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

被引：42

作者：

Angebault, Claire ^{[1
]}

Charif, Majida ^{[1
,2
]}

Guegen, Naig ^{[2
]}

Piro-Megy, Camille ^{[1
]}

de Camaret, Benedicte Mousson ^{[3
]}

Procaccio, Vincent ^{[2
]}

Guichet, Pierre-Olivier ^{[1
]}

Hebrard, Maxime ^{[1
]}

Manes, Gael ^{[1
]}

Leboucq, Nicolas ^{[4
]}

Rivier, Francois ^{[5
,6
]}

Hamel, Christian P. ^{[1
,7
]}

Lenaers, Guy ^{[1
,2
]}

Roubertie, Agathe ^{[1
,5
]}

机构：

[1] Univ Montpellier I&II, Inst Neurosci Montpellier, F-34091 Montpellier 5, France

[2] IBS CHU Angers, Dept Biochim & Genet, F-49933 Angers 9, France

[3] CHU Bron, Ctr Biochim & Biol Mol, Malad Hereditaires Metab Pathol Mitochondriales, F-69677 Bron, France

[4] CHU Gui Chauliac, Serv Neuroradiol, F-34295 Montpellier, France

[5] CHU Gui Chauliac, Serv Neuropediat, F-34295 Montpellier, France

[6] Univ Montpellier, CNRS UMR 9214, INSERM U1046, PhyMedExp, F-34295 Montpellier 5, France

[7] Ctr Reference Genet Sensory Dis, F-34295 Montpellier, France

来源：

HUMAN MOLECULAR GENETICS | 2015年 / 24卷 / 14期

关键词：

CELL-DEATH; CLINICAL-FEATURES; GRIM-19; INTERFERON; REGULATOR; PROTEIN;

D O I：

10.1093/hmg/ddv133

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：3948 / 3955

页数：8