Background:The KCNH2-encoded Kv11.1 hERG (human ether-a-go-go related gene) potassium channel is a critical regulator of cardiomyocyte action potential duration (APD). The majority of type 2 long-QT syndrome (LQT2) stems from trafficking defective KCNH2 mutations. Recently, Food and Drug Administration-approved cystic fibrosis protein trafficking chaperone, lumacaftor, has been proposed as novel therapy for LQT2. Here, we test the efficacy of lumacaftor treatment in patient-specific induced pluripotent stem cell-cardiomyocytes (iPSC-CMs) derived from 2 patients with known LQT2 trafficking defective mutations and a patient with novel KCNH2 variant, p.R685P.Methods:Patient-specific iPSC-CM models of KCNH2-G604S, KCNH2-N633S, and KCNH2-R685P were generated from 3 unrelated patients diagnosed with severe LQT2 (rate-corrected QT>500 ms). Lumacaftor efficacy was also tested by ANEPPS, FluoVolt, and ArcLight voltage dye-based APD90 measurements.Results:All 3 mutations were hERG trafficking defective in iPSC-CMs. While lumacaftor treatment failed to rescue the hERG trafficking defect in TSA201 cells, lumacaftor rescued channel trafficking for all mutations in the iPSC-CM model. All 3 mutations conferred a prolonged APD90 compared with control. While lumacaftor treatment rescued the phenotype of KCNH2-N633S and KCNH2-R685P, lumacaftor paradoxically prolonged the APD90 in KCNH2-G604S iPSC-CMs. Lumacaftor-mediated APD90 rescue was affected by rapidly activating delayed rectifier K+ current blocker consistent with the increase of rapidly activating delayed rectifier K+ current by lumacaftor is the underlying mechanism of the LQT2 rescue.Conclusions:While lumacaftor is an effective hERG channel trafficking chaperone and may be therapeutic for LQT2, we urge caution. Without understanding the functionality of the mutant channel to be rescued, lumacaftor therapy could be harmful.

中文翻译：

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Lumacaftor 用于贩运缺陷型 2 型长 QT 综合征致病变异 p.G604S、p.N633S 和 p.R685P，使用患者特定的重新设计的心肌细胞的承诺和潜在危险。

背景：KCNH2编码的 Kv11.1 hERG（人类 ether-a-go-go 相关基因）钾通道是心肌细胞动作电位持续时间 (APD) 的关键调节因子。大多数 2 型长 QT 综合征 (LQT2) 源于贩卖有缺陷的KCNH2突变。最近，食品和药物管理局批准的囊性纤维化蛋白运输伴侣 lumacaftor 已被提议作为 LQT2 的新疗法。在这里，我们测试了 lumacaftor 治疗在患者特异性诱导多能干细胞心肌细胞 (iPSC-CMs) 中的疗效，这些细胞来自 2 名具有已知 LQT2 运输缺陷突变的患者和一名具有新型 KCNH2 变异体 p.R685P 的患者。方法：患者- KCNH2-G604S、KCNH2-N633S 和 KCNH2-R685P 的特定 iPSC-CM 模型由 3 名诊断为严重 LQT2（速率校正 QT>500 ms）的无关患者生成。Lumacaftor 功效还通过 ANEPPS、FluoVolt 和 ArcLight 基于电压染料的 APD90 测量进行了测试。结果：所有 3 种突变都是 iPSC-CM 中的 hERG 运输缺陷。虽然 lumacaftor 治疗未能挽救 TSA201 细胞中的 hERG 运输缺陷，lumacaftor 拯救了 iPSC-CM 模型中所有突变的通道贩运。与对照相比，所有 3 种突变都赋予了延长的 APD90。虽然 lumacaftor 治疗挽救了 KCNH2-N633S 和 KCNH2-R685P 的表型，但 lumacaftor 却矛盾地延长了 KCNH2-G604S iPSC-CM 中的 APD90。Lumacaftor 介导的 APD90 拯救受到快速激活延迟整流 K+ 电流阻滞剂的影响，与 lumacaftor 快速激活延迟整流 K+ 电流的增加是 LQT2 拯救的潜在机制。结论：虽然 lumacaftor 是一种有效的 hERG 通道运输伴侣，并且可能对 LQT2 有治疗作用，我们敦促谨慎。如果不了解要拯救的突变通道的功能，lumacaftor 疗法可能是有害的。