Mutation in NDUFA13/GRIM19 leads to early onset hypotonia, dyskinesia and sensorial deficiencies, and mitochondrial complex I instability
Mutation in NDUFA13/GRIM19 leads to early onset hypotonia, dyskinesia and sensorial deficiencies, and mitochondrial complex I instability
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DOI：
10.1093/hmg/ddv133
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发表时间：
2015-07-15
影响因子：
3.5
通讯作者：
Roubertie, Agathe
中科院分区：
文献类型：
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作者：
Angebault, Claire;Charif, Majida;Roubertie, Agathe
线粒体复合体I(CI)缺陷是导致神经系统疾病的主要原因，其中Leber遗传性视神经病变和Leigh综合征最为常见。在这里，我们描述了编码CI亚单位的NDUFA13/GRIM19基因的第一个生发致病突变，这两个姐妹患有早发性低眼压、运动障碍和感觉障碍，包括严重的视神经病变。生化分析显示，患者肌肉活检组织中CI酶活性显著降低，成纤维细胞CI驱动的呼吸减少，而复合体II、III和IV的活性几乎不受影响。Western blotts显示，NDUFA13蛋白、CI全酶和超复合体在线粒体中的丰度显著降低，这种情况在对照细胞中通过沉默NDUFA13而重现。因此，我们在这里建立了在NDUFA13基因中发现的第一个突变与严重但缓慢演变的影响中枢神经系统的临床表现之间的相关性。
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.