title: Characterization of the cardiac sodium channel SCN5A mutation, N1325S, in single murine ventricular myocytes.
abstract: The N(1325)S mutation in the cardiac sodium channel gene SCN5A causes the type-3 long-QT syndrome but the arrhythmogenic trigger associated with N(1325)S has not been characterized. In this study, we investigated the triggers for cardiac events in the expanded N(1325)S family. Among 11 symptomatic patients with document triggers, six died suddenly during sleep or while sitting (bradycardia-induced trigger), three died suddenly, and two developed syncope due to stress and excitement (non-bradycardia-induced). Patch-clamping studies revealed that the late sodium current (I(Na,L)) generated by mutation N(1325)S in ventricular myocytes from TG-NS/LQT3 mice was reduced with increased pacing, which explains bradycardia-induced mortalities in the family. The non-bradycardic triggers are related to the finding that APD became prolonged and unstable at increasing rates, often with alternating repolarization phases which was corrected with verapamil. This implies that Ca2+ influx and intracellular Ca2+ ([Ca2+]i) ions are involved and that [Ca2+]i inhomogeneity may be the underlying mechanisms behind non-bradycardia LQT3 arrhythmogenesis associated with mutation N(1325)S.
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Sandro L
authors.initials: SL
authors.lastname: Yong
authors.forename: Ying
authors.initials: Y
authors.lastname: Ni
authors.forename: Teng
authors.initials: T
authors.lastname: Zhang
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Qing K
authors.initials: QK
authors.lastname: Wang
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D006339:Heart Rate / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology; D015640:Ion Channel Gating / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000502:physiology*; D013329:Structure-Activity Relationship; D016276:Ventricular Function
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse; D015222:Sodium Channels; D002118:Calcium