Identification of rare variants in cardiac sodium channel beta4-subunit gene SCN4B associated with ventricular tachycardia.
Identification of rare variants in cardiac sodium channel beta4-subunit gene SCN4B associated with ventricular tachycardia.
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鉴定与室性心动过速相关的心脏钠通道β4亚基基因SCN4B的罕见变异。
DOI：
10.1007/s00438-019-01567-7
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Wang Qing K
中科院分区：
文献类型：
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作者：
Yang Qin;Xiong Hongbo;Xu Chengqi;Huang Yuan;Tu Xin;Wu Gang;Fu Fenfen;Wang Zhijie;Wang Longfei;Zhao Yuanyuan;Li Sisi;Huang Yufeng;Wang Chuchu;Wang Dan;Yao Yufeng;Wang Fan;Wang Yongbo;Xue Yu;Wang Pengyun;Chen Qiuyun;Pu Jielin;Wang Qing K
室性心动过速（VT）是心脏性猝死的主要原因，其主要致病基因尚不清楚，SCN 4 B编码的Navβ4是电压门控性钠通道复合物，参与心脏动作电位的产生和传导。我们假设SCN 4 B基因变异增加了VT的风险。我们使用高分辨率熔解分析，然后进行桑格测序，筛选199例VT患者，以确定SCN 4 B的非同义变体。在VT患者中发现了两种SCN 4 B的非同义杂合变异，包括4例VT患者的p.Gly8Ser和1例VT患者的p.Ala145Ser。病例对照关联研究用于评估两个独立人群中变异p.Gly8Ser与VT之间的关联（人群1中299例VT病例与981例对照，人群2中270例VT患者与639例对照）。在人群1中发现p.Gly8Ser与VT之间存在显著相关性（P= 1.21 × 10−4，比值比或OR = 11.04），在人群2中证实了这一发现（P= 0.03，OR = 3.62）。在合并人群中，这种关联仍然非常显著（P= 3.09 × 10−5，OR = 6.17）。p.Gly8Ser与特发性室性心动过速之间也存在显著相关性（P= 1.89 × 10−5，OR = 7.27）。Western blotting功能分析显示，p.Gly8Ser和p.Ala145Ser突变体均显著降低了Navβ4的表达水平。根据2015年ACMG标准和指南，p.Gly8Ser和p.Ala145Ser可分别归类为致病性和可能致病性变体。我们的数据表明，SCN 4 B是常见VT和特发性VT的易感基因，并将罕见的SCN 4 B变异与常见VT联系起来，这些变异具有较大的影响（OR = 6.17-7.27）。
Ventricular tachycardia (VT) causes sudden cardiac death, however, the majority of risk genes for VT remain unknown.SCN4Bencodes a β-subunit, Navβ4, for the voltage-gated cardiac sodium channel complex involved in generation and conduction of the cardiac action potential. We hypothesized that genomic variants inSCN4Bincrease the risk of VT. We used high-resolution melt analysis followed by Sanger sequencing to screen 199 VT patients to identify nonsynonymous variants inSCN4B. Two nonsynonymous heterozygous variants inSCN4Bwere identified in VT patients, including p.Gly8Ser in four VT patients and p.Ala145Ser in one VT patient. Case–control association studies were used to assess the association between variant p.Gly8Ser and VT in two independent populations for VT (299 VT cases vs. 981 controls in population 1 and 270 VT patients vs. 639 controls in population 2). Significant association was identified between p.Gly8Ser and VT in population 1 (P= 1.21 × 10−4, odds ratio or OR = 11.04), and the finding was confirmed in population 2 (P= 0.03, OR = 3.62). The association remained highly significant in the combined population (P= 3.09 × 10−5, OR = 6.17). Significant association was also identified between p.Gly8Ser and idiopathic VT (P= 1.89 × 10−5, OR = 7.27). Functional analysis with Western blotting showed that both p.Gly8Ser and p.Ala145Ser variants significantly reduced the expression level of Navβ4. Based on 2015 ACMG Standards and Guidelines, p.Gly8Ser and p.Ala145Ser can be classified as the pathogenic and likely pathogenic variant, respectively. Our data suggest thatSCN4Bis a susceptibility gene for common VT and idiopathic VT and link rareSCN4Bvariants with large effects (OR = 6.17–7.27) to common VT.