Novel Missense Mutation in the SCN5A Gene Associated With Brugada Syndrome Bidirectionally Affecting Blocking Actions of Antiarrhythmic Drugs
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Accession number;05A0202009
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| Title;Novel Missense Mutation in the SCN5A Gene Associated With Brugada Syndrome Bidirectionally Affecting Blocking Actions of Antiarrhythmic Drugs |
| Author;
ITO HIDEKI
(Kanazawa Univ., Graduate School, JPN)
SHIMIZU MASAMI
(Kanazawa Univ., Graduate School, JPN)
TAKATA SHIGEO
(Sch. of Med., Kanazawa Univ.)
MABUCHI HIROSHI
(Kanazawa Univ., Graduate School, JPN)
IMOTO KEIJI
(Shizenkagakukenkyukiko Seirigakuken)
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Journal Title;J Cardiol
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Journal Code:Y0264A
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ISSN:0914-5087
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VOL.45;NO.2;PAGE.85-87(2005)
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| Figure&Table&Reference;FIG.1 |
| Pub. Country;Japan |
| Language;Japanese |
| Abstract;Background. Brugada syndrome is an inherited cardiac disorder caused by mutations in the SCN5A gene encoding the cardiac sodium channel .ALPHA. subunit, which can lead to ventricular fibrillation and sudden death. Inattentive use of antiarrhythmic drugs potentially triggers fatal cardiac arrhythmias through further reduction of sodium current (INa). Methods and Results. 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 .BETA.1 subunit in HEK293 cells showed that the voltage-dependence of activation was positively shifted by 16mV 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. Conclusions. 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. (author abst.) |
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