Department of Pediatrics and Pediatric Neurology, Faculty of Medicine, Georg August University, Göttingen, Germany.
Hum Mutat. 2012 Aug;33(8):1207-15. doi: 10.1002/humu.22099. Epub 2012 May 16.
Copper (Cu) is a trace metal that readily gains and donates electrons, a property that renders it desirable as an enzyme cofactor but dangerous as a source of free radicals. To regulate cellular Cu metabolism, an elaborate system of chaperones and transporters has evolved, although no human Cu chaperone mutations have been described to date. We describe a child from a consanguineous family who inherited homozygous mutations in the SLC33A1, encoding an acetyl CoA transporter, and in CCS, encoding the Cu chaperone for superoxide dismutase. The CCS mutation, p.Arg163Trp, predicts substitution of a highly conserved arginine residue at position 163, with tryptophan in domain II of CCS, which interacts directly with superoxide dismutase 1 (SOD1). Biochemical analyses of the patient's fibroblasts, mammalian cell transfections, immunoprecipitation assays, and Lys7Δ (CCS homolog) yeast complementation support the pathogenicity of the mutation. Expression of CCS was reduced and binding of CCS to SOD1 impaired. As a result, this mutation causes reduced SOD1 activity and may impair other mechanisms important for normal Cu homeostasis. CCS-Arg163Trp represents the primary example of a human mutation in a gene coding for a Cu chaperone.
铜（Cu）是一种易获得和捐赠电子的微量元素，这种特性使其成为酶辅助因子的理想选择，但也使其成为自由基的来源，具有潜在的危险。为了调节细胞内 Cu 代谢，已经进化出了一套精细的伴侣蛋白和转运蛋白系统，尽管迄今为止尚未描述过人类 Cu 伴侣蛋白的突变。我们描述了一个来自近亲家庭的孩子，他继承了编码乙酰辅酶 A 转运蛋白的 SLC33A1 和编码超氧化物歧化酶 Cu 伴侣蛋白的 CCS 的同源纯合突变。CCS 突变 p.Arg163Trp 预测在位置 163 的高度保守精氨酸被色氨酸取代，而 CCS 的 II 结构域与超氧化物歧化酶 1（SOD1）直接相互作用。对患者成纤维细胞的生化分析、哺乳动物细胞转染、免疫沉淀分析和 Lys7Δ（CCS 同源物）酵母互补实验均支持该突变的致病性。CCS 的表达减少，CCS 与 SOD1 的结合受损。因此，这种突变导致 SOD1 活性降低，并可能损害其他对正常 Cu 内稳态很重要的机制。CCS-Arg163Trp 代表编码 Cu 伴侣蛋白的人类基因突变的主要实例。
