title: Molecular and biochemical characterization of a unique mutation in CCS, the human copper chaperone to superoxide dismutase.
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.
authors.affiliation: Department of Pediatrics and Pediatric Neurology, Faculty of Medicine, Georg August University, Göttingen, Germany. phuppke@med.uni-goettingen.de
authors.forename: Peter
authors.initials: P
authors.lastname: Huppke
authors.forename: Cornelia
authors.initials: C
authors.lastname: Brendel
authors.forename: Georg Christoph
authors.initials: GC
authors.lastname: Korenke
authors.forename: Iris
authors.initials: I
authors.lastname: Marquardt
authors.forename: Anthony
authors.initials: A
authors.lastname: Donsante
authors.forename: Ling
authors.initials: L
authors.lastname: Yi
authors.forename: Julia D
authors.initials: JD
authors.lastname: Hicks
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Steinbach
authors.forename: Callum
authors.initials: C
authors.lastname: Wilson
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.forename: Lisbeth Birk
authors.initials: LB
authors.lastname: Møller
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Kaler
authors.forename: Jutta
authors.initials: J
authors.lastname: Gärtner
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: C114678:CCS protein, human; D018832:Molecular Chaperones; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1