Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms
Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms
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DOI：
10.1016/j.hrthm.2005.06.032
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发表时间：
2005-10-01
期刊：
影响因子：
5.5
通讯作者：
Tsutsui, H
中科院分区：
文献类型：
--
作者：
Makita, N;Sasaki, K;Tsutsui, H
背景先天性心房静止与SCN 5A有关。在心房静止中观察到的不完全收缩部分归因于心房特异性缝隙连接蛋白40（Cx40）多态性的双基因遗传。本研究的目的是确定在一个心房停顿家族中发现的一种新的SCN 5A突变的临床和生物物理学特征。静止期患者接受SCN 5A和包括Cx40在内的心房特异性基因的遗传筛查。野生型（WT）和突变的SCN 5A通道在异源表达系统中的生物物理特性进行了研究，使用全细胞膜片钳technique.RESULTS新的SCN 5A突变L212 P被确定在先证者（年龄11岁）和他的父亲。父亲的窦性心律正常。先证者体表心电图无P波，起搏不能夺获右心房。重组L212 P钠通道在电压依赖性激活和电压依赖性激活中均表现出较大的超极化位移。（WT：-48.1 +/- 0.9 mV; L212 P：-63.5 +/- 1.5 mV; P < .001）和失活（VvIT：-86.6 +/-0.9 mV; L212 P：-95.6 +/-0.8 mV; P < .001）和延迟的失活恢复。进一步筛选可能减轻L212 P功能障碍的遗传变异显示，先证者，但不是他的父亲，携带Cx40多态性遗传自他的无症状mother.CONCLUSION这些结果表明，SCN 5A的遗传缺陷最有可能是心房停顿的基础。Cx40多态性的共同遗传是一个可能的遗传因素，修改这种遗传性心律失常的临床表现。
BACKGROUND Congenital atrial standstill has been linked to SCN5A. Incomplete penetrance observed in atrial standstill has been attributed in part to the digenic inheritance of polymorphisms in the atrial-specific gap junction connexin 40 (Cx40) in conjunction with an SCN5A mutation.OBJECTIVES The purpose of this study was to determine the clinical and biophysical characteristics of a novel SCN5A mutation identified in a family with atrial standstill.METHODS Family members of an apparently sporadic case of atrial standstill underwent genetic screening of SCN5A and atrial-specific genes including Cx40. Biophysical properties of the wild-type (WT) and mutant SCN5A channels in a heterologous expression system were studied using the whole-cell patch clamp technique.RESULTS The novel SCN5A mutation L212P was identified in the proband (age 11 years) and his father. The father was in normal sinus rhythm. The proband had no P waves on surface ECG, and his right atrium could not be captured by pacing. The recombinant L212P Na channel showed a large hyperpolarizing shift in both the voltage dependence of activation (WT: -48.1 +/- 0.9 mV; L212P: -63.5 +/- 1.5 mV; P < .001) and inactivation (VvIT: -86.6 +/- 0.9 mV; L212P: -95.6 +/- 0.8 mV; P < .001) and delayed recovery from inactivation. Further screenings for genetic variations that might mitigate L212P dysfunction revealed that the proband, but not his father, carries Cx40 polymorphisms inherited from his asymptomatic mother.CONCLUSION These results suggest that genetic defects in SCN5A most likely underlie atrial standstill. Coinheritance of Cx40 polymorphisms is a possible genetic factor that modifies the clinical manifestation of this inherited arrhythmia.