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


Autoria(s): Angebault Prouteau, Claire; Charif, Majida; Guegen, Naig; Piro-Mégy, Camille; Mousson De Camaret, Bénédicte; Procaccio, Vincent; Guichet, Pierre-Olivier; Hebrard, Maxime; Manes, Gael; Leboucq, Nicolas; Rivier, François; Hamel, Christian; Lenaers, Guy; Roubertie, Agathe
Contribuinte(s)

Biologie Neurovasculaire et Mitochondriale Intégrée ; Université d'Angers (UA) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)

Data(s)

2015

Resumo

International audience

<p>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.</p>

Identificador

hal-01392228

https://hal.archives-ouvertes.fr/hal-01392228

DOI : 10.1093/hmg/ddv133

OKINA : ua14267

Idioma(s)

en

Publicador

HAL CCSD

Relação

info:eu-repo/semantics/altIdentifier/doi/10.1093/hmg/ddv133

Fonte

ISSN: 1460-2083

Human molecular genetics online

https://hal.archives-ouvertes.fr/hal-01392228

Human molecular genetics online, 2015, 24 (14), pp.3948-55. <http://hmg.oxfordjournals.org/content/24/14/3948>. <10.1093/hmg/ddv133>

http://hmg.oxfordjournals.org/content/24/14/3948

Palavras-Chave #[SDV] Life Sciences [q-bio]
Tipo

info:eu-repo/semantics/article

Journal articles