Novel Mechanisms of Trafficking Defect Caused by KCNQ1 Mutations Found in Long QT Syndrome
Novel Mechanisms of Trafficking Defect Caused by KCNQ1 Mutations Found in Long QT Syndrome
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DOI：
10.1074/jbc.m109.017293
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发表时间：
2009-12-11
影响因子：
4.8
通讯作者：
Kimura, Akinori
中科院分区：
文献类型：
--
作者：
Sato, Akinori;Arimura, Takuro;Kimura, Akinori
长QT综合征（LQTS）是一种遗传性心律失常，由心脏离子通道（包括钾通道KvLQT 1）基因突变引起。LQTS的遗传通常为常染色体显性遗传，但在伴有听力损失的LQTS患者中可观察到常染色体隐性遗传。在这项研究中，我们调查了KCNQ 1突变，缺失（delV 595）和移码（P631 fs/19），这是在复合杂合子状态下确定的两个常染色体隐性LQTS患者不伴有听力损失的功能改变。功能分析表明，这两个突变损害细胞表面表达由于运输缺陷。突变严重影响外向钾电流，没有明显的显性负效应。发现delV 595损害亚基结合，而P631 fs/19由于新添加的含有两个保留基序（R（633）GR和（RLR）-L-646）的19个氨基酸序列而保留在内质网中。这是首次报道心肌离子通道转运异常的新机制，为LQTS的分子机制研究提供了新的思路。
Long QT syndrome (LQTS) is a hereditary arrhythmia caused by mutations in genes for cardiac ion channels, including a potassium channel, KvLQT1. Inheritance of LQTS is usually autosomal-dominant, but autosomal-recessive inheritance can be observed in patients with LQTS accompanied by hearing loss. In this study, we investigated the functional alterations caused by KCNQ1 mutations, a deletion (delV595) and a frameshift (P631fs/19), which were identified in compound heterozygous state in two patients with autosomal-recessive LQTS not accompanied by hearing loss. Functional analyses showed that both mutations impaired cell surface expression due to trafficking defects. The mutations severely affected outward potassium currents without apparent dominant negative effects. It was found that delV595 impaired subunit binding, whereas P631fs/19 was retained in endoplasmic reticulum due to the newly added 19-amino acid sequence containing two retention motifs (R(633)GR and (RLR)-L-646). This is the first report of novel mechanisms for trafficking abnormality of cardiac ion channels, providing us new insights into the molecular mechanisms of LQTS.