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

Abstract

KCNQ1 and KCNE1 encode Kv7.1 and KCNE1, respectively, the poreforming and the accessory subunits of the slow delayed rectifier potassium current, IKs. KCNQ1 mutations are associated with long and short QT syndrome. The aim of this study was to characterize the biophysical and cellular pheno-type of a KCNQ1 missense mutation, F279I, found in a 23 years old man with a QTc of 356 ms and a family history of sudden cardiac death (SCD). Experiments were performed using perforated patch-clamp, western blot, coimmunoprecipitation, biotinylation and immunocytochemistry techniques in HEK293, COS7 cells and in cardiomyocytes transfected with WT Kv7.1/KCNE1 or F279I Kv7.1/KCNE1 channels. In the absence of KCNE1, F279I Kv7.1 current exhibited less degree of inactivation than WT Kv7.1. Also, functional analysis of F279I Kv7.1 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 IKs. The coassembly between F279I Kv7.1 channels and KCNE1 was markedly decreased compared with WT Kv7.1 channels, as revealed by coimmunoprecipitation and FRET experiments. All these effects contribute to the increase of IKs when channels incorporate F279I Kv7.1 subunits, as shown by a computer model simulation of these data that predicts a shortening of the action potential consistent with the patient phenotype. In conclusion, the F279I mutation induces a gain of function of IKs due to an impaired gating modulation of Kv7.1 induced by KCNE1; leading to a shortening of the cardiac action potential.