title: Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome.
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 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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: N
authors.initials: N
authors.lastname: Katsanis
authors.forename: P L
authors.initials: PL
authors.lastname: Beales
authors.forename: M O
authors.initials: MO
authors.lastname: Woods
authors.forename: R A
authors.initials: RA
authors.lastname: Lewis
authors.forename: J S
authors.initials: JS
authors.lastname: Green
authors.forename: P S
authors.initials: PS
authors.lastname: Parfrey
authors.forename: S J
authors.initials: SJ
authors.lastname: Ansley
authors.forename: W S
authors.initials: WS
authors.lastname: Davidson
authors.forename: J R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000483:Alleles; D020788:Bardet-Biedl Syndrome / Q000235:genetics*; D001483:Base Sequence; D002874:Chromosome Mapping; D003241:Consanguinity; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D016368:Frameshift Mutation; D017353:Gene Deletion; D008040:Genetic Linkage; D005838:Genotype; D056385:Group II Chaperonins; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007668:Kidney / Q000002:abnormalities*; D008297:Male; D018895:Microsatellite Repeats; D018832:Molecular Chaperones / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D009765:Obesity / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D012164:Retinal Diseases / Q000235:genetics*
chemical_list: D018076:DNA, Complementary; C414726:MKKS protein, human; D018832:Molecular Chaperones; D056385:Group II Chaperonins