Overlapping Cardiac Phenotype Associated with a Familial Mutation in the Voltage Sensor of the KCNQ1 Channel

Cellular Physiology and Biochemistry

关键词: Oocyte;    Kv7.1;    KvLQT1;    KCNE;    Heart;    Arrhythmia;   

DOI  :  10.1159/000178470

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

Background Cardiac action potential repolarisation is determined by K⁺ currents including I_Ks. I_Ks channels are heteromeric channels composed of KCNQ1 and KCNE E-subunits. Mutations in KCNQ1 are associated with sinus bradycardia, familial atrial fibrillation (fAF) and/or short QT syndrome as a result of gain-of-function, and long QT syndrome (LQTS) due to loss-of-function in the ventricles. Here, we report that the missense mutation R231C located in S4 voltage sensor domain is associated with a combined clinical phenotype of sinus bradycardia, fAF and LQTS. We aim to understand the molecular basis of the complex clinical phenotype. Methods We expressed and functionally analyzed the respective channels kinetics in Xenopus laevis oocytes. The molecular nature of the residue R231 was studied by homology modeling and molecular dynamics simulation. Results As a result, the mutation reduced voltage sensitivity of channels, possibly due to neutralization of the positive charge of the arginine side chain substituted by cysteine. Modeling suggested that the charge carrying side chain of R231 is positioned suitably to transfer transmembrane voltages into conformational energy. Further, the mutation altered the functional interactions with KCNE subunits. Conclusion The mutation acted in a E-subunit dependent manner, suggesting I_Ks function altered by the presence of different KCNE subunits in sinus node, atria and ventricles as the molecular basis of sinus bradycardia, fAF and LQTS in mutation carriers.

【 授权许可】

CC BY-NC-ND