A new KCNQ1 mutation at the S5 segment that impairs its association with KCNE1 is responsible for short QT syndrome

Aims KCNQ1 and KCNE1 encode K(v)7.1 and KCNE1, respectively, the pore-forming and the accessory subunits of the slow delayed rectifier potassium current, I-Ks. KCNQ1 mutations are associated with long and short QT syndrome. The aim of this study was to characterize the biophysical and cellular phenotype of a KCNQ1 missense mutation, F279I, found in a 23-year-old man with a corrected QT interval (QTc) of 356 ms and a family history of sudden cardiac death. Methods and results Experiments were performed using perforated patch-clamp, western blot, co-immunoprecipitation, biotinylation, and immunocytochemistry techniques in HEK293, COS7 cells and in cardiomyocytes transfected with WT K(v)7.1/KCNE1 or F279I K(v)7.1/KCNE1 channels. In the absence of KCNE1, F279I K(v)7.1 current exhibited a lesser degree of inactivation than WT K(v)7.1. Also, functional analysis of F279I K(v)7.1 in the presence of KCNE1 revealed a negative shift in the activation curve and an acceleration of the activation kinetics leading to a gain of function in I-Ks. The co-assembly between F279I K(v)7.1 channels and KCNE1 was markedly decreased compared with WT K(v)7.1 channels, as revealed by co-immunoprecipitation and Foster Resonance Energy Transfer experiments. All these effects contribute to the increase of I-Ks when channels incorporate F279I K(v)7.1 subunits, as shown by a computer model simulation of these data that predicts a shortening of the action potential (AP) consistent with the patient phenotype. Conclusion The F279I mutation induces a gain of function of I-Ks due to an impaired gating modulation of K(v)7.1 induced by KCNE1, leading to a shortening of the cardiac AP