The Gene INPPL1, Encoding the Lipid Phosphatase SHIP2, Is a Candidate for Type 2 Diabetes In Rat and Man-Reference-Cited by-同舟云学术

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

Published:2002-07-01 Issue:7 Volume:51 Page:2012-2017
ISSN:0012-1797
Container-title:Diabetes
language:en
Short-container-title:

Author:

Marion Evelyne¹,Kaisaki Pamela Jane²,Pouillon Valérie¹,Gueydan Cyril³,Levy Jonathan C.⁴,Bodson André⁵,Krzentowski Georges⁵,Daubresse Jean-Claude⁶,Mockel Jean⁷,Behrends Jens⁸,Servais Geneviève⁹,Szpirer Claude¹⁰,Kruys Véronique³,Gauguier Dominique²,Schurmans Stéphane¹

Affiliation:

1. IRIBHM (Institut de Recherches en Biologie Humaine et Moléculaire), IBMM (Institut de Biologie et de Médecine Moléculaires), ULB (Université Libre de Bruxelles), Gosselies, Belgium

2. Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, U.K.

3. Laboratoire de Chimie Biologique, IBMM, ULB, Gosselies, Belgium

4. Diabetes Research Laboratories, University of Oxford, Headington, U.K.

5. Department of Internal Medicine, Endocrinology-Diabetology, C.H.U. (Centre Hospitalier Universitaire) de Charleroi, site de Jumet, Jumet, Belgium

6. Department of Internal Medicine, Endocrinology-Diabetology, C.H.U. de Charleroi, Charleroi, Belgium

7. Department of Endocrinology, Hopital Erasme, ULB, Brussels, Belgium

8. Department of Clinical Endocrinology, Medical School Hannover, Germany

9. Department of Immunology, C.H.U. Brugmann-Huderf, ULB, Brussels, Belgium

10. Laboratoire 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.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

Link

https://journals.org/diabetes/diabetes/article-pdf/51/7/2012/340748/db0702002012.pdf

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