Na Channel Mutation That Causes Both Brugada Syndrome and Long-QT Syndrome Phenotypes: A Simulation Study of Mechanism (INa1795insD Mutant Midmyocardial Cell)

Na Channel Mutation That Causes Both Brugada Syndrome and Long-QT Syndrome Phenotypes: A Simulation Study of Mechanism

Model Status

This CellML model represents the INa1795insD M cell. For more details on the curation status of this model please see this separate notes document.

Model Structure

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.

The original paper reference is cited below:

Na⁺ Channel Mutation That Causes Both Brugada and Long-QT Syndrome Phenotypes: A Simulation Study of Mechanism, Colleen E. Clancy and Yoram Rudy, 2002, Circulation , 105, 1208-1213. PubMed ID: 11889015

A Markovian model for the wild-type cardiac Na⁺ channel, embedded within an updated version of the Luo-Rudy dynamic model. C, indicates a closed channel state; IC, a closed-inactivation state; IF, a fast inactivation state; IM, an intermediate inactivation state, and O, an open state.

A Markovian model for the mutant 1795insD cardiac Na⁺ channel, embedded within an updated version of the Luo-Rudy dynamic model. U (upper) indicates background mode of gating; L (lower), represents a small population of bursting channels which fail to inactivate.