长 QT 综合征患者中 LQT1 和 LQT2 表型重叠，与 KCNQ1 和 KCNH2 功能丧失变异相关。
Overlapping LQT1 and LQT2 phenotype in a patient with long QT syndrome associated with loss-of-function variations in KCNQ1 and KCNH2.
机构信息
Masonic Medical Research Laboratory, Utica, New York 13501, USA.
出版信息
Can J Physiol Pharmacol. 2010 Dec;88(12):1181-90. doi: 10.1139/Y10-094.
Long QT syndrome (LQTS) is an inherited disorder characterized by prolonged QT intervals and potentially life-threatening arrhythmias. Mutations in 12 different genes have been associated with LQTS. Here we describe a patient with LQTS who has a mutation in KCNQ1 as well as a polymorphism in KCNH2. The proband (MMRL0362), a 32-year-old female, exhibited multiple ventricular extrasystoles and one syncope. Her ECG (QT interval corrected for heart rate (QTc) = 518ms) showed an LQT2 morphology in leads V4-V6 and LQT1 morphology in leads V1-V2. Genomic DNA was isolated from lymphocytes. All exons and intron borders of 7 LQTS susceptibility genes were amplified and sequenced. Variations were detected predicting a novel missense mutation (V110I) in KCNQ1, as well as a common polymorphism in KCNH2 (K897T). We expressed wild-type (WT) or V110I Kv7.1 channels in CHO-K1 cells cotransfected with KCNE1 and performed patch-clamp analysis. In addition, WT or K897T Kv11.1 were also studied by patch clamp. Current-voltage (I-V) relations for V110I showed a significant reduction in both developing and tail current densities compared with WT at potentials >+20 mV (p < 0.05; n = 8 cells, each group), suggesting a reduction in IKs currents. K897T- Kv11.1 channels displayed a significantly reduced tail current density compared with WT-Kv11.1 at potentials >+10 mV. Interestingly, channel availability assessed using a triple-pulse protocol was slightly greater for K897T compared with WT (V0.5 = -53.1 ± 1.13 mV and -60.7 ± 1.15 mV for K897T and WT, respectively; p < 0.05). Comparison of the fully activated I-V revealed no difference in the rectification properties between WT and K897T channels. We report a patient with a loss-of-function mutation in KCNQ1 and a loss-of-function polymorphism in KCNH2. Our results suggest that a reduction of both IKr and IKs underlies the combined LQT1 and LQT2 phenotype observed in this patient.
长 QT 综合征（LQTS）是一种以 QT 间期延长和潜在致命性心律失常为特征的遗传性疾病。12 个不同基因的突变与 LQTS 相关。在这里，我们描述了一位患有 LQTS 的患者，其 KCNQ1 基因突变以及 KCNH2 多态性。先证者（MMRL0362）是一位 32 岁的女性，表现出多发室性期前收缩和一次晕厥。她的心电图（QT 间期校正心率（QTc）= 518ms）在 V4-V6 导联表现为 LQT2 形态，在 V1-V2 导联表现为 LQT1 形态。从淋巴细胞中提取基因组 DNA。扩增并测序 7 个 LQTS 易感性基因的所有外显子和内含子边界。检测到了一种新的错义突变（V110I）在 KCNQ1 中的预测，以及 KCNH2 中的常见多态性（K897T）。我们在共转染 KCNE1 的 CHO-K1 细胞中表达野生型（WT）或 V110I Kv7.1 通道，并进行膜片钳分析。此外，还通过膜片钳研究了 WT 或 K897T Kv11.1。与 WT 相比，V110I 的电流-电压（I-V）关系在>+20 mV 的电位下，I-V 关系显示出发育电流和尾电流密度显著降低（p < 0.05；n = 8 个细胞，每组），提示 IKs 电流减少。与 WT-Kv11.1 相比，K897T-Kv11.1 通道在>+10 mV 的电位下显示出明显降低的尾电流密度。有趣的是，使用三脉冲方案评估的通道可用性对于 K897T 略大于 WT（V0.5 = -53.1 ± 1.13 mV 和 -60.7 ± 1.15 mV 分别为 K897T 和 WT；p < 0.05）。完全激活的 I-V 比较显示 WT 和 K897T 通道之间的整流特性没有差异。我们报告了一位 KCNQ1 功能丧失突变和 KCNH2 功能丧失多态性的患者。我们的结果表明，该患者观察到的 LQT1 和 LQT2 表型的基础是 IKr 和 IKs 的减少。
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