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  Identification of a gene causing the most common form of bardet-biedl syndrome and uses thereofUSPTO Application #: 20060110761Title: Identification of a gene causing the most common form of bardet-biedl syndrome and uses thereof Abstract: The present invention relates to the identification of a gene, mutated at the most common locus now designated BBS1, that is involved in the genetic disease Bardet Biedl Syndrome (BBS), which is characterized by such diverse symptoms as obesity, diabetes, hypogonadism, mental retardation, renal cancer and other renal abnormalities, retinopathy and polydactyly or limb deformities. The human BBS1 protein disclosed herein is composed of 17 exons and spans approximately 23 kb. Methods of use for the gene, for example in diagnosis and therapy of BBS and in drug screening, also are described. (end of abstract)
Agent: Fulbright & Jaworski L.L.P. - Austin, TX, US Inventors: Val C. Sheffield, Kirk Mykytyn, Darryl Y. Nishimura, Edwin M. Stone, Charles C. Searby USPTO Applicaton #: 20060110761 - Class: 435006000 (USPTO) Related Patent Categories: Chemistry: Molecular Biology And Microbiology, Measuring Or Testing Process Involving Enzymes Or Micro-organisms; Composition Or Test Strip Therefore; Processes Of Forming Such Composition Or Test Strip, Involving Nucleic Acid The Patent Description & Claims data below is from USPTO Patent Application 20060110761. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE(S) TO RELATED APPLICATION(S) [0001] This application is related to, and claims a benefit of priority under 35 U.S.C. .sctn. 119(e) and/or 35 U.S.C. .sctn. 120 from, copending U.S. Ser. No. 60/384,212, filed May 30, 2002, the entire contents of which are hereby expressly incorporated by reference for all purposes. BACKGROUND OF THE INVENTION [0003] 1. Field of the Invention [0004] The present invention relates to the fields of genetics and molecular biology. More particular the invention relates to the identification of a gene that is involved in Bardet-Biedl Syndrome (BBS), designated here as BBS1. Defects in this gene are associated with a variety of clinical symptoms including diabetes, hypogonadism, renal cancer and other renal defects, retinopathy, limb deformity or polydactyly, mental retardation and obesity. The invention further provides methods of screening for therapeutic compositions. [0005] 2. Description of Related Art [0006] Bardet-Biedl Syndrome (BBS) is a rare, autosomal recessive disorder characterized by obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation, and hypogenitalism (Bardet, 1920; Biedl, 1922; Solis-Cohen and Weiss, 1924; Green et al., 1989). Patients with BBS are also at increased risk for diabetes mellitus, hypertension and congenital heart disease (Green et al., 1989; Harnett et al., 1988; Elbedour et al., 1994). A high frequency of renal abnormalities is also associated with this disorder. The mental retardation is often mild. Obesity begins early in infancy, and complications of obesity including diabetes mellitus and hypertension occur later in life. The associated retinal degeneration is usually severe and most patients become blind prior to 20 years of age. A recent report also provides evidence of an increased incidence of renal cell carcinoma (kidney cancer) as well as kidney malformations in BBS subjects. [0007] The incidence of BBS varies between populations. A relatively high incidence of BBS is found in the mixed Arab populations of Kuwait and the Bedouin tribes throughout the Middle East, most likely due to the high rate of consanguinity in these populations. A relatively high frequency of BBS has also been reported in New Foundland. [0008] BBS has been shown to display a remarkable degree of non-allelic genetic heterogeneity. The disorder was first shown to be genetically heterogenous based on mapping studies performed in large inbred Bedouin kindreds from Israel. The large number of traditional consanguineous marriages within these groups make it possible to identify inbred kindreds with multiple affected individuals that are large enough for independent linkage analysis. [0009] Once thought to be a homogeneous autosomal recessive disorder, BBS is now known to map to at least six loci: 11q13 (BBS1), 16q21 (BBS2), 3p13-p12 (BBS3), 15q22.3-q23 (BBS4), 2q31 (BBS5), and 20p12 (BBS6) (Kwitck-Black et al., 1993; Leppert et al., 1994; Sheffield et al., 1994; Carmi et al., 1995; Young et al., 1999; Slavotinek et al., 2000; Katsanis et al., 2000). There has been considerable interest in identifying the genes that