title: Distinct functional defect of three novel Brugada syndrome related cardiac sodium channel mutations.
abstract: The Brugada syndrome is characterized by ST segment elevation in the right precodial leads V1-V3 on surface ECG accompanied by episodes of ventricular fibrillation causing syncope or even sudden death. The molecular and cellular mechanisms that lead to Brugada syndrome are not yet completely understood. However, SCN5A is the most well known responsible gene that causes Brugada syndrome. Until now, more than a hundred mutations in SCN5A responsible for Brugada syndrome have been described. Functional studies of some of the mutations have been performed and show that a reduction of human cardiac sodium current accounts for the pathogenesis of Brugada syndrome. Here we reported three novel SCN5A mutations identified in patients with Brugada syndrome in Taiwan (p.I848fs, p.R965C, and p.1876insM). Their electrophysiological properties were altered by patch clamp analysis. The p.I848fs mutant generated no sodium current. The p.R965C and p.1876insM mutants produced channels with steady state inactivation shifted to a more negative potential (9.4 mV and 8.5 mV respectively), and slower recovery from inactivation. Besides, the steady state activation of p.1876insM was altered and was shifted to a more positive potential (7.69 mV). In conclusion, the SCN5A channel defect related to Brugada syndrome might be diverse but all resulted in a decrease of sodium current.
authors.affiliation: Institute of Pharmacology, School of Medicine, National Taiwan University, Taipei, Taiwan. b87403047@ntu.edu.tw
authors.forename: Chia-Hsiang
authors.initials: CH
authors.lastname: Hsueh
authors.forename: Wen-Pin
authors.initials: WP
authors.lastname: Chen
authors.forename: Jiunn-Lee
authors.initials: JL
authors.lastname: Lin
authors.forename: Chia-Ti
authors.initials: CT
authors.lastname: Tsai
authors.forename: Yen-Bin
authors.initials: YB
authors.lastname: Liu
authors.forename: Jyh-Ming
authors.initials: JM
authors.lastname: Juang
authors.forename: Hsuan-Ming
authors.initials: HM
authors.lastname: Tsao
authors.forename: Ming-Jai
authors.initials: MJ
authors.lastname: Su
authors.forename: Ling-Ping
authors.initials: LP
authors.lastname: Lai
mesh_terms: D053840:Brugada Syndrome / Q000235:genetics* / Q000503:physiopathology; D002460:Cell Line; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D006801:Humans; D015640:Ion Channel Gating; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism; D013624:Taiwan; D062547:Voltage-Gated Sodium Channel beta-1 Subunit
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C470379:SCN1B protein, human; C568320:SCN5A protein, human; D015222:Sodium Channels; D062547:Voltage-Gated Sodium Channel beta-1 Subunit