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.

Figure 1

Recessive inheritance of IVS3-2A→G, an exon 4 splice-acceptor mutation, in Saudi Arabian family KK021.

Figure 2

Evolutionary conservation of residues involved in complex inheritance of BBS. A, Alignment of BBS4 amino acid sequences of human (Hsa), mouse (Mmu), bovine (Bta), and Drosophila (Dme). Mutant alleles, indicated by asterisks (*), are named above the sequence. Because of a substantial sequence divergence, the amino acid sequence of an M. thermautotrophicus (Mth) OGT is shown only at the residues mutated in BBS. The predicted tetratricopeptide domain is boxed. B, Alignment, at residues 547–566, between human BBS2 peptide sequence and mouse, rat (Rno), and zebrafish (Dre) BBS2 peptide sequence, to illustrate the evolutionary conservation of the threonine residue at position 558. Note that T558I has previously been reported as T560I (Katsanis et al. 2001a).

Figure 3

Examples of complex inheritance involving BBS4 and other loci. “wt” denotes wild type. A, Potential triallelic inheritance between BBS1 and BBS4, in family AR153. This family is genetically excluded from the inheritance of recessive BBS4 mutations and bears haplotypes consistent with linkage across BBS1, yet both patients inherited a heterozygous L327P BBS4 mutation. B, Potential tetra-allelic inheritance between BBS2 and BBS4, in family PB043. The affected individual (PB043-01) has inherited a homozygous T558I BBS2 mutation and a homozygous A364E BBS4 mutation. Confirmation, by restriction analysis, of mutations in family PB043 is also shown: the T558I allele generates 68-bp and 175-bp SspI fragments, whereas the A364E allele generates a 33-bp MboI fragment.