摘要
Aims Brugada syndrome (BrS) is characterized by arrhythmias leading to sudden cardiac death. BrS is caused, in part, by mutations in the SCN5A gene, which encodes the sodium channel alpha-subunit Na(v)1.5. Here. we aimed to characterize the biophysical properties and consequences of a novel BrS SCN5A mutation.
Methods and results SCN5A was screened for mutations in a mate patient with type-1 BrS pattern ECG. Witd-type (WT) and mutant Na(v)1.5 channels were expressed in HEK293 cells. Sodium currents (I-Na) were analysed using the whole-cell patch-clamp technique at 37 degrees C. The electrophysiological effects of the mutation were simulated using the Luo-Rudy model, into which the transient outward current (I-to) was incorporated. A new mutation (C1850S) was identified in the Na(v)1.5 C-terminal domain. In HEK293 cells, mutant I-Na density was decreased by 62% at -20 mV. Inactivation of mutant I-Na was accelerated in a voltage-dependent manner and the steady-state inactivation curve was shifted by 11.6 mV towards negative potentials. No change was observed regarding activation characteristics. Altogether, these biophysical alterations decreased the availability of I-Na. In the simulations, the I-to density necessary to precipitate repolarization differed minimally between the two genotypes. In contrast, the mutation greatly affected conduction across a structural heterogeneity and precipitated conduction block.
Conclusion Our data confirm that mutations of the C-terminal domain of Na(v)1.5 alter the inactivation of the channel and support the notion that conduction alterations may play a significant rote in the pathogenesis of BrS.
- 出版日期2008-6-1