Electrophysiological characterization of SCN5A mutations causing long QT (E1784K) and Brugada (R1512W and R1432G) syndromes

Abstract

The different clinical manifestations of these three mutations most probably originate from the distinct electrophysiological abnormalities of the mutant cardiac sodium channels reported in this study.

The genetic basis of Brugada syndrome: A mutation update

“…Other mutations lead to absolutely no I Na , for example, R367H [Vatta et al, 2002b], G1406R [Kyndt et al, 2001], and R1432G [Deschenes et al, 2000]. In some cases, the picture is more complex, as with the Y1795H mutation with reduced current decay, increased late persistent I Na , but increased inactivation and, as the total result, reduced I Na current density [Rivolta et al, 2001].…”

Nav1.5/R1193Q polymorphism is associated with both long QT and Brugada syndromes

“…Wild-type and mutant channels were expressed in the tsA201 cell line, and sodium currents were recorded in the whole cell configuration as previously described (19).…”

Link Between SCN5A Mutation and the Brugada Syndrome ECG Phenotype Simulation Study

“…3,5 This is thought to be one of the possible cellular mechanisms of the ST-segment elevation in BS. 3,5,6 The transmural dispersion of repolarization in the RV is capable of precipitating phase 2 reentry (P2R) and subsequent circus movement reentry, 5,7-9 but because it does not always do so, the precise mechanisms of P2R and VF in BS have remained unclear.The finding of enhanced ST-segment elevation by fast sodium current (INa) blockers 3,10 and of the SCN5A-mutaCirculation Journal Vol.69, May 2005 tions in BS [11][12][13][14][15][16] suggests that INa as well as Ito plays a major role in the pathogenesis of BS. Although various abnormalities in the current phenotype have been reported in SCN5A mutations, it is difficult to identify the abnormality in kinetics that causes specific phenotypes of the disease in experimental models.…”

“…tions in BS [11][12][13][14][15][16] suggests that INa as well as Ito plays a major role in the pathogenesis of BS. Although various abnormalities in the current phenotype have been reported in SCN5A mutations, it is difficult to identify the abnormality in kinetics that causes specific phenotypes of the disease in experimental models.…”

“…In the present study we evaluated how such kinetic changes affect the occurrence of P2R and ER in our model by modifying the voltage-dependent kinetics of INa according to observations that have been reported in the Brugada-related SCN5A mutations. [11][12][13][14][15][16] We also investigated the effect of INa blockade in each simulated SCN5A mutation to identify the mechanism of the INa-blockerinduced ST-segment elevation only in patients with BS. 3,10the signal-averaged electrocardiogram (ECG) 3,19,20 are commonly observed in BS, the presence of diseased myocardium with a conduction disturbance has been thought to be a cellular basis for the syndrome.…”