cause BBS because some of the components of the phenotype are common. The first BBS gene (MKKS) was identified independently by two groups that hypothesized that mutations in the gene causing McKusick-Kaufman syndome (MKS) could also cause BBS. MKS is an autosomal recessive disorder characterized by post-axial polydactyly, as well as genital and cardiac anomalies. Mutations in the MKKS gene, a putative chaperonin gene, appear to account for approximately 10% of BBS cases. The mechanism by which mutations in the MKKS gene cause BBS has not been determined. [0010] BBS6 was shown to be caused by mutations in the MKKS gene (Slavotinek et al., 2000; Katsanis et al., 2000), mutations which also cause McKusick-Kaufman syndrome (hydrometrocolpos, post-axial polydactyly, and congenital heart defects) (Robinow and Shaw, 1979; Stone et al., 2000). In addition, the inventors recently used positional cloning to identify the genes causing BBS2 (Nishimura et al., 2001) and BBS4 (Mykytyn et al., 2001, and U.S. Ser. No. 60/281,487 filed Apr. 3, 2001). The BBS6 protein has similarity to a T. acidophilum chaperonin (Stone et al., 2000), whereas BBS2 and BBS4 have no significant similarity to chaperonins, nor other known protein families. Recently, it has been suggested that three mutant alleles (two at one locus, and a third at a second locus) may be required for manifestation of BBS (triallelic inheritance) (Katsanis et al., 2001). A seventh BBS locus has been postulated based on the fact that a few small BBS pedigrees do not appear to map to any of the known loci. [0011] Interest in the identification of genes causing BBS stem from the pleiotrophic nature of the disorder, and the fact that identification of BBS genes may provide important insight into biochemical and developmental pathways involved in common complex disorders including obesity and diabetes mellitus. SUMMARY OF THE INVENTION [0012] Thus, in one aspect of the invention, there is provided an isolated and purified nucleic acid encoding a human BSS1 polypeptide. The amino acid sequence of SEQ ID NO:2 is exemplary, as are the nucleic acid sequence of SEQ ID NO:1. In addition, variants of the sequence included one or more of the changes selected from the group consisting of 1655G>T, 1179T>G, 432+1G>A, 851delA, (-3).sub.--37del, 339T.fwdarw.G, 342delG, 599.sub.--604del, 1040delT, 1130.sub.--1134del, 1318C.fwdarw.T, 1514.sub.--1515del, and 1553T.fwdarw.C. The nucleic acid may further comprise a promoter, for example, an inducible promoter, a constitutive promoter, or a tissue specific promoter. It may also comprise a selectable marker, a poly-adenylation signal and/or an origin of replication. [0013] The nucleic acid may be part of a replicable vector, for example a viral vector such as a retroviral vector, an adenoviral vector, an adeno-associated viral vector, a herpes viral vector, a polyoma viral vector, a vaccinia viral vector or a lentiviral vector. The viral vector may be located within a viral particle. The vector also may be a non-viral vector. [0014] In another embodiment, there is provided an oligonucleotide of 10 to about 50 bases comprising at least 10 consecutive bases of SEQ ID NO:1 or the complement thereof. The oligonucleotide may be 10, 15, 20, 25, 30, 35, 40, 45 or 50 bases in length, and may have 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 consecutive bases of SEQ ID NO: 1. [0015] In still another embodiment, there is provided an isolated and purified human BBS1 polypeptide, for example, comprising the sequence of SEQ ID NO:2. The BBS1 polypeptide also may be fused to a non-BBS1 polypeptide. [0016] In yet another embodiment, there is provided a method of expressing a BBS1 polypeptide comprising transforming a host cell with an expression construct encoding a BBS1 polypeptide and culturing said host cell under conditions supporting expression of said BBS1 polypeptide. The host cell maybe a prokaryotic or a eukaryotic cell. The method may further comprise purifying said BBS1 polypeptide. The expression construct may comprise an inducible promoter, and the method may further comprise providing to said host cell and inducer of said promoter. [0017] In still yet another embodiment, there is provided a peptide of 8 about to 50 residues comprising at least 5 consecutive residues of SEQ ID NO:2. The peptide may be 10, 15, 20, 25, 30, 35, 40, 45 or 50 residues in length, and may comprise 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 , 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 consecutive residues of SEQ ID NO:2. The peptide may be bound to a carrier