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

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) in the gene coding for Malate Dehydrogenase 2 (MDH2) that we have identified as segregating with hyperglycemia in two such unrelated families. The MDH2 enzyme is localized to the mitochondria where it catalyzes the reversible oxidation of malate to oxaloacetate, utilizing the NAD/NADH cofactor system in the tricarboxylic acid cycle. MDH2 also plays a pivotal role in the malate-aspartate shuttle that operates in the metabolic coordination between cytosol and mitochondria. By molecular dynamic simulation, both the Arg52Cys and Val160Met substitutions were found to severely alter the atomic dynamics of the MDH2 structure. MDH2 enzymatic activity was significantly increased (p In conclusion, our data point to MDH2 as a new diabetogene, heterozygous mutations of which cause hyperglycemia in families presenting with multigenerational diabetes. Disclosure P. Jungtrakoon: None. S. Pezzilli: None. A. Marucci: None. L. Pannone: None. E. Flex: None. T. Biagini: None. P. Buranasupkajorn: None. O. Ludovico: None. L. Mercuri: None. T. Hastings: None. R. Di Paola: None. F. Alberico: None. C. Mendonca: None. J. Ceron: None. M. Porta de la Riva: None. L. Marselli: None. T. Mazza: None. S. Martinelli: None. V. Trischitta: None. A. Doria: Research Support; Self; Sanofi-Aventis. S. Prudente: None.