Basal body dysfunction is a likely cause of pleiotropic Bardet–Biedl syndrome

Abstract

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized primarily by retinal dystrophy, obesity, polydactyly, renal malformations and learning disabilities. Although five BBS genes have been cloned, the molecular basis of this syndrome remains elusive. Here we show that BBS is probably caused by a defect at the basal body of ciliated cells. We have cloned a new BBS gene, BBS8, which encodes a protein with a prokaryotic domain, pilF, involved in pilus formation and twitching mobility. In one family, a homozygous null BBS8 mutation leads to BBS with randomization of left-right body axis symmetry, a known defect of the nodal cilium. We have also found that BBS8 localizes specifically to ciliated structures, such as the connecting cilium of the retina and columnar epithelial cells in the lung. In cells, BBS8 localizes to centrosomes and basal bodies and interacts with PCM1, a protein probably involved in ciliogenesis. Finally, we demonstrate that all available Caenorhabditis elegans BBS homologues are expressed exclusively in ciliated neurons, and contain regulatory elements for RFX, a transcription factor that modulates the expression of genes associated with ciliogenesis and intraflagellar transport.

Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouse

“…These data support the hypothesis that ciliary defects underlie the pleiotropic BBS phenotype 6 . Our previous in vitro studies also indicated that suppression of BBS4 mRNA caused marked disorganization of centrosomal microtubules 7 .…”

“…The olfactory epithelia of adult wild-type and Bbs4 -/-mice were exposed to a brief pulse (60 ms; arrows) of vapor-phase odorants and EOGs were recorded. (a) Representative EOG traces upon exposure to water or dilute solutions of heptaldehyde (7-AL extracted RNA with the Trizol reagent from dissected hearts and kidneys of Bbs1 and Bbs4 heterozygotes and mutant homozygotes and carried out RT-PCR using gene-specific primers 6 . Primer sequences are available on request.…”

“…Loss of function of either BBS protein affected the olfactory, but not the respiratory, epithelium, causing severe reduction of the ciliated border, disorganization of the dendritic microtubule network and trapping of olfactory ciliary proteins in dendrites and cell bodies. Our data indicate that BBS proteins have a role in the microtubule organization of mammalian ciliated cells and that anosmia might be a useful determinant of other pleiotropic disorders with a suspected ciliary involvement.BBS is caused by mutations in at least eight loci, seven of which have been identified 6,[8][9][10][11][12][13][14] . Although the sequences of the BBS proteins have not provided any clues to their function, BBS4, BBS5 and BBS8 are localized to the basal body of cultured cells and at ciliated borders in tissues 6,7,10 .…”

“…BBS is caused by mutations in at least eight loci, seven of which have been identified 6,[8][9][10][11][12][13][14] . Although the sequences of the BBS proteins have not provided any clues to their function, BBS4, BBS5 and BBS8 are localized to the basal body of cultured cells and at ciliated borders in tissues 6,7,10 .…”

“…Although the sequences of the BBS proteins have not provided any clues to their function, BBS4, BBS5 and BBS8 are localized to the basal body of cultured cells and at ciliated borders in tissues 6,7,10 . In addition, all known orthologs of the mammalian BBS proteins are expressed specifically in ciliated sensory neurons in Caenorhabditis elegans 6,10 , raising the possibility that disruption of these proteins will lead to ciliary defects.…”