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author Ait-El-Mkadem, Samira
Dayem-Quere, Manal
Gusic, Mirjana
Chaussenot, Annabelle
Bannwarth, Sylvie
François, Bérengère
Genin, Emmanuelle C.
Fragaki, Konstantina
Volker-Touw, Catharina L.M.
Vasnier, Christelle
Serre, Valérie
van Gassen, Koen L.I.
Lespinasse, Françoise
Richter, Susan
Eisenhofer, Graeme
Rouzier, Cécile
Mochel, Fanny
De Saint-Martin, Anne
Abi Warde, Marie-Thérèse
de Sain-van der Velde, Monique G.M.
Jans, Judith J.M.
Amiel, Jeanne
Avsec, Ziga
Mertes, Christian
Haack, Tobias B.
Strom, Tim
Meitinger, Thomas
Bonnen, Penelope E.
Taylor, Robert W.
Gagneur, Julien
van Hasselt, Peter M.
Rötig, Agnès
Delahodde, Agnès
Prokisch, Holger
Fuchs, Sabine A.
Paquis-Flucklinger, Véronique
author_facet Ait-El-Mkadem, Samira
Dayem-Quere, Manal
Gusic, Mirjana
Chaussenot, Annabelle
Bannwarth, Sylvie
François, Bérengère
Genin, Emmanuelle C.
Fragaki, Konstantina
Volker-Touw, Catharina L.M.
Vasnier, Christelle
Serre, Valérie
van Gassen, Koen L.I.
Lespinasse, Françoise
Richter, Susan
Eisenhofer, Graeme
Rouzier, Cécile
Mochel, Fanny
De Saint-Martin, Anne
Abi Warde, Marie-Thérèse
de Sain-van der Velde, Monique G.M.
Jans, Judith J.M.
Amiel, Jeanne
Avsec, Ziga
Mertes, Christian
Haack, Tobias B.
Strom, Tim
Meitinger, Thomas
Bonnen, Penelope E.
Taylor, Robert W.
Gagneur, Julien
van Hasselt, Peter M.
Rötig, Agnès
Delahodde, Agnès
Prokisch, Holger
Fuchs, Sabine A.
Paquis-Flucklinger, Véronique
author_sort Ait-El-Mkadem, Samira
collection PubMed
description 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.
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spelling pubmed-52230292017-07-05 Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy Ait-El-Mkadem, Samira Dayem-Quere, Manal Gusic, Mirjana Chaussenot, Annabelle Bannwarth, Sylvie François, Bérengère Genin, Emmanuelle C. Fragaki, Konstantina Volker-Touw, Catharina L.M. Vasnier, Christelle Serre, Valérie van Gassen, Koen L.I. Lespinasse, Françoise Richter, Susan Eisenhofer, Graeme Rouzier, Cécile Mochel, Fanny De Saint-Martin, Anne Abi Warde, Marie-Thérèse de Sain-van der Velde, Monique G.M. Jans, Judith J.M. Amiel, Jeanne Avsec, Ziga Mertes, Christian Haack, Tobias B. Strom, Tim Meitinger, Thomas Bonnen, Penelope E. Taylor, Robert W. Gagneur, Julien van Hasselt, Peter M. Rötig, Agnès Delahodde, Agnès Prokisch, Holger Fuchs, Sabine A. Paquis-Flucklinger, Véronique Am J Hum Genet Report 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. Elsevier 2017-01-05 2016-12-15 /pmc/articles/PMC5223029/ /pubmed/27989324 http://dx.doi.org/10.1016/j.ajhg.2016.11.014 Text en © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Report
Ait-El-Mkadem, Samira
Dayem-Quere, Manal
Gusic, Mirjana
Chaussenot, Annabelle
Bannwarth, Sylvie
François, Bérengère
Genin, Emmanuelle C.
Fragaki, Konstantina
Volker-Touw, Catharina L.M.
Vasnier, Christelle
Serre, Valérie
van Gassen, Koen L.I.
Lespinasse, Françoise
Richter, Susan
Eisenhofer, Graeme
Rouzier, Cécile
Mochel, Fanny
De Saint-Martin, Anne
Abi Warde, Marie-Thérèse
de Sain-van der Velde, Monique G.M.
Jans, Judith J.M.
Amiel, Jeanne
Avsec, Ziga
Mertes, Christian
Haack, Tobias B.
Strom, Tim
Meitinger, Thomas
Bonnen, Penelope E.
Taylor, Robert W.
Gagneur, Julien
van Hasselt, Peter M.
Rötig, Agnès
Delahodde, Agnès
Prokisch, Holger
Fuchs, Sabine A.
Paquis-Flucklinger, Véronique
Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy
title Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy
title_full Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy
title_fullStr Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy
title_full_unstemmed Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy
title_short Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy
title_sort mutations in mdh2, encoding a krebs cycle enzyme, cause early-onset severe encephalopathy
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223029/
https://www.ncbi.nlm.nih.gov/pubmed/27989324
http://dx.doi.org/10.1016/j.ajhg.2016.11.014
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