title: BBS4 is a minor contributor to Bardet-Biedl syndrome and may also participate in triallelic inheritance.
abstract: 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.
authors.affiliation: Department of Molecular Genetics, Baylor College of Medicine, Houston, USA. katsanis@jhmi.edu
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Erica R
authors.initials: ER
authors.lastname: Eichers
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ansley
authors.forename: Richard Alan
authors.initials: RA
authors.lastname: Lewis
authors.forename: Hülya
authors.initials: H
authors.lastname: Kayserili
authors.forename: Bethan E
authors.initials: BE
authors.lastname: Hoskins
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scambler
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D020788:Bardet-Biedl Syndrome / Q000235:genetics*; D015331:Cohort Studies; D017124:Conserved Sequence; D019143:Evolution, Molecular; D005260:Female; D005808:Genes, Recessive; D005838:Genotype; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: C429655:BBS4 protein, human; D008869:Microtubule-Associated Proteins; D011506:Proteins