Malate Dehydrogenase 2 (MDH2) as a New Diabetogene Causing Hyperglycemia in Families with Multigenerational Diabetes

摘要: We are pursuing the identification of new diabetogenes by whole exome sequencing in families with multigenerational diabetes that do not carry MODY-gene mutations. Here we report two gain-of- function mutations (c.154 C>T p.Arg52Cys and c.478 G>A p.Val160Met) gene coding for Malate Dehydrogenase 2 (MDH2) have identified as segregating hyperglycemia such unrelated families. The MDH2 enzyme is localized to mitochondria where it catalyzes reversible oxidation malate oxaloacetate, utilizing NAD/NADH cofactor system tricarboxylic acid cycle. also plays a pivotal role malate-aspartate shuttle operates metabolic coordination between cytosol mitochondria. By molecular dynamic simulation, both Arg52Cys Val160Met substitutions were found severely alter atomic dynamics structure. enzymatic activity was significantly increased (p In conclusion, our data point diabetogene, heterozygous which cause presenting diabetes. Disclosure P. Jungtrakoon: None. S. Pezzilli: A. Marucci: L. Pannone: E. Flex: T. Biagini: Buranasupkajorn: O. Ludovico: Mercuri: Hastings: R. Di Paola: F. Alberico: C. Mendonca: J. Ceron: M. Porta de la Riva: Marselli: Mazza: Martinelli: V. Trischitta: Doria: Research Support; Self; Sanofi-Aventis. Prudente: