title: Correction of the copper transport defect of Menkes patient fibroblasts by expression of the Menkes and Wilson ATPases.
abstract: Menkes' disease is a fatal, X-linked, copper deficiency disorder that results from defective copper efflux from intestinal cells and inadequate copper delivery to other tissues, leading to deficiencies of critical copper-dependent enzymes. Wilson's disease is an autosomally inherited, copper toxicosis disorder resulting from defective biliary excretion of copper, which leads to copper accumulation in the liver. The ATP7A and ATP7B genes that are defective in patients with Menkes' and Wilson's diseases, respectively, encode transmembrane, P-type ATPase proteins (ATP7A or MNK and ATP7B or WND, respectively) that function to translocate copper across cellular membranes. In this study, the cDNAs derived from a normal human ATP7A gene and the murine ATP7B homologue, Atp7b, were separately transfected into an immortalized fibroblast cell line obtained from a Menkes' disease patient. Both MNK and WND expressed from plasmid constructs were able to correct the copper accumulation and copper retention phenotype of these cells. However, the two proteins responded differently to elevated extracellular copper levels. Although MNK showed copper-induced trafficking from the trans-Golgi network to the plasma membrane, in the same cell line the intracellular location of WND did not appear to be affected by elevated copper.
authors.affiliation: The Murdoch Institute Royal Children's Hospital, Parkville 3052, Australia.
authors.forename: S L
authors.initials: SL
authors.lastname: La Fontaine
authors.forename: S D
authors.initials: SD
authors.lastname: Firth
authors.forename: J
authors.initials: J
authors.lastname: Camakaris
authors.forename: A
authors.initials: A
authors.lastname: Englezou
authors.forename: M B
authors.initials: MB
authors.lastname: Theophilos
authors.forename: M J
authors.initials: MJ
authors.lastname: Petris
authors.forename: M
authors.initials: M
authors.lastname: Howie
authors.forename: P J
authors.initials: PJ
authors.lastname: Lockhart
authors.forename: M
authors.initials: M
authors.lastname: Greenough
authors.forename: H
authors.initials: H
authors.lastname: Brooks
authors.forename: R R
authors.initials: RR
authors.lastname: Reddel
authors.forename: J F
authors.initials: JF
authors.lastname: Mercer
mesh_terms: D000251:Adenosine Triphosphatases / Q000096:biosynthesis* / Q000235:genetics / Q000302:isolation & purification; D001692:Biological Transport; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000302:isolation & purification; D027682:Cation Transport Proteins; D002451:Cell Compartmentation; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D005347:Fibroblasts; D005455:Fluorescent Antibody Technique; D006801:Humans; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins / Q000096:biosynthesis
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases