Dysfunction of ATP7B Splicing Variant Caused by Enhanced Interaction With COMMD1 in Wilson DiseaseSummary
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+1...
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Elsevier
2025-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X24001735 |
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| author | Donghu Zhou Huaduan Zi Xiaoxi Yang Xiaojin Li Yanmeng Li Anjian Xu Bei Zhang Wei Zhang Xiaojuan Ou Jidong Jia Jian Huang Hong You |
| author_facet | Donghu Zhou Huaduan Zi Xiaoxi Yang Xiaojin Li Yanmeng Li Anjian Xu Bei Zhang Wei Zhang Xiaojuan Ou Jidong Jia Jian Huang Hong You |
| author_sort | Donghu Zhou |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9f706b19e13f4b33b71f93fef9e223bc |
| institution | Kabale University |
| issn | 2352-345X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj-art-9f706b19e13f4b33b71f93fef9e223bc2025-01-17T04:49:35ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2025-01-01192101418Dysfunction of ATP7B Splicing Variant Caused by Enhanced Interaction With COMMD1 in Wilson DiseaseSummaryDonghu Zhou0Huaduan Zi1Xiaoxi Yang2Xiaojin Li3Yanmeng Li4Anjian Xu5Bei Zhang6Wei Zhang7Xiaojuan Ou8Jidong Jia9Jian Huang10Hong You11Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University; Beijing, China; Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China; National Clinical Research Center for Digestive Diseases, Beijing, China; Correspondence Address correspondence to: Donghu Zhou, Capital Medical University Affiliated Beijing Friendship Hospital, 95 Yongan Road, Beijing, Beijing 100050, China.Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University; Beijing, China; Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China; National Clinical Research Center for Digestive Diseases, Beijing, ChinaBeijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University; Beijing, China; Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China; National Clinical Research Center for Digestive Diseases, Beijing, ChinaBeijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University; Beijing, China; Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China; National Clinical Research Center for Digestive Diseases, Beijing, ChinaBeijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University; Beijing, China; Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China; National Clinical Research Center for Digestive Diseases, Beijing, ChinaBeijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University; Beijing, China; Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China; National Clinical Research Center for Digestive Diseases, Beijing, ChinaBeijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University; Beijing, China; Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China; National Clinical Research Center for Digestive Diseases, Beijing, ChinaClinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China; National Clinical Research Center for Digestive Diseases, Beijing, China; Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, ChinaClinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China; National Clinical Research Center for Digestive Diseases, Beijing, China; Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, ChinaClinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China; National Clinical Research Center for Digestive Diseases, Beijing, China; Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, ChinaBeijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University; Beijing, China; Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China; National Clinical Research Center for Digestive Diseases, Beijing, China; Jian Huang, Capital Medical University Affiliated Beijing Friendship Hospital, 95 Yongan Road, Beijing, Beijing 100050, China.Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University; Beijing, China; Clinical Research Center for Rare Liver Diseases, Capital Medical University, Beijing, China; National Clinical Research Center for Digestive Diseases, Beijing, China; Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China; Hong You, Capital Medical University Affiliated Beijing Friendship Hospital, 95 Yongan Road, Beijing, Beijing 100050, China.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.http://www.sciencedirect.com/science/article/pii/S2352345X24001735ATP7BCellular LocalizationCOMMD1Protein StabilitySplicing MutationWilson Disease |
| spellingShingle | Donghu Zhou Huaduan Zi Xiaoxi Yang Xiaojin Li Yanmeng Li Anjian Xu Bei Zhang Wei Zhang Xiaojuan Ou Jidong Jia Jian Huang Hong You Dysfunction of ATP7B Splicing Variant Caused by Enhanced Interaction With COMMD1 in Wilson DiseaseSummary Cellular and Molecular Gastroenterology and Hepatology ATP7B Cellular Localization COMMD1 Protein Stability Splicing Mutation Wilson Disease |
| title | Dysfunction of ATP7B Splicing Variant Caused by Enhanced Interaction With COMMD1 in Wilson DiseaseSummary |
| title_full | Dysfunction of ATP7B Splicing Variant Caused by Enhanced Interaction With COMMD1 in Wilson DiseaseSummary |
| title_fullStr | Dysfunction of ATP7B Splicing Variant Caused by Enhanced Interaction With COMMD1 in Wilson DiseaseSummary |
| title_full_unstemmed | Dysfunction of ATP7B Splicing Variant Caused by Enhanced Interaction With COMMD1 in Wilson DiseaseSummary |
| title_short | Dysfunction of ATP7B Splicing Variant Caused by Enhanced Interaction With COMMD1 in Wilson DiseaseSummary |
| title_sort | dysfunction of atp7b splicing variant caused by enhanced interaction with commd1 in wilson diseasesummary |
| topic | ATP7B Cellular Localization COMMD1 Protein Stability Splicing Mutation Wilson Disease |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X24001735 |
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