Voltage-shift of the current activation in HERG S4 mutation (R534C) in LQT2

Objective: Recently, a novel missense mutation (R534C) in the S4 region of human ether-a-go-go-related gene (HERG) was identified in one Japanese LQT2 family. The S4 region presumably functions as a voltage sensor. However, i t has not yet been addressed whether the S4 region of HERG indeed functions as a voltage sensor, and whether these residues play any role in abnormal channel function in cardiac repolarization. Methods: We characterized the e lectrophysiological properties of the R534C mutation using the heterologous expression system in Xenopus oocytes. Whole cell currents were recorded in oocytes injected with wild-type cRNA, R534C cRNA, or a combination of both . Results: Clinical features - QTc intervals of all affected patients with R534C mutation in HERG are prolonged ranging from 460 to 680 ms (averaged Q Tc interval>540 ms). One member of this family had experienced sudden cardi ac arrest, and other suffered from recurrent palpitation. Electrophysiology - Oocytes injected with R534C cRNA did express functional channels with al tered channel gating. Kinetic analyses revealed that the R534C mutation shi fted the voltage-dependence of HERO channel activation to a negative direct ion, accelerated activation and deactivation time course, and reduced stead y-state inactivation. Quantitative analyses revealed that this mutation did not cause apparent dominant-negative suppression. Computer simulation - In corporating the kinetic alterations of R534C, however, did not reproduce pr olonged action potential duration (APD). Conclusions: The data revealed tha t arginine at position 534 in the S4 region of HERG is indeed involved in v oltage-dependence of channel activation as a voltage sensor. Our examinatio n indicated that HERO current suppression in R534C mutation was the least s evere among other mutations that have been electrophysiologicaly examined, while affected patients did show significant QT prolongation. This suggest that another unidentified factor(s) that prolong APD might be present. (C) 1999 Elsevier Science B.V. All rights reserved.