title: Inhibition of cardiac delayed rectifier K+ current by overexpression of the long-QT syndrome HERG G628S mutation in transgenic mice.
abstract: Mutations in the HERG gene are linked to the LQT2 form of the inherited long-QT syndrome. Transgenic mice were generated expressing high myocardial levels of a particularly severe form of LQT2-associated HERG mutation (G628S). Hearts from G628S mice appeared normal except for a modest enlargement seen only in females. Ventricular myocytes isolated from adult wild-type hearts consistently exhibited an inwardly rectifying E-4031-sensitive K+ current resembling the rapidly activating cardiac delayed rectifier K+ current (Ikr) in its time and voltage dependence; this current was not found in cells isolated from G628S mice. Action 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 physiological rates and temperature (200 to 400 bpm, 37 degrees C). ECG intervals, including QT duration, were unchanged, although minor aberrancies were 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 correlated with sex-based differences in action potential duration. These results establish the presence of IKr in the adult mouse ventricle and demonstrate the ability of the G628S mutation to exert a dominant negative effect on endogenous IKr in vivo, leading to the expected LQT2 phenotype of prolonged repolarization at the single cell level but not QT prolongation in the intact animal. The model may be useful in dissecting repolarization currents in the mouse heart and as a means of examining the mechanism(s) by which the G628S mutation exerts its dominant negative effect on native cardiac cells in vivo.
authors.affiliation: From the Divisions of Molecular Genetics and Cardiovascular and Metabolic Diseases, Wyeth-Ayerst Research, Princeton, NJ, USA.
authors.forename: P
authors.initials: P
authors.lastname: Babij
authors.forename: G R
authors.initials: GR
authors.lastname: Askew
authors.forename: B
authors.initials: B
authors.lastname: Nieuwenhuijsen
authors.forename: C M
authors.initials: CM
authors.lastname: Su
authors.forename: T R
authors.initials: TR
authors.lastname: Bridal
authors.forename: B
authors.initials: B
authors.lastname: Jow
authors.forename: T M
authors.initials: TM
authors.lastname: Argentieri
authors.forename: J
authors.initials: J
authors.lastname: Kulik
authors.forename: L J
authors.initials: LJ
authors.lastname: DeGennaro
authors.forename: W
authors.initials: W
authors.lastname: Spinelli
authors.forename: T J
authors.initials: TJ
authors.lastname: Colatsky
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D051668:Delayed Rectifier Potassium Channels; D004195:Disease Models, Animal; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D015870:Gene Expression; D006352:Heart Ventricles / Q000166:cytology; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008955:Models, Cardiovascular; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009154:Mutation; D009206:Myocardium / Q000473:pathology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger / Q000235:genetics; D015534:Trans-Activators; D016276:Ventricular Function
chemical_list: D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D051668:Delayed Rectifier Potassium Channels; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D015534:Trans-Activators