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


Journal Article

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.

Full Text

Cited Authors

  • Fan, Y; Esmail, MA; Ansley, SJ; Blacque, OE; Boroevich, K; Ross, AJ; Moore, SJ; Badano, JL; May-Simera, H; Compton, DS; Green, JS; Lewis, RA; van Haelst, MM; Parfrey, PS; Baillie, DL; Beales, PL; Katsanis, N; Davidson, WS; Leroux, MR

Published Date

  • September 2004

Published In

Volume / Issue

  • 36 / 9

Start / End Page

  • 989 - 993

PubMed ID

  • 15314642

Pubmed Central ID

  • 15314642

International Standard Serial Number (ISSN)

  • 1061-4036

Digital Object Identifier (DOI)

  • 10.1038/ng1414


  • eng

Conference Location

  • United States