Functional dominant-negative mutation of sodium channel subunit gene SCN3B associated with atrial fibrillation in a Chinese GeneID population.
Functional dominant-negative mutation of sodium channel subunit gene SCN3B associated with atrial fibrillation in a Chinese GeneID population.
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DOI：
10.1016/j.bbrc.2010.06.042
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发表时间：
2010-07-16
影响因子：
3.1
通讯作者：
Wang, Qing K.
中科院分区：
文献类型：
--
作者：
Wang, Pengyun;Yang, Qinbo;Wu, Xiaofen;Yang, Yanzong;Shi, Lisong;Wang, Chuchu;Wu, Gang;Xia, Yunlong;Yang, Bo;Zhang, Rongfeng;Xu, Chengqi;Cheng, Xiang;Li, Sisi;Zhao, Yuanyuan;Fu, Fenfen;Liao, Yuhua;Fang, Fang;Chen, Qiuyun;Tu, Xin;Wang, Qing K.
关键词：
房颤是临床上最常见的心律失常，占卒中的15%以上。在房颤患者中已发现心脏钠通道α，β1和β2亚单位基因(SCN5A、SCN1B和SCN2B)突变。我们假设钠通道β3亚单位基因SCN3B的突变也与房颤有关。为了验证这一假设，我们对477例房颤患者(28.5%)进行了SCN3B基因所有编码外显子和外显子-内含子边界的大规模测序分析。在一名46岁的孤立性房颤患者中发现了一种新的A130V突变，而在500名对照组中没有这种突变。突变A130V显著降低HEK293/NaV1.5稳定细胞系的心肌钠电流密度，但对激活、失活和通道失活的动力学无显著影响。当与野生型SCN3B共表达时，A130V突变体SCN3B否定了野生型SCN3B的功能，表明A130V以显性负机制起作用。生物素化质膜蛋白提取物的Western印迹分析表明，A130V不影响细胞表面NaV1.5或SCN3B的表达，提示突变体A130V SCN3B可能不抑制钠离子的转运，而是由于其作为通道复合体的组成部分而影响钠离子的传导。本研究首次发现了与房颤相关的SCN3B突变，提示SCN3B突变可能是房颤的一个新的致病因素。
Atrial fibrillation (AF) is the most common cardiac arrhythmia in the clinic, and accounts for more than 15% of strokes. Mutations in cardiac sodium channel α, β1 and β2 subunit genes (SCN5A, SCN1B, and SCN2B) have been identified in AF patients. We hypothesize that mutations in the sodium channel β3 subunit gene SCN3B are also associated with AF. To test this hypothesis, we carried out a large scale sequencing analysis of all coding exons and exon-intron boundaries of SCN3B in 477 AF patients (28.5% lone AF) from the GeneID Chinese Han population. A novel A130V mutation was identified in a 46 year-old patient with lone AF, and the mutation was absent in 500 controls. Mutation A130V dramatically decreased the cardiac sodium current density when expressed in HEK293/Nav1.5 stable cell line, but did not have significant effect on kinetics of activation, inactivation, and channel recovery from inactivation. When co-expressed with wild type SCN3B, the A130V mutant SCN3B negated the function of wild type SCN3B, suggesting that A130V acts by a dominant negative mechanism. Western blot analysis with biotinylated plasma membrane protein extracts revealed that A130V did not affect cell surface expression of Nav1.5 or SCN3B, suggesting that mutant A130V SCN3B may not inhibit sodium channel trafficking, instead may affect conduction of sodium ions due to its malfunction as an integral component of the channel complex. This study identifies the first AF-associated mutation in SCN3B, and suggests that mutations in SCN3B may be a new pathogenic cause of AF.
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DOI：
10.1161/circep.108.779181
发表时间：
2009-06
期刊：
Circulation. Arrhythmia and electrophysiology
影响因子：
--
作者：
Watanabe H;Darbar D;Kaiser DW;Jiramongkolchai K;Chopra S;Donahue BS;Kannankeril PJ;Roden DM
通讯作者：
Roden DM
DOI：
10.1111/j.1748-1716.2009.02048.x
发表时间：
2010-01
期刊：
Acta physiologica (Oxford, England)
影响因子：
--
作者：
Hakim P;Brice N;Thresher R;Lawrence J;Zhang Y;Jackson AP;Grace AA;Huang CL
通讯作者：
Huang CL
影响因子：
64.8
作者：
Tian, XL;Kadaba, R;Wang, Q
通讯作者：
Wang, Q
影响因子：
24
作者：
Makiyama, Takeru;Akao, Masaharu;Horie, Minoru
通讯作者：
Horie, Minoru
影响因子：
10.8
作者：
Valdivia, Carmen R.;Medeiros-Domingo, Argelia;Makielski, Jonathan C.
通讯作者：
Makielski, Jonathan C.