Multiple Mechanisms of Na + Channel– Linked Long-QT Syndrome

Abstract

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 (ΔKPQ), 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 ΔKPQ 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 ΔKPQ phenotype the most severe.