Multiple mechanisms of Na+ channel--linked long-QT syndrome
Dumaine, R.; Wang, Q.; Keating, M.T.; Hartmann, H.A.; Schwartz, P.J.; Brown, A.M.; Kirsch, G.E.
Circulation Research 78(5): 916-924
1996
ISSN/ISBN: 0009-7330 PMID: 8620612 Document Number: 460864
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 mutations 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.