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Letters to Nature

Nature 425, 628-633 (9 October 2003) | doi:10.1038/nature02030; Received 24 June 2003; Accepted 8 September 2003; Published online 21 September 2003

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

Stephen J. Ansley1,8, Jose L. Badano1,8, Oliver E. Blacque3,8, Josephine Hill4, Bethan E. Hoskins1,4, Carmen C. Leitch1, Jun Chul Kim3, Alison J. Ross4, Erica R. Eichers5, Tanya M. Teslovich1, Allan K. Mah3, Robert C. Johnsen3, John C. Cavender7, Richard Alan Lewis5,6, Michel R. Leroux3, Philip L. Beales4 & Nicholas Katsanis1,2

  1. Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland 21287, USA
  2. Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland 21287, USA
  3. Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, V5A 1S6 Canada
  4. Molecular Medicine Unit, Institute of Child Health, University College London, London WC1N 1EH, UK
  5. Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA
  6. Departments of Ophthalmology, Pediatrics, and Medicine, Baylor College of Medicine, Houston, Texas 77030, USA
  7. King Khaled Eye Hospital, Riyadh, 11462, Saudi Arabia
  8. These authors contributed equally to this work

Correspondence to: Nicholas Katsanis1,2 Email: katsanis@jhmi.edu
Nucleotide sequences for the two BBS8 splice isoforms (AY366523 (long isoform) and AY366524 (short isoform)) have been deposited in GenBank.

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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 cloned1, 2, 3, 4, 5, 6, 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.