Functional characterization of Bardet-Biedl syndrome proteins

Bardet-Biedl syndrome (BBS) is a heterogeneous disorder characterized by complex symptoms, including retinitis pigmentosa, polydactyly, hypogonadism, renal anomaly, obesity, and diabetic mellitus. Despite the rare nature of the disease, BBS has been a subject of interest because patients manifest conditions that are commonly encountered in the general population, such as renal anomaly, obesity and diabetes. At least eight genes (BBSI-8) are known to be linked to the syndrome, and all have been cloned. Because mutations in any BBS gene give rise to a common set of symptoms that cannot distinguish which gene is affected, it has been hypothesized that all BBS proteins participate in the same cellular process. Recent studies with C. elegans showed that BBS genes are expressed exclusively in neuronal cells containing cilia but not in non-ciliated cells, suggesting that cellular activities related to ciliogenesis may be the underlying pathogenic mechanism of BBS. The regulation of the C. elegans BBS genes by a ciliogenic RFX-type transcription factor, DAF- 19, further provides evidence that the BBS genes are involved in cilia biogenesis andlor function. Here we show that two BBS proteins, BBS4 and BBS6, localize to the centrosome, an organelle involved in diverse cellular activities including cell division, microtubule organization, intracellular transport, and ciliogenesis. BBS4 localizes to the centriolar satellites of centrosomes and basal bodies (modified centrioles) of primary cilia. It interacts with pl50Glued subunit of the dynein motor complex, and the silencing of the gene causes the rnislocalization of a centrosomal protein, PCMl suggesting that BBS4 may function as an adaptor protein connecting the dynein motor complex and its protein cargo. BBS6 localizes to the pericentriolar material (PCM), a proteinaceous tube structure surrounding centrosomes, and BBS6 silencing leads to multi-nucleated and multi-centrosomal cells with defects in cytokinesis, a process that requires the transport of endosomal vesicles to the midbody. Both BBS4 and BBS6 are expressed exclusively within ciliated tissues in mice, suggesting that BBS proteins function in intracellular transport as well as intraflagellar transport in ciliated cells, and that the dysfunction of these ciliated cells during development likely gives rise to specific and pleiotropic symptoms in BBS patients.