A novel mutation in KCNQ1 associated with a potent dominant negative effect as the basis for the LQT1 form of the long QT syndrome
A novel mutation in KCNQ1 associated with a potent dominant negative effect as the basis for the LQT1 form of the long QT syndrome
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DOI：
10.1111/j.1540-8167.2007.00889.x
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发表时间：
2007-09-01
影响因子：
2.7
通讯作者：
Antzelevitch, Charles
中科院分区：
文献类型：
--
作者：
Aizawa, Yoshiyasu;Ueda, Kazuo;Antzelevitch, Charles
KCNQ 1基因新突变与LQT 1.引言：长QT综合征（LQTS）是一种遗传性疾病，其特征是QT间期延长和危及生命的多形性室性快速性心律失常。KCNQ 1突变引起的LQT 1是LQTS最常见的形式。方法和结果：诊断为LQTS的患者进行了KCNQ 1，KCNH 2，KCNE 1，KCNE 2，KCNJ 2和SCN 5A的疾病相关突变筛查。在KCNQ 1中发现了一个新的突变，该突变是由KCNQ 1第5节第275位密码子的苯丙氨酸（Delta F275）缺失引起的，该突变是由第824-826位的三个碱基缺失引起的。生成野生型（WT）和Delta F275-KCNQ 1构建体，并与KCNE 1构建体一起瞬时转染到CHO-K1细胞中，以使用传统的全细胞膜片钳技术表征缓慢激活的延迟整流电流（IK）的特性。转染WT-KCNQ 1和KCNE 1（1：1.3摩尔比）的细胞产生具有IKs特征的缓慢激活外向电流。在-40 mV下测量的尾电流密度为381.3 +/- 62.6 pA/pF（n = 11），随后两秒步进至+60 mV。用Delta F275-KCNQ 1和KCNE 1转染的细胞基本上不显示电流。(Tail电流密度：0.8 +/- 2.1 pA/pF，n = 11，P = 0.00001 vs WT）。共转染WT-和Delta F275-KCNQ 1（50/50），沿着KCNE 1，产生很少或没有电流（尾电流密度：10.3 +/- 3.5 pA/pF，n = 11，P = 0.00001 vs WT单独），表明一种有效的显性负效应。结论：KCNQ 1基因的Delta F275突变与IKs功能的显性负性效应有关，该突变导致IKs功能几乎完全丧失，是LQT 1型LQTS的基础。
Novel Mutation in KCNQ1 as a Cause of LQT1.Introduction: Long QT Syndrome (LQTS) is an inherited disorder characterized by prolonged QT intervals and life-threatening polymorphic ventricular tachyarrhythmias. LQT1 caused by KCNQ1 mutations is the most common form of LQTS.Methods and Results: Patients diagnosed with LQTS were screened for disease-associated mutations in KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2, and SCN5A. A novel mutation was identified in KCNQ1 caused by a three-base deletion at the position 824-826, predicting a deletion of phenylalanine at codon 275 in segment 5 of KCNQ1 (Delta F275). Wild-type (WT) and Delta F275-KCNQ1 constructs were generated and transiently transfected together with a KCNE1 construct in CHO-K1 cells to characterize the properties of the slowly activating delayed rectifier current (IKs) using conventional whole-cell patch-clamp techniques. Cells transfected with WT-KCNQ1 and KCNE1 (1:1.3 molar ratio) produced slowly activating outward current with the characteristics of IKs. Tail current density measured at -40 mV following a two-second step to +60 mV was 381.3 +/- 62.6 pA/pF (n = 11). Cells transfected with Delta F275-KCNQ1 and KCNE1 exhibited essentially no current. (Tail current density: 0.8 +/- 2.1 pA/pF, n = 11, P = 0.00001 vs WT). Cotransfection of WT- and Delta F275- KCNQ1 (50/50), along with KCNE1, produced little to no current (tail current density: 10.3 +/- 3.5 pA/pF, n = 11, P = 0.00001 vs WT alone), suggesting a potent dominant negative effect. Immunohistochemistry showed normal membrane trafficking of Delta F275-KCNQ1.Conclusion: Our data suggest that a Delta F275 mutation in KCNQ1 is associated with a very potent dominant negative effect leading to an almost complete loss of function of IKs and that this defect underlies a LQT1 form of LQTS.