Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
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Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder with locus heterogeneity. None of the 'responsible' genes have previously been identified. Some BBS cases (approximately 10%) remain unassigned to the five previously mapped loci. McKusick-Kaufma syndrome (MKS) includes hydrometrocolpos, postaxial polydactyly and congenital heart disease, and is also inherited in an autosomal recessive manner. We ascertained 34 unrelated probands with classic features of BBS including retinitis pigmentosa (RP), obesity and polydactyly. The probands were from families unsuitable for linkage because of family size. We found MKKS mutations in four typical BBS probands (Table 1). The first is a 13-year-old Hispanic girl with severe RP, PAP, mental retardation and obesity (BMI >40). She was a compound heterozygote for a missense (1042GA, G52D) and a nonsense (1679TA, Y264stop) mutation in exon 3. Cloning and sequencing of the separate alleles confirmed that the mutations were present in trans. A second BBS proband (from Newfoundland), born to consanguineous parents, was homozygous for two deletions (1316delC and 1324-1326delGTA) in exon 3, predicting a frameshift. An affected brother was also homozygous for the deletions, whereas an unaffected sibling had two normal copies of MKKS. Both the proband and her affected brother had RP, PAP, mild mental retardation, morbid obesity (BMI >50 and 37, respectively), lobulated kidneys with prominent calyces and diabetes mellitus (diagnosed at ages 33 and 30, respectively). A deceased sister (DNA unavailable) had similar phenotypic features (RP with blindness by age 13, BMI >45, abnormal glucose tolerance test and IQ=64, vaginal atresia and syndactyly of both feet). Both parents and the maternal grandfather were heterozygous for the deletions. Genotyping with markers from the MKKS region confirmed homozygosity at 20p12 in both affected individuals.
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PMID:Mutations in MKKS cause Bardet-Biedl syndrome. 1097 38

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder predominantly characterized by obesity, retinal dystrophy, polydactyly, learning difficulties, hypogenitalism and renal malformations, with secondary features that include diabetes mellitus, endocrinological dysfunction and behavioural abnormalities. Despite an initial expectation of genetic homogeneity due to relative clinical uniformity, five BBS loci have been reported, with evidence for additional loci in the human genome; however, no genes for BBS have yet been identified. We performed a genome screen with BBS families from Newfoundland that were excluded from BBS1-5 and identified linkage with D20S189. Fine-mapping reduced the critical interval to 1.9 cM between D20S851 and D20S189, encompassing a chaperonin-like gene. Mutations in this gene were recently reported to be associated with McKusick-Kaufman syndrome (MKKS; ref. 8). Given both the mapping position and clinical similarities of these two syndromes, we screened MKKS and identified mutations in five Newfoundland and two European-American BBS pedigrees. Most are frameshift alleles that are likely to result in a non-functional protein. Our data suggest that a complete loss of function of the MKKS product, and thus an inability to fold a range of target proteins, is responsible for the clinical manifestations of BBS.
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PMID:Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome. 1097 51

Bardet-Biedl syndrome (BBS, MIM 209900) is a heterogeneous autosomal recessive disorder characterized by obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation, and hypogenitalism. The disorder is also associated with diabetes mellitus, hypertension, and congenital heart disease. Six distinct BBS loci map to 11q13 (BBS1), 16q21 (BBS2), 3p13-p12 (BBS3), 15q22.3-q23 (BBS4), 2q31 (BBS5), and 20p12 (BBS6). Although BBS is rare in the general population (<1/100,000), there is considerable interest in identifying the genes causing BBS because components of the phenotype, such as obesity and diabetes, are common. We and others have demonstrated that BBS6 is caused by mutations in the gene MKKS (refs. 12,13), mutation of which also causes McKusick-Kaufman syndrome (hydrometrocolpos, post-axial polydactyly, and congenital heart defects). MKKS has sequence homology to the alpha subunit of a prokaryotic chaperonin in the thermosome Thermoplasma acidophilum. We recently identified a novel gene that causes BBS2. The BBS2 protein has no significant similarity to other chaperonins or known proteins. Here we report the positional cloning and identification of mutations in BBS patients in a novel gene designated BBS4.
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PMID:Identification of the gene that, when mutated, causes the human obesity syndrome BBS4. 1138 Dec 70

Bardet-Biedl syndrome (BBS, OMIM 209900) is a genetic disorder with the primary features of obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation and hypogenitalism. Individuals with BBS are also at increased risk for diabetes mellitus, hypertension and congenital heart disease. What was once thought to be a homogeneous autosomal recessive disorder 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). There has been considerable interest in identifying the genes that underlie BBS, because some components of the phenotype are common. Cases of BBS mapping ro BBS6 are caused by mutations in MKKS; mutations in this gene also cause McKusick-Kaufman syndrome (hydrometrocolpos, post-axial polydactyly and congenital heart defects). In addition, we recently used positional cloning to identify the genes underlying BBS2 (ref. 16) and BBS4 (ref. 17). The BBS6 protein has similarity to a Thermoplasma acidophilum chaperonin, whereas BBS2 and BBS4 have no significant similarity to chaperonins. It has recently been suggested that three mutated alleles (two at one locus, and a third at a second locus) may be required for manifestation of BBS (triallelic inheritance). Here we report the identification of the gene BBS1 and show that a missense mutation of this gene is a frequent cause of BBS. In addition, we provide data showing that this common mutation is not involved in triallelic inheritance.
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PMID:Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome. 1211 55

McKusick-Kaufman syndrome (MKS) is an autosomal recessive disorder characterized by post-axial polydactyly, congenital heart defects and hydrometrocolpos, a congenital structural abnormality of female genitalia. Mutations in the MKKS gene have also been shown to cause some cases of Bardet-Biedl syndrome (BBS) which is characterized by obesity, pigmentary retinopathy, polydactyly, renal abnormalities and hypogenitalism with secondary features of hypertension and diabetes. Although there is overlap in clinical features between MKS and BBS, MKS patients are not obese and do not develop retinopathy or have learning disabilities. To further explore the pathophysiology of BBS and the related disorder MKS, we have developed an Mkks(-/-) mouse model. This model shows that the absence of Mkks leads to retinal degeneration through apoptosis, failure of spermatozoa flagella formation, elevated blood pressure and obesity. The obesity is associated with hyperphagia and decreased activity. In addition, neurological screening reveals deficits in olfaction and social dominance. The mice do not have polydactyly or vaginal abnormalities. The phenotype of the Mkks(-/-) mice closely resembles the phenotype of other mouse models of BBS (Bbs2(-/-) and Bbs4(-/-)). These observations suggest that the complete absence of MKKS leads to BBS while the MKS phenotype is likely to be due to specific mutations.
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PMID:Mkks-null mice have a phenotype resembling Bardet-Biedl syndrome. 1577 95