Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

McKusick-Kaufman syndrome (MKKS) is a rare, recessively inherited syndrome reported mainly in young children and is characterised by vaginal atresia with hydrometrocolpos, postaxial polydactyly, and congenital heart defect. Bardet-Biedl syndrome (BBS) is the generic name for a genetically heterogeneous group of autosomal recessive disorders characterised by retinal dystrophy or retinitis pigmentosa (appearing usually between 10 and 20 years of age), postaxial polydactyly, obesity, nephropathy, and mental disturbances, or, occasionally, mental retardation. Typically, MKKS is diagnosed (and reported) in very young children, whereas the diagnosis of BBS often is delayed to the teenage years. We report here a series of nine patients diagnosed in infancy with MKKS because of the presence of vaginal atresia and postaxial polydactyly, who later developed obesity and retinal dystrophy, thus turning out to be instances of BBS. The overlap of BBS and MKKS is a real diagnostic pitfall and its importance has to be stressed, for genetic counselling, for clinical management and follow up, and for molecular approaches. The diagnosis of MKKS should be considered with caution in all published cases described exclusively in the neonatal period and in those with mental retardation. We strongly recommend all children seen in infancy with a diagnosis of MKKS to be re-evaluated for RP and other signs of BBS.
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PMID:Hydrometrocolpos and polydactyly: a common neonatal presentation of Bardet-Biedl and McKusick-Kaufman syndromes. 1046 9

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

Hydrometrocolpos (HMC) and post-axial polydactyly (PAP) are common to both McKusick-Kaufman syndrome (MKS) and Bardet-Biedl syndrome (BBS). We review reported cases of MKS and BBS presenting with HMC and PAP early in life to determine if there are clinical features that allow discrimination between the two syndromes as the primary features of retinitis pigmentosa, obesity, learning disability in BBS are age-dependent. We did not find any phenotypic features that allowed reliable differentiation between the two syndromes in the neonatal period. However, uterine, ovarian, and fallopian tube anomalies are more common in BBS patients, and it may be that these clinical features prove to be useful discriminating features. We conclude that sporadic female infants with HMC and PAP cannot be diagnosed with MKS until at least age 5 years and that monitoring for the complications of BBS should be performed in these patients.
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PMID:Phenotypic overlap of McKusick-Kaufman syndrome with bardet-biedl syndrome: a literature review. 1110 25

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized primarily by obesity, polydactyly, retinal dystrophy, and renal disease. The significant genetic and clinical heterogeneity of this condition have substantially hindered efforts to positionally clone the numerous BBS genes, because the majority of available pedigrees are small and the disorder cannot be assigned to any of the six known BBS loci. Consequently, the delineation of critical BBS intervals, which would accelerate the discovery of the underlying genetic defect(s), becomes difficult, especially for loci with minor contributions to the syndrome. We have collected a cohort of 163 pedigrees from diverse ethnic backgrounds and have evaluated them for mutations in the recently discovered BBS6 gene (MKKS) on chromosome 20 and for potential assignment of the disorder to any of the other known BBS loci in the human genome. Using a combination of mutational and haplotype analysis, we describe the spectrum of BBS6 alterations that are likely to be pathogenic; propose substantially reduced critical intervals for BBS2, BBS3, and BBS5; and present evidence for the existence of at least one more BBS locus. Our data also suggest that BBS6 is a minor contributor to the syndrome and that some BBS6 alleles may act in conjunction with mutations at other BBS loci to cause or modify the BBS phenotype.
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PMID:Genetic and mutational analyses of a large multiethnic Bardet-Biedl cohort reveal a minor involvement of BBS6 and delineate the critical intervals of other loci. 1117 9

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) is a genetically heterogeneous disorder characterized by multiple clinical features that include pigmentary retinal dystrophy, polydactyly, obesity, developmental delay, and renal defects. BBS is considered an autosomal recessive disorder, and recent positional cloning efforts have identified two BBS genes (BBS2 and BBS6). We screened our cohort of 163 BBS families for mutations in both BBS2 and BBS6 and report the presence of three mutant alleles in affected individuals in four pedigrees. In addition, we detected unaffected individuals in two pedigrees who carry two BBS2 mutations but not a BBS6 mutation. We therefore propose that BBS may not be a single-gene recessive disease but a complex trait requiring three mutant alleles to manifest the phenotype. This triallelic model of disease transmission may be important in the study of both Mendelian and multifactorial disorders.
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PMID:Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder. 1156 25

