Makiyama Takeru, Akao Masaharu, Shizuta Satoshi, Doi Takahiro, Nishiyama Kei, Oka Yuko, Ohno Seiko, Nishio Yukiko, Tsuji Keiko, Itoh Hideki, Kimura Takeshi, Kita Toru, Horie Minoru
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
J Am Coll Cardiol. 2008 Oct 14;52(16):1326-34. doi: 10.1016/j.jacc.2008.07.013.
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).
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).
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.
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.
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.
本研究描述了在一个日本孤立性心房颤动（AF）家系中发现的心脏钠（Na+）通道基因SCN5A的一种新型杂合功能获得性突变。
SCN5A突变与多种遗传性心律失常相关，但SCN5A的功能获得型调节仅与1种表型相关，即3型长QT综合征（LQTS3）。
我们研究了一个常染色体显性遗传性AF的日本家系，该家系的多名成员在年轻时出现AF发作或频发房性早搏。
31岁的先证者接受了射频导管消融术，在此期间记录到右心房有大量异位激动和兴奋性增加。突变分析在SCN5A中鉴定出一种新型错义突变M1875T。进一步研究显示该突变在所有受影响个体中呈家族聚集性。使用全细胞膜片钳对M1875T Na+通道进行功能检测，结果显示出明显的功能获得型调节；稳态失活电压依赖性的V(1/2)出现显著的去极化偏移（+16.4 mV）；且无持续性Na+电流，而持续性Na+电流是LQTS3的一个决定性机制。突变通道的这些生物物理特性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。
我们鉴定出一种与家族性AF相关的新型SCN5A突变。突变通道表现出心脏Na+通道的功能获得型调节，这是一种导致心房兴奋性增加和家族性AF的新机制。这是SCN5A功能获得性突变产生的一种新表型，与LQTS3不同。
