The Gene INPPL1, Encoding the Lipid Phosphatase SHIP2, Is a Candidate for Type 2 Diabetes In Rat and Man
- Evelyne Marion1,
- Pamela Jane Kaisaki2,
- Valérie Pouillon1,
- Cyril Gueydan3,
- Jonathan C. Levy4,
- André Bodson5,
- Georges Krzentowski5,
- Jean-Claude Daubresse6,
- Jean Mockel7,
- Jens Behrends8,
- Geneviève Servais9,
- Claude Szpirer10,
- Véronique Kruys3,
- Dominique Gauguier2 and
- Stéphane Schurmans1
- 1IRIBHM (Institut de Recherches en Biologie Humaine et Moléculaire), IBMM (Institut de Biologie et de Médecine Moléculaires), ULB (Université Libre de Bruxelles), Gosselies, Belgium
- 2Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, U.K.
- 3Laboratoire de Chimie Biologique, IBMM, ULB, Gosselies, Belgium
- 4Diabetes Research Laboratories, University of Oxford, Headington, U.K.
- 5Department of Internal Medicine, Endocrinology-Diabetology, C.H.U. (Centre Hospitalier Universitaire) de Charleroi, site de Jumet, Jumet, Belgium
- 6Department of Internal Medicine, Endocrinology-Diabetology, C.H.U. de Charleroi, Charleroi, Belgium
- 7Department of Endocrinology, Hopital Erasme, ULB, Brussels, Belgium
- 8Department of Clinical Endocrinology, Medical School Hannover, Germany
- 9Department of Immunology, C.H.U. Brugmann-Huderf, ULB, Brussels, Belgium
- 10Laboratoire de Biologie du Développement, IBMM, ULB, Gosselies, Belgium
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.
Address correspondence and reprint requests to Stéphane Schurmans, IRIBHM-IBMM-ULB, rue des Professeurs Jeener et Brachet 12, 6041 Gosselies, Belgium. E-mail:.
Received for publication 5 March 2002 and accepted in revised form 8 May 2002. Posted on the World Wide Web at http://www.diabetes.org/diabetes/rapidpubs.shtml on 7 June 2002.
ARE, adenylate/uridylate-rich element; HA, hemagglutinin A; MAP, mitogen-activated protein; PKB, protein kinase B; QTL, quantitative trait locus; SH, Src homology; SV40, simian virus 40; UTR, untranslated region.