title: A novel mutation in the SCN5A gene is associated with Brugada syndrome.
abstract: Brugada syndrome (BS) is an inherited cardiac disorder associated with a high risk of sudden cardiac death and is caused by mutations in the SCN5A gene encoding the cardiac sodium channel alpha-subunit (Na(v)1.5). The aim of this study was to identify the genetic cause of familial BS and characterize the electrophysiological properties of a novel SCN5A mutation (W1191X). Four families and one patient with BS were screened for SCN5A mutations by PCR and direct sequencing. Wild-type (WT) and mutant Na(v)1.5 channels were expressed in tsA201 cells, and the sodium currents (I(Na)) were analyzed using the whole-cell patