INHIBITION OF CARDIAC DELAYED RECTIFIER K-QT SYNDROME HERG G628S MUTATION IN TRANSGENIC MICE( CURRENT BY OVEREXPRESSION OF THE LONG)

Mutations in the HERG gene are linked to the LQT2 form of the inherite d long-QT syndrome. Transgenic mice were generated expressing high myo cardial levels of a particularly severe form of LQT2-associated HERG m utation (G628S). Hearts from G628S mice appeared normal except for a m odest enlargement seen only in females. Ventricular myocytes isolated from adult wild-type hearts consistently exhibited an inwardly rectify ing E-4031-sensitive K+ current resembling the rapidly activating card iac delayed rectifier K+ current (I-Kr) in its time and voltage depend ence; this current was not found in cells isolated from G625S mice. Ac tion potential duration was significantly prolonged in single myocytes from G628S ventricle (cycle length=1 second, 26 degrees C) but not in recordings from intact ventricular strips studied at more physiologic al rates and temperature (200 to 400 bpm, 37 degrees C). ECG intervals , including QT duration, were unchanged, although minor aberrancies we re noted in 20% (16/80) of the G628S mice studied, primarily involving the QRS complex and, more rarely, T-wave morphology. The aberrations were more commonly observed in females than males but could not be cor related with sex-based differences in action potential duration. These results establish the presence of I-Kr in the adult mouse ventricle a nd demonstrate the ability of the G628S mutation to exert a dominant n egative effect on endogenous I-Kr in vivo, leading to the expected LQT 2 phenotype of prolonged repolarization at the single cell level but n ot QT prolongation in the intact animal. The model may be useful in di ssecting repolarization currents in the mouse heart and as a means of examining the mechanism(s) by which the G628S mutation exerts its domi nant negative effect on native cardiac cells in vivo.