Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism
Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism
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DOI：
10.1161/circulationaha.105.570200
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发表时间：
2006-01-24
期刊：
影响因子：
37.8
通讯作者：
January, CT
中科院分区：
文献类型：
--
作者：
Anderson, CL;Delisle, BP;January, CT
背景- KCNH2或人类以太-a-go-go相关基因（hERG）编码心脏快速激活延迟整流K+电流（I-Kr）的Kv11.1 α亚基。2型先天性长qt综合征（LQT2）是KCNH2突变导致Kv11.1通道功能丧失的结果。已经确定了几种机制，包括Kv11.1通道合成的破坏（1类），蛋白质运输（2类），门控（3类）或渗透（4类）。对于少数2类LQT2-Kv11.1通道，有可能增加Kv11.1电流（I-Kv11.1）的表面膜表达。我们验证了以下假设：(1)大多数LQT2错义突变产生运输缺陷的Kv11.1通道，(2)它们的运输缺陷表型可以被纠正。方法与结果-在HEK293细胞中表达野生型(WT)- kv11.1通道和34个错义LQT2-Kv11.1通道。通过Western blot分析，28个LQT2-Kv11.1通道具有运输缺陷（2类）表型。对于大多数这些突变，当细胞在降低温度（27℃）下孵育24小时或在药物E4031或thapsigargin中孵育时，2类表型可以得到纠正。6个LQT2-Kv11.1通道中有4个具有野生型样转运表型，但不会导致Kv11.1功能丧失，这表明这些通道是不常见的序列变异。结论：本研究首次确定了LQT2中Kv11.1通道功能缺失的显性2类机制，并报告了许多这些突变通道的2类表型可以被纠正。这表明，如果能够开发出纠正蛋白质转运异常的治疗策略，可能会为LQT2患者提供临床益处。
Background - The KCNH2 or human ether-a-go-go related gene (hERG) encodes the Kv11.1 alpha-subunit of the rapidly activating delayed rectifier K+ current (I-Kr) in the heart. Type 2 congenital long-QT syndrome (LQT2) results from KCNH2 mutations that cause loss of Kv11.1 channel function. Several mechanisms have been identified, including disruption of Kv11.1 channel synthesis (class 1), protein trafficking (class 2), gating (class 3), or permeation (class 4). For a few class 2 LQT2-Kv11.1 channels, it is possible to increase surface membrane expression of Kv11.1 current (I-Kv11.1). We tested the hypotheses that (1) most LQT2 missense mutations generate trafficking-deficient Kv11.1 channels, and (2) their trafficking-deficient phenotype can be corrected.Methods and Results - Wild-type (WT)-Kv11.1 channels and 34 missense LQT2-Kv11.1 channels were expressed in HEK293 cells. With Western blot analyses, 28 LQT2-Kv11.1 channels had a trafficking-deficient (class 2) phenotype. For the majority of these mutations, the class 2 phenotype could be corrected when cells were incubated for 24 hours at reduced temperature (27 degrees C) or in the drugs E4031 or thapsigargin. Four of the 6 LQT2-Kv11.1 channels that had a wild-type- like trafficking phenotype did not cause loss of Kv11.1 function, which suggests that these channels are uncommon sequence variants.Conclusions - This is the first study to identify a dominant mechanism, class 2, for the loss of Kv11.1 channel function in LQT2 and to report that the class 2 phenotype for many of these mutant channels can be corrected. This suggests that if therapeutic strategies to correct protein trafficking abnormalities can be developed, it may offer clinical benefits for LQT2 patients.