학술논문
A Variant of GJD2, Encoding for Connexin 36, Alters the Function of Insulin Producing β-Cells.
Document Type
Academic Journal
Author
Cigliola V; Department of Genetic Medicine and Development, University of Geneva Faculty of Medicine, Geneva, Switzerland.; Populaire C; Centre Hospitalier Régional Universitaire Besançon, Besançon, France.; Pierri CL; Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.; Deutsch S; Joint Genome Institute, Walnut Creek, California, United States of America.; Haefliger JA; Department of Medicine, CHUV, Lausanne, Switzerland.; Fadista J; Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Malmö, Sweden.; Lyssenko V; Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Malmö, Sweden.; Steno Diabetes Center A/S, Gentofte, Denmark.; Groop L; Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Malmö, Sweden.; Rueedi R; Department of Computational Biology, University of Lausanne, Rue du Bugnon 27, 1011, Lausanne, Switzerland.; Swiss Institute of Bioinformatics, 1015, Lausanne, Switzerland.; Thorel F; Department of Genetic Medicine and Development, University of Geneva Faculty of Medicine, Geneva, Switzerland.; Herrera PL; Department of Genetic Medicine and Development, University of Geneva Faculty of Medicine, Geneva, Switzerland.; Meda P; Department of Cell Physiology and Metabolism, University of Geneva Faculty of Medicine, Geneva, Switzerland.
Source
Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
Subject
Language
English
Abstract
Signalling through gap junctions contributes to control insulin secretion and, thus, blood glucose levels. Gap junctions of the insulin-producing β-cells are made of connexin 36 (Cx36), which is encoded by the GJD2 gene. Cx36-null mice feature alterations mimicking those observed in type 2 diabetes (T2D). GJD2 is also expressed in neurons, which share a number of common features with pancreatic β-cells. Given that a synonymous exonic single nucleotide polymorphism of human Cx36 (SNP rs3743123) associates with altered function of central neurons in a subset of epileptic patients, we investigated whether this SNP also caused alterations of β-cell function. Transfection of rs3743123 cDNA in connexin-lacking HeLa cells resulted in altered formation of gap junction plaques and cell coupling, as compared to those induced by wild type (WT) GJD2 cDNA. Transgenic mice expressing the very same cDNAs under an insulin promoter revealed that SNP rs3743123 expression consistently lead to a post-natal reduction of islet Cx36 levels and β-cell survival, resulting in hyperglycemia in selected lines. These changes were not observed in sex- and age-matched controls expressing WT hCx36. The variant GJD2 only marginally associated to heterogeneous populations of diabetic patients. The data document that a silent polymorphism of GJD2 is associated with altered β-cell function, presumably contributing to T2D pathogenesis.