Although Bardet–Biedl syndrome (BBS) is a rare, recessive disease, it is of interest to human geneticists because its diverse clinical characteristics include diabetes, obesity, hypertension and congenital heart disease. But BBS is also genetically complex, involving six distinct loci (BBS1–BBS6). The characterization of BBS6 had raised expectations that the BBS proteins might act in a chaperone complex, although the recently discovered BBS2 encodes a protein of unknown function. Now, Val Sheffield and colleagues have discovered BBS4 , which encodes a protein with homology to O-linked N-acetylglucosamine transferase (OGT), adding to the questions that surround the functions of BBS proteins.

Myktyn et al. located BBS4, which had been previously mapped to chromosome 15, by haplotype analysis in three consanguineous BBS4 (chromosome 15) pedigrees. Sequence from the candidate interval revealed several candidate genes, one of which was mutated in five of six BBS4 families. The mutation spectrum included a homozygous G→C transversion in exon 12, predicted to cause an Arg to Pro substitution, which segregated completely with BBS in a large Bedouin kindred. Other mutations were predicted to disrupt splicing. Interestingly, a 6-kb deletion that encompassed two exons of BBS4 was found in two unrelated BBS families — affected individuals had identical breakpoints in Alu elements flanking the deletion. The authors speculate that similar Alu-associated BBS4 mutations might be found in other BBS families because the high frequency of Alu repeats in BBS4 could predispose it to mutation by unequal homologous recombination.

It still remains to be shown how BBS4 contributes to the BBS phenotype, but there are some clues as to its function. In humans, OGT has been implicated in insulin resistance and diabetes, and the BBS4 protein has a motif that facilitates protein interactions. There are still more pieces of the BBS puzzle to come, and fitting together the BBS proteins into functional pathways is clearly an important goal for this field. In doing so, it will hopefully reveal rare insights into the molecular mechanisms that contribute to the common diseases of diabetes, obesity and hypertension, and to congenital heart disease.