Mutations in sodium channel β1- and β2-subunits associated with atrial fibrillation.
Mutations in sodium channel β1- and β2-subunits associated with atrial fibrillation.
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DOI：
10.1161/circep.108.779181
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发表时间：
2009-06
期刊：
影响因子：
--
通讯作者：
Roden DM
中科院分区：
文献类型：
--
作者：
Watanabe H;Darbar D;Kaiser DW;Jiramongkolchai K;Chopra S;Donahue BS;Kannankeril PJ;Roden DM
我们和其他人报道了AF患者心脏优势钠通道基因SCN 5A的突变。我们还报道了SCN 1B与Brugada综合征和孤立的心脏传导疾病相关。在这里，我们测试了4个钠通道β亚基基因SCN 1B-SCN 4 B突变有助于心房颤动（AF）易感性的假设。对480例AF患者（118例孤立性AF患者和362例AF和心血管疾病患者）和548例对照（188例种族定义的匿名受试者和360例无AF受试者）进行了4种β亚基基因突变筛查。使用电生理学研究来研究突变的β-亚基对SCN 5A介导的电流的影响。我们在AF患者中鉴定了SCN 1B中的2种非同义变体（导致R85 H，D153 N）和SCN 2B中的2种变体（R28 Q，R28 W）。这些变体发生在哺乳动物中高度保守的残基上，并且在对照中不存在。4例突变携带者中3例心电图右胸导联ST段鞍背型抬高。在人心房和心室中检测到编码SCN 1B和SCN 2B的转录本。在使用中国仓鼠卵巢细胞的异源表达研究中，与野生型亚基的共表达相比，突变的β1-或β2-亚基减少了SCN 5A介导的电流并改变了通道门控。在AF患者中发现了钠通道β亚基功能缺失突变，并与独特的ECG表型相关。这些发现进一步支持了钠电流降低增强房颤易感性的假设。
We and others have reported mutations in the cardiac predominant sodium channel gene SCN5A in patients with AF. We also have reported that SCN1B is associated with Brugada syndrome and isolated cardiac conduction disease. Here we tested the hypothesis that mutations in the 4 sodium channel β-subunit genes SCN1B – SCN4B contribute to atrial fibrillation (AF) susceptibility. Screening for mutations in the 4 β-subunit genes was performed in 480 patients with AF (118 patients with lone AF and 362 patients with AF and cardiovascular disease) and 548 controls (188 ethnically-defined anonymized subjects and 360 subjects without AF). The effects of mutant β-subunits on SCN5A mediated currents were studied using electrophysiological studies. We identified 2 non-synonymous variants in SCN1B (resulting in R85H, D153N) and 2 in SCN2B (R28Q, R28W) in patients with AF. These occur at residues highly conserved across mammals, and were absent in controls. In 3 of 4 mutation carriers, the electrocardiograms showed saddle back type ST-segment elevation in the right precordial leads. Transcripts encoding both SCN1B and SCN2B were detected in human atrium and ventricle. In heterologous expression studies using Chinese hamster ovary cells, the mutant β1- or β2-subunits reduced SCN5A mediated current and altered channel gating compared to coexpression of wild-type subunits. Loss of function mutations in sodium channel β-subunits were identified in patients with AF, and were associated with a distinctive ECG phenotype. These findings further support the hypothesis that decreased sodium current enhances AF susceptibility.