Heart rhythm O2 · 2026
Personalized in vitro models reveal functional impact of a KCNH2 mutation and enable drug screening in LQTS2.
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Zheng Bingyu, Zhu Yue, Sun Mingyu, Cheng Hongyi, Zhang Shimeng, Cai Cheng, Gu Kai, An Yanzun, Ding Xiangwei, Zhang Feng, Cui Chang, Chen Minglong
Аннотация
BACKGROUND: Long QT syndrome is clinically associated with recurrent ventricular tachycardia and sudden cardiac death. Mutations in KCNH2, which encodes the pore-forming potassium channel subunit human ether-a-go-go-related gene (Kv11.1), are associated with long QT syndrome type 2 (LQTS2).
OBJECTIVE: We aimed to investigate the pathogenicity and personalized therapy for a patient with LQTS2 carrying a novel KCNH2 heterozygous mutation F431L.
METHODS: This study aimed to evaluate the expression and function of the channel protein, we conducted immunoblotting and whole-cell patch-clamp recordings. In addition, patient-specific human-induced pluripotent stem cell-derived cardiomyocytes were combined with a heart-on-chip platform to validate the pathogenicity of this heterozygous variant and investigate the pharmacologic candidates for phenotypic rescue.
RESULTS: In HEK293 cells overexpressing the mutant KCNH2, a significant reduction in human ether-a-go-go-related gene membrane abundance was observed. The heterozygous variant led to decreased current density and alterations in voltage-dependent activation (positively shifted) and inactivation (negatively shifted) compared with the wild type. Correspondingly, patient-specific human-induced pluripotent stem cell-derived cardiomyocytes harboring the heterozygous KCNH2 F431L mutation displayed reduced current density and prolonged action potential duration. Moreover, LQTS2 patient-specific engineered cardiac tissues replicated the disease phenotype with extended field potential duration. Drug screening on the heart-on-chip platform indicated the potential therapeutic efficacy of the slowly activating delayed rectifier potassium current channel agonist ML277 and the proteasome inhibitor MG101.
CONCLUSION: The F431L mutation in KCNH2 was pathogenic, characterized by both channel instability and functional impairments. Our study also highlighted the feasibility of using a patient-specific microphysiological system for individualized treatment in ion-channel diseases.
OBJECTIVE: We aimed to investigate the pathogenicity and personalized therapy for a patient with LQTS2 carrying a novel KCNH2 heterozygous mutation F431L.
METHODS: This study aimed to evaluate the expression and function of the channel protein, we conducted immunoblotting and whole-cell patch-clamp recordings. In addition, patient-specific human-induced pluripotent stem cell-derived cardiomyocytes were combined with a heart-on-chip platform to validate the pathogenicity of this heterozygous variant and investigate the pharmacologic candidates for phenotypic rescue.
RESULTS: In HEK293 cells overexpressing the mutant KCNH2, a significant reduction in human ether-a-go-go-related gene membrane abundance was observed. The heterozygous variant led to decreased current density and alterations in voltage-dependent activation (positively shifted) and inactivation (negatively shifted) compared with the wild type. Correspondingly, patient-specific human-induced pluripotent stem cell-derived cardiomyocytes harboring the heterozygous KCNH2 F431L mutation displayed reduced current density and prolonged action potential duration. Moreover, LQTS2 patient-specific engineered cardiac tissues replicated the disease phenotype with extended field potential duration. Drug screening on the heart-on-chip platform indicated the potential therapeutic efficacy of the slowly activating delayed rectifier potassium current channel agonist ML277 and the proteasome inhibitor MG101.
CONCLUSION: The F431L mutation in KCNH2 was pathogenic, characterized by both channel instability and functional impairments. Our study also highlighted the feasibility of using a patient-specific microphysiological system for individualized treatment in ion-channel diseases.