Dysfunction of ATP7B Splicing Variant Caused by Enhanced Interaction With COMMD1 in Wilson Disease

作者：Donghu Zhou, Huaduan Zi, Xiaoxi Yang, Xiaojin Li, Yanmeng Li, Anjian Xu, Bei Zhang, Wei Zhang, Xiaojuan Ou, Jidong Jia, Jian Huang, Hong You · 发表于：Cellular and Molecular Gastroenterology and Hepatology · 年份：2024 · DOI：10.1016/j.jcmgh.2024.101418 · 被引用次数：12 · 研究领域：Trace Elements in Health、Aluminum toxicity and tolerance in plants and animals、Drug Transport and Resistance Mechanisms

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 fo...