95% of researchers rate our articles as excellent or good
Learn more about the work of our research integrity team to safeguard the quality of each article we publish.
Find out more
ORIGINAL RESEARCH article
Front. Cardiovasc. Med.
Sec. Cardiovascular Genetics and Systems Medicine
Volume 12 - 2025 | doi: 10.3389/fcvm.2025.1524909
Pathogenic KCNH2-G53S variant in the PAS domain influences the electrophysiological phenotype in long QT syndrome type 2
Provisionally accepted
Dasom Mun 1 Ji-Young Kang 1 Malgeum Park 1 Gyeongseo Yoo 1 Nuri Yun 2
YouMi Hwang 3
Boyoung Joung 1*- 1 College of Medicine, Yonsei University, Seoul, Republic of Korea
- 2 GNTPharma Science and Technology Center for Health, Incheon, Republic of Korea
- 3 The Catholic University College of Medicine, Suwon, Republic of Korea
Background: Long QT syndrome type 2 (LQT2) is an arrythmia caused by loss-of-function mutations in KCNH2, leading to impaired Kv11.1 channel function.Objective: 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).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 Ca 2+ dynamics were characterized using Fluo-4 dye.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; P = 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; P = 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.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.
Keywords: Long QT syndrome type 2, KCNH2 G53S, PAS domain, variant, hiPSC-CMs Long QT syndrome type 2, kcnh2, hiPSC-CMs
Received: 08 Nov 2024; Accepted: 27 Mar 2025.
Copyright: © 2025 Mun, Kang, Park, Yoo, Yun, Hwang and Joung. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Boyoung Joung, College of Medicine, Yonsei University, Seoul, Republic of Korea
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.