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

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.     

Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome

RAB, ADP-ribosylation factors (ARFs) and ARF-like (ARL) proteins belong to the Ras superfamily of small GTP-binding proteins and are essential for various membrane-associated intracellular trafficking processes. None of the approximately 50 known members of this family are linked to human disease. Using a bioinformatic screen for ciliary genes in combination with mutational analyses, we identified ARL6 as the gene underlying Bardet-Biedl syndrome type 3, a multisystemic disorder characterized by obesity, blindness, polydactyly, renal abnormalities and cognitive impairment. We uncovered four different homozygous substitutions in ARL6 in four unrelated families affected with Bardet-Biedl syndrome, two of which disrupt a threonine residue important for GTP binding and function of several related small GTP-binding proteins. Analysis of the Caenorhabditis elegans ARL6 homolog indicates that it is specifically expressed in ciliated cells, and that, in addition to the postulated cytoplasmic functions of ARL proteins, it undergoes intraflagellar transport. These findings implicate a small GTP-binding protein in ciliary transport and the pathogenesis of a pleiotropic disorder.     

Mutations of PKD1 in ADPKD2 cysts suggest a pathogenic effect of trans-heterozygous mutations

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2. The products of these genes associate to form heteromeric complexes. Several models have been proposed to explain the mechanism of cyst formation. Here we find somatic mutations of PKD2 in 71% of ADPKD2 cysts analysed. Clonal somatic mutations of PKD1 were identified in a subset of cysts that lacked PKD2 mutations.