Molecular and Biochemical Characterization of a Unique Mutation in CCS, the Human Copper Chaperone to Superoxide Dismutase

作者：Huppke Peter^*; Brendel Cornelia; Korenke Georg Christoph; Marquardt Iris; Donsante Anthony; Yi Ling; Hicks Julia D; Steinbach Peter J; Wilson Callum; Elpeleg Orly; Moller Li**eth Birk; Christodoulou John; Kaler Stephen G; Gaertner Jutta

来源：Human Mutation, 2012, 33(8): 1207-1215.

DOI：10.1002/humu.22099

• CCS
• SOD1
• copper
• chaperone

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%26apos;s fibroblasts, mammalian cell transfections, immunoprecipitation assays, and Lys71 (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. Hum Mutat 33:1207-1215.

• 出版日期2012-8
• 单位NIH