Abstract
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 New-foundland 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.
Original language | English (US) |
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Pages (from-to) | 67-70 |
Number of pages | 4 |
Journal | Nature Genetics |
Volume | 26 |
Issue number | 1 |
DOIs | |
State | Published - Sep 2000 |
Funding
We thank the families described for cooperation and the Kleberg Genotyping Center for expertise and fluorescent microsatellites. This study was supported in part by a National Eye Institute, NIH, grant EY12666 (N.K.), the Foundation Fighting Blindness (R.A.L., J.R.L.), the Wellcome Trust (P.L.B.), the Kidney Foundation of Canada, the Canadian Medical Research Council and the Janeway Foundation (J.S.G., P.S.P., W.S.D.).
ASJC Scopus subject areas
- Genetics