Na(+) channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism

Circulation. 2002 Mar 12;105(10):1208-13. doi: 10.1161/hc1002.105183.

Abstract

Background: Complex physiological interactions determine the functional consequences of gene abnormalities and make mechanistic interpretation of phenotypes extremely difficult. A recent example is a single mutation in the C terminus of the cardiac Na(+) channel, 1795insD. The mutation causes two distinct clinical syndromes, long QT (LQT) and Brugada, leading to life-threatening cardiac arrhythmias. Coexistence of these syndromes is seemingly paradoxical; LQT is associated with enhanced Na(+) channel function, and Brugada with reduced function.

Methods and results: Using a computational approach, we demonstrate that the 1795insD mutation exerts variable effects depending on the myocardial substrate. We develop Markov models of the wild-type and 1795insD cardiac Na(+) channels. By incorporating the models into a virtual transgenic cell, we elucidate the mechanism by which 1795insD differentially disrupts cellular electrical behavior in epicardial and midmyocardial cell types. We provide a cellular mechanistic basis for the ECG abnormalities observed in patients carrying the 1795insD gene mutation.

Conclusions: We demonstrate that the 1795insD mutation can cause both LQT and Brugada syndromes through interaction with the heterogeneous myocardium in a rate-dependent manner. The results highlight the complexity and multiplicity of genotype-phenotype relationships, and the usefulness of computational approaches in establishing a mechanistic link between genetic defects and functional abnormalities.

Publication types

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

MeSH terms

  • Action Potentials / physiology
  • Arrhythmias, Cardiac / etiology*
  • Computer Simulation*
  • Electrocardiography
  • Heart Ventricles / cytology
  • Humans
  • Internet
  • Ion Channel Gating / physiology
  • Long QT Syndrome / etiology
  • Markov Chains
  • Models, Cardiovascular*
  • Mutation / physiology*
  • Myocardium / metabolism
  • NAV1.5 Voltage-Gated Sodium Channel
  • Phenotype
  • Reproducibility of Results
  • Sodium / metabolism
  • Sodium Channels / physiology*
  • Structure-Activity Relationship
  • Ventricular Function

Substances

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