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

Circ Res. 2001 Apr 13;88(7):740-5. doi: 10.1161/hh0701.089668.


Variant 3 of the congenital long-QT syndrome (LQTS-3) is caused by mutations in the gene encoding the alpha subunit of the cardiac Na(+) channel. In the present study, we report a 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 and a 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 (V(1/2)) 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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Amino Acid Substitution
  • Arrhythmias, Cardiac / diagnosis*
  • Arrhythmias, Cardiac / genetics
  • Cell Line
  • Conserved Sequence
  • DNA Mutational Analysis
  • Electrocardiography
  • Heart / physiopathology*
  • Humans
  • Ion Channel Gating / drug effects
  • Ion Channel Gating / genetics
  • Kidney / cytology
  • Kidney / drug effects
  • Kidney / metabolism
  • Long QT Syndrome / diagnosis*
  • Long QT Syndrome / genetics*
  • Long QT Syndrome / physiopathology
  • Male
  • Mutation
  • NAV1.5 Voltage-Gated Sodium Channel
  • Patch-Clamp Techniques
  • Phenotype
  • Sodium / metabolism
  • Sodium Channels / genetics*
  • Sodium Channels / metabolism
  • Tetrodotoxin / pharmacology
  • Transfection


  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN5A protein, human
  • Sodium Channels
  • Tetrodotoxin
  • Sodium