title: Mutation in NDUFA13/GRIM19 leads to early onset hypotonia, dyskinesia and sensorial deficiencies, and mitochondrial complex I instability.
abstract: Mitochondrial complex I (CI) deficiencies are causing debilitating neurological diseases, among which, the Leber Hereditary Optic Neuropathy and Leigh Syndrome are the most frequent. Here, we describe the first germinal pathogenic mutation in the NDUFA13/GRIM19 gene encoding a CI subunit, in two sisters with early onset hypotonia, dyskinesia and sensorial deficiencies, including a severe optic neuropathy. Biochemical analysis revealed a drastic decrease in CI enzymatic activity in patient muscle biopsies, and reduction of CI-driven respiration in fibroblasts, while the activities of complex II, III and IV were hardly affected. Western blots disclosed that the abundances of NDUFA13 protein, CI holoenzyme and super complexes were drastically reduced in mitochondrial fractions, a situation that was reproduced by silencing NDUFA13 in control cells. Thus, we established here a correlation between the first mutation yet identified in the NDUFA13 gene, which induces CI instability and a severe but slowly evolving clinical presentation affecting the central nervous system.
authors.affiliation: Institut des Neurosciences de Montpellier, Université de Montpellier I et II, BP 74103, 34 091 Montpellier Cedex 5, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Angebault
authors.affiliation: Institut des Neurosciences de Montpellier, Université de Montpellier I et II, BP 74103, 34 091 Montpellier Cedex 5, France, Département de Biochimie et Génétique, IBS-CHU Angers, 49933 Angers Cedex 9, France.
authors.forename: Majida
authors.initials: M
authors.lastname: Charif
authors.affiliation: Département de Biochimie et Génétique, IBS-CHU Angers, 49933 Angers Cedex 9, France.
authors.forename: Naig
authors.initials: N
authors.lastname: Guegen
authors.affiliation: Institut des Neurosciences de Montpellier, Université de Montpellier I et II, BP 74103, 34 091 Montpellier Cedex 5, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Piro-Megy
authors.affiliation: Maladies Héréditaires du Métabolisme-Pathologies Mitochondriales, Centre de Biochimie et Biologie Moléculaire, 69 677 CHU Bron, France.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Mousson de Camaret
authors.affiliation: Département de Biochimie et Génétique, IBS-CHU Angers, 49933 Angers Cedex 9, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Procaccio
authors.affiliation: Institut des Neurosciences de Montpellier, Université de Montpellier I et II, BP 74103, 34 091 Montpellier Cedex 5, France.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Guichet
authors.affiliation: Institut des Neurosciences de Montpellier, Université de Montpellier I et II, BP 74103, 34 091 Montpellier Cedex 5, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Hebrard
authors.affiliation: Institut des Neurosciences de Montpellier, Université de Montpellier I et II, BP 74103, 34 091 Montpellier Cedex 5, France.
authors.forename: Gael
authors.initials: G
authors.lastname: Manes
authors.affiliation: Service de Neuroradiologie and.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Leboucq
authors.affiliation: Service de Neuropédiatrie, CHU Gui de Chauliac, 34 295 Montpellier, France, PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, 34295 Montpellier cedex 5, France and.
authors.forename: François
authors.initials: F
authors.lastname: Rivier
authors.affiliation: Institut des Neurosciences de Montpellier, Université de Montpellier I et II, BP 74103, 34 091 Montpellier Cedex 5, France, Centre of Reference for Genetic Sensory Diseases, 34 295 Montpellier, France.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Hamel
authors.affiliation: Institut des Neurosciences de Montpellier, Université de Montpellier I et II, BP 74103, 34 091 Montpellier Cedex 5, France, Département de Biochimie et Génétique, IBS-CHU Angers, 49933 Angers Cedex 9, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Lenaers
authors.affiliation: Institut des Neurosciences de Montpellier, Université de Montpellier I et II, BP 74103, 34 091 Montpellier Cedex 5, France, Service de Neuropédiatrie, CHU Gui de Chauliac, 34 295 Montpellier, France, a-roubertie@chu-montpellier.fr.
authors.forename: Agathe
authors.initials: A
authors.lastname: Roubertie
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D020820:Dyskinesias / Q000235:genetics*; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D028361:Mitochondrial Diseases / Q000235:genetics*; D009123:Muscle Hypotonia / Q000235:genetics*; D009154:Mutation; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D016366:Open Reading Frames; D010375:Pedigree
chemical_list: D051017:Apoptosis Regulatory Proteins; D009247:NADH, NADPH Oxidoreductases; C439057:NDUFA13 protein, human; D042967:Electron Transport Complex I