title: Subcellular localization of ALMS1 supports involvement of centrosome and basal body dysfunction in the pathogenesis of obesity, insulin resistance, and type 2 diabetes.
abstract: Alström syndrome is a rare autosomal recessive disorder caused by mutations in a novel gene of unknown function, ALMS1. Central features of Alström syndrome include obesity, insulin resistance, and type 2 diabetes, and therefore investigating ALMS1 function stands to offer new insights into the pathogenesis of these common conditions. To begin this process, we have analyzed the subcellular localization and tissue distribution of ALMS1 by immunofluorescence. We show that ALMS1 is widely expressed and localizes to centrosomes and to the base of cilia. Fibroblasts with disrupted ALMS1 assemble primary cilia and microtubule cytoskeletons that appear normal, suggesting that the Alström syndrome phenotype results from impaired function rather than abnormal development. Coupled with recent data on the complex phenotype of Bardet-Biedl syndrome, our findings imply an unexpected central role for basal body and centrosome dysfunction in the pathogenesis of obesity, insulin resistance, and type 2 diabetes. Unraveling the molecular mechanisms underlying the Alström syndrome phenotype will be important in the search for new therapeutic targets for these conditions.
authors.affiliation: Human Genetics Division, University of Southampton, Duthie Building (MP808), Southampton General Hospital, Tremona Road, Southampton SO16 6YD, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Hearn
authors.forename: Cosma
authors.initials: C
authors.lastname: Spalluto
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Phillips
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Renforth
authors.forename: Nane
authors.initials: N
authors.lastname: Copin
authors.forename: Neil A
authors.initials: NA
authors.lastname: Hanley
authors.forename: David I
authors.initials: DI
authors.lastname: Wilson
mesh_terms: D000595:Amino Acid Sequence; D000906:Antibodies; D018797:Cell Cycle Proteins; D018385:Centrosome / Q000378:metabolism*; D017124:Conserved Sequence; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007333:Insulin Resistance / Q000502:physiology*; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D009765:Obesity / Q000503:physiopathology*; D010446:Peptide Fragments / Q000032:analysis; D011506:Proteins / Q000032:analysis* / Q000235:genetics; D013577:Syndrome
chemical_list: C490729:ALMS1 protein, human; D000906:Antibodies; D018797:Cell Cycle Proteins; D010446:Peptide Fragments; D011506:Proteins