title: Clinical and electrophysiological characteristics of Brugada syndrome caused by a missense mutation in the S5-pore site of SCN5A.
abstract: Brugada syndrome is an inherited cardiac disorder caused by mutations in the SCN5A gene encoding the cardiac sodium channel alpha-subunit, and potentially leads to ventricular fibrillation and sudden death. We report a case of a novel SCN5A mutation associated with Brugada syndrome. A 51-year-old man suffered from recurrent nocturnal syncopal attacks due to polymorphic ventricular tachycardia. His electrocardiogram showed ST-segment elevation in V1-V3 leads, but there was no evidence of structural heart disease. DNA sequence analysis of SCN5A in this patient revealed a missense mutation (R282H) in the S5-pore region of domain I. This mutational change was not present in 100 healthy Japanese controls. In the patient's family, a 36-year-old brother had died suddenly. Genetic analysis identified two other carriers of the R282H mutation, who had ST-segment elevation and slightly increased QRS widths, but they experienced no syncopal episodes or ventricular fibrillation. Electrophysiological investigation of the R282H mutant channel expressed in cultured cells showed a severe reduction in sodium current density and a mild positive shift of activation curve. R282H did not enhance intermediate inactivation. Single-channel conductance of R282H was slightly decreased compared with WT. The electrophysiological characteristics of the R282H channel are suggested to be closely related to the clinical phenotype of Brugada syndrome.
authors.affiliation: Department of Information Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Itoh
authors.forename: Masami
authors.initials: M
authors.lastname: Shimizu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mabuchi
authors.forename: Keiji
authors.initials: K
authors.lastname: Imoto
mesh_terms: D004252:DNA Mutational Analysis; D004594:Electrophysiology / Q000379:methods; D005500:Follow-Up Studies; D015870:Gene Expression; D005819:Genetic Markers; D006329:Heart Conduction System / Q000503:physiopathology*; D006339:Heart Rate / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010375:Pedigree; D016133:Polymerase Chain Reaction; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome; D014693:Ventricular Fibrillation / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D005819:Genetic Markers; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels