Isolated complex III (CIII) deficiencies are among the least frequently diagnosed mitochondrial disorders. Clinical symptoms range from isolated myopathy to severe multi-systemic disorders with early death and disability. To date, we know of pathogenic variants in genes encoding five out of 10 subunits and five out of 13 assembly factors of CIII. Here we describe rare bi-allelic variants in the gene of a catalytic subunit of CIII, UQCRFS1, which encodes the Rieske iron-sulfur protein, in two unrelated individuals. Affected children presented with low CIII activity in fibroblasts, lactic acidosis, fetal bradycardia, hypertrophic cardiomyopathy, and alopecia totalis. Studies in proband-derived fibroblasts showed a deleterious effect of the variants on UQCRFS1 protein abundance, mitochondrial import, CIII assembly, and cellular respiration. Complementation studies via lentiviral transduction and overexpression of wild-type UQCRFS1 restored mitochondrial function and rescued the cellular phenotype, confirming UQCRFS1 variants as causative for CIII deficiency. We demonstrate that mutations in UQCRFS1 can cause mitochondrial disease, and our results thereby expand the clinical and mutational spectrum of CIII deficiencies.

中文翻译：

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双等位基因UQCRFS1变体与线粒体复合物缺乏症III，心肌病和脱发相关。

孤立的复合物III（CIII）缺陷是最不常被诊断的线粒体疾病之一。临床症状从孤立的肌病到严重的多系统疾病，包括早期死亡和残疾。迄今为止，我们知道了编码CIII的10个亚基中的5个和13个装配因子中的5个的基因中的致病变异。在这里，我们描述了CIII催化亚基UQCRFS1中的罕见双等位基因变体，该基因在两个不相关的个​​体中编码Rieske铁硫蛋白。受影响的儿童在成纤维细胞，乳酸性酸中毒，胎儿心动过缓，肥厚型心肌病和总秃发中CIII活性低。对先证者成纤维细胞的研究表明，这些变体对UQCRFS1蛋白丰度，线粒体输入，CIII组装和细胞呼吸作用具有有害作用。通过慢病毒转导和野生型UQCRFS1的过表达进行的补充研究恢复了线粒体功能并拯救了细胞表型，证实UQCRFS1变体是CIII缺乏的病因。我们证明，UQCRFS1中的突变可引起线粒体疾病，我们的结果从而扩大了CIII缺陷的临床和突变谱。