A Possible Explanation for the Low Penetrance of Pathogenic KCNE1 Variants in Long QT Syndrome Type 5

Long QT syndrome (LQTS) is an inherited cardiac rhythm disorder associated with increased incidence of cardiac arrhythmias and sudden death. LQTS type 5 (LQT5) is caused by dominant mutant variants of KCNE1, a regulatory subunit of the voltage-gated ion channels generating the cardiac potassium current I_Ks. While mutant LQT5 KCNE1 variants are known to inhibit I_Ks amplitudes in heterologous expression systems, cardiomyocytes from a transgenic rabbit LQT5 model displayed unchanged I_Ks amplitudes, pointing towards the critical role of additional factors in the development of the LQT5 phenotype in vivo. In this study, we demonstrate that KCNE3, a candidate regulatory subunit of I_Ks channels minimizes the inhibitory effects of LQT5 KCNE1 variants on I_Ks amplitudes, while current deactivation is accelerated. Such changes recapitulate I_Ks properties observed in LQT5 transgenic rabbits. We show that KCNE3 accomplishes this by displacing the KCNE1 subunit within the I_Ks ion channel complex, as evidenced by a dedicated biophysical assay. These findings depict KCNE3 as an integral part of the I_Ks channel complex that regulates I_Ks function in cardiomyocytes and modifies the development of the LQT5 phenotype.