The Gene INPPL1, Encoding the Lipid Phosphatase SHIP2, Is a Candidate for Type 2 Diabetes In Rat and Man

  1. Evelyne Marion1,
  2. Pamela Jane Kaisaki2,
  3. Valérie Pouillon1,
  4. Cyril Gueydan3,
  5. Jonathan C. Levy4,
  6. André Bodson5,
  7. Georges Krzentowski5,
  8. Jean-Claude Daubresse6,
  9. Jean Mockel7,
  10. Jens Behrends8,
  11. Geneviève Servais9,
  12. Claude Szpirer10,
  13. Véronique Kruys3,
  14. Dominique Gauguier2 and
  15. Stéphane Schurmans1
  1. 1IRIBHM (Institut de Recherches en Biologie Humaine et Moléculaire), IBMM (Institut de Biologie et de Médecine Moléculaires), ULB (Université Libre de Bruxelles), Gosselies, Belgium
  2. 2Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, U.K.
  3. 3Laboratoire de Chimie Biologique, IBMM, ULB, Gosselies, Belgium
  4. 4Diabetes Research Laboratories, University of Oxford, Headington, U.K.
  5. 5Department of Internal Medicine, Endocrinology-Diabetology, C.H.U. (Centre Hospitalier Universitaire) de Charleroi, site de Jumet, Jumet, Belgium
  6. 6Department of Internal Medicine, Endocrinology-Diabetology, C.H.U. de Charleroi, Charleroi, Belgium
  7. 7Department of Endocrinology, Hopital Erasme, ULB, Brussels, Belgium
  8. 8Department of Clinical Endocrinology, Medical School Hannover, Germany
  9. 9Department of Immunology, C.H.U. Brugmann-Huderf, ULB, Brussels, Belgium
  10. 10Laboratoire de Biologie du Développement, IBMM, ULB, Gosselies, Belgium

    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.

    Footnotes

    • Address correspondence and reprint requests to Stéphane Schurmans, IRIBHM-IBMM-ULB, rue des Professeurs Jeener et Brachet 12, 6041 Gosselies, Belgium. E-mail: sschurma{at}ulb.ac.be.

      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.

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