Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome

Yanli Fan, Muneer A Esmail, Stephen J Ansley, Oliver E Blacque, Keith Boroevich, Alison J Ross, Susan J Moore, Jose L Badano, Helen May-Simera, Deanna S Compton, Jane S Green, Richard Alan Lewis, Mieke M van Haelst, Patrick S Parfrey, David L Baillie, Philip L Beales, Nicholas Katsanis, William S Davidson, Michel R Leroux

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

RAB, 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 processes. None of the approximately 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 impairment. 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 binding and function 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.

Original languageEnglish
Pages (from-to)989-93
Number of pages5
JournalNature Genetics
Volume36
Issue number9
DOIs
Publication statusPublished - Sep 2004

Cite this

Fan, Y., Esmail, M. A., Ansley, S. J., Blacque, O. E., Boroevich, K., Ross, A. J., ... Leroux, M. R. (2004). Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome. Nature Genetics, 36(9), 989-93. https://doi.org/10.1038/ng1414