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.

Figure 1

Distribution of mutations along BBS1. Exons are depicted as blue bars and the position of each mutation is shown above. Arrows indicate the positions of the start and termination codons, whereas asterisks indicate mutations reported previously by Mykytyn et al. (2002); scale is approximate. The BBS1 protein has no discernible domains, with the exception of a region of similarity between residues 187–377 with BBS2 and BBS7 that potentially encodes a six-bladed β-propeller (Badano et al. 2003).

Figure 2

Triallelic inheritance involving BBS1. A, Pedigree PB56, in which both the affected mother and affected daughter are M390R homozygous and also carry an M472V mutation in BBS4. B, Pedigree AR396, in which the affected sib carries two BBS1 mutations (M390R and Q291X) and a BBS6 mutation, S326P. C, Family AR241, in which the affected sibs have two BBS2 mutations (R315Q/R315Q; IVS1+1G) and a single BBS1 mutation (M390R). Dashes indicate that these individuals were either unavailable or unwilling to participate in the study.

Figure 3

Two M390R mutations are not sufficient for pathogenesis. In pedigrees PB006 (A) and PB029 (B), the unaffected father is homozygous for the common M390R allele, as are all affected individuals. A third mutation has not yet been found in these two families.

Figure 4

Analysis of triallelism. A, Bar graph demonstrating the distribution of recessive and complex alleles in each of the five cloned BBS genes. The relative contribution of one or two alleles is also indicated. B, Pie chart depicting the prevalence of locus combinations in families with complex BBS. Combinations were scored irrespective of the number of alleles provided by each locus. Numbers outside each slice indicate how many families exhibit each locus combination.

Figure 5

Evolutionary analysis of mutations involved in complex inheritance. The conservation of each of the mutant BBS1, BBS2, BBS4, and BBS6 alleles involved in complex inheritance was examined by comparing the predicted protein sequences of all known BBS genes with orthologs and homologs from all available species. The region around each relevant residue is also shown. Blue represents identities, and yellow represents conservative substitutions.