Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome
Copyright policy )Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome
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.
- Amsterdam UMC Netherlands
- Erasmus University Rotterdam Netherlands
- Johns Hopkins University United States
- Baylor College of Medicine United States
- Amsterdam University Medical Centers Netherlands
Models, Molecular, Molecular Sequence Data, Neurons/cytology, Cilia/metabolism, Models, GTP-Binding Proteins, Humans, Cilia, Membrane Proteins/genetics, GTP-Binding Proteins/genetics, Bardet-Biedl Syndrome, ras, Neurons, Base Sequence, ADP-Ribosylation Factors, Molecular, Membrane Proteins, Pedigree, Genes, ras, Genes, Mutation, ADP-Ribosylation Factors/genetics, Bardet-Biedl Syndrome/genetics
Models, Molecular, Molecular Sequence Data, Neurons/cytology, Cilia/metabolism, Models, GTP-Binding Proteins, Humans, Cilia, Membrane Proteins/genetics, GTP-Binding Proteins/genetics, Bardet-Biedl Syndrome, ras, Neurons, Base Sequence, ADP-Ribosylation Factors, Molecular, Membrane Proteins, Pedigree, Genes, ras, Genes, Mutation, ADP-Ribosylation Factors/genetics, Bardet-Biedl Syndrome/genetics
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