{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["12"],"submitter":["Mun D"],"pubmed_abstract":["<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<sup>G53S</sup> variant and a healthy control using non-integrative Sendai virus-mediated reprogramming. Their electrophysiological properties were assessed using microelectrode arrays (MEA), and Ca<sup>2+</sup> dynamics were characterized using Fluo-4 dye.<h4>Results</h4>The patient harboring KCNH2<sup>G53S</sup> experienced aborted sudden cardiac death at 22 years of age, was diagnosed with LQT, and had an implantable cardioverter-defibrillator (ICD) implanted. KCNH2<sup>G53S</sup> hiPSC-CMs expressed less KCNH2 than normal CMs. Transcriptomic analysis of KCNH2<sup>G53S</sup> 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<sup>G53S</sup> 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<sup>G53S</sup> 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<sup>G53S</sup> 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<sup>G53S</sup> mutation, which showed abnormal electrophysiology and impaired calcium handling, provides a basis for developing improved management strategies for patients with LQT2."],"journal":["Frontiers in cardiovascular medicine"],"pagination":["1524909"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12014601"],"repository":["biostudies-literature"],"pubmed_title":["Pathogenic KCNH2-G53S variant in the PAS domain influences the electrophysiological phenotype in long QT syndrome type 2."],"pmcid":["PMC12014601"],"pubmed_authors":["Joung B","Kang JY","Park M","Mun D","Yoo G","Yun N","Hwang Y"],"additional_accession":[]},"is_claimable":false,"name":"Pathogenic KCNH2-G53S variant in the PAS domain influences the electrophysiological phenotype in long QT syndrome type 2.","description":"<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<sup>G53S</sup> variant and a healthy control using non-integrative Sendai virus-mediated reprogramming. Their electrophysiological properties were assessed using microelectrode arrays (MEA), and Ca<sup>2+</sup> dynamics were characterized using Fluo-4 dye.<h4>Results</h4>The patient harboring KCNH2<sup>G53S</sup> experienced aborted sudden cardiac death at 22 years of age, was diagnosed with LQT, and had an implantable cardioverter-defibrillator (ICD) implanted. KCNH2<sup>G53S</sup> hiPSC-CMs expressed less KCNH2 than normal CMs. Transcriptomic analysis of KCNH2<sup>G53S</sup> 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<sup>G53S</sup> 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<sup>G53S</sup> 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<sup>G53S</sup> 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<sup>G53S</sup> mutation, which showed abnormal electrophysiology and impaired calcium handling, provides a basis for developing improved management strategies for patients with LQT2.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025","modification":"2025-07-02T03:04:59.123Z","creation":"2025-07-02T03:04:59.123Z"},"accession":"S-EPMC12014601","cross_references":{"pubmed":["40271129"],"doi":["10.3389/fcvm.2025.1524909"]}}