Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technical University Munich, 81675 Munich, Germany.
Charité-Universitätsmedizin Berlin, corporate member of the Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health: NeuroCure Cluster of Excellence, 10117 Berlin, Germany; Charité-Universitätsmedizin Berlin, corporate member of the Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health: Department of Neuropediatrics, 13353 Berlin, Germany.
Am J Hum Genet. 2020 Jan 2;106(1):102-111. doi: 10.1016/j.ajhg.2019.12.005. Epub 2019 Dec 26.
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.
孤立的复合物 III（CIII）缺陷是最不常诊断的线粒体疾病之一。临床症状从孤立性肌病到严重的多系统疾病不等，伴有早逝和残疾。迄今为止，我们已经在编码 CIII 的 10 个亚基中的 5 个和 13 个组装因子中的 5 个的基因中发现了致病性变异。在这里，我们描述了两个无关个体中 CIII 催化亚基基因 UQCRFS1 的罕见双等位基因变异。受影响的儿童在成纤维细胞中表现出 CIII 活性降低、乳酸酸中毒、胎儿心动过缓、肥厚型心肌病和全秃。在来自先证者的成纤维细胞中的研究表明，这些变异对 UQCRFS1 蛋白丰度、线粒体导入、CIII 组装和细胞呼吸有有害影响。通过慢病毒转导和野生型 UQCRFS1 的过表达进行的互补研究恢复了线粒体功能并挽救了细胞表型，证实 UQCRFS1 变异是 CIII 缺陷的原因。我们证明 UQCRFS1 的突变可导致线粒体疾病，因此我们的结果扩展了 CIII 缺陷的临床和突变谱。
