A novel missense mutation in the SCN5A gene associated with Brugada syndrome bidirectionally affecting blocking actions of antiarrhythmic drugs
A novel missense mutation in the SCN5A gene associated with Brugada syndrome bidirectionally affecting blocking actions of antiarrhythmic drugs
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DOI：
10.1111/j.1540-8167.2005.40711.x
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发表时间：
2005-05-01
影响因子：
2.7
通讯作者：
Imoto, K
中科院分区：
文献类型：
--
作者：
Itoh, H;Shimizu, M;Imoto, K
Brugada综合征和钠通道阻滞。Brugada综合征是一种遗传性心脏疾病，由编码心脏钠通道α亚基的SCN 5A基因突变引起，可导致心室颤动和猝死。不小心使用抗心律失常药物可能会通过进一步降低钠电流（I-Na）引发致命的心律失常。我们研究了一个Brugada综合征病例的分子机制，该病例对Ic类抗肿瘤药物无反应。对Brugada综合征患者的分子遗传学研究发现了SCN 5A中的一种新突变，该突变导致结构域I（IS 6）的S6中丝氨酸取代天冬酰胺（N406 S）。在这种情况下，用匹西卡尼（一种Ic类抗心律失常药物）进行的激发试验未能加重ST段抬高。在HEK 293细胞中与β 1亚基一起表达的N406 S-突变体通道的电生理分析表明，激活的电压依赖性正移了16 mV，中间失活增强。而紧张性阻滞的pilsicainide没有改变N406 S通道，使用依赖性阻滞pilsicainide几乎完全废除，与阴性激发试验的临床结果一致。相反，N406 S通道显示出比野生型通道更强的奎尼丁使用依赖性阻断。我们证明了一个新的Brugada突变N406 S，这是与不协调的影响，阻断作用的抗肿瘤药物，以及多通道门控缺陷。我们强调抗肿瘤药物可能对通道突变的患者产生不可预测的作用。
Brugada Syndrome and Sodium Channel Blockade. Brugada syndrome is an inherited cardiac disorder caused by mutations in the SCN5A gene encoding the cardiac sodium channel alpha subunit, which can lead ventricular fibrillation and sudden death. Inattentive use of antiarrhythmic drugs potentially triggers fatal cardiac arrhythmias through further reduction of sodium current (I-Na). We studied the molecular mechanism underlying a case of Brugada syndrome that showed no response to a class Ic antiarrhythmic drug. Molecular genetic studies of a patient with Brugada syndrome identified a novel mutation in SCN5A, which causes substitution of serine for asparagine (N406S) in S6 of domain I (IS6). The provocation test with pilsicainide, a class Ic antiarrhythmic drug, failed to exacerbate ST-segment elevation in this case. Electrophysiological analyses of the N406S-mutant channel expressed together with the beta 1 subunit in HEK293 cells showed that the voltage dependence of activation was positively shifted by 16 mV and that intermediate inactivation was enhanced. Whereas tonic block by pilsicainide was not changed in the N406S channel, use-dependent block by pilsicainide was almost completely abolished, consistent with the clinical findings of the negative provocation test. In contrast, the N406S channel showed stronger use-dependent block by quinidine than the wild-type channel. We demonstrate a novel Brugada mutation N406S, which is associated with the discordant effects on blocking actions of antiarrhythmic drugs as well as the multiple channel gating defects. We emphasis that an antiarrhythmic drug may exert unpredicted effects in patients with channel mutations.