التفاصيل البيبلوغرافية
| العنوان: |
Dysfunction of ATP7B Splicing Variant Caused by Enhanced Interaction With COMMD1 in Wilson DiseaseSummary |
| المؤلفون: |
Donghu Zhou, Huaduan Zi, Xiaoxi Yang, Xiaojin Li, Yanmeng Li, Anjian Xu, Bei Zhang, Wei Zhang, Xiaojuan Ou, Jidong Jia, Jian Huang, Hong You |
| المصدر: |
Cellular and Molecular Gastroenterology and Hepatology, Vol 19, Iss 2, Pp 101418- (2025) |
| بيانات النشر: |
Elsevier, 2025. |
| سنة النشر: |
2025 |
| المجموعة: |
LCC:Diseases of the digestive system. Gastroenterology |
| مصطلحات موضوعية: |
ATP7B, Cellular Localization, COMMD1, Protein Stability, Splicing Mutation, Wilson Disease, Diseases of the digestive system. Gastroenterology, RC799-869 |
| الوصف: |
Background & Aims: The association between Wilson disease and various ATP7B mutations is well-established; however, the molecular mechanism underlying the functional consequence of these mutations, particularly the splicing mutations, remains unclear. This study focused on the ATP7B c.1543+1G>C variant, to reveal a universal pathogenic mechanism of the ATP7B mutants with altered N-terminus. Methods: The splicing assay and RNA pull-down were performed to explore the mechanism of the aberrant splicing. The ATP7B knockout HuH-7 cell line and Atp7b-/- mice were created, and the functional consequence of the mutant ATP7B were evaluated in vitro and in vivo. Results: The c.1543+1G>C mutation resulted in the skipping of ATP7B exon 3, and the mutant ATP7B showed a loss of trans-Golgi network localization and was degraded via the ubiquitin-proteasome pathway, facilitated by enhanced interactions with COMMD1. Elevated intercellular copper concentration and reduced survival rate were observed in HuH-7 cells expressing mutant ATP7B. Restoration of wild-type ATP7B in Atp7b-/- mice resulted in a substantial improvement in phenotype, whereas mice treated with mutant ATP7B did not demonstrate equivalent benefits. Conclusions: Our research investigated the pathogenicity and mechanism of ATP7B c.1543+1G>C variant, with particular focus on its enhanced interaction with COMMD1 as a potential universal mechanism contributing to the dysfunction of various ATP7B variants. These findings provide a foundation for the development of innovative therapeutic strategies that target abnormal splicing events in a range of hereditary diseases, including Wilson disease. |
| نوع الوثيقة: |
article |
| وصف الملف: |
electronic resource |
| اللغة: |
English |
| تدمد: |
2352-345X |
| Relation: |
http://www.sciencedirect.com/science/article/pii/S2352345X24001735; https://doaj.org/toc/2352-345X |
| DOI: |
10.1016/j.jcmgh.2024.101418 |
| URL الوصول: |
https://doaj.org/article/9f706b19e13f4b33b71f93fef9e223bc |
| رقم الانضمام: |
edsdoj.9f706b19e13f4b33b71f93fef9e223bc |
| قاعدة البيانات: |
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