Hydrogen sulfide, a signaling molecule formed mainly from cysteine, is catabolized by sulfide:quinone oxidoreductase (gene SQOR). Toxic hydrogen sulfide exposure inhibits complex IV. We describe children of two families with pathogenic variants in SQOR. Exome sequencing identified variants; SQOR enzyme activity was measured spectrophotometrically, protein levels evaluated by western blotting, and mitochondrial function was assayed. In family A, following a brief illness, a 4‐year‐old girl presented comatose with lactic acidosis and multiorgan failure. After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh‐like lesions on brain imaging. She died shortly after. Her 8‐year‐old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex. Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation. Both patients were homozygous for c.637G > A, which we identified as a founder mutation in the Lehrerleut Hutterite with a carrier frequency of 1 in 13. The resulting p.Glu213Lys change disrupts hydrogen bonding with neighboring residues, resulting in severely reduced SQOR protein and enzyme activity, whereas sulfide generating enzyme levels were unchanged. In family B, a boy had episodes of encephalopathy and basal ganglia lesions. He was homozygous for c.446delT and had severely reduced fibroblast SQOR enzyme activity and protein levels. SQOR dysfunction can result in hydrogen sulfide accumulation, which, consistent with its known toxicity, inhibits complex IV resulting in energy failure. In conclusion, SQOR deficiency represents a new, potentially treatable, cause of Leigh disease.

中文翻译：

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SQOR 中编码硫化物：醌氧化还原酶的致病变异是 Leigh 病的潜在可治疗原因。

硫化氢是一种主要由半胱氨酸形成的信号分子，由硫化物：醌氧化还原酶（基因SQOR）分解代谢。有毒的硫化氢暴露会抑制复合物 IV。我们在SQOR 中描述了具有致病性变异的两个家庭的孩子. 外显子组测序鉴定的变异；通过分光光度法测量 SQOR 酶活性，通过蛋白质印迹评估蛋白质水平，并测定线粒体功能。家庭 A 中，一名 4 岁女孩在短暂患病后出现昏迷，并伴有乳酸酸中毒和多器官功能衰竭。稳定后，她仍然昏迷，低渗，有神经风暴发作，乳酸升高，脑成像显示 Leigh 样病变。不久她就去世了。她 8 岁的姐姐出现了迅速致命的昏迷，伴有乳酸酸中毒，基底节和左皮质有病变。肌肉和肝脏组织中分离出的复合物 IV 活性降低，但复合物 IV 蛋白水平和复合物形成正常。两名患者均为 c.637G > A 纯合子，我们将其鉴定为 Lehrerleut Hutterite 中的创始突变，携带频率为 13 . 在 B 族中，一名男孩患有脑病和基底节病变。他是 c.446delT 纯合子，成纤维细胞 SQOR 酶活性和蛋白质水平严重降低。SQOR 功能障碍会导致硫化氢积累，这与其已知的毒性一致，会抑制复合体 IV，导致能量衰竭。总之，SQOR 缺乏代表了 Leigh 病的一个新的、可能可治疗的原因。Glu213Lys 的变化破坏了与相邻残基的氢键，导致 SQOR 蛋白和酶活性严重降低，而生成硫化物的酶水平没有变化。在 B 族中，一名男孩患有脑病和基底节病变。他是 c.446delT 纯合子，成纤维细胞 SQOR 酶活性和蛋白质水平严重降低。SQOR 功能障碍会导致硫化氢积累，这与其已知的毒性一致，会抑制复合体 IV，导致能量衰竭。总之，SQOR 缺乏代表了 Leigh 病的一个新的、可能可治疗的原因。Glu213Lys 的变化破坏了与相邻残基的氢键，导致 SQOR 蛋白和酶活性严重降低，而生成硫化物的酶水平没有变化。在 B 族中，一名男孩患有脑病和基底节病变。他是 c.446delT 纯合子，成纤维细胞 SQOR 酶活性和蛋白质水平严重降低。SQOR 功能障碍会导致硫化氢积累，这与其已知的毒性一致，会抑制复合体 IV，导致能量衰竭。总之，SQOR 缺乏代表了 Leigh 病的一个新的、可能可治疗的原因。他是 c.446delT 纯合子，成纤维细胞 SQOR 酶活性和蛋白质水平严重降低。SQOR 功能障碍会导致硫化氢积累，这与其已知的毒性一致，会抑制复合体 IV，导致能量衰竭。总之，SQOR 缺乏代表了 Leigh 病的一个新的、可能可治疗的原因。他是 c.446delT 纯合子，成纤维细胞 SQOR 酶活性和蛋白质水平严重降低。SQOR 功能障碍会导致硫化氢积累，这与其已知的毒性一致，会抑制复合体 IV，导致能量衰竭。总之，SQOR 缺乏代表了 Leigh 病的一个新的、可能可治疗的原因。