Mutations in MKKS cause obesity, retinal dystrophy and renal malformationsassociated with Bardet-Biedl syndrome

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder predominantl y characterized by obesity, retinal dystrophy, polydactyly, learning diffic ulties, hypogenitalism and renal malformations, with secondary features tha t include diabetes mellitus, endocrinological dysfunction and behavioural a bnormalities(1,2) Despite an initial expectation of genetic homogeneity due to relative clinical uniformity, five BBS loci have been reported, with ev idence for additional loci in the human genome(3-7); however, no genes for BBS have yet been identified. We performed a genome screen with BBS familie s from Newfoundland that were excluded from BBS1-5 and identified linkage w ith D205189. Fine-mapping reduced the critical interval to 1.9 cM between D 20S851 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 N ewfoundland and two European-American BBS pedigrees. Most are frameshift al leles that are likely to result in a non-functional protein. Our data sugge st that a complete loss of function of the MKKS product, and thus an inabil ity to fold a range of target proteins, is responsible for the clinical man ifestations of BBS.