ArticleProceedings of the National Academy of Sciences of the United States of America2011
Cellular copper levels determine the phenotype of the Arg875 variant of ATP7B/Wilson disease protein.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 50 citations in OpenAlex.
- Copper in Human Health and Disease: Insights from Inherited Disorders.Physiology (Bethesda, Md.) · 2026Review
- ATPase copper transporting beta contributes to cisplatin resistance as a regulatory factor of extracellular vesicles in head and neck squamous cell carcinoma.Cancer gene therapy · 2026Article
- Recent advances in research on high-frequency mutations in the ATP7B gene associated with Wilson disease in the Chinese population: from genetic evolution to precision medicine.Frontiers in molecular biosciences · 2026Review
- Clinical and genetic characterization of patients with late onset Wilson's disease.NPJ genomic medicine · 2024Article
- Spectrum of Pathogenic Variants of the ATP7B Gene and Genotype-Phenotype Correlation in Eastern Eurasian Patient Cohorts with Wilson's Disease.Biomedicines · 2024Article
- Epidemiology of Wilson's Disease and Pathogenic Variants of theInternational journal of molecular sciences · 2024Review
- Copper binding leads to increased dynamics in the regulatory N-terminal domain of full-length human copper transporter ATP7B.PLoS computational biology · 2022Article
- Role of Copper on Mitochondrial Function and Metabolism.Frontiers in molecular biosciences · 2021Review
- Retromer retrieves the Wilson disease protein ATP7B from endolysosomes in a copper-dependent manner.Journal of cell science · 2020Article
- Analysis of Wilson disease mutations revealed that interactions between different ATP7B mutants modify their properties.Scientific reports · 2020Article
- Metallothioneins regulate ATP7A trafficking and control cell viability during copper deficiency and excess.Scientific reports · 2020Article
- Single nucleotide polymorphisms in the human ATP7B gene modify the properties of the ATP7B protein.Metallomics : integrated biometal science · 2019Article
- Genetics and epigenetic factors of Wilson disease.Annals of translational medicine · 2019Review
- ATP7A and ATP7B copper transporters have distinct functions in the regulation of neuronal dopamine-β-hydroxylase.The Journal of biological chemistry · 2018Article
- Cerebrospinal Fluid-Directed rAAV9-rsATP7A Plus Subcutaneous Copper Histidinate Advance Survival and Outcomes in a Menkes Disease Mouse Model.Molecular therapy. Methods & clinical development · 2018Article
- A glimpse into the regulation of the Wilson disease protein, ATP7B, sheds light on the complexity of mammalian apical trafficking pathways.Metallomics : integrated biometal science · 2018Review
- The metal chaperone Atox1 regulates the activity of the human copper transporter ATP7B by modulating domain dynamics.The Journal of biological chemistry · 2017Article
- The genetics of Wilson disease.Handbook of clinical neurology · 2017Review
- The Activity of Menkes Disease Protein ATP7A Is Essential for Redox Balance in Mitochondria.The Journal of biological chemistry · 2016Article
- The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders.Disease models & mechanisms · 2016Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
In human disorders, the genotype-phenotype relationships are often complex and influenced by genetic and/or environmental factors. Wilson disease (WD) is a monogenic disorder caused by mutations in the copper-transporting P-type ATPase ATP7B. WD shows significant phenotypic diversity even in patients carrying identical mutations; the basis for such diverse manifestations is unknown. We demonstrate that the 2623A/G polymorphism (producing the Gly(875) → Arg substitution in the A-domain of ATP7B) drastically alters the intracellular properties of ATP7B, whereas copper reverses the effects. Under basal conditions, the common Gly(875) variant of ATP7B is targeted to the trans-Golgi network (TGN) and transports copper into the TGN lumen. In contrast, the Arg(875) variant is located in the endoplasmic reticulum (ER) and does not deliver copper to the TGN. Elevated copper corrects the ATP7B-Arg(875) phenotype. Addition of only 0.5-5 μM copper triggers the exit of ATP7B-Arg(875) from the ER and restores copper delivery to the TGN. Analysis of the recombinant A-domains by NMR suggests that the ER retention of ATP7B-Arg(875) is attributable to increased unfolding of the Arg(875)-containing A-domain. Copper is not required for the folding of ATP7B-Arg(875) during biosynthesis, but it stabilizes protein and stimulates its activity. A chemotherapeutical drug, cisplatin, that mimics a copper-bound state of ATP7B also corrects the "disease-like" phenotype of ATP7B-Arg(875) and promotes its TGN targeting and transport function. We conclude that in populations harboring the Arg(875) polymorphism, the levels of bioavailable copper may play a vital role in the manifestations of WD.
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