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Analysis of Wilson disease mutations revealed that interactions between different ATP7B mutants modify their properties
Wilson disease (WD) is an autosomal-recessive disorder caused by mutations in the copper (Cu)-transporter ATP7B. Thus far, studies of WD mutations have been limited to analysis of ATP7B mutants in the homozygous states. However, the majority of WD patients are compound-heterozygous, and how differen...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418023/ https://www.ncbi.nlm.nih.gov/pubmed/32778786 http://dx.doi.org/10.1038/s41598-020-70366-7 |
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author | Roy, Shubhrajit McCann, Courtney J. Ralle, Martina Ray, Kunal Ray, Jharna Lutsenko, Svetlana Jayakanthan, Samuel |
author_facet | Roy, Shubhrajit McCann, Courtney J. Ralle, Martina Ray, Kunal Ray, Jharna Lutsenko, Svetlana Jayakanthan, Samuel |
author_sort | Roy, Shubhrajit |
collection | PubMed |
description | Wilson disease (WD) is an autosomal-recessive disorder caused by mutations in the copper (Cu)-transporter ATP7B. Thus far, studies of WD mutations have been limited to analysis of ATP7B mutants in the homozygous states. However, the majority of WD patients are compound-heterozygous, and how different mutations on two alleles impact ATP7B properties is unclear. We characterized five mutations identified in Indian WD patients, first by expressing each alone and then by co-expressing two mutants with dissimilar properties. Mutations located in the regulatory domains of ATP7B—A595T, S1362A, and S1426I—do not affect ATP7B targeting to the trans-Golgi network (TGN) but reduce its Cu-transport activity. The S1362A mutation also inhibits Cu-dependent trafficking from the TGN. The G1061E and G1101R mutations, which are located within the ATP-binding domain, cause ATP7B retention in the endoplasmic reticulum, inhibit Cu-transport, and lower ATP7B protein abundance. Co-expression of the A595T and G1061E mutations, which mimics the compound-heterozygous state of some WD patients, revealed an interaction between these mutants that altered their intracellular localization and trafficking under both low and high Cu conditions. These findings highlight the need to study WD variants in both the homozygous and compound-heterozygous states to better understand the genotype–phenotype correlations and incomplete penetrance observed in WD. |
format | Online Article Text |
id | pubmed-7418023 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-74180232020-08-13 Analysis of Wilson disease mutations revealed that interactions between different ATP7B mutants modify their properties Roy, Shubhrajit McCann, Courtney J. Ralle, Martina Ray, Kunal Ray, Jharna Lutsenko, Svetlana Jayakanthan, Samuel Sci Rep Article Wilson disease (WD) is an autosomal-recessive disorder caused by mutations in the copper (Cu)-transporter ATP7B. Thus far, studies of WD mutations have been limited to analysis of ATP7B mutants in the homozygous states. However, the majority of WD patients are compound-heterozygous, and how different mutations on two alleles impact ATP7B properties is unclear. We characterized five mutations identified in Indian WD patients, first by expressing each alone and then by co-expressing two mutants with dissimilar properties. Mutations located in the regulatory domains of ATP7B—A595T, S1362A, and S1426I—do not affect ATP7B targeting to the trans-Golgi network (TGN) but reduce its Cu-transport activity. The S1362A mutation also inhibits Cu-dependent trafficking from the TGN. The G1061E and G1101R mutations, which are located within the ATP-binding domain, cause ATP7B retention in the endoplasmic reticulum, inhibit Cu-transport, and lower ATP7B protein abundance. Co-expression of the A595T and G1061E mutations, which mimics the compound-heterozygous state of some WD patients, revealed an interaction between these mutants that altered their intracellular localization and trafficking under both low and high Cu conditions. These findings highlight the need to study WD variants in both the homozygous and compound-heterozygous states to better understand the genotype–phenotype correlations and incomplete penetrance observed in WD. Nature Publishing Group UK 2020-08-10 /pmc/articles/PMC7418023/ /pubmed/32778786 http://dx.doi.org/10.1038/s41598-020-70366-7 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Roy, Shubhrajit McCann, Courtney J. Ralle, Martina Ray, Kunal Ray, Jharna Lutsenko, Svetlana Jayakanthan, Samuel Analysis of Wilson disease mutations revealed that interactions between different ATP7B mutants modify their properties |
title | Analysis of Wilson disease mutations revealed that interactions between different ATP7B mutants modify their properties |
title_full | Analysis of Wilson disease mutations revealed that interactions between different ATP7B mutants modify their properties |
title_fullStr | Analysis of Wilson disease mutations revealed that interactions between different ATP7B mutants modify their properties |
title_full_unstemmed | Analysis of Wilson disease mutations revealed that interactions between different ATP7B mutants modify their properties |
title_short | Analysis of Wilson disease mutations revealed that interactions between different ATP7B mutants modify their properties |
title_sort | analysis of wilson disease mutations revealed that interactions between different atp7b mutants modify their properties |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418023/ https://www.ncbi.nlm.nih.gov/pubmed/32778786 http://dx.doi.org/10.1038/s41598-020-70366-7 |
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