Molecular and biochemical characterization of a unique mutation in CCS, the human copper chaperone to superoxide dismutase

Authors

  • Peter Huppke,

    Corresponding author
    1. Department of Pediatrics and Pediatric Neurology, Faculty of Medicine, Georg August University, Göttingen, Germany
    • Department of Pediatrics and Pediatric Neurology, Georg August University, Faculty of Medicine, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany.
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  • Cornelia Brendel,

    1. Department of Pediatrics and Pediatric Neurology, Faculty of Medicine, Georg August University, Göttingen, Germany
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  • Georg Christoph Korenke,

    1. Department of Pediatric Neurology, Children's Hospital, Oldenburg, Germany
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  • Iris Marquardt,

    1. Department of Pediatric Neurology, Children's Hospital, Oldenburg, Germany
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  • Anthony Donsante,

    1. 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
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  • Ling Yi,

    1. 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
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  • Julia D. Hicks,

    1. 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
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  • Peter J. Steinbach,

    1. Center for Molecular Modeling, Center for Information Technology, National Institutes of Health, Bethesda, Maryland
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  • Callum Wilson,

    1. National Metabolic Service, Starship Children's Hospital, Auckland, New Zealand
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  • Orly Elpeleg,

    1. Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel
    2. Department of Genetic and Metabolic Diseases, Hadassah, Hebrew University Medical Center, Jerusalem, Israel
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  • Lisbeth Birk Møller,

    1. Center for Applied Human Molecular Genetics, Kennedy Center, Glostrup, Denmark
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  • John Christodoulou,

    1. Western Sydney Genetics Program, The Children's Hospital at Westmead, Hawkesbury Rd, Westmead, Australia
    2. Disciplines of Pediatrics and Child Health and Genetic Medicine, University of Sydney, Sydney, Australia
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  • Stephen G. Kaler,

    1. 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
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    • These two authors contributed equally to this work.

  • Jutta Gärtner

    1. Department of Pediatrics and Pediatric Neurology, Faculty of Medicine, Georg August University, Göttingen, Germany
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    • These two authors contributed equally to this work.


  • Communicated by Daniel F. Nebert

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. Hum Mutat 33:1207–1215. © 2012 Wiley Periodicals, Inc.

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