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

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).

METHODS

We generated hiPSC-CMs from a patient harboring the KCNH2 variant and a healthy control using non-integrative Sendai virus-mediated reprogramming. Their electrophysiological properties were assessed using microelectrode arrays (MEA), and Ca dynamics were characterized using Fluo-4 dye.

RESULTS

The patient harboring KCNH2 experienced aborted sudden cardiac death at 22 years of age, was diagnosed with LQT, and had an implantable cardioverter-defibrillator (ICD) implanted. KCNH2 hiPSC-CMs expressed less KCNH2 than normal CMs. Transcriptomic analysis of KCNH2 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 hiPSC-CMs than in control (545.3 ± 176.3 ms vs. 339.9 ± 44.5 ms;  0.019). Corrected field potential duration was significantly longer in KCNH2 hiPSC-CMs than in control (318.0 ± 66.3 ms vs. 234.5 ± 21.0 ms;  0.015), indicating altered electrophysiology. KCNH2 hiPSC-CMs exhibited significantly increased calcium transient amplitude and prolonged calcium wave duration under isoproterenol stimulation, indicating exacerbated abnormal calcium handling.

CONCLUSION

Our analysis of hiPSC-CMs carrying a heterozygous KCNH2 mutation, which showed abnormal electrophysiology and impaired calcium handling, provides a basis for developing improved management strategies for patients with LQT2.