A novel SCN5A gain-of-function mutation M1875T associated with familial atrial fibrillation
A novel SCN5A gain-of-function mutation M1875T associated with familial atrial fibrillation
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DOI：
10.1016/j.jacc.2008.07.013
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发表时间：
2008-10-14
影响因子：
24
通讯作者：
Horie, Minoru
中科院分区：
文献类型：
--
作者：
Makiyama, Takeru;Akao, Masaharu;Horie, Minoru
目的本研究描述了在一个日本孤立性心房颤动（AF）家系中发现的一种新的心脏钠（Na+）通道基因SCN 5A的杂合功能获得性突变。背景SCN 5A突变与多种遗传性心律失常有关，但SCN 5A的功能获得性类型调节仅与一种表型有关，长QT综合征3型（LQTS 3）。方法我们研究了一个日本常染色体显性遗传性房颤家族，该家族多名成员在年轻时表现出房颤发作或频繁的房性早搏。结果31岁的先证者接受了射频导管消融术，在此期间，记录了大量异位放电和整个右心房的兴奋性增加。突变分析发现了一个新的错义突变，M1875 T，在SCN 5A。进一步的调查显示，在所有受影响的个体中，这种突变具有家族聚集性。使用全细胞膜片钳对M1875 T Na+通道进行的功能测定证明了明显的功能增益型调节;稳态失活的电压依赖性V-1/2中的显著去极化偏移（+16.4mV）;并且没有持续的Na+电流，这是LQTS 3的定义机制.这些突变通道的生物物理特征可能与所有受影响个体的心房兴奋性增加和QT间期正常有关。结论我们发现了一种与家族性AF相关的新的SCN 5A突变。突变通道显示出对心脏Na+通道的功能获得型调节，这是一种新的机制，诱发心房兴奋性增加和家族性AF。这是一种新的表型，由SCN 5A功能获得性突变引起，与LQTS 3不同。
Objectives This study describes a novel heterozygous gain- of- function mutation in the cardiac sodium (Na+) channel gene, SCN5A, identified in a Japanese family with lone atrial fibrillation (AF).Background SCN5A mutations have been associated with a variety of inherited arrhythmias, but the gain- of- function type modulation in SCN5A is associated with only 1 phenotype, long-QT syndrome type 3 (LQTS3).Methods We studied a Japanese family with autosomal dominant hereditary AF, multiple members of which showed an onset of AF or frequent premature atrial contractions at a young age.Results The 31- year- old proband received radiofrequency catheter ablation, during which time numerous ectopic firings and increased excitability throughout the right atrium were documented. Mutational analysis identified a novel missense mutation, M1875T, in SCN5A. Further investigations revealed the familial aggregation of this mutation in all of the affected individuals. Functional assays of the M1875T Na+ channels using a whole- cell patch- clamp demonstrated a distinct gain- of- function type modulation; a pronounced depolarized shift (+ 16.4 mV) in V-1/2 of the voltage dependence of steady- state inactivation; and no persistent Na+ current, which is a defining mechanism of LQTS3. These biophysical features of the mutant channels are potentially associated with increased atrial excitability and normal QT interval in all of the affected individuals.Conclusions We identified a novel SCN5A mutation associated with familial AF. The mutant channels displayed a gain- of- function type modulation of cardiac Na+ channels, which is a novel mechanism predisposing to increased atrial excitability and familial AF. This is a new phenotype resulting from the SCN5A gain-of-function mutations and is distinct from LQTS3.