SCN5A mutations associate with arrhythmic dilated cardiomyopathy and commonly localize to the voltage-sensing mechanism.
SCN5A mutations associate with arrhythmic dilated cardiomyopathy and commonly localize to the voltage-sensing mechanism.
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DOI：
10.1016/j.jacc.2010.09.084
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发表时间：
2011-05-24
影响因子：
24
通讯作者：
Mestroni, Luisa
中科院分区：
文献类型：
--
作者：
McNair, William P.;Sinagra, Gianfranco;Taylor, Matthew R. G.;Di Lenarda, Andrea;Ferguson, Debra A.;Salcedo, Ernesto E.;Slavov, Dobromir;Zhu, Xiao;Caldwell, John H.;Mestroni, Luisa
本研究的目的是明确心脏电压门控钠离子通道SCN 5A在扩张型心肌病（DCM）病因学中的作用。扩张型心肌病与SCN 5A基因突变有关，但这些相关性的频率、表型和致病性质仍是目前研究的重点。自1991年以来，DCM先证者和家族成员已被纳入家族性心肌病登记处，并通过临床表型进行广泛评估。从289个DCM家族中的338个个体获得基因组脱氧核糖核酸样品，并通过变性高效液相色谱和序列分析筛选SCN 5A突变。我们在DCM家族中鉴定了5个SCN 5A错义突变，包括新突变E446 K、F1520 L和V1279 I，以及先前报道的突变D1275 N和R222 Q。在我们研究的15名SCN 5A突变携带者中，14名（93%）表现出心律失常：室上性心律失常（13/15），包括病窦综合征（5/15）和房颤（9/15），室性心动过速（5/15）和传导疾病（9/15）。在1.7%的DCM家族中检测到SCN 5A突变。SCN 5A中所有报告的DCM突变的三分之二（9个中的6个）定位于高度保守的同源S3和S4跨膜区段，表明该通道的电压敏感机制的破坏导致DCM的共享机制。SCN 5A突变携带者显示出具有临床和诊断意义的强烈的免疫模式，这并不奇怪。
The aim of this study was to discern the role of the cardiac voltage-gated sodium ion channel SCN5A in the etiology of dilated cardiomyopathy (DCM). Dilated cardiomyopathy associates with mutations in the SCN5A gene, but the frequency, phenotype, and causative nature of these associations remain the focus of ongoing investigation. Since 1991, DCM probands and family members have been enrolled in the Familial Cardiomyopathy Registry and extensively evaluated by clinical phenotype. Genomic deoxyribonucleic acid samples from 338 individuals among 289 DCM families were obtained and screened for SCN5A mutations by denaturing high-performance liquid chromatography and sequence analysis. We identified 5 missense SCN5A mutations among our DCM families, including novel mutations E446K, F1520L, and V1279I, as well as previously reported mutations D1275N and R222Q. Of 15 SCN5A mutation carriers in our study, 14 (93%) manifested arrhythmia: supraventricular arrhythmia (13 of 15), including sick sinus syndrome (5 of 15) and atrial fibrillation (9 of 15), ventricular tachycardia (5 of 15), and conduction disease (9 of 15). Mutations in SCN5A were detected in 1.7% of DCM families. Two-thirds (6 of 9) of all reported DCM mutations in SCN5A localize to the highly conserved homologous S3 and S4 transmembrane segments, suggesting a shared mechanism of disruption of the voltage-sensing mechanism of this channel leading to DCM. Not surprisingly, SCN5A mutation carriers show a strong arrhythmic pattern that has clinical and diagnostic implications.
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影响因子：
16.2
作者：
Aggarwal, SK;MacKinnon, R
通讯作者：
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120.7
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56.9
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通讯作者：
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