Mutations of the mitochondrial carrier translocase channel subunit TIM22 cause early-onset mitochondrial myopathy.
Mutations of the mitochondrial carrier translocase channel subunit TIM22 cause early-onset mitochondrial myopathy.
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线粒体载体转位酶通道亚基 TIM22 的突变会导致早发性线粒体肌病。
DOI：
10.1093/hmg/ddy305
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发表时间：
2018
影响因子：
3.5
通讯作者：
Rehling,Peter
中科院分区：
文献类型：
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作者：
Pacheu-Grau,David;Callegari,Sylvie;Emperador,Sonia;Thompson,Kyle;Aich,Abhishek;Topol,SarahE;Spencer,EmilyG;McFarland,Robert;Ruiz-Pesini,Eduardo;Torkamani,Ali;Taylor,RobertW;Montoya,Julio;Rehling,Peter
线粒体外膜和内膜的转座促进了蛋白质进入线粒体，这些转座专门用于高度特异性的客户蛋白子集。线粒体载体转座酶（TIM22 complex）将线粒体代谢物载体和转座酶亚基（TIM23、TIM17A/B和TIM22）等多跨越蛋白插入线粒体内膜。这两种底物都是线粒体代谢功能和生物发生所必需的。在这里，我们报告一个患者，在1.5岁时被诊断为神经肌肉表现，包括张力低下，胃食管反流疾病和持续升高的血清和脑脊液乳酸（CSF）。患者成纤维细胞显示氧化能力降低和线粒体形态改变。使用跨线粒体杂交细胞系，我们排除了线粒体DNA中的候选变体作为这些影响的原因。全外显子组测序鉴定出TIM22基因（NM_013337）的复合杂合变异体，导致一个等位基因（p.Tyr25Ter）过早截断，第二个等位基因TIM22蛋白在膜间隙区域的保守残基（p.Val33Leu）发生点突变。尽管TIM22的mRNA转录物升高，生化分析显示TIM22蛋白水平较低，TIM22复合物形成更严重不足。与载体转位酶功能缺陷一致，发现内膜中的载体蛋白数量减少。这是首次报道载体转座酶TIM22孔形成亚基的致病变异，影响代谢物交换关键的线粒体内膜蛋白的生物发生。
Protein import into mitochondria is facilitated by translocases within the outer and the inner mitochondrial membranes that are dedicated to a highly specific subset of client proteins. The mitochondrial carrier translocase (TIM22 complex) inserts multispanning proteins, such as mitochondrial metabolite carriers and translocase subunits (TIM23, TIM17A/B and TIM22), into the inner mitochondrial membrane. Both types of substrates are essential for mitochondrial metabolic function and biogenesis. Here, we report on a subject, diagnosed at 1.5 years, with a neuromuscular presentation, comprising hypotonia, gastroesophageal reflux disease and persistently elevated serum and Cerebrospinal fluid lactate (CSF). Patient fibroblasts displayed reduced oxidative capacity and altered mitochondrial morphology. Using trans-mitochondrial cybrid cell lines, we excluded a candidate variant in mitochondrial DNA as causative of these effects. Whole-exome sequencing identified compound heterozygous variants in theTIM22gene (NM_013337), resulting in premature truncation in one allele (p.Tyr25Ter) and a point mutation in a conserved residue (p.Val33Leu), within the intermembrane space region, of the TIM22 protein in the second allele. Although mRNA transcripts ofTIM22were elevated, biochemical analyses revealed lower levels of TIM22 protein and an even greater deficiency of TIM22 complex formation. In agreement with a defect in carrier translocase function, carrier protein amounts in the inner membrane were found to be reduced. This is the first report of pathogenic variants in the TIM22 pore-forming subunit of the carrier translocase affecting the biogenesis of inner mitochondrial membrane proteins critical for metabolite exchange.