Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet-Biedl syndrome (BBS3)

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous, pleiotropic human disorder characterized by obesity, retinopathy, polydactyly, renal and cardiac malformations, learning disabilities, and hypogenitalism. Eight BBS loci have been mapped, and seven genes have been identified. BBS3 was previously mapped to chromosome 3 by linkage analysis in a large Israeli Bedouin kindred. The rarity of other families mapping to the BBS3 locus has made it difficult to narrow the disease interval sufficiently to identify the gene by positional cloning. We hypothesized that the genomes of model organisms that contained the orthologues to known BBS genes would also likely contain a BBS3 orthologue. Therefore, comparative genomic analysis was performed to prioritize BBS candidate genes for mutation screening. Known BBS proteins were compared with the translated genomes of model organisms to identify a subset of organisms in which these proteins were conserved. By including multiple organisms that have relatively small genome sizes in the analysis, the number of candidate genes was reduced, and a few genes mapping to the BBS3 interval emerged as the best candidates for this disorder. One of these genes, ADP-ribosylation factor-like 6 (ARL6), contains a homozygous stop mutation that segregates completely with the disease in the Bedouin kindred originally used to map the BBS3 locus, identifying this gene as the BBS3 gene. These data illustrate the power of comparative genomic analysis for the study of human disease and identifies a novel BBS gene.