The N588K mutation in KCNH2 shifted HERG current rectification to >+80 mV compared to >+10 mV for wild-type, abolishing inactivation over the physiological range and increasing ventricular I(Kr).
Does the N588K mutation in KCNH2 alter HERG current characteristics compared to wild-type in mammalian cells?
The N588K mutation abolishes HERG current rectification, leading to increased ventricular I(Kr) and preferential repolarization changes that may explain arrhythmogenesis in Short QT syndrome.
Short QT syndrome (SQTS) is characterized by ventricular arrhythmias and sudden death. One form of SQTS is caused by mutation N588K in human ether-a-go-go-related gene (HERG). In this study we sought to determine the potential role of N588K in arrhythmias.We measured the characteristics of HERG current generated by wild-type (WT) KCNH2 and the N588K mutant channel expressed in mammalian TSA201 cells.Whole-cell patch-clamp recordings of WT HERG currents showed the usual rapid onset of inactivation (rectification) at potentials more positive than +10 mV. In contrast, N588K currents rectified at potentials over +80 mV. Over the physiological range of potentials, N588K currents do not inactivate. During an action potential clamp, WT currents displayed a "hump" like waveform with slow activation kinetics and a rapid increase during phase 3 repolarization. In contrast, N588K currents were proportional to the amplitude of the action potential and displayed a dome-like configuration and a much larger current during the initial phases in the ventricle. Purkinje cell action potentials display a more negative phase 2 repolarization than the ventricle and elicited much smaller WT and N588K currents of similar amplitudes.Physiologically the N588K mutation abolishes rectification of HERG currents and specifically increases I(Kr) in the ventricle with minimal effects on the Purkinje fiber action potential duration. Such preferential prolongation may explain the separation of the T and U waves observed in the ECG of SQTS patients and lead to re-excitation of the ventricle endocardium.
Cordeiro et al. (2005) studied Short QT syndrome. N588K mutation in KCNH2 vs. Wild-type KCNH2 was evaluated on HERG current characteristics. The N588K mutation in KCNH2 shifted HERG current rectification to >+80 mV compared to >+10 mV for wild-type, abolishing inactivation over the physiological range and increasing ventricular I(Kr).