Novel heterozygous mutation c.4282G>T in the SCN5A gene in a family with Brugada syndrome

Brugada syndrome (BrS) is a rare, inherited arrhythmia syndrome. The most well-known gene that is responsible for causing BrS is SCN5A, which encodes the human cardiac Na+ channel (Na(v)1.5) alpha subunit. To date, it has been reported that >100 mutations in SCN5A can cause BrS. In the present study, a novel BrS-associated Na(v)1.5 mutation, A1428S, was identified in a proband who was successfully resuscitated from an episode of sudden collapse during walking. This mutation was further confirmed by polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis, which showed that the PCR fragment containing the mutation A1428S could be cut by the restriction enzyme Nsi1, yielding two shorter DNA fragments of 329 and 159 bp, which were not present in family members homozygous for the wild-type (WT) allele. Furthermore, the electrophysiological properties were analyzed by patch clamp technique. Current density was decreased in the A1428S mutant compared that in the WT. However, neither the steady-state activation or inactivation, nor the recovery from inactivation exhibited changes between the A1428S mutant and the WT. In conclusion, the results of this study are consistent with the hypothesis that a reduction in Na(v)1.5 channel function is involved in the pathogenesis of BrS. The structural-functional study of the Na(v)1.5 channel enhances the present understanding the pathophysiological function of the channel.