molecule, for example, by a linker. Also provided are a monoclonal antibody and a polyclonal antiserum that binds immunologically to a polypeptide comprising the sequence of SEQ ID NO:2. The antibodies may be bound to a support. [0018] In still further embodiments, there are provided a method of diagnosing Bardet-Biedl Syndrome (BBS), a method of diagnosing an individual genetically predisposed to obesity, diabetes mellitus, retinopathy, kidney cancer (renal carcinoma) and other renal abnormalities, hypogonadism, mental retardation, polydactyly or limb defects, comprising identifying a mutation in a BBS1 polypeptide or nucleic acid. The method may comprise identifying a mutation in a BBS1 polypeptide, for example, using immunologic analysis with a BBS1-binding monoclonal antibody or polyclonal antiserum (e.g., ELISA, RIA, or Western blot). [0019] Alternatively, the method may comprise identifying a mutation in a BBS1 nucleic acid, either mRNA, genomic DNA or cDNA. The method may comprise amplification of said nucleic acid, hybridization of said nucleic acid to a labeled nucleic acid probe, and/or sequencing of a BBS1 nucleic acid. Again, the method may identify a mutation selected from the group consisting of 1655G>T, 1179T>G, 432+1G>A, 851delA, (-3).sub.--37del, 339T.fwdarw.G, 342delG, 599.sub.--604del, 1040delT, 1130.sub.--1134del, 1318C.fwdarw.T, 1514.sub.--1515del, and 1553T.fwdarw.C. [0020] In still other embodiments, there are provided: [0021] a method of screening for a modulator of BBS1 expression comprising (a) providing a cell expressing a BBS1 polypeptide; (b) contacting said cell with a candidate modulator; (c) measuring BBS1 expression; and (d) comparing said BBS1 expression in the presence of said candidate modulator with the expression of BBS1 in the absence of said candidate modulator; wherein a difference in the expression of BBS1 in the presence of said candidate modulator, as compared with the expression of BBS1 in the absence of said candidate modulator, identifies said candidate modulator as a modulator of BBS1 expression; and [0022] a method of screening for a modulator of BBS1 expression comprising (a) providing a cell that comprises an expression construct encoding an indicator polypeptide under the control of a BBS1 polypeptide; (b) contacting said cell with a candidate modulator; (c) measuring expression of said indicator polypeptide; [0023] and (d) comparing said expression of said indicator polypeptide in the presence of said candidate modulator with the expression of said indicator polypeptide in the absence of said candidate modulator; wherein a difference in the expression of said indicator polypeptide in the presence of said candidate modulator, as compared with the expression of said indicator polypeptide in the absence of said candidate modulator, identifies said candidate modulator as a modulator of BBS1 expression; and [0024] a method of producing a modulator of BBS1 expression comprising (a) providing a cell expressing a BBS1 polypeptide; (b) contacting said cell with a candidate modulator; (c) measuring BBS1 expression; (d) comparing said BBS1 expression in the presence of said candidate modulator with the expression of BBS1 in the absence of said candidate modulator; wherein a difference in the expression of [0025] BBS1 in the presence of said candidate modulator, as compared with the expression of BBS1 in the absence of said candidate modulator, identifies said candidate modulator as a modulator of BBS1 expression; and (e) producing the modulator; and [0026] a modulator of BBS1 expression produced according to the method comprising (a) providing a cell expressing a BBS1 polypeptide; (b) contacting said cell with a candidate modulator; (c) measuring BBS1 expression; (d) comparing said BBS1 expression in the presence of said candidate modulator with the expression of BBS1 in the absence of said candidate modulator; wherein a difference in the expression of BBS1 in the presence of said candidate modulator, as compared with the expression of BBS1 in the absence of said candidate modulator, identifies said candidate modulator as a modulator of BBS1 expression; and (e) producing the modulator. [0027] Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. Continue reading... Full patent description for Identification of a gene causing the most common form of bardet-biedl syndrome and uses thereof Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Identification of a gene causing the most common form of bardet-biedl syndrome and uses thereof patent application. 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