Novel arrhythmogenic mechanism revealed by a long-QT syndrome mutation in the cardiac Na+ channel

H. Abriel, C. Cabo, X. H T Wehrens, I. Rivolta, H. K. Motoike, M. Memmi, C. Napolitano, S. G. Priori, R. S. Kass

Research output: Contribution to journalArticlepeer-review


Variant 3 of the congenital long-QT syndrome (LQTS-3) is caused by mutations in the gene encoding the α subunit of the cardiac Na+ channel. In the present study, we reporta novel LQTS-3 mutation, E1295K (EK), and describe its functional consequences when expressed in HEK293 cells. The clinical phenotype of the proband indicated QT interval prolongation in the absence of T-wave morphological abnormalities anda steep QT/R-R relationship, consistent with an LQTS-3 lesion. However, biophysical analysis of mutant channels indicates that the EK mutation changes channel activity in a manner that is distinct from previously investigated LQTS-3 mutations. The EK mutation causes significant positive shifts in the half-maximal voltage (V1/2) of steady-state inactivation and activation (+5.2 and +3.4 mV, respectively). These gating changes shift the window of voltages over which Na+ channels do not completely inactivate without altering the magnitude of these currents. The change in voltage dependence of window currents suggests that this alteration in the voltage dependence of Na+ channel gating may cause marked changes in action potential duration because of the unique voltage-dependent rectifying properties of cardiac K+ channels that underlie the plateau and terminal repolarization phases of the action potential. Na+ channel window current is likely to have a greater effect on net membrane current at more positive potentials (EK channels) where total K+ channel conductance is low than at more negative potentials (wild-type channels), where total K+ channel conductance is high. These findings suggest a fundamentally distinct mechanism of arrhythmogenesis for congenital LQTS-3.

Original languageEnglish
Pages (from-to)740-745
Number of pages6
JournalCirculation Research
Issue number7
Publication statusPublished - Apr 13 2001


  • Arrhythmias
  • Genetics
  • Long-QT syndrome
  • Na channel

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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