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. While mutant LQT5 KCNE1 variants are known to inhibit I amplitudes in heterologous expression systems, cardiomyocytes from a transgenic rabbit LQT5 model displayed unchanged I 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 channels minimizes the inhibitory effects of LQT5 KCNE1 variants on I amplitudes, while current deactivation is accelerated. Such changes recapitulate I properties observed in LQT5 transgenic rabbits. We show that KCNE3 accomplishes this by displacing the KCNE1 subunit within the I ion channel complex, as evidenced by a dedicated biophysical assay. These findings depict KCNE3 as an integral part of the I channel complex that regulates I function in cardiomyocytes and modifies the development of the LQT5 phenotype.