A sodium channel pore mutation causing Brugada syndrome
A sodium channel pore mutation causing Brugada syndrome
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DOI：
10.1016/j.hrthm.2006.09.031
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发表时间：
2007-01-01
期刊：
影响因子：
5.5
通讯作者：
Dudley, Samuel C., Jr.
中科院分区：
文献类型：
--
作者：
Pfahnl, Arnold E.;Viswanathan, Prakash C.;Dudley, Samuel C., Jr.
Brugada和长QT 3型综合征与钠通道突变有关，临床上可引起心律失常，导致猝死。我们在一个Brugada综合征家族中发现了一个新的苏氨酸-异亮氨酸错义突变，位于心脏钠通道（SCN 5A）结构域I孔衬区附近的353位（T353 I）。男性和女性携带者在年轻时都有症状，具有典型的Brugada型心电图改变，校正QT间期相对正常。我们发现，与野生型通道相比，含有T353 I突变的SCN 5A的异源表达导致峰值宏观钠电流降低74% +/-6%。与绿色荧光蛋白融合的T353 I突变通道的构建体未能正确地运输到肌膜，其中大比例的通道被隔离在细胞内。过夜暴露于0.1 mM的钠通道阻断剂美西律，将T353 I通道向膜的运输增加至接近正常水平，但突变体通道显示出显著的晚期电流，其为200 ms时峰值钠电流的1.6% +/- 0.2%，结论：携带T353 I突变的患者的临床表现是Brugada综合征，可以用心脏Na+通道运输缺陷。然而，当缺陷得到改善时，突变的通道具有与长QT综合征一致的生物物理特性。缺乏与长QT综合征相关的表型变化可以解释为T353 I诱导的运输缺陷减少了肌膜上存在持续电流的突变通道的数量。
BACKGROUND Brugada and long QT type 3 syndromes are linked to sodium channel mutations and clinically cause arrhythmias that lead to sudden death. We have identified a novel threonine-to-isoleucine missense mutation at position 353 (T353I) adjacent to the pore-lining region of domain I of the cardiac sodium channel (SCN5A) in a family with Brugada syndrome. Both male and female carriers are symptomatic at young ages, have typical Brugada-type electrocardiogram changes, and have relatively normal corrected QT intervals.OBJECTIVES To characterize the properties of the newly identified cardiac sodium channel (SCN5A) mutation at the cellular level.RESULTS Using whole-cell voltage clamp, we found that heterologous expression of SCN5A containing the T353I mutation resulted in 74% +/- 6% less peak macroscopic sodium current when compared with wild-type channels. A construct of the T353I mutant channel fused with green fluorescent protein failed to traffic properly to the sarcolemma, with a large proportion of channels sequestered intracellularly. Overnight exposure to 0.1 mM mexiletine, a Na+ channel blocking agent, increased T353I channel trafficking to the membrane to near normal levels, but the mutant channels showed a significant late current that was 1.6% +/- 0.2% of peak sodium current at 200 ms, a finding seen with long QT mutations.CONCLUSIONS The clinical presentation of patients carrying the T353I mutation is that of Brugada syndrome and could be explained by a cardiac Na+ channel trafficking defect. However, when the defect was ameliorated, the mutated channels had biophysical properties consistent with long QT syndrome. The lack of phenotypic changes associated with the long QT syndrome could be explained by a T353I-induced trafficking defect reducing the number of mutant channels with persistent currents present at the sarcolemma.