Prapaporn Jungtrakoon Thamtarana1,2, Antonella Marucci3, Luca Pannone4, Amélie Bonnefond5,6,7, Serena Pezzilli8,9, Tommaso Biagini10, Patinut Buranasupkajorn1, Timothy Hastings1, Christine Mendonca1, Lorella Marselli11, Rosa Di Paola3, Zuroida Abubakar2, Luana Mercuri8, Federica Alberico8, Elisabetta Flex12, Julian Ceròn13, Montserrat Porta-de-la-Riva13, Ornella Ludovico14, Massimo Carella15, Simone Martinelli12, Piero Marchetti11, Tommaso Mazza10, Philippe Froguel5,6,7, Vincenzo Trischitta3,16, Alessandro Doria1, Sabrina Prudente8. 1. Research Division, Joslin Diabetes Center, and Harvard Medical School, Boston, MA, USA. 2. Cellular and Molecular Biology of Diabetes Research Group, Siriraj Center of Research Excellence for Diabetes and Obesity, Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. 3. Research Unit of Diabetes and Endocrine Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. 4. Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy. 5. Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, France. 6. Université de Lille, CHU de Lille, Lille, France. 7. Department of Metabolism, Imperial College London, London, UK. 8. Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo,Italy. 9. Medical Genetics, University of Chieti, Chieti, Italy. 10. Unit of Bioinformatics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo,Italy. 11. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. 12. Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy. 13. Modeling human diseases in C. elegans. Genes, Diseases and Therapies Program, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain. 14. Department of Clinical Sciences, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo,Italy. 15. Research Unit of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo,Italy. 16. Department of Experimental Medicine, Sapienza University, Rome, Italy.
Abstract
CONTEXT: Genes causing familial forms of diabetes mellitus are only partially known. OBJECTIVE: We set out to identify the genetic cause of hyperglycemia in multigenerational families with an apparent autosomal dominant form of adult-onset diabetes not due to mutations in known monogenic diabetes genes. METHODS: Existing whole-exome sequencing (WES) data were used to identify exonic variants segregating with diabetes in 60 families from the United States and Italy. Functional studies were carried out in vitro (transduced MIN6-K8 cells) and in vivo (Caenorhabditis elegans) to assess the diabetogenic potential of 2 variants in the malate dehydrogenase 2 (MDH2) gene linked with hyperglycemia in 2 of the families. RESULTS: A very rare mutation (p.Arg52Cys) in MDH2 strongly segregated with hyperglycemia in 1 family from the United States. An infrequent MDH2 missense variant (p.Val160Met) also showed disease cosegregation in a family from Italy, although with reduced penetrance. In silico, both Arg52Cys and Val160Met were shown to affect MDH2 protein structure and function. In transfected HepG2 cells, both variants significantly increased MDH2 enzymatic activity, thereby decreasing the NAD+/NADH ratio-a change known to affect insulin signaling and secretion. Stable expression of human wild-type MDH2 in MIN6-K8 cell lines enhanced glucose- and GLP-1-stimulated insulin secretion. This effect was blunted by the Cys52 or Met160 substitutions. Nematodes carrying equivalent changes at the orthologous positions of the mdh-2 gene showed impaired glucose-stimulated insulin secretion. CONCLUSION: Our findings suggest a central role of MDH2 in human glucose homeostasis and indicate that gain of function variants in this gene may be involved in the etiology of familial forms of diabetes.
CONTEXT: Genes causing familial forms of diabetes mellitus are only partially known. OBJECTIVE: We set out to identify the genetic cause of hyperglycemia in multigenerational families with an apparent autosomal dominant form of adult-onset diabetes not due to mutations in known monogenic diabetes genes. METHODS: Existing whole-exome sequencing (WES) data were used to identify exonic variants segregating with diabetes in 60 families from the United States and Italy. Functional studies were carried out in vitro (transduced MIN6-K8 cells) and in vivo (Caenorhabditis elegans) to assess the diabetogenic potential of 2 variants in the malate dehydrogenase 2 (MDH2) gene linked with hyperglycemia in 2 of the families. RESULTS: A very rare mutation (p.Arg52Cys) in MDH2 strongly segregated with hyperglycemia in 1 family from the United States. An infrequent MDH2 missense variant (p.Val160Met) also showed disease cosegregation in a family from Italy, although with reduced penetrance. In silico, both Arg52Cys and Val160Met were shown to affect MDH2 protein structure and function. In transfected HepG2 cells, both variants significantly increased MDH2 enzymatic activity, thereby decreasing the NAD+/NADH ratio-a change known to affect insulin signaling and secretion. Stable expression of human wild-type MDH2 in MIN6-K8 cell lines enhanced glucose- and GLP-1-stimulated insulin secretion. This effect was blunted by the Cys52 or Met160 substitutions. Nematodes carrying equivalent changes at the orthologous positions of the mdh-2 gene showed impaired glucose-stimulated insulin secretion. CONCLUSION: Our findings suggest a central role of MDH2 in human glucose homeostasis and indicate that gain of function variants in this gene may be involved in the etiology of familial forms of diabetes.
Authors: A Doria; Y Yang; M Malecki; S Scotti; J Dreyfus; C O'Keeffe; T Orban; J H Warram; A S Krolewski Journal: Diabetes Care Date: 1999-02 Impact factor: 19.112
Authors: Samira Ait-El-Mkadem; Manal Dayem-Quere; Mirjana Gusic; Annabelle Chaussenot; Sylvie Bannwarth; Bérengère François; Emmanuelle C Genin; Konstantina Fragaki; Catharina L M Volker-Touw; Christelle Vasnier; Valérie Serre; Koen L I van Gassen; Françoise Lespinasse; Susan Richter; Graeme Eisenhofer; Cécile Rouzier; Fanny Mochel; Anne De Saint-Martin; Marie-Thérèse Abi Warde; Monique G M de Sain-van der Velde; Judith J M Jans; Jeanne Amiel; Ziga Avsec; Christian Mertes; Tobias B Haack; Tim Strom; Thomas Meitinger; Penelope E Bonnen; Robert W Taylor; Julien Gagneur; Peter M van Hasselt; Agnès Rötig; Agnès Delahodde; Holger Prokisch; Sabine A Fuchs; Véronique Paquis-Flucklinger Journal: Am J Hum Genet Date: 2016-12-15 Impact factor: 11.025
Authors: Katrin Bender; Pierre Maechler; Neville H McClenaghan; Peter R Flatt; Philip Newsholme Journal: Clin Sci (Lond) Date: 2009-09-01 Impact factor: 6.124