Fodstad Heidi, Bendahhou Saïd, Rougier Jean-Sébastien, Laitinen-Forsblom Päivi J, Barhanin Jacques, Abriel Hugues, Schild Laurent, Kontula Kimmo, Swan Heikki
Biomedicum Helsinki and Department of Medicine, University of Helsinki, Finland, and Service of Cardiology, University Hospital, Lausanne, Switzerland.
Ann Med. 2006;38(4):294-304. doi: 10.1080/07853890600756065.
Mutations of at least six different genes have been found to cause long QT syndrome (LQTS), an inherited arrhythmic disorder characterized by a prolonged QT interval on the electrocardiogram (ECG), ventricular arrhythmias and risk of sudden death.
The aims were to define the yet undetermined phenotypic characteristics of two founder mutations and to study clinical features in compound heterozygotes identified during the course of the study.
To maximize identification of the compound heterozygotes, we used an extended group of LQTS patients comprising 700 documented or suspected cases. Functional studies were carried out upon transient expression in COS-7 or HEK293 cells.
The KCNQ1 IVS7-2A>G (KCNQ1-FinB) mutation associated with a mean QTc interval of 464 ms and a complete loss-of-channel function. The HERG R176W (HERG-FinB) mutation caused a reduction in current density as well as slight acceleration of the deactivation kinetics in vitro, and its carriers had a mean QTc of 448 ms. The HERG R176W mutation was also present in 3 (0.9%) out of 317 blood donors. A total of six compound heterozygotes were identified who had the HERG R176W mutation in combination with a previously reported LQTS mutation (KCNQ1 G589D or IVS7-2A>G). When present simultaneously with an apparent LQTS-causing mutation, the HERG R176W mutation may exert an additional in vivo phenotypic effect.
The HERG R176W mutation represents a population-prevalent mutation predisposing to LQTS. Compound heterozygosity for mutant LQTS genes may modify the clinical picture in LQTS.
已发现至少六种不同基因的突变可导致长QT综合征（LQTS），这是一种遗传性心律失常疾病，其特征为心电图（ECG）上QT间期延长、室性心律失常和猝死风险。
目的是确定两种奠基者突变尚未明确的表型特征，并研究在研究过程中鉴定出的复合杂合子的临床特征。
为了最大限度地鉴定复合杂合子，我们使用了一组扩大的LQTS患者，包括700例有记录或疑似病例。在COS-7或HEK293细胞中瞬时表达后进行功能研究。
KCNQ1 IVS7-2A>G（KCNQ1-FinB）突变与平均QTc间期464毫秒及通道功能完全丧失相关。HERG R176W（HERG-FinB）突变导致体外电流密度降低以及失活动力学略有加速，其携带者的平均QTc为448毫秒。在317名献血者中，有3名（0.9%）也存在HERG R176W突变。总共鉴定出6名复合杂合子，他们具有HERG R176W突变与先前报道的LQTS突变（KCNQ1 G589D或IVS7-2A>G）的组合。当与明显的导致LQTS的突变同时存在时，HERG R176W突变可能在体内发挥额外的表型效应。
HERG R176W突变是一种在人群中普遍存在的易患LQTS的突变。突变的LQTS基因的复合杂合性可能会改变LQTS的临床表现。
