title: Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome.
abstract: Bardet-Biedl syndrome is a genetically and clinically heterogeneous disorder caused by mutations in at least seven loci (BBS1-7), five of which are cloned (BBS1, BBS2, BBS4, BBS6, and BBS7). Genetic and mutational analyses have indicated that, in some families, a combination of three mutant alleles at two loci (triallelic inheritance) is necessary for pathogenesis. To date, four of the five known BBS loci have been implicated in this mode of oligogenic disease transmission. We present a comprehensive analysis of the spectrum, distribution, and involvement in non-Mendelian trait transmission of mutant alleles in BBS1, the most common BBS locus. Analyses of 259 independent families segregating a BBS phenotype indicate that BBS1 participates in complex inheritance and that, in different families, mutations in BBS1 can interact genetically with mutations at each of the other known BBS genes, as well as at unknown loci, to cause the phenotype. Consistent with this model, we identified homozygous M390R alleles, the most frequent BBS1 mutation, in asymptomatic individuals in two families. Moreover, our statistical analyses indicate that the prevalence of the M390R allele in the general population is consistent with an oligogenic rather than a recessive model of disease transmission. The distribution of BBS oligogenic alleles also indicates that all BBS loci might interact genetically with each other, but some genes, especially BBS2 and BBS6, are more likely to participate in triallelic inheritance, suggesting a variable ability of the BBS proteins to interact genetically with each other.
authors.affiliation: Molecular Medicine Unit, Institute of Child Health, University College London, United Kingdom.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
authors.forename: Jose L
authors.initials: JL
authors.lastname: Badano
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Ross
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ansley
authors.forename: Bethan E
authors.initials: BE
authors.lastname: Hoskins
authors.forename: Brigitta
authors.initials: B
authors.lastname: Kirsten
authors.forename: Charles A
authors.initials: CA
authors.lastname: Mein
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scambler
authors.forename: Richard Alan
authors.initials: RA
authors.lastname: Lewis
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D020788:Bardet-Biedl Syndrome / Q000235:genetics*; D015331:Cohort Studies; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D005787:Gene Frequency; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: C464790:Bbs1 protein, human; D008869:Microtubule-Associated Proteins; D011506:Proteins