A novel SCN5A mutation manifests as a malignant form of long QT syndrome with perinatal onset of tachycardia/bradycardia

Cardiovasc Res. 2004 Nov 1;64(2):268-78. doi: 10.1016/j.cardiores.2004.07.007.


Objective: Congenital long QT syndrome (LQTS) with in utero onset of the rhythm disturbances is associated with a poor prognosis. In this study we investigated a newborn patient with fetal bradycardia, 2:1 atrioventricular block and ventricular tachycardia soon after birth.

Methods: Mutational analysis and DNA sequencing were conducted in a newborn. The 2:1 atrioventricular block improved to 1:1 conduction only after intravenous lidocaine infusion or a high dose of mexiletine, which also controlled the ventricular tachycardia.

Results: A novel, spontaneous LQTS-3 mutation was identified in the transmembrane segment 6 of domain IV of the Na(v)1.5 cardiac sodium channel, with a G-->A substitution at codon 1763, which changed a valine (GTG) to a methionine (ATG). The proband was heterozygous but the mutation was absent in the parents and the sister. Expression of this mutant channel in tsA201 mammalian cells by site-directed mutagenesis revealed a persistent tetrodotoxin-sensitive but lidocaine-resistant current that was associated with a positive shift of the steady-state inactivation curve, steeper activation curve and faster recovery from inactivation. We also found a similar electrophysiological profile for the neighboring V1764M mutant. But, the other neighboring I1762A mutant had no persistent current and was still associated with a positive shift of inactivation.

Conclusions: These findings suggest that the Na(v)1.5/V1763M channel dysfunction and possible neighboring mutants contribute to a persistent inward current due to altered inactivation kinetics and clinically congenital LQTS with perinatal onset of arrhythmias that responded to lidocaine and mexiletine.

Publication types

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

MeSH terms

  • Bradycardia / genetics
  • Bradycardia / metabolism
  • Cell Line
  • DNA Mutational Analysis
  • Female
  • Humans
  • Infant, Newborn
  • Lidocaine / pharmacology
  • Long QT Syndrome / genetics*
  • Long QT Syndrome / metabolism
  • Male
  • Mutation*
  • Myocardium / metabolism*
  • NAV1.5 Voltage-Gated Sodium Channel
  • Patch-Clamp Techniques
  • Sequence Analysis, DNA
  • Sodium Channels / genetics*
  • Sodium Channels / metabolism
  • Tachycardia, Ventricular / genetics
  • Tachycardia, Ventricular / metabolism
  • Tetrodotoxin / pharmacology
  • Transfection / methods


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