The Phenotypic Spectrum of a MutationHotspot Responsible for theShort QT Syndrome.
The Phenotypic Spectrum of a MutationHotspot Responsible for theShort QT Syndrome.
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导致短 QT 综合征的突变热点的表型谱。
DOI：
10.1016/j.jacep.2016.11.013
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发表时间：
2017-07-01
期刊：
影响因子：
--
通讯作者：
Barajas-Martinez, Hector
中科院分区：
文献类型：
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作者：
Hu, Dan;Li, Yang;Barajas-Martinez, Hector
目的：本研究旨在评估与短QT综合征（SQTS）相关的一个明显热点突变的表型和功能表达。背景：SQTS是一种罕见的通道病，与危及生命的心律失常和心源性猝死（SCD）的高风险相关。方法：对诊断为SQTS的先证者及其家族成员进行临床和遗传评估。KCNH 2野生型（WT）和突变基因在HEK 293细胞中瞬时表达，并使用全细胞膜片钳和动作电位（AP）钳技术记录电流。结果：在7个无关家族的18名成员（10名男性;中位年龄：24.0岁）中鉴定出KCNH 2-T618 I。所有携带者均表现出100%的表达率。7个家系18人有SCD。先证者和所有携带者的平均QTc间期分别为294.1 ± 23.8ms和313.2 ± 23.8ms。7名携带者接受了植入式心律转复除颤器。5例患者中，奎尼丁在适当血药浓度下可有效延长QTc间期，但3例仍有室性早搏或非持续性室性心动过速。苄普地尔成功地预防了1例QTc间期延长19 ms的药物难治性室颤。KCNE 2的功能研究显示，与WT相比，纯合子（119.0%）和杂合子（74.6%）表达的IKr（快速激活延迟整流钾通道）尾电流密度显著增加。AP钳记录显示IKr较大，峰值复极化电流发生在突变体与WT channel.CONCLUSIONS：我们报告的临床特征和生物物理特性的高度频繁的突变，有助于遗传上确定的SQTS先证者。这些发现扩展了我们对SQTS中KCNH 2通道缺陷谱的理解。
OBJECTIVES: This study sought to evaluate the phenotypic and functional expression of an apparent hotspot mutation associated with short QT syndrome (SQTS).BACKGROUND: SQTS is a rare channelopathy associated with a high risk of life-threatening arrhythmias and sudden cardiac death (SCD).METHODS: Probands diagnosed with SQTS and their family members were evaluated clinically and genetically. KCNH2 wild-type (WT) and mutant genes were transiently expressed in HEK293 cells, and currents were recorded using whole-cell patch clamp and action potential (AP) clamp techniques.RESULTS: KCNH2-T618I was identified in 18 members of 7 unrelated families (10 men; median age: 24.0 years). All carriers showed 100% penetrance with variable expressivity. Eighteen members in 7 families had SCD. The average QTc intervals of probands and all carriers was 294.1 ± 23.8 ms and 313.2 ± 23.8 ms, respectively. Seven carriers received an implantable cardioverter-defibrillator. Quinidine with adequate plasma levels was effective in prolonging QTc intervals among 5 cases, but 3 cases still had premature ventricular contraction or nonsustained ventricular tachycardia. Bepridil successfully prevented drug-refractory ventricular fibrillation in 1 case with 19-ms prolongation of the QTc interval. Functional studies with KCNE2 revealed a significant increase of IKr (rapidly activating delayed rectifier potassium channel) tail-current density in homozygous (119.0%) and heterozygous (74.6%) expression compared with WT. AP clamp recordings showed IKr was larger, and peak repolarizing current occurred earlier in mutant versus WT channels.CONCLUSIONS: We reported the clinical characteristics and biophysical properties of the highly frequent mutation that contributes to genetically identified SQTS probands. These findings extend our understanding of the spectrum of KCNH2 channel defects in SQTS.