Molecular and biochemical characterization of a unique mutation in CCS, the human copper chaperone to superoxide dismutase |
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| Authors: | Huppke Peter Brendel Cornelia Korenke Georg Christoph Marquardt Iris Donsante Anthony Yi Ling Hicks Julia D Steinbach Peter J Wilson Callum Elpeleg Orly Møller Lisbeth Birk Christodoulou John Kaler Stephen G Gärtner Jutta |
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| Affiliation: | 1. Department of Pediatrics and Pediatric Neurology, Faculty of Medicine, Georg August University, G?ttingen, Germany;2. Department of Pediatric Neurology, Children's Hospital, Oldenburg, Germany;3. Unit on Human Copper Metabolism, Molecular Medicine Program, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland;4. Center for Molecular Modeling, Center for Information Technology, National Institutes of Health, Bethesda, Maryland;5. National Metabolic Service, Starship Children's Hospital, Auckland, New Zealand;6. Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel;7. Department of Genetic and Metabolic Diseases, Hadassah, Hebrew University Medical Center, Jerusalem, Israel;8. Center for Applied Human Molecular Genetics, Kennedy Center, Glostrup, Denmark;9. Western Sydney Genetics Program, The Children's Hospital at Westmead, Hawkesbury Rd, Westmead, Australia;10. Disciplines of Pediatrics and Child Health and Genetic Medicine, University of Sydney, Sydney, Australia |
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| Abstract: | 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. |
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| Keywords: | CCS SOD1 copper chaperone |
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