A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction,Human Mutation

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A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction
Human Mutation ( IF 3.3 ) Pub Date : 2020-11-10 , DOI: 10.1002/humu.24137
Liesbeth T M Wintjes ₁ , Maina Kava _{2,

3} , Frans A van den Brandt ₁ , Mariël A M van den Brand ₄ , Oksana Lapina ₅ , Yngve T Bliksrud ₆ , Mari A Kulseth ₇ , Silja S Amundsen ₇ , Terje R Selberg ₈ , Marion Ybema-Antoine ₄ , Omar A Z Tutakhel ₁ , Lawrence Greed ₉ , David R Thorburn _{10,

11} , Trine Tangeraas ₁₂ , Shanti Balasubramaniam ₁₃ , Richard J T Rodenburg _{1,

4}

Affiliation

Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud Centre for Mitochondrial Medicine, Radboudumc, Nijmegen, The Netherlands.
Department of Neurology, Perth Children's Hospital, Perth, Western Australia, Australia.
School of Pediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia.
Department of Pediatrics, Radboud Centre for Mitochondrial Medicine, Radboudumc, Nijmegen, The Netherlands.
Department for Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway.
Norwegian National Unit for Diagnostics of Congenital Metabolic Disorders, Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Department of Pediatrics, Ostfold Hospital Trust, Kalnes, Norway.
Department of Clinical Biochemistry, PathWest, Perth, Western Australia, Australia.
Murdoch Children's Research Institute and Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Victoria, Australia.
Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia.
Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.

COX16 is involved in the biogenesis of cytochrome‐c‐oxidase (complex IV), the terminal complex of the mitochondrial respiratory chain. We present the first report of two unrelated patients with the homozygous nonsense variant c.244C>T(p. Arg82*) in COX16 with hypertrophic cardiomyopathy, encephalopathy and severe fatal lactic acidosis, and isolated complex IV deficiency. The absence of COX16 protein expression leads to a complete loss of the holo‐complex IV, as detected by Western blot in patient fibroblasts. Lentiviral transduction of patient fibroblasts with wild‐type COX16 complementary DNA rescued complex IV biosynthesis. We hypothesize that COX16 could play a role in the copper delivery route of the COX2 module as part of the complex IV assembly. Our data provide clear evidence for the pathogenicity of the COX16 variant as a cause for the observed clinical features and the isolated complex IV deficiency in these two patients and that COX16 deficiency is a cause for mitochondrial disease.

中文翻译：

COX16 的一种新变体导致细胞色素 c 氧化酶缺乏、严重的致命性新生儿乳酸酸中毒、脑病、心肌病和肝功能障碍

COX16 参与细胞色素-c-氧化酶（复合物 IV）的生物合成，细胞色素-c-氧化酶是线粒体呼吸链的末端复合物。我们首次报告了两名不相关的患者，他们在 COX16 中具有纯合无义变异 c.244C>T(p.Arg82*)，伴有肥厚性心肌病、脑病和严重的致命性乳酸酸中毒，以及孤立的复合体 IV 缺乏症。正如患者成纤维细胞中的蛋白质印迹所检测的那样，COX16 蛋白表达的缺失导致全息复合物 IV 的完全丧失。具有野生型COX16的患者成纤维细胞的慢病毒转导互补 DNA 拯救了复杂的 IV 生物合成。我们假设 COX16 可能在 COX2 模块的铜输送路线中发挥作用，作为复杂 IV 组件的一部分。我们的数据提供了明确的证据，证明COX16变异的致病性是导致这两名患者观察到的临床特征和孤立的复合体 IV 缺乏的原因，并且 COX16 缺乏是线粒体疾病的原因。

更新日期：2020-11-10

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