Bardet-Biedl syndrome (BBS) is an uncommon multisystemic disorder characterized primarily by retinal dystrophy, obesity, polydactyly, and renal dysfunction. BBS has been modeled historically as an autosomal recessive trait, under which premise six independent BBS loci (BBS1-BBS6) have been mapped in the human genome. However, extended mutational analyses of BBS2 and BBS6, the first two BBS genes cloned, suggest that BBS exhibits a more complex pattern of inheritance, in which three mutations at two loci simultaneously are necessary and sufficient in some families to manifest the phenotype. We evaluated the spectrum of mutations in the recently identified BBS4 gene with a combination of haplotype analysis and mutation screening on a multiethnic cohort of 177 families. Consistent with predictions from previous genetic analyses, our data suggest that mutations in BBS4 contribute to BBS in <3% of affected families. Furthermore, integrated mutational data from all three currently cloned BBS genes raise the possibility that BBS4 may participate in triallelic inheritance with BBS2 and BBS1, but not the other known loci. Establishment of the loci pairing in triallelism is likely to be important for the elucidation of the functional relationships among the different BBS proteins.
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PMID:BBS4 is a minor contributor to Bardet-Biedl syndrome and may also participate in triallelic inheritance. 1201 87

McKusick-Kaufman syndrome comprises hydrometrocolpos, polydactyly, and congenital heart defects and overlaps with Bardet-Biedl syndrome, comprising retinitis pigmentosa, polydactyly, obesity, mental retardation, and renal and genital anomalies. Bardet-Biedl syndrome is genetically heterogeneous with three cloned genes ( BBS2, BBS4, and MKKS) and at least three other known loci ( BBS1, BBS3, and BBS5). Both McKusick-Kaufman syndrome and Bardet-Biedl syndrome are inherited in an autosomal recessive pattern, and both syndromes are caused by mutations in the MKKS gene. However, mutations in MKKS are found in only 4%-11% of unselected Bardet-Biedl syndrome patients. We hypothesized that an analysis of patients with atypical Bardet-Biedl syndrome and McKusick-Kaufman syndrome (Group I; 15 probands) and patients with Bardet-Biedl syndrome who had linkage results inconsistent with linkage to the other loci (Group II; 12 probands) could increase the MKKS mutation yield. Both mutant alleles were identified in only two families in Group II. Single (heterozygous) sequence variations were found in three Group I families and in two Group II families. Combining these results with previously published data showed that only one mutant allele was detected in nearly half of all patients screened to date, suggesting that unusual mutational mechanisms or patterns of inheritance may be involved. However, sequencing of the BBS2 gene in these patients did not provide any evidence of digenic or "triallelic" inheritance. The frequency of detected mutations in MKKS in Group II patients was 24%, i.e., six times higher than the published rate for unselected BBS patients, suggesting that small-scale linkage analyses may be useful in suitable families.
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PMID:Mutation analysis of the MKKS gene in McKusick-Kaufman syndrome and selected Bardet-Biedl syndrome patients. 1210 42

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 (MKKS) is a rare autosomal recessive genetic disease with classical hexadactyly and hydrocolpos in females and sometimes cardiac abnormality. We report such a case diagnosed just before birth with a favourable outcome. From this case we describe and discuss all the prenatal sonographic signs which are not always present. On the genetic side, the gene has recently been localized together with the mutation responsible for MKKS. The phenotypic relationship between MKKS which has a good prognosis and Bardet-Biedl syndrome (BBS) with a worse prognosis requires great caution before diagnosing MKKS and a long follow-up is necessary to recognize obesity, growth retardation and pigmentary retinitis.
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PMID:McKusik-Kaufman syndrome: prenatal diagnosis, genetics and follow up. 1242 74


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