Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy

Ait-El-Mkadem S, Dayem-Quere M, Gusic M, Chaussenot A, Bannwarth S, Francois B, Genin EC, Fragaki K, Volker-Touw CLM, Vasnier C, Serre V, Van Gassen KLI, Lespinasse F, Richter S, Eisenhofer G, Rouzier C, Mochel F, De Saint-Martin A, Warde MTA, De Sain-Van Der Velde MGM, Jans JJM, Amiel J, Avsec Z, Mertes C, Haack TB, Strom T, Meitinger T, Bonnen PE, Taylor RW, Gagneur J, Van Hasselt PM, Rotig A, Delahodde A, Prokisch H, Fuchs SA, Paquis-Flucklinger V (2017)

Publication Type: Journal article

Publication year: 2017

Journal

American Journal of Human Genetics Elsevier (Cell Press)

Book Volume: 100

Pages Range: 151-159

Journal Issue: 1

DOI: 10.1016/j.ajhg.2016.11.014

Abstract

MDH2 encodes mitochondrial malate dehydrogenase (MDH), which is essential for the conversion of malate to oxaloacetate as part of the proper functioning of the Krebs cycle. We report bi-allelic pathogenic mutations in MDH2 in three unrelated subjects presenting with early-onset generalized hypotonia, psychomotor delay, refractory epilepsy, and elevated lactate in the blood and cerebrospinal fluid. Functional studies in fibroblasts from affected subjects showed both an apparently complete loss of MDH2 levels and MDH2 enzymatic activity close to null. Metabolomics analyses demonstrated a significant concomitant accumulation of the MDH substrate, malate, and fumarate, its immediate precursor in the Krebs cycle, in affected subjects’ fibroblasts. Lentiviral complementation with wild-type MDH2 cDNA restored MDH2 levels and mitochondrial MDH activity. Additionally, introduction of the three missense mutations from the affected subjects into Saccharomyces cerevisiae provided functional evidence to support their pathogenicity. Disruption of the Krebs cycle is a hallmark of cancer, and MDH2 has been recently identified as a novel pheochromocytoma and paraganglioma susceptibility gene. We show that loss-of-function mutations in MDH2 are also associated with severe neurological clinical presentations in children.

Involved external institutions

Centre Hospitalier Universitaire de Nice / CHU de Nice FR France (FR) Technische Universität München (TUM) DE Germany (DE) University of Nice Sophia Antipolis / Université Nice Sophia Antipolis FR France (FR) University Medical Centre Utrecht (UMC Utrecht) NL Netherlands (NL) École Polytechnique - Université Paris-Saclay FR France (FR) University of Paris 7 - Denis Diderot / Université Paris VII Denis Diderot FR France (FR) Technische Universität Dresden DE Germany (DE) University of Paris 6 - Pierre et Marie Curie / Université Paris VI Pierre et Marie Curie (UPMC) FR France (FR) Hôpitaux universitaires de Strasbourg (HUS) / University Hospital Strasbourg FR France (FR) Hôpital Necker-Enfants malades FR France (FR) Houston Texas Medical Center US United States (USA) (US) Newcastle University GB United Kingdom (GB) University of Paris 5 - René Descartes / Université Paris V René Descartes FR France (FR)

How to cite

APA:

Ait-El-Mkadem, S., Dayem-Quere, M., Gusic, M., Chaussenot, A., Bannwarth, S., Francois, B.,... Paquis-Flucklinger, V. (2017). Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy. American Journal of Human Genetics, 100(1), 151-159. https://dx.doi.org/10.1016/j.ajhg.2016.11.014

MLA:

Ait-El-Mkadem, Samira, et al. "Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy." American Journal of Human Genetics 100.1 (2017): 151-159.

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