title: The gene INPPL1, encoding the lipid phosphatase SHIP2, is a candidate for type 2 diabetes in rat and man.
abstract: Genetic susceptibility to type 2 diabetes involves many genes, most of which are still unknown. The lipid phosphatase SHIP2 is a potent negative regulator of insulin signaling and sensitivity in vivo and is thus a good candidate gene. Here we report the presence of SHIP2 gene mutations associated with type 2 diabetes in rats and humans. The R1142C mutation specifically identified in Goto-Kakizaki (GK) and spontaneously hypertensive rat strains disrupts a potential class II ligand for Src homology (SH)-3 domain and slightly impairs insulin signaling in cell culture. In humans, a deletion identified in the SHIP2 3' untranslated region (UTR) of type 2 diabetic subjects includes a motif implicated in the control of protein synthesis. In cell culture, the deletion results in reporter messenger RNA and protein overexpression. Finally, genotyping of a cohort of type 2 diabetic and control subjects showed a significant association between the deletion and type 2 diabetes. Altogether, our results show that mutations in the SHIP2 gene contribute to the genetic susceptibility to type 2 diabetes in rats and humans.
authors.affiliation: IRIBHM (Institut de Recherches en Biologie Humaine et Moléculaire), IBMM (Institut de Biologie et de Médecine Moléculaires), ULB (Université Libre de Bruxelles), rue des Professeurs Jeener et Brachet 122, 6041 Gosselies, Belgium.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Marion
authors.forename: Pamela Jane
authors.initials: PJ
authors.lastname: Kaisaki
authors.forename: Valérie
authors.initials: V
authors.lastname: Pouillon
authors.forename: Cyril
authors.initials: C
authors.lastname: Gueydan
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Levy
authors.forename: André
authors.initials: A
authors.lastname: Bodson
authors.forename: Georges
authors.initials: G
authors.lastname: Krzentowski
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Daubresse
authors.forename: Jean
authors.initials: J
authors.lastname: Mockel
authors.forename: Jens
authors.initials: J
authors.lastname: Behrends
authors.forename: Geneviève
authors.initials: G
authors.lastname: Servais
authors.forename: Claude
authors.initials: C
authors.lastname: Szpirer
authors.forename: Véronique
authors.initials: V
authors.lastname: Kruys
authors.forename: Dominique
authors.initials: D
authors.lastname: Gauguier
authors.forename: Stéphane
authors.initials: S
authors.lastname: Schurmans
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002460:Cell Line; D002874:Chromosome Mapping; D015331:Cohort Studies; D006224:Cricetinae; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics*; D005784:Gene Amplification; D017930:Genes, Reporter; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007668:Kidney / Q000196:embryology / Q000201:enzymology; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012016:Reference Values; D017384:Sequence Deletion; D014162:Transfection; D018909:src Homology Domains / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D011994:Recombinant Proteins; D008156:Luciferases; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases