcc agagtcctgg gagcataaag gggtagatga  23880  
               
               
                   
               
               
                 gagaccaagt ctaactgcag ccctgggcct gaggctccgt ctgctttgcc ataggtgcct  23940  
               
               
                   
               
               
                 acgaccgctt cctgccctac attctcatgg gaagtctgac catcctgaca gccatcctca  24000  
               
               
                   
               
               
                 ccttgtttct cccagagagc ttcggtaccc cactcccaga caccattgac cagatgctaa  24060  
               
               
                   
               
               
                 gagtcaaagg gtaagaagac ctcctctgtc agtgttgatg cactgggtct gggtctggcc  24120  
               
               
                   
               
               
                 aggtctcagg agcccctcac aatagagcta ctcgcaaact ccctctcaca gacaccatgg  24180  
               
               
                   
               
               
                 actagtttag ccattaaagg gttgtaaatg gcaaggtgct tacttatagc ccatcctctc  24240  
               
               
                   
               
               
                 tggtctgttc ctgtgtggac atgtcactat acacatctcc atggcagtag ccgcactgga  24300  
               
               
                   
               
               
                 taactcagag gctagaagaa acctttcaga atctgctgca ggattctctt cccagggaag  24360  
               
               
                   
               
               
                 atatcctcag ttcttgtttg tttggagact gggaggcatc tttttaaaat gtgttactga  24420  
               
               
                   
               
               
                 catatttttg cttgttttta tagaatgaaa cacagaaaaa ctccaagtca cacaaggatg  24480  
               
               
                   
               
               
                 ttaaaagatg gtcaagaaag gcccacaatc cttaaaagca cagccttcta acatcgcttc  24540  
               
               
                   
               
               
                 cagtaaggga gaaactgaag aggaaagact gtcttgccag aaatggccag cttgtgcaga  24600  
               
               
                   
               
               
                 ctccgagtcc ttcagtgaca aaggcctttg ctgtttgtcc tcttgacctg tgtctgactt  24660  
               
               
                   
               
               
                 gctcctggat gggcacccac actcagaggc tacatatggc cctagagcac caccttcctc  24720  
               
               
                   
               
               
                 tagggacact ggggctacct acagacaact tcatctaagt cctaactatt acaatgatgg  24780  
               
               
                   
               
               
                 actcagcacc tccaaagcag ttaatttttc actagaacca gtgagatctg gaggaatgtg  24840  
               
               
                   
               
               
                 agaagcatat gctaaatgta cattttaatt ttagactact tgaaaaggcc cctaataagg  24900  
               
               
                   
               
               
                 ctagaggtct aagtccccca cccctttccc cactcccctc tagtggtgaa ctttagagga  24960  
               
               
                   
               
               
                 aaaggaagta attgcacaag gagtttgatt cttacctttt ctcagttaca gaggacatta  25020  
               
               
                   
               
               
                 actggatcat tgcttcccca gggcaggaga gcgcagagct agggaaagtg aaaggtaatg  25080  
               
               
                   
               
               
                 aagatggagc agaatgagca gatgcagatc accagcaaag tgcactgatg tgtgagctct  25140  
               
               
                   
               
               
                 taagaccact cagcatgacg actgagtaga cttgtttaca tctgatcaaa gcactgggct  25200  
               
               
                   
               
               
                 tgtccaggct cataataaat gctccattga atctactatt cttgttttcc actgctgtgg  25260  
               
               
                   
               
               
                 aaacctcctt gctactatag cgtcttatgt atggtttaaa ggaaatttat caggtgagag  25320  
               
               
                   
               
               
                 agatgagcaa cgttgtcttt tctctcaaag ctgtaatgtg ggttttgttt tactgtttat  25380  
               
               
                   
               
               
                 ttgtttgttg ttgtatcctt ttctccttgt tatttgccct tcagaatgca cttgggaaag  25440  
               
               
                   
               
               
                 gctggttcct tagcctcctg gtttgtgtct tttttttttt ttttttaaac acagaatcac  25500  
               
               
                   
