Wu Geru, Ai Tomohiko, Kim Jeffrey J, Mohapatra Bhagyalaxmi, Xi Yutao, Li Zhaohui, Abbasi Shahrzad, Purevjav Enkhsaikhan, Samani Kaveh, Ackerman Michael J, Qi Ming, Moss Arthur J, Shimizu Wataru, Towbin Jeffrey A, Cheng Jie, Vatta Matteo
Electrophysiology Research Laboratory, Texas Heart Institute/St. Luke's Episcopal Hospital, Houston, Texas, USA.
Circ Arrhythm Electrophysiol. 2008 Aug;1(3):193-201. doi: 10.1161/CIRCEP.108.769224.
Long-QT syndrome (LQTS) is an inherited disorder associated with sudden cardiac death. The cytoskeletal protein syntrophin-alpha(1) (SNTA1) is known to interact with the cardiac sodium channel (hNa(v)1.5), and we hypothesized that SNTA1 mutations might cause phenotypic LQTS in patients with genotypically normal hNa(v)1.5 by secondarily disturbing sodium channel function.
Mutational analysis of SNTA1 was performed on 39 LQTS patients (QTc> or =480 ms) with previously negative genetic screening for the known LQTS-causing genes. We identified a novel A257G-SNTA1 missense mutation, which affects a highly conserved residue, in 3 unrelated LQTS probands but not in 400 ethnic-matched control alleles. Only 1 of these probands had a preexisting family history of LQTS and sudden death with an additional intronic variant in KCNQ1. Electrophysiological analysis was performed using HEK-293 cells stably expressing hNa(v)1.5 and transiently transfected with either wild-type or mutant SNTA1 and, in neonatal rat cardiomyocytes, transiently transfected with either wild-type or mutant SNTA1. In both HEK-293 cells and neonatal rat cardiomyocytes, increased peak sodium currents were noted along with a 10-mV negative shift of the onset and peak of currents of the current-voltage relationships. In addition, A257G-SNTA1 shifted the steady-state activation (V(h)) leftward by 9.4 mV, whereas the voltage-dependent inactivation kinetics and the late sodium currents were similar to wild-type SNTA1.
SNTA1 is a new susceptibility gene for LQTS. A257G-SNTA1 can cause gain-of-function of Na(v)1.5 similar to the LQT3.
长QT综合征（LQTS）是一种与心源性猝死相关的遗传性疾病。已知细胞骨架蛋白α-1肌养蛋白（SNTA1）与心脏钠通道（hNa(v)1.5）相互作用，我们推测SNTA1突变可能通过继发干扰钠通道功能，在基因型正常的hNa(v)1.5患者中导致表型LQTS。
对39例长QT综合征患者（QTc≥480毫秒）进行了SNTA1突变分析，这些患者先前对已知的导致长QT综合征的基因进行了阴性基因筛查。我们在3例无关的长QT综合征先证者中鉴定出一种新的A257G-SNTA1错义突变，该突变影响一个高度保守的残基，而在400个种族匹配的对照等位基因中未发现。这些先证者中只有1例有长QT综合征和猝死的家族病史，其KCNQ1基因还有一个内含子变异。使用稳定表达hNa(v)1.5并瞬时转染野生型或突变型SNTA1的HEK-293细胞进行电生理分析，并在新生大鼠心肌细胞中瞬时转染野生型或突变型SNTA1。在HEK-293细胞和新生大鼠心肌细胞中，均观察到钠电流峰值增加，同时电流-电压关系曲线的起始和峰值负移10 mV。此外，A257G-SNTA1使稳态激活（V(h)）向左移位9.4 mV，而电压依赖性失活动力学和晚期钠电流与野生型SNTA1相似。
SNTA1是长QT综合征的一个新的易感基因。A257G-SNTA1可导致Na(v)1.5功能增强，类似于LQT3。
