A new KCNQ1 mutation at the S5 segment that impairs its association with KCNE1 is responsible for short QT syndrome. (13th July 2015)

• Record Type: Journal Article
• Authors: Moreno, Cristina; Oliveras, Anna; de la Cruz, Alicia; Bartolucci, Chiara; Muñoz, Carmen; Salar, Eladia; Gimeno, Juan R.; Severi, Stefano; Comes, Nuria; Felipe, Antonio; González, Teresa; Lambiase, Pier; Valenzuela, Carmen
• Is Part Of: Cardiovascular research. Volume 107:Number 4(2015)
• Page Start: 613
• Page End: 623
• Publication Date: 2015-07-13
• Subjects: Kv7.1 -- KCNE1 -- Short QT syndrome -- FRET -- Electrophysiology; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvv196
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: KCNQ1 and KCNE1 encode Kv 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 Kv 7.1/KCNE1 or F279I Kv 7.1/KCNE1 channels. In the absence of KCNE1, F279I Kv 7.1 current exhibited a lesser degree of inactivation than WT Kv 7.1. Also, functional analysis of F279I Kv 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 Kv 7.1 channels and KCNE1 was markedly decreased compared with WT Kv 7.1 channels, as revealed by co-immunoprecipitation and Föster Resonance Energy Transfer experiments. All these effects contribute to the increase of I Ks when channels incorporate F279I Kv 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 Kv 7.1 induced by KCNE1, leading to a shortening of the cardiac AP.