Novel characteristics of a trafficking-defective G572R-hERG channel linked to hereditary long QT syndrome
Novel characteristics of a trafficking-defective G572R-hERG channel linked to hereditary long QT syndrome
复制标题
与遗传性长 QT 综合征相关的运输缺陷 G572R-hERG 通道的新特征。
DOI：
10.1016/s0828-282x(10)70439-6
复制
发表时间：
2010-10-01
影响因子：
6.2
通讯作者：
Huang, Chen
中科院分区：
文献类型：
--
作者：
Lian, Jiangfang;Huang, Na;Huang, Chen
BACKGROUND: The congenital long QT syndrome is a heterogeneous genetic disease associated with delayed cardiac repolarization, prolonged QT intervals, the development of ventricular arrhythmias and sudden death. Type 2 congenital long QT syndrome (LQT2) results from KCNH2 or hERG gene mutations. hERG encodes the K(v)11.1 alpha subunit of the rapidly activating delayed rectifier K+ current in the heart. Studies of mutant hERG channels indicate that most LQT2 missense mutations generate trafficking-deficient K(v)11.1 channels.OBJECTIVE: To identify the mechanism underlying G572R-hERG by using molecular and electrophysiological analyses.METHODS AND RESULTS: To elucidate the electrophysiological properties of the G572R-hERG mutant channels, mutant hERG subunits were heterologously expressed in HEK293 cells alone or in combination with wild-type (WT)-hERG subunits. Patch-clamp techniques were used to record currents, and double immunofluorescence protein tagging and Western blotting were performed to examine the cellular trafficking of mutant subunits. When expressed alone, G572R-hERG subunits were not present in the cell membrane and did not produce detectable currents. When coexpressed with WT-hERG subunits, G572R-hERG decreased current density and altered gating properties of the WT-hERG channel.CONCLUSION: The hERG-associated missense mutation G572R, like most LQT2 missense mutations, generates a trafficking-deficient phenotype. Furthermore, G572R-hERG causes a loss of function in hERG by a strong dominant negative effect on the WT-hERG channel.
