biostudies-literatureUnknown12Mun D<h4>Background</h4>Long QT syndrome type 2 (LQT2) is an arrythmia caused by loss-of-function mutations in KCNH2, leading to impaired Kv11.1 channel function.<h4>Objective</h4>To better understand LQT2, we examined the electrophysiological differences related to the G53S variant, which is located within the PAS domain of KCNH2, using patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs).<h4>Methods</h4>We generated hiPSC-CMs from a patient harboring the KCNH2^G53S variant and a healthy control using non-integrative Sendai virus-mediated reprogramming. Their electrophysiological properties were assessed using microelectrode arrays (MEA), and Ca²⁺ dynamics were characterized using Fluo-4 dye.<h4>Results</h4>The patient harboring KCNH2^G53S experienced aborted sudden cardiac death at 22 years of age, was diagnosed with LQT, and had an implantable cardioverter-defibrillator (ICD) implanted. KCNH2^G53S hiPSC-CMs expressed less KCNH2 than normal CMs. Transcriptomic analysis of KCNH2^G53S hiPSC-CMs revealed 3,857 differentially expressed genes, highlighting significant changes in pathways related to LQT2 development. Action potential duration was significantly longer in KCNH2^G53S hiPSC-CMs than in control (545.3 ± 176.3 ms vs. 339.9 ± 44.5 ms; <i>P =</i> 0.019). Corrected field potential duration was significantly longer in KCNH2^G53S hiPSC-CMs than in control (318.0 ± 66.3 ms vs. 234.5 ± 21.0 ms; <i>P =</i> 0.015), indicating altered electrophysiology. KCNH2^G53S hiPSC-CMs exhibited significantly increased calcium transient amplitude and prolonged calcium wave duration under isoproterenol stimulation, indicating exacerbated abnormal calcium handling.<h4>Conclusion</h4>Our analysis of hiPSC-CMs carrying a heterozygous KCNH2^G53S mutation, which showed abnormal electrophysiology and impaired calcium handling, provides a basis for developing improved management strategies for patients with LQT2.Frontiers in cardiovascular medicine1524909https://www.ebi.ac.uk/biostudies/studies/S-EPMC12014601biostudies-literaturePathogenic KCNH2-G53S variant in the PAS domain influences the electrophysiological phenotype in long QT syndrome type 2.PMC12014601Joung BKang JYPark MMun DYoo GYun NHwang YfalsePathogenic KCNH2-G53S variant in the PAS domain influences the electrophysiological phenotype in long QT syndrome type 2.<h4>Background</h4>Long QT syndrome type 2 (LQT2) is an arrythmia caused by loss-of-function mutations in KCNH2, leading to impaired Kv11.1 channel function.<h4>Objective</h4>To better understand LQT2, we examined the electrophysiological differences related to the G53S variant, which is located within the PAS domain of KCNH2, using patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs).<h4>Methods</h4>We generated hiPSC-CMs from a patient harboring the KCNH2^G53S variant and a healthy control using non-integrative Sendai virus-mediated reprogramming. Their electrophysiological properties were assessed using microelectrode arrays (MEA), and Ca²⁺ dynamics were characterized using Fluo-4 dye.<h4>Results</h4>The patient harboring KCNH2^G53S experienced aborted sudden cardiac death at 22 years of age, was diagnosed with LQT, and had an implantable cardioverter-defibrillator (ICD) implanted. KCNH2^G53S hiPSC-CMs expressed less KCNH2 than normal CMs. Transcriptomic analysis of KCNH2^G53S hiPSC-CMs revealed 3,857 differentially expressed genes, highlighting significant changes in pathways related to LQT2 development. Action potential duration was significantly longer in KCNH2^G53S hiPSC-CMs than in control (545.3 ± 176.3 ms vs. 339.9 ± 44.5 ms; <i>P =</i> 0.019). Corrected field potential duration was significantly longer in KCNH2^G53S hiPSC-CMs than in control (318.0 ± 66.3 ms vs. 234.5 ± 21.0 ms; <i>P =</i> 0.015), indicating altered electrophysiology. KCNH2^G53S hiPSC-CMs exhibited significantly increased calcium transient amplitude and prolonged calcium wave duration under isoproterenol stimulation, indicating exacerbated abnormal calcium handling.<h4>Conclusion</h4>Our analysis of hiPSC-CMs carrying a heterozygous KCNH2^G53S mutation, which showed abnormal electrophysiology and impaired calcium handling, provides a basis for developing improved management strategies for patients with LQT2.2025-01-01T00:00:00Z20252025-07-02T03:04:59.123Z2025-07-02T03:04:59.123ZS-EPMC120146014027112910.3389/fcvm.2025.1524909