AUTHOR=Mun Dasom , Kang Ji-Young , Park Malgeum , Yoo Gyeongseo , Yun Nuri , Hwang YouMi , Joung Boyoung 

TITLE=Pathogenic KCNH2-G53S variant in the PAS domain influences the electrophysiological phenotype in long QT syndrome type 2

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 12 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2025.1524909

DOI=10.3389/fcvm.2025.1524909

ISSN=2297-055X

ABSTRACT=BackgroundLong QT syndrome type 2 (LQT2) is an arrythmia caused by loss-of-function mutations in KCNH2, leading to impaired Kv11.1 channel function.ObjectiveTo 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).MethodsWe generated hiPSC-CMs from a patient harboring the KCNH2G53S 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.ResultsThe patient harboring KCNH2G53S experienced aborted sudden cardiac death at 22 years of age, was diagnosed with LQT, and had an implantable cardioverter-defibrillator (ICD) implanted. KCNH2G53S hiPSC-CMs expressed less KCNH2 than normal CMs. Transcriptomic analysis of KCNH2G53S hiPSC-CMs revealed 3,857 differentially expressed genes, highlighting significant changes in pathways related to LQT2 development. Action potential duration was significantly longer in KCNH2G53S hiPSC-CMs than in control (545.3 ± 176.3 ms vs. 339.9 ± 44.5 ms; P = 0.019). Corrected field potential duration was significantly longer in KCNH2G53S hiPSC-CMs than in control (318.0 ± 66.3 ms vs. 234.5 ± 21.0 ms; P = 0.015), indicating altered electrophysiology. KCNH2G53S hiPSC-CMs exhibited significantly increased calcium transient amplitude and prolonged calcium wave duration under isoproterenol stimulation, indicating exacerbated abnormal calcium handling.ConclusionOur analysis of hiPSC-CMs carrying a heterozygous KCNH2G53S mutation, which showed abnormal electrophysiology and impaired calcium handling, provides a basis for developing improved management strategies for patients with LQT2.