               
               
                 tctggcaatt gtctgcagct gccactggtg caaggcctta ccagccctag cctctagcac  25560  
               
               
                   
               
               
                 ttctctaagt gccaaaaaca gtgtcattgt gtgtgttcct ttcttgatac ttagtcatgg  25620  
               
               
                   
               
               
                 gaggatatta caaaaaagaa atttaaattg tgttcatagt ctttcagagt agctcacttt  25680  
               
               
                   
               
               
                 agtcctgtaa ctttattggg tgatattttg tgttcagtgt aattgtcttc tctttgctga  25740  
               
               
                   
               
               
                 ttatgttacc atggtactcc taaagcatat gcctcacctg gttaaaaaag aacaaacatg  25800  
               
               
                   
               
               
                 tttttgtgaa agctactgaa gtgccttggg aaatgagaaa gttttaataa gtaaaatgat  25860  
               
               
                   
               
               
                 tttttaaata t                                                       25871  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 6  
               
               
                 &lt;211&gt; LENGTH: 24  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: Description of Artificial Sequence:Artificially  
               
               
                       Synthesized Primer Sequence  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 6  
               
               
                   
               
               
                 gcaggaccaa ggcggcggtg tcag                                            24  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 7  
               
               
                 &lt;211&gt; LENGTH: 24  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: Description of Artificial Sequence:Artificially  
               
               
                       Synthesized Primer Sequence  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 7  
               
               
                   
               
               
                 agactagagg aaaaacggga tagc                                            24  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 8  
               
               
                 &lt;211&gt; LENGTH: 24  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: Description of Artificial Sequence:Artificially  
               
               
                       Synthesized Primer Sequence  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 8  
               
               
                   
               
               
                 agatttttag gagcaagcgt taga                                            24  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 9  
               
               
                 &lt;211&gt; LENGTH: 24  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: Description of Artificial Sequence:Artificially  
               
               
                       Synthesized Primer Sequence  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 9  
               
               
                   
               
               
                 gaggcagaca ccgtggcact acta                                            24  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 10  
               
               
                 &lt;211&gt; LENGTH: 24  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: Description of Artificial Sequence:Artificially  
               
               
                       Synthesized Primer Sequence  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 10  
               
               
                   
               
               
                 ttcacaccca cttactggat ggat                                            24  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 11  
               
               
                 &lt;211&gt; LENGTH: 24  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: Description of Artificial Sequence:Artificially  
               
               
                       Synthesized Primer Sequence  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 11  
               
               
                   
               
               
                 attctgtttt gttttggctc tttt                                            24  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 12  
               
               
                 &lt;211&gt; LENGTH: 24  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: Description of Artificial Sequence:Artificially  
               
               
                       Synthesized Primer Sequence  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 12  
               
               
                   
               
               
                 agcagggcct gggctgacat agac                                            24  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 13  
               
               
                 &lt;211&gt; LENGTH: 24  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: Description of Artificial Sequence:Artificially  
               
               
                       Synthesized Primer Sequence  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 13  
               
               
                   
               
               
                 aaaggacctg actccaagat gata                                            24  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 14  
               
               
                 &lt;211&gt; LENGTH: 24  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: Description of Artificial Sequence:Artificially  
               
               
                       Synthesized Primer Sequence  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 14  
               
               
                   
               
               
                 tctgaccacc tcttcttccc atac                                            24  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 15  
               
               
                 &lt;211&gt; LENGTH: 24  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: Description of Artificial Sequence:Artificially  
               
               
                       Synthesized Primer Sequence  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 15  
               
               
                   
               
               
                 gcctcctcag ccactgtcgg taac                                            24  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 16  
               
               
                 &lt;211&gt; LENGTH: 24  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: Description of Artificial Sequence:Artificially  
               
               
                       Synthesized Primer Sequence  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 16  
               
               
                   
               
               
                 atgttgttcc ttttgttatc ttat                                            24  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 17  
               
               
                 &lt;211&gt; LENGTH: 24  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: Description of Artificial Sequence:Artificially  
               
               
                       Synthesized Primer Sequence  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 17  
               
               
                   
               
               
                 cttgttttct tgtgtatcgt tatc                                            24  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 18  
               
               
                 &lt;211&gt; LENGTH: 24  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: Description of Artificial Sequence:Artificially  
               
               
                       Synthesized Primer Sequence  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 18  
               
               
                   
               
               
                 tatgtttgtt ttgctctcaa tagc                                            24  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 19  
               
               
                 &lt;211&gt; LENGTH: 24  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: Description of Artificial Sequence:Artificially  
               
               
                       Synthesized Primer Sequence  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 19  
               
               
                   
               
               
                 tctgtgagag ggagtttgcg agta                                            24  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 20  
               
               
                 &lt;211&gt; LENGTH: 24  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: Description of Artificial Sequence:Artificially  
               
               
                       Synthesized Primer Sequence  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 20  
               
               
                   
               
               
                 tacgaccgct tcctgcccta catt                                            24  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 21  
               
               
                 &lt;211&gt; LENGTH: 24  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: Description of Artificial Sequence:Artificially  
               
               
                       Synthesized Primer Sequence  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 21  
               
               
                   
               
               
                 tcattctgct ccatcttcat tacc                                            24  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 22  
               
               
                 &lt;211&gt; LENGTH: 33  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: Description of Artificial Sequence:Artificially  
               
               
                       Synthesized Primer Sequence  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 22  
               
               
                   
               
               
                 gataagctta cggtgtcccc ttattcccat acg                                  33  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 23  
               
               
                 &lt;211&gt; LENGTH: 24  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: Description of Artificial Sequence:Artificially  
               
               
                       Synthesized Primer Sequence  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 23  
               
               
                   
               
               
                 cccatgccaa caaggacaaa aagc                                            24  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 24  
               
               
                 &lt;211&gt; LENGTH: 24  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: Description of Artificial Sequence:Artificially  
               
               
                       Synthesized Primer Sequence  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 24  
               
               
                   
               
               
                 tgtttttcgt gggtgtgctg atgg                                            24  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 25  
               
               
                 &lt;211&gt; LENGTH: 24  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Artificial Sequence  
               
               
                 &lt;220&gt; FEATURE:  
               
               
                 &lt;223&gt; OTHER INFORMATION: Description of Artificial Sequence:Artificially  
               
               
                       Synthesized Primer Sequence  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 25  
               
               
                   
               
               
                 acagaacaga aaagccctca gtca                                            24  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 26  
               
               
                 &lt;211&gt; LENGTH: 10  
               
               
                 &lt;212&gt; TYPE: PRT  
               
               
                 &lt;213&gt; ORGANISM: Homo sapiens  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 26  
               
               
                   
               
               
                 Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu  
               
               
                  1               5                  10  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 27  
               
               
                 &lt;211&gt; LENGTH: 17  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Mus musculus  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 27  
               
               
                   
               
               
                 tcctgtggct gaccata                                                    17  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 28  
               
               
                 &lt;211&gt; LENGTH: 17  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Mus musculus  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 28  
               
               
                   
               
               
                 tcctgtggcg gaccata                                                    17  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 29  
               
               
                 &lt;211&gt; LENGTH: 22  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Homo sapiens  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 29  
               
               
                   
               
               
                 agggcggcat gccgggacta cg                                              22  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 30  
               
               
                 &lt;211&gt; LENGTH: 19  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Homo sapiens  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 30  
               
               
                   
               
               
                 cttgcagtga aacctggtg                                                  19  
               
               
                   
               
               
                   
               
               
                 &lt;210&gt; SEQ ID NO 31  
               
               
                 &lt;211&gt; LENGTH: 19  
               
               
                 &lt;212&gt; TYPE: DNA  
               
               
                 &lt;213&gt; ORGANISM: Homo sapiens  
               
               
                   
               
               
                 &lt;400&gt; SEQUENCE: 31  
               
               
                   
               
               
                 tttgccataa gtgcctacg                                                  19