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

Lookup NU author(s): Professor Robert Taylor

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


Publication metadata

Author(s): 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

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2017

Volume: 100

Issue: 1

Pages: 151-159

Print publication date: 05/01/2017

Online publication date: 15/12/2016

Acceptance date: 16/11/2016

Date deposited: 28/02/2017

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press

URL: http://dx.doi.org/10.1016/j.ajhg.2016.11.014

DOI: 10.1016/j.ajhg.2016.11.014


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Funding

Funder referenceFunder name
Fondation Maladies Rares
Fondation pour la Recherche Medicale
Lily Foundation
UK National Health Service Highly Specialised "Rare Mitochondrial Disorders of Adults and Children" Service in Newcastle upon Tyne
01GM1603German Bundesministerium fur Bildung and Forschung (BMBF) through the E-Rare project GENOMIT
096919/Z/11/ZWellcome Trust Strategic Award
317433EU FP7 Mitochondrial European Educational Training Project
633974EU Horizon2020 Collaborative Research Project SOUND
FKZ 01ZX1405CBMBF through the Juniorverbund in der Systemmedizin "mitOmics"
G0601943Medical Research Council Centre for Neuromuscular Diseases
R01NS083726NIH National Institute of Neurological Disorders and Stroke
(01GM1603
096919/Z/11/ZWellcome Trust
317433
633974
FKZ 01ZX1405C
G0601943
R01NS083726

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