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<0.01) in HepG2 cells transfected with either MDH2_T154 or MDH2_A478 as compared to WT_MDH2, despite no differences in MDH2 protein expression levels. Increased MDH2 activity is known to decrease NAD/NADH ratio—a biochemical alteration reported to affect both insulin signaling and secretion. In genetically modified C. elegans strains obtained by means of CRISPR/Cas9, the Arg52Cys mutant exhibited a significantly (p<0.05) prolonged lifespan and increased Paraquat resistance and lipid storage when compared to WT strains. These changes resemble those reported for C. elegans with defective insulin signaling—a condition which in humans predisposes to both insulin resistance and inadequate insulin secretion.

In conclusion, our data point to MDH2 as a new diabetogene, heterozygous mutations of which cause hyperglycemia in families presenting with multigenerational diabetes.