Mutations in a Member of the Ras Superfamily of Small GTP-binding Proteins Causes Bardet-Biedl Syndrome

Nat Genet. 2004 Sep;36(9):989-93. doi: 10.1038/ng1414. Epub 2004 Aug 15.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / genetics*
  • Bardet-Biedl Syndrome / genetics*
  • Base Sequence
  • Cilia / metabolism
  • GTP-Binding Proteins / genetics
  • Genes, ras*
  • Humans
  • Membrane Proteins / genetics*
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation*
  • Neurons / cytology
  • Pedigree

Substances

  • Membrane Proteins
  • ADP-ribosylation factor related proteins
  • GTP-Binding Proteins
  • ARL6 protein, human
  • ADP-Ribosylation Factors

Associated data

  • RefSeq/NM_018010
  • RefSeq/NM_032146
  • RefSeq/NM_182896