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Hum Mol Genet. 2015 Jul 15;24(14):3948-55. doi: 10.1093/hmg/ddv133. Epub 2015 Apr 21.

Mutation in NDUFA13/GRIM19 leads to early onset hypotonia, dyskinesia and sensorial deficiencies, and mitochondrial complex I instability.

Author information

1
Institut des Neurosciences de Montpellier, Université de Montpellier I et II, BP 74103, 34 091 Montpellier Cedex 5, France.
2
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.
3
Département de Biochimie et Génétique, IBS-CHU Angers, 49933 Angers Cedex 9, France.
4
Maladies Héréditaires du Métabolisme-Pathologies Mitochondriales, Centre de Biochimie et Biologie Moléculaire, 69 677 CHU Bron, France.
5
Service de Neuroradiologie and.
6
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.
7
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.
8
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.

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.

PMID:
25901006
DOI:
10.1093/hmg/ddv133
[Indexed for MEDLINE]

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