Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies.
Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies.
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DOI：
10.1016/j.ajhg.2017.08.015
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发表时间：
2017-10-05
影响因子：
9.8
通讯作者：
Prokisch H
中科院分区：
文献类型：
--
作者：
Feichtinger RG;Oláhová M;Kishita Y;Garone C;Kremer LS;Yagi M;Uchiumi T;Jourdain AA;Thompson K;D'Souza AR;Kopajtich R;Alston CL;Koch J;Sperl W;Mastantuono E;Strom TM;Wortmann SB;Meitinger T;Pierre G;Chinnery PF;Chrzanowska-Lightowlers ZM;Lightowlers RN;DiMauro S;Calvo SE;Mootha VK;Moggio M;Sciacco M;Comi GP;Ronchi D;Murayama K;Ohtake A;Rebelo-Guiomar P;Kohda M;Kang D;Mayr JA;Taylor RW;Okazaki Y;Minczuk M;Prokisch H
补体成分1 Q亚成分结合蛋白（C1 QBP;也称为p32）是一种多室蛋白，其确切功能尚不清楚。它是一种进化上保守的多功能蛋白，主要定位于线粒体基质中，并在炎症和感染过程、线粒体核糖体生物合成以及细胞凋亡和核转录的调节中发挥作用。它具有N-末端线粒体靶向肽，其在输入线粒体基质后被蛋白水解加工，在那里它形成以甜甜圈状结构组织的同源三聚体复合物。虽然C1 QBP已被报道对许多细胞过程发挥多效性的影响，我们在这里报告4个人从不相关的家庭，在C1 QBP的双等位基因突变导致线粒体能量代谢的缺陷。婴儿表现为心肌病伴多系统受累（肝、肾和脑），儿童和成人表现为肌病和进行性眼外肌麻痹。在所有受影响的个体中，发现了与迟发性肌病病例中线粒体DNA多个缺失累积相关的多个线粒体修复链缺陷。稳态C1 QBP水平下降，在所有个人的样本，导致复合物I，III和IV的合成链酶缺乏症。C1 qbp −/−小鼠胚胎成纤维细胞（MEFs）通过显示氧化磷酸化（OXPHOS）的多重缺陷而类似于人类疾病表型。与野生型互补，但不诱变，C1 qbp恢复OXPHOS蛋白水平和线粒体酶活性在C1 qbp −/− MEFs。C1 QBP缺乏症是一种重要的线粒体疾病，其临床范围从婴儿乳酸性酸中毒到儿童（心脏）肌病和迟发性进行性眼外肌麻痹。
Complement component 1 Q subcomponent-binding protein (C1QBP; also known as p32) is a multi-compartmental protein whose precise function remains unknown. It is an evolutionary conserved multifunctional protein localized primarily in the mitochondrial matrix and has roles in inflammation and infection processes, mitochondrial ribosome biogenesis, and regulation of apoptosis and nuclear transcription. It has an N-terminal mitochondrial targeting peptide that is proteolytically processed after import into the mitochondrial matrix, where it forms a homotrimeric complex organized in a doughnut-shaped structure. Although C1QBP has been reported to exert pleiotropic effects on many cellular processes, we report here four individuals from unrelated families where biallelic mutations in C1QBP cause a defect in mitochondrial energy metabolism. Infants presented with cardiomyopathy accompanied by multisystemic involvement (liver, kidney, and brain), and children and adults presented with myopathy and progressive external ophthalmoplegia. Multiple mitochondrial respiratory-chain defects, associated with the accumulation of multiple deletions of mitochondrial DNA in the later-onset myopathic cases, were identified in all affected individuals. Steady-state C1QBP levels were decreased in all individuals’ samples, leading to combined respiratory-chain enzyme deficiency of complexes I, III, and IV. C1qbp−/− mouse embryonic fibroblasts (MEFs) resembled the human disease phenotype by showing multiple defects in oxidative phosphorylation (OXPHOS). Complementation with wild-type, but not mutagenized, C1qbp restored OXPHOS protein levels and mitochondrial enzyme activities in C1qbp−/− MEFs. C1QBP deficiency represents an important mitochondrial disorder associated with a clinical spectrum ranging from infantile lactic acidosis to childhood (cardio)myopathy and late-onset progressive external ophthalmoplegia.