Nature Genetics
36, 989 - 993 (2004)
Published online: 15 August 2004; | doi:10.1038/ng1414
Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndromeYanli Fan1, 8, Muneer A Esmail1, 8, Stephen J Ansley2, Oliver E Blacque1, Keith Boroevich1, Alison J Ross3, Susan J Moore4, Jose L Badano2, Helen May-Simera3, Deanna S Compton1, Jane S Green5, Richard Alan Lewis6, Mieke M van Haelst7, Patrick S Parfrey4, David L Baillie1, Philip L Beales3, Nicholas Katsanis2, William S Davidson1
& Michel R Leroux11
Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, B.C. V5A 1S6, Canada. 2
Institute of Genetic Medicine, and Wilmer Eye Institute, Johns Hopkins University, 733 North Broadway, Baltimore, Maryland 21205, USA. 3
Molecular Medicine Unit, Institute of Child Health, University College London, London WC1 1EH, UK. 4
Department of Clinical Epidemiology, Memorial University, St John's, Newfoundland, Canada. 5
Department of Medical Genetics, Memorial University, St John's, Newfoundland, Canada. 6
Departments of Molecular and Human Genetics, Ophthalmology, Pediatrics, and Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. 7
Department of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands. 8
These authors contributed equally to this work.
Correspondence should be addressed to William S Davidson wdavidso@sfu.ca or Michel R Leroux leroux@sfu.caRAB, ADP-ribosylation factors (ARFs) and ARF-like (ARL) proteins belong to the Ras superfamily of small GTP-binding proteins and are essential for various membrane-associated intracellular trafficking processes1,
2. None of the  50 known members of this family are linked to human disease. Using a bioinformatic screen for ciliary genes in combination with mutational analyses, we identified ARL6 as the gene underlying Bardet-Biedl syndrome type 3, a multisystemic disorder characterized by obesity, blindness, polydactyly, renal abnormalities and cognitive impairment3,
4. We uncovered four different homozygous substitutions in ARL6 in four unrelated families affected with Bardet-Biedl syndrome, two of which disrupt a threonine residue important for GTP binding5 and function5,
6,
7 of several related small GTP-binding proteins. Analysis of the Caenorhabditis elegans ARL6 homolog indicates that it is specifically expressed in ciliated cells, and that, in addition to the postulated cytoplasmic functions of ARL proteins, it undergoes intraflagellar transport. These findings implicate a small GTP-binding protein in ciliary transport and the pathogenesis of a pleiotropic disorder.
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