title: A Variant of GJD2, Encoding for Connexin 36, Alters the Function of Insulin Producing β-Cells.
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.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Faculty of Medicine, Geneva, Switzerland.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cigliola
authors.affiliation: Centre Hospitalier Régional Universitaire Besançon, Besançon, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Populaire
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
authors.forename: Ciro L
authors.initials: CL
authors.lastname: Pierri
authors.affiliation: Joint Genome Institute, Walnut Creek, California, United States of America.
authors.forename: Samuel
authors.initials: S
authors.lastname: Deutsch
authors.affiliation: Department of Medicine, CHUV, Lausanne, Switzerland.
authors.forename: Jacques-Antoine
authors.initials: JA
authors.lastname: Haefliger
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Malmö, Sweden.
authors.forename: João
authors.initials: J
authors.lastname: Fadista
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Malmö, Sweden.|Steno Diabetes Center A/S, Gentofte, Denmark.
authors.forename: Valeriya
authors.initials: V
authors.lastname: Lyssenko
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Malmö, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.affiliation: Department of Computational Biology, University of Lausanne, Rue du Bugnon 27, 1011, Lausanne, Switzerland.|Swiss Institute of Bioinformatics, 1015, Lausanne, Switzerland.
authors.forename: Rico
authors.initials: R
authors.lastname: Rueedi
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Faculty of Medicine, Geneva, Switzerland.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Thorel
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Faculty of Medicine, Geneva, Switzerland.
authors.forename: Pedro Luis
authors.initials: PL
authors.lastname: Herrera
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva Faculty of Medicine, Geneva, Switzerland.
authors.forename: Paolo
authors.initials: P
authors.lastname: Meda
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics*; D000097004:Gap Junction delta-2 Protein
chemical_list: D017630:Connexins; D012333:RNA, Messenger; D000097004:Gap Junction delta-2 Protein