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Abstract：
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.
摘要：
孤立的复合物III（CIII）缺陷是最不经常诊断的线粒体疾病之一。临床症状范围从孤立的肌病到严重的多系统疾病，并伴有早期死亡和残疾。迄今为止,我们知道在编码CIII的10个亚基中的5个和13个装配因子中的5个的基因中存在致病变异。在这里，我们描述了CIII催化亚基基因中罕见的双等位基因变异，编码Rieske铁硫蛋白的UQCRFS1，两个不相关的人。受影响的儿童在成纤维细胞中呈现低CIII活性，乳酸性酸中毒,胎儿心动过缓,肥厚型心肌病,和脱发。在先证源的成纤维细胞中的研究显示变体对UQCRFS1蛋白丰度的有害影响，线粒体进口，CIII总成,和细胞呼吸。通过慢病毒转导和野生型UQCRFS1过表达的互补研究恢复了线粒体功能并挽救了细胞表型，确认UQCRFS1变体是CIII缺乏症的病因。我们证明UQCRFS1的突变可以引起线粒体疾病，我们的结果从而扩大了CIII缺陷的临床和突变谱。
