title: Multiple mechanisms of Na+ channel--linked long-QT syndrome.
abstract: Inheritable long-QT syndrome (LQTS) is a disease in which delayed ventricular repolarization leads to cardiac arrhythmias and the possibility of sudden death. In the chromosome 3-linked disease, one mutation of the cardiac Na+ channel gene results in a deletion of residues 1505 to 1507 (Delta KPQ), and two mutation result in substitutions (N1325S and R1644H). We compared all three mutant-channel phenotypes by heterologous expression in Xenopus oocytes. Each produced a late phase of inactivation-resistant, mexiletine- and tetrodotoxin-sensitive whole-cell currents, but the underlying mechanisms were different at the single-channel level. N1325S and R1644H showed dispersed reopenings after the initial transient, whereas Delta KPQ showed both dispersed reopenings and long-lasting bursts. Thus, two distinct biophysical defects underlie the in vitro phenotype of persistent current in Na+ channel-linked LQTS, and the additive effects of both are responsible for making the Delta KPQ phenotype the most severe.
authors.affiliation: Rammelkamp Center for Research, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: R
authors.initials: R
authors.lastname: Dumaine
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.forename: M T
authors.initials: MT
authors.lastname: Keating
authors.forename: H A
authors.initials: HA
authors.lastname: Hartmann
authors.forename: P J
authors.initials: PJ
authors.lastname: Schwartz
authors.forename: A M
authors.initials: AM
authors.lastname: Brown
authors.forename: G E
authors.initials: GE
authors.lastname: Kirsch
mesh_terms: D000818:Animals; D004553:Electric Conductivity; D015640:Ion Channel Gating / Q000502:physiology; D008133:Long QT Syndrome / Q000503:physiopathology*; D009154:Mutation / Q000502:physiology; D009865:Oocytes; D010641:Phenotype; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology*; D014981:Xenopus
chemical_list: D015222:Sodium Channels