Additional gene variants reduce effectiveness of beta-blockers in the LQT1 form of long QT syndrome
Additional gene variants reduce effectiveness of beta-blockers in the LQT1 form of long QT syndrome
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DOI：
10.1046/j.1540-8167.2004.03212.x
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发表时间：
2004-02-01
影响因子：
2.7
通讯作者：
Horie, M
中科院分区：
文献类型：
--
作者：
Kobori, A;Sarai, N;Horie, M
LQT1 的其他突变。简介：β 受体阻滞剂广泛用于预防与长 QT 综合征 (LQTS) 相关的致命心脏事件，尤其是 KCNQ1 相关 LQTS (LQT1) 患者。然而，一些 LQT1 患者对此疗法无效。方法和结果：18 名有症状的 LQTS 患者（12 个家庭）被基因诊断为具有杂合 KCNQ1 变异，并接受了 β 受体阻滞剂治疗。尽管在平均 70 个月的随访期间继续接受治疗，但仍有 4 名成员（3 个家庭）出现心脏事件复发。其中 3 名患者（2 个家庭）具有相同的突变 [A341V (KCNQ1)]；另一个是R243H（KCNQ1）。后者服用了阿普林定，这似乎是造成这一事件的原因。通过使用异源哺乳动物表达系统的功能测定，我们发现A341V（KCNQ1）是一种功能丧失型突变（非显性失活）。进一步的基因筛查显示，一个 A341V (KCNQ1) 家族与 S706C (KCNH2) 共分离，另一个与 G144S (KCNJ2) 共分离。 S706C (KCNH2) 突变的功能分析发现，表达的杂合 KCNH2 通道的电流密度降低，激活曲线出现正移 (+8 mV)。基于KYOTO模型进行动作电位模拟研究，以估计额外基因修饰剂的影响。在模拟LQT1+2和LQT1+7的两种模型中，在β-肾上腺素能刺激的情况下，与LQT1模型相比，早期后除极的发生率有所增加。结论：不同LQTS相关基因的多个突变可能会改变临床特征。对 β 受体阻滞剂治疗耐药的 LQT1 患者可能需要扩大基因调查。
Additional Mutations in LQT1.Introduction: Beta-blockers are widely used to prevent the lethal cardiac events associated with the long QT syndrome (LQTS), especially in KCNQ1-related LQTS (LQT1) patients. Some LQT1 patients, however, are refractory to this therapy.Methods and Results: Eighteen symptomatic LQTS patients (12 families) were genetically diagnosed as having heterozygous KCNQ1 variants and received beta-blocker therapy. Cardiac events recurred in 4 members (3 families) despite continued therapy during mean follow-up of 70 months. Three of these patients (2 families) had the same mutation [A341V (KCNQ1)]; and the other had R243H (KCNQ1). The latter patient took aprindine, which seemed to be responsible for the event. By functional assay using a heterologous mammalian expression system, we found that A341V (KCNQ1) is a loss-of-function type mutation (not dominant negative). Further genetic screening revealed that one A341V (KCNQ1) family cosegregated with S706C (KCNH2) and another with G144S (KCNJ2). Functional assay of the S706C (KCNH2) mutation was found to reduce the current density of expressed heterozygous KCNH2 channels with a positive shift (+8 mV) of the activation curve. Action potential simulation study was conducted based on the KYOTO model to estimate the influence of additional gene modifiers. In both models mimicking LQT1 plus 2 and LQT1 plus 7, the incidence of early afterdepolarization was increased compared with the LQT1 model under the setting of beta-adrenergic stimulation.Conclusion: Multiple mutations in different LQTS-related genes may modify clinical characteristics. Expanded gene survey may be required in LQT1 patients who are resistant to beta-blocker therapy.