Brugada syndrome is an inherited cardiac disorder caused by mutations in the 
SCN5A gene encoding the cardiac sodium channel alpha subunit, which can lead 
ventricular fibrillation and sudden death. Inattentive use of antiarrhythmic 
drugs potentially triggers fatal cardiac arrhythmias through further reduction 
of sodium current (I(Na)). We studied the molecular mechanism underlying a case 
of Brugada syndrome that showed no response to a class Ic antiarrhythmic drug. 
Molecular genetic studies of a patient with Brugada syndrome identified a novel 
mutation in SCN5A, which causes substitution of serine for asparagine (N406S) in 
S6 of domain I (IS6). The provocation test with pilsicainide, a class Ic 
antiarrhythmic drug, failed to exacerbate ST-segment elevation in this case. 
Electrophysiological analyses of the N406S-mutant channel expressed together 
with the beta1 subunit in HEK293 cells showed that the voltage dependence of 
activation was positively shifted by 16 mV and that intermediate inactivation 
was enhanced. Whereas tonic block by pilsicainide was not changed in the N406S 
channel, use-dependent block by pilsicainide was almost completely abolished, 
consistent with the clinical findings of the negative provocation test. In 
contrast, the N406S channel showed stronger use-dependent block by quinidine 
than the wild-type channel. We demonstrate a novel Brugada mutation N406S, which 
is associated with the discordant effects on blocking actions of antiarrhythmic 
drugs as well as the multiple channel gating defects. We emphasis that an 
antiarrhythmic drug may exert unpredicted effects in patients with channel 
mutations.