These two authors contributed equally to this work.
Molecular and biochemical characterization of a unique mutation in CCS, the human copper chaperone to superoxide dismutase†
Article first published online: 16 MAY 2012
© 2012 Wiley Periodicals, Inc.
Volume 33, Issue 8, pages 1207–1215, August 2012
How to Cite
Huppke, P., Brendel, C., Korenke, G. C., Marquardt, I., Donsante, A., Yi, L., Hicks, J. D., Steinbach, P. J., Wilson, C., Elpeleg, O., Møller, L. B., Christodoulou, J., Kaler, S. G. and Gärtner, J. (2012), Molecular and biochemical characterization of a unique mutation in CCS, the human copper chaperone to superoxide dismutase. Hum. Mutat., 33: 1207–1215. doi: 10.1002/humu.22099
Communicated by Daniel F. Nebert
- Issue published online: 13 JUL 2012
- Article first published online: 16 MAY 2012
- Accepted manuscript online: 16 APR 2012 01:19PM EST
- Manuscript Accepted: 30 MAR 2012
- Manuscript Received: 20 JAN 2012
- Intramural Research Program of the US National Institutes of Health. Grant Number: Project #HD008768-08
- The German Research Foundation. Grant Number: GA 354/9-1
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. Hum Mutat 33:1207–1215. © 2012 Wiley Periodicals, Inc.