A Computational Modeling Investigation into SCN10A Linked Brugada Syndrome

Abstract

A functional role for the sodium channel NaV1.8 in the heart is unclear. Mutations and polymorphisms in SCN10A, the gene encoding NaV1.8, have recently been linked to Brugada Syndrome, an inherited cardiac disease that causes sudden death. The Brugada Syndrome is detected on an ECG by the hallmark appearance of coved type ST-segment elevation (J-wave) and is associated with a loss of NaV channel function in the heart. While wild-type NaV1.8 has been shown in recent studies to modify and promote NaV1.5 mediated current, two mutations in the SCN10A gene, R14L and R1268Q, result in a loss of cardiac NaV function. We utilized a computational modeling and simulation approach to predict if mutation induced loss of function in the cardiac INa by R14L and R1268Q is a plausible mechanism of the Brugada Syndrome phenotype. We have developed models of the R14L and R1268Q NaV1.8 mutations and their interactions with the canonical cardiac Na channel, NaV1.5, based on published experimental data. We then used these models to predict the effect of the mutations on cardiac cellular excitability and computed electrograms from simulated tissue. The model predicts that in the single cell, both two mutations result in major depression of cellular excitability, but action potentials were successfully generated throughout the range of physiological pacing frequencies. In the tissue level simulations, the predictions were very different: Simulated tissue homozygous for either mutation resulted in complete failure of propagation. When we tested the effect of the heterozygous (50%) mutant effect, the simulation predicted the hallmark appearance of coved type ST-segment elevation (J-wave). Our results suggest that the defects in the SCN10A gene that modify INa in the heart can explain the clinically observed phenotype in patients.