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

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Long-QT and Brugada syndrome have both been linked with mutations in the SCN5A gene, which encodes the alpha subunit of the cardiac sodium channel. The specific mutation discussed here is a single mutation in the C terminus of the cardiac Na⁺ channel, 1795insD. In LQT syndrome, the mutation causes a gain in Na⁺ function, which leads to a persistent I_Na , which in turn causes a prolonged action potential duration that can facilitate the development of arrythmogenic early afterdepolarisations (EADs). These EADs are manifested on the body surface ECG as a longer QT interval. Conversely, the SCN5A mutation in Brugada syndrome reduces I_Na . This has the effect of supressing the action potential plateau in cells with prominent I_to (such as right ventricular epicardial cells), which is manifested as ST-segment elevation on the ECG.

The fact that a mutation in the same gene can have two apparently opposite affects on the phenotype illustrates how complex physiological interactions determine the functional consequences of gene expression. Within the myocardium, ion channel proteins are non-uniformly expressed, resulting in an intrinsic heterogeneity. In this 2002 study, Colleen Clancy and Yoram Rudy use a computational approach to demonstrate how heterogeneity in the myocardium allows seemingly paradoxical phenotypes associated with the 1795insD mutation to coexist. They develop Markov models of the wild type () and 1795insD () cardiac Na⁺ channels. These are embedded within the Luo-Rudy dynamic model of a ventricular cell. The particular version of the model which is used here has been updated with a slowly activating, delayed-rectifier potassium current (I_Ks ), as described in Viswanathan et al., 1999, and the model also incorporates a transient outward potassium current (I_to ), as described by Dumaine et al., 1999.

By incorporating the Markov models into a virtual cell, Clancy and Rudy were able to elucidate the mechanisms by which 1795insD differentially disrupts cellular electrophysiological behaviour. The results of their model simulations suggest that the interaction between the myocardial electrophysiological heterogeneity and the mutation-induced changes in I_Na provide the foundation for the development of both ECG ST-segment elevation (in Brugada syndrome) and QT interval prolongation (in Long-QT syndrome) in a rate-dependent manner. This study emphasises the complexity of genotype-phenotype relationships, and also the value of computational simulations in determining the link between the genetic mutations and functional abnormalities.

The complete 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

The raw CellML description of the Clancy and Rudy 2002 models can be downloaded in various formats as described in .

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.