Mutations in Complex I Assembly Factor TMEM126B Result in Muscle Weakness and Isolated Complex I Deficiency
Mutations in Complex I Assembly Factor TMEM126B Result in Muscle Weakness and Isolated Complex I Deficiency
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DOI：
10.1016/j.ajhg.2016.05.022
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发表时间：
2016-07-07
影响因子：
9.8
通讯作者：
Rotig, Agnes
中科院分区：
文献类型：
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作者：
Sanchez-Caballero, Laura;Ruzzenente, Benedetta;Rotig, Agnes
线粒体复合体I缺乏导致过多的往往严重的临床表型表现在幼儿期。在这里，我们报告了三个复杂i缺乏的成人受试者，他们的临床症状相对较轻，包括孤立的进行性运动引起的肌痛和运动不耐受，但后期发展正常。外显子组测序和靶向外显子组测序显示TMEM126B存在复合杂合突变，编码一个复合体I组装因子。进一步的生化分析显示成纤维细胞有严重的复合物I缺乏，这是由组装缺陷引起的。慢病毒与野生型cDNA的互补恢复了复合物I缺陷，证明了这些突变的致病性。进一步的配体分析表明，配体I的组装缺陷发生在其膜组件的组装过程中。我们的研究结果表明，TMEM126B缺陷可导致复合I缺乏，有趣的是，这种症状只会在运动后出现。
Mitochondrial complex I deficiency results in a plethora of often severe clinical phenotypes manifesting in early childhood. Here, we report on three complex-I-deficient adult subjects with relatively mild clinical symptoms, including isolated, progressive exercise-induced myalgia and exercise intolerance but with normal later development. Exome sequencing and targeted exome sequencing revealed compound-heterozygous mutations in TMEM126B, encoding a complex I assembly factor. Further biochemical analysis of subject fibroblasts revealed a severe complex I deficiency caused by defective assembly. Lentiviral complementation with the wild-type cDNA restored the complex I deficiency, demonstrating the pathogenic nature of these mutations. Further complexome analysis of one subject indicated that the complex I assembly defect occurred during assembly of its membrane module. Our results show that TMEM126B defects can lead to complex I deficiencies and, interestingly, that symptoms can occur only after exercise.