Kcnh2 Mutant Rats Recapitulate Long Qt Rhythm and Embryonic Development Defects

Kv11.1 potassium channel encoded by Kcnh2 gene is crucial in conducting the rapid delayed rectifier K+ current in cardiomyocytes. KCNH2 mutant leads to long QT syndrome, and involves in intrauterine fetal loss in human. However, previous efforts to understand the mechanism using mouse models failed to reproduce the human pathological phenotypes. Here, we generated Kcnh2 knockout rat based on edited ES cells, and found that Kcnh2+/- model successfully displayed the arrhythmia of prolonged QTc interval which could be then corrected using beta blocker, while the whole cell current of cardiomyocyte of newborn rats displayed normal status. Kcnh2-/- rats, however, shown embryonic lethality on the day 11.5 due to heart configuration defect. Dataset analysis suggested KCNH2 was really crucial during the development of compact cardiomyocytes by comparing human embryonic heart single cell of 6.5-7 post-conception weeks. Apoptosis was also found to be trigged in the homozygote embryos, which could attribute to the failure to form a complex of ERG with ITGB1 that was essential to prevent the process via inhibiting FOXO3A. The present work recapitulates the classic pathological LQT phenotype in rats by editing Kcnh2, and revealed a basic mechanism of KCNH2 in maintaining embryonic heart development, hereby, providing evidence for understanding the dual role of the classic gene in both heart development and ion conduction.