Chang Chien-Chih, Acharfi Said, Wu Mei-Hwan, Chiang Fu-Tien, Wang Jou-Kou, Sung Tseng-Chen, Chahine Mohamed
Department of Pediatrics, College of Medicine, National Taiwan University, National Taiwan University Hospital, No. 7, Chung-Shen South Road, Taipei, 100 Taiwan.
Cardiovasc Res. 2004 Nov 1;64(2):268-78. doi: 10.1016/j.cardiores.2004.07.007.
Congenital long QT syndrome (LQTS) with in utero onset of the rhythm disturbances is associated with a poor prognosis. In this study we investigated a newborn patient with fetal bradycardia, 2:1 atrioventricular block and ventricular tachycardia soon after birth.
Mutational analysis and DNA sequencing were conducted in a newborn. The 2:1 atrioventricular block improved to 1:1 conduction only after intravenous lidocaine infusion or a high dose of mexiletine, which also controlled the ventricular tachycardia.
A novel, spontaneous LQTS-3 mutation was identified in the transmembrane segment 6 of domain IV of the Na(v)1.5 cardiac sodium channel, with a G-->A substitution at codon 1763, which changed a valine (GTG) to a methionine (ATG). The proband was heterozygous but the mutation was absent in the parents and the sister. Expression of this mutant channel in tsA201 mammalian cells by site-directed mutagenesis revealed a persistent tetrodotoxin-sensitive but lidocaine-resistant current that was associated with a positive shift of the steady-state inactivation curve, steeper activation curve and faster recovery from inactivation. We also found a similar electrophysiological profile for the neighboring V1764M mutant. But, the other neighboring I1762A mutant had no persistent current and was still associated with a positive shift of inactivation.
These findings suggest that the Na(v)1.5/V1763M channel dysfunction and possible neighboring mutants contribute to a persistent inward current due to altered inactivation kinetics and clinically congenital LQTS with perinatal onset of arrhythmias that responded to lidocaine and mexiletine.
宫内即出现节律紊乱的先天性长QT综合征（LQTS）预后较差。在本研究中，我们调查了一名出生后不久即出现胎儿心动过缓、2:1房室传导阻滞和室性心动过速的新生儿患者。
对一名新生儿进行了突变分析和DNA测序。仅在静脉输注利多卡因或高剂量美西律后，2:1房室传导阻滞才改善为1:1传导，同时这两种药物也控制了室性心动过速。
在心脏钠通道Na(v)1.5第四结构域的跨膜片段6中鉴定出一种新的自发性LQTS-3突变，密码子1763处发生G→A替换，导致缬氨酸（GTG）变为甲硫氨酸（ATG）。先证者为杂合子，但父母和妹妹中未发现该突变。通过定点诱变在tsA201哺乳动物细胞中表达该突变通道，发现其具有持续的河豚毒素敏感但利多卡因耐药电流，这与稳态失活曲线的正向移位、更陡峭的激活曲线以及更快的失活恢复相关。我们还发现相邻的V1764M突变体具有相似的电生理特征。但是，另一个相邻的I1762A突变体没有持续电流，并且仍然与失活的正向移位相关。
这些发现表明，Na(v)1.5/V1763M通道功能障碍以及可能的相邻突变体由于失活动力学改变导致持续内向电流，临床上导致先天性LQTS并伴有围产期心律失常发作，对利多卡因和美西律有反应。
