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

Colleen E Clancy, Yoram Rudy

Research output: Contribution to journalArticle

238 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1208-1213
Number of pages6
JournalCirculation
Volume105
Issue number10
DOIs
StatePublished - Mar 12 2002
Externally publishedYes

Keywords

  • Arrhythmia
  • Brugada syndrome
  • Genes
  • Long-QT syndrome
  • Sodium

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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