title: Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus.
abstract: Bardet-Biedl syndrome (BBS) is a pleiotropic genetic disorder with substantial inter- and intrafamilial variability, that also exhibits remarkable genetic heterogeneity, with seven mapped BBS loci in the human genome. Recent data have demonstrated that BBS may be inherited either as a simple Mendelian recessive or as an oligogenic trait, since mutations at two loci are sometimes required for pathogenesis. This observation suggests that genetic interactions between the different BBS loci may modulate the phenotype, thus contributing to the clinical variability of BBS. We present three families with two mutations in either BBS1 or BBS2, in which some but not all patients carry a third mutation in BBS1, BBS2 or the putative chaperonin BBS6. In each example, the presence of three mutant alleles correlates with a more severe phenotype. For one of the missense alleles, we also demonstrate that the introduction of the mutation in mammalian cells causes a dramatic mislocalization of the protein compared with the wild-type. These data suggest that triallelic mutations are not always necessary for disease manifestation, but might potentiate a phenotype that is caused by two recessive mutations at an independent locus, thus introducing an additional layer of complexity on the genetic modeling of oligogenicity.
authors.affiliation: Institute of Genetic Medicine, Johns Hopkins University, 600 North Wolfe Street, Baltimore, MD 21287, USA.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Badano
authors.forename: Jun Chul
authors.initials: JC
authors.lastname: Kim
authors.forename: Bethan E
authors.initials: BE
authors.lastname: Hoskins
authors.forename: Richard Alan
authors.initials: RA
authors.lastname: Lewis
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ansley
authors.forename: David J
authors.initials: DJ
authors.lastname: Cutler
authors.forename: Claudio
authors.initials: C
authors.lastname: Castellan
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
authors.forename: Michel R
authors.initials: MR
authors.lastname: Leroux
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
mesh_terms: D020788:Bardet-Biedl Syndrome / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D056385:Group II Chaperonins; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins; D018832:Molecular Chaperones / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D011506:Proteins / Q000235:genetics*
chemical_list: C464790:Bbs1 protein, human; C473309:Bbs2 protein, human; C414726:MKKS protein, human; D008869:Microtubule-Associated Proteins; D018832:Molecular Chaperones; D011506:Proteins; D056385:Group II Chaperonins