Multiple mechanisms of Na+ channel--linked long-QT syndrome.
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.
Dumaine
R
R
Rammelkamp Center for Research, Case Western Reserve University, Cleveland, Ohio, USA.
Wang
Q
Q
Keating
M T
MT
Hartmann
H A
HA
Schwartz
P J
PJ
Brown
A M
AM
Kirsch
G E
GE
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
D015222:Sodium Channels