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Lamin A mutation impairs interaction with nucleoporin NUP155 and disrupts nucleocytoplasmic transport in atrial fibrillation
Author(s) -
Han Meng,
Zhao Miao,
Cheng Chen,
Huang Yuan,
Han Shengna,
Li Wenjuan,
Tu Xin,
Luo Xuan,
Yu Xiaoling,
Liu Yinan,
Chen Qiuyun,
Ren Xiang,
Wang Qing Kenneth,
Ke Tie
Publication year - 2019
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23691
Subject(s) - lamin , nucleoporin , biology , mutation , nuclear lamina , nuclear pore , microbiology and biotechnology , hsp70 , nuclear transport , genetics , nuclear protein , cell nucleus , nucleus , gene , heat shock protein , transcription factor
Abstract Atrial fibrillation (AF) is the most common cardiac arrhythmia. Here, we show the identification and functional characterization of one AF‐associated mutation p.Arg399Cys in lamin A/C. Co‐immunoprecipitation and GST pull‐down assays demonstrate that lamin A/C interacts with NUP155, which is a nucleoporin and causes AF when mutated. Lamin A/C mutation p.Arg399Cys impairs the interaction between lamin A/C and NUP155, and increases extractability of NUP155 from the nuclear envelope (NE). Mutation p.Arg399Cys leads to aggregation of lamin A/C in the nucleus, although it does not impair the integrity of NE upon cellular stress. Mutation p.Arg399Cys inhibits the export of HSP70 mRNA and the nuclear import of HSP70 protein. Electrophysiological studies show that mutation p.Arg399Cys decreases the peak cardiac sodium current by decreasing the cell surface expression level of cardiac sodium channel Na v 1.5, but does not affect I Kr potassium current. In conclusion, our results indicate that lamin A/C mutation p.Arg399Cys weakens the interaction between nuclear lamina (lamin A/C) and the nuclear pore complex (NUP155), leading to the development of AF. The findings provide a novel molecular mechanism for the pathogenesis of AF.