ArticleProceedings of the National Academy of Sciences of the United States of America2014
Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers, 1 of them a synthesis that pooled it.
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Who cites it
35 citing papers in PubMed, 1 synthesis or guideline pooled it, 51 citations in OpenAlex.
- Wilson disease-causing mutations in the carboxyl terminus of ATP7B regulates its localization and Golgi exit selectively in the unpolarized cells.Metallomics : integrated biometal science · 2023Pooled it
- Clinical characteristics and genetic features of patients with Wilson's disease in southwestern China.Orphanet journal of rare diseases · 2026Article
- The pathogenesis of liver fibrosis in Wilson's disease: hepatocyte injury and regulation mediated by copper metabolism dysregulation.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2026Review
- Multiscale computational genomics in Wilson disease: from atomic dynamics to clinical prediction.Frontiers in genetics · 2026Review
- Transition metal transporting P-type ATPases: terminal metal-binding domains serve as sensors for autoinhibitory tails.The FEBS journal · 2025Article
- Computational studies on the functional and structural impact of pathogenic mutations in enzymes.Protein science : a publication of the Protein Society · 2025Review
- Functional Screen of Wilson Disease ATP7B Variants Reveals Residual Transport Activities.Human mutation · 2025Article
- Clinical and genetic characterization of patients with late onset Wilson's disease.NPJ genomic medicine · 2024Article
- Regulation of the apico-basolateral trafficking polarity of the homologous copper-ATPases ATP7A and ATP7B.Journal of cell science · 2024Article
- Epidemiology of Wilson's Disease and Pathogenic Variants of theInternational journal of molecular sciences · 2024Review
- Early Onset of Wilson's Disease and Possible Role of Disease-Modifying Genes: A Case Report and Literature Review.Case reports in hepatology · 2024Article
- Human-modified canids in human-modified landscapes: The evolutionary consequences of hybridization for grey wolves and free-ranging domestic dogs.Evolutionary applications · 2021Article
- 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
- [Progress in molecular mechanism of hepatolenticular degeneration induced by ATP7B gene mutation].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2020Review
- Article
- An enhanced workflow for variant interpretation in UniProtKB/Swiss-Prot improves consistency and reuse in ClinVar.Database : the journal of biological databases and curation · 2019Article
- [Misdiagnosis of Wilson's disease despite positive genetics].Der Nervenarzt · 2018Article
- Manganese transport and toxicity in polarized WIF-B hepatocytes.American journal of physiology. Gastrointestinal and liver physiology · 2018Article
- Role of the Golgi Apparatus in the Blood-Brain Barrier: Golgi Protection May Be a Targeted Therapy for Neurological Diseases.Molecular neurobiology · 2018Review
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
Wilson disease (WD) is a monogenic autosomal-recessive disorder of copper accumulation that leads to liver failure and/or neurological deficits. WD is caused by mutations in ATP7B, a transporter that loads Cu(I) onto newly synthesized cupro-enzymes in the trans-Golgi network (TGN) and exports excess copper out of cells by trafficking from the TGN to the plasma membrane. To date, most WD mutations have been shown to disrupt ATP7B activity and/or stability. Using a multidisciplinary approach, including clinical analysis of patients, cell-based assays, and computational studies, we characterized a patient mutation, ATP7B(S653Y), which is stable, does not disrupt Cu(I) transport, yet renders the protein unable to exit the TGN. Bulky or charged substitutions at position 653 mimic the phenotype of the patient mutation. Molecular modeling and dynamic simulation suggest that the S653Y mutation induces local distortions within the transmembrane (TM) domain 1 and alter TM1 interaction with TM2. S653Y abolishes the trafficking-stimulating effects of a secondary mutation in the N-terminal apical targeting domain. This result indicates a role for TM1/TM2 in regulating conformations of cytosolic domains involved in ATP7B trafficking. Taken together, our experiments revealed an unexpected role for TM1/TM2 in copper-regulated trafficking of ATP7B and defined a unique class of WD mutants that are transport-competent but trafficking-defective. Understanding the precise consequences of WD-causing mutations will facilitate the development of advanced mutation-specific therapies.
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