Multiple arrhythmic syndromes in a newborn, owing to a novel mutation in SCN5A
Multiple arrhythmic syndromes in a newborn, owing to a novel mutation in SCN5A
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DOI：
10.1139/y11-070
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发表时间：
2011-10-01
影响因子：
2.1
通讯作者：
Antzelevitch, Charles
中科院分区：
文献类型：
--
作者：
Calloe, Kirstine;Schmitt, Nicole;Antzelevitch, Charles
背景。 SCN5A 基因突变与布鲁格达综合征 (BrS)、传导疾病、长 QT 综合征 (LQT3)、心房颤动 (AF) 以及产前和新生儿室性心律失常有关。客观的。本研究的目的是表征在患有胎儿混乱性房性心动过速、产后室内传导延迟和 QT 间期延长的新生儿中发现的 Na(v)1.5 的新突变。方法。分离了基因组 DNA，并对 15 个离子通道基因的所有外显子和内含子边界进行了测序，揭示了 SCN5A 中的一个新的错义突变 (Q270K)。 Na(v)1.5 野生型 (WT) 和 Q270K 在带有和不带有 Na(v)beta 1 亚基的 CHO-K1 中表达。结果。膜片钳分析显示，与 WT 相比，Q270K 的峰值钠通道电流 (I(Na)) 密度降低了 40%。 Q270K 中 I(Na) 的快速和慢速衰减明显较慢。 Q270K 通道的稳态激活和失活转移到正电位，并且窗口电流增加。与 WT 通道相比，河豚毒素敏感的晚期 I(Na) 增加了近 3 倍。雷诺嗪降低 WT 和 Q270K 通道中的晚期 I(Na)，同时对峰值 I(Na) 影响最小。结论。 SCN5A 中的 Q270K 突变会降低峰值 I(Na)，同时增加晚期 I(Na)，因此可能是婴儿发生房性心动过速、心室内传导延迟和 QT 间期延长的基础。
Background. Mutations in the SCN5A gene have been linked to Brugada syndrome (BrS), conduction disease, Long QT syndrome (LQT3), atrial fibrillation (AF), and to pre- and neonatal ventricular arrhythmias. Objective. The objective of this study is to characterize a novel mutation in Na(v)1.5 found in a newborn with fetal chaotic atrial tachycardia, postpartum intraventricular conduction delay, and QT interval prolongation. Methods. Genomic DNA was isolated and all exons and intron borders of 15 ion-channel genes were sequenced, revealing a novel missense mutation (Q270K) in SCN5A. Na(v)1.5 wild type (WT) and Q270K were expressed in CHO-K1 with and without the Na(v)beta 1 subunit. Results. Patch-clamp analysis showed similar to 40% reduction in peak sodium channel current (I(Na)) density for Q270K compared with WT. Fast and slow decay of I(Na) were significantly slower in Q270K. Steady-state activation and inactivation of Q270K channels were shifted to positive potentials, and window current was increased. The tetrodotoxin-sensitive late I(Na) was increased almost 3-fold compared with WT channels. Ranolazine reduced late I(Na) in WT and Q270K channels, while exerting minimal effects on peak I(Na). Conclusion. The Q270K mutation in SCN5A reduces peak I(Na) while augmenting late I(Na), and may thus underlie the development of atrial tachycardia, intraventricular conduction delay, and QT interval prolongation in an infant.