{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T21:01:37Z","timestamp":1778187697925,"version":"3.51.4"},"reference-count":30,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2005,5,5]],"date-time":"2005-05-05T00:00:00Z","timestamp":1115251200000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cardiovasc electrophysiol"],"published-print":{"date-parts":[[2005,5]]},"abstract":"<jats:p>Brugada syndrome is an inherited cardiac disorder caused by mutations in the <jats:italic>SCN5A<\/jats:italic> gene encoding the cardiac sodium channel \u03b1 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<jats:sub>Na<\/jats:sub>). 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 <jats:italic>SCN5A<\/jats:italic>, 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\u2010segment elevation in this case. Electrophysiological analyses of the N406S\u2010mutant channel expressed together with the \u03b21 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\u2010dependent 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\u2010dependent block by quinidine than the wild\u2010type 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.<\/jats:p>","DOI":"10.1111\/j.1540-8167.2005.40711.x","type":"journal-article","created":{"date-parts":[[2005,5,5]],"date-time":"2005-05-05T15:31:57Z","timestamp":1115307117000},"page":"486-493","source":"Crossref","is-referenced-by-count":31,"title":["A Novel Missense Mutation in the <i>SCN5A<\/i> Gene Associated with Brugada Syndrome Bidirectionally Affecting Blocking Actions of Antiarrhythmic 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