Hasegawa Kanae, Ohno Seiko, Ashihara Takashi, Itoh Hideki, Ding Wei-Guang, Toyoda Futoshi, Makiyama Takeru, Aoki Hisaaki, Nakamura Yoshihide, Delisle Brian P, Matsuura Hiroshi, Horie Minoru
Department of Cardiovascular Biology and Medicine, Niigata University School of Medical and Dental Sciences, Niigata, Japan; Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
Heart Rhythm. 2014 Jan;11(1):67-75. doi: 10.1016/j.hrthm.2013.09.073. Epub 2013 Oct 1.
Atrial fibrillation (AF) is one of the most common cardiac arrhythmias. In some patients, the disease is inheritable; however, hereditary aspects of AF remain not fully elucidated.
The purpose of this study was to identify genetic backgrounds that contribute to juvenile-onset AF and to define the mechanism.
In 30 consecutive juvenile-onset AF patients (onset age <50 years), we screened AF-related genes (KCNQ1, KCNH2, KCNE1-3, KCNE5, KCNJ2, SCN5A). We analyzed the function of mutant channels using whole-cell patch-clamp techniques and computer simulations.
Among the juvenile-onset AF patients, we identified three mutations (10%): SCN5A-M1875T, KCNJ2-M301K, and KCNQ1-G229D. Because KCNQ1 variant (G229D) identified in a 16-year-old boy was novel, we focused on the proband. The G229D-IKs was found to induce a large instantaneous activating component without deactivation after repolarization to -50 mV. In addition, wild-type (WT)/G229D-IKs (WT and mutant coexpression) displayed both instantaneous and time-dependent activating currents. Compared to WT-IKs, the tail current densities in WT/G229D-IKs were larger at test potentials between -130 and -40 mV but smaller at test potentials between 20 and 50 mV. Moreover, WT/G229D-IKs resulted in a negative voltage shift for current activation (-35.2 mV) and slower deactivation. WT/G229D-IKs conducted a large outward current induced by an atrial action potential waveform, and computer simulation incorporating the WT/G229D-IKs results revealed that the mutation shortened atrial but not ventricular action potential.
A novel KCNQ1-G229D mutation identified in a juvenile-onset AF patient altered the IKs activity and kinetics, thereby increasing the arrhythmogenicity to AF.
心房颤动（AF）是最常见的心律失常之一。在一些患者中，该疾病具有遗传性；然而，AF的遗传方面仍未完全阐明。
本研究的目的是确定导致青少年期AF的遗传背景并明确其机制。
在30例连续的青少年期AF患者（发病年龄<50岁）中，我们筛查了AF相关基因（KCNQ1、KCNH2、KCNE1 - 3、KCNE5、KCNJ2、SCN5A）。我们使用全细胞膜片钳技术和计算机模拟分析了突变通道的功能。
在青少年期AF患者中，我们鉴定出三个突变（10%）：SCN5A - M1875T、KCNJ2 - M301K和KCNQ1 - G229D。由于在一名16岁男孩中鉴定出的KCNQ1变异体（G229D）是新的，我们重点研究了先证者。发现G229D - IKs在复极化至 - 50 mV后诱导出一个大的瞬时激活成分且无失活。此外，野生型（WT）/G229D - IKs（WT和突变体共表达）显示出瞬时和时间依赖性激活电流。与WT - IKs相比，WT/G229D - IKs在 - 130至 - 40 mV的测试电位下尾电流密度更大，但在20至50 mV的测试电位下更小。此外，WT/G229D - IKs导致电流激活的负电压偏移（ - 35.2 mV）和失活减慢。WT/G229D - IKs传导由心房动作电位波形诱导的大外向电流，结合WT/G229D - IKs结果的计算机模拟显示该突变缩短了心房动作电位但未缩短心室动作电位。
在一名青少年期AF患者中鉴定出的新的KCNQ1 - G229D突变改变了IKs活性和动力学，从而增加了AF的致心律失常性。
