The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders.

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  • Additional Information
    • Source:
      Publisher: Company of Biologists Ltd Country of Publication: England NLM ID: 101483332 Publication Model: Print Cited Medium: Internet ISSN: 1754-8411 (Electronic) Linking ISSN: 17548403 NLM ISO Abbreviation: Dis Model Mech Subsets: MEDLINE
    • Publication Information:
      Original Publication: Cambridge : Company of Biologists Ltd., c2008-
    • Subject Terms:
      Disease Models, Animal*; Adenosine Triphosphatases/*genetics ; Cation Transport Proteins/*genetics ; Copper/*toxicity ; Hepatolenticular Degeneration/*genetics ; Menkes Kinky Hair Syndrome/*genetics; Amino Acid Sequence ; Animals ; Copper-Transporting ATPases ; Dogs ; Endoplasmic Reticulum/metabolism ; Female ; Genetic Variation ; Genome-Wide Association Study ; Genotype ; Hep G2 Cells ; Humans ; Liver/metabolism ; Male ; Molecular Sequence Data ; Mutation, Missense ; Phenotype ; Protein Structure, Tertiary ; Sequence Analysis, DNA ; Sequence Homology, Amino Acid
    • Abstract:
      The deleterious effects of a disrupted copper metabolism are illustrated by hereditary diseases caused by mutations in the genes coding for the copper transporters ATP7A and ATP7B. Menkes disease, involving ATP7A, is a fatal neurodegenerative disorder of copper deficiency. Mutations in ATP7B lead to Wilson disease, which is characterized by a predominantly hepatic copper accumulation. The low incidence and the phenotypic variability of human copper toxicosis hamper identification of causal genes or modifier genes involved in the disease pathogenesis. The Labrador retriever was recently characterized as a new canine model for copper toxicosis. Purebred dogs have reduced genetic variability, which facilitates identification of genes involved in complex heritable traits that might influence phenotype in both humans and dogs. We performed a genome-wide association study in 235 Labrador retrievers and identified two chromosome regions containing ATP7A and ATP7B that were associated with variation in hepatic copper levels. DNA sequence analysis identified missense mutations in each gene. The amino acid substitution ATP7B:p.Arg1453Gln was associated with copper accumulation, whereas the amino acid substitution ATP7A:p.Thr327Ile partly protected against copper accumulation. Confocal microscopy indicated that aberrant copper metabolism upon expression of the ATP7B variant occurred because of mis-localization of the protein in the endoplasmic reticulum. Dermal fibroblasts derived from ATP7A:p.Thr327Ile dogs showed copper accumulation and delayed excretion. We identified the Labrador retriever as the first natural, non-rodent model for ATP7B-associated copper toxicosis. Attenuation of copper accumulation by the ATP7A mutation sheds an interesting light on the interplay of copper transporters in body copper homeostasis and warrants a thorough investigation of ATP7A as a modifier gene in copper-metabolism disorders. The identification of two new functional variants in ATP7A and ATP7B contributes to the biological understanding of protein function, with relevance for future development of therapy.
      (© 2016. Published by The Company of Biologists Ltd.)
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    • Contributed Indexing:
      Keywords: ATP7A; ATP7B; Dog; Liver
    • Accession Number:
      0 (Cation Transport Proteins)
      789U1901C5 (Copper)
      EC 3.6.1.- (Adenosine Triphosphatases)
      EC 7.2.2.8 (ATP7A protein, human)
      EC 7.2.2.8 (ATP7B protein, human)
      EC 7.2.2.8 (Copper-Transporting ATPases)
    • Publication Date:
      Date Created: 20160110 Date Completed: 20161018 Latest Revision: 20191210
    • Publication Date:
      20221213
    • Accession Number:
      PMC4728329
    • Accession Number:
      10.1242/dmm.020263
    • Accession Number:
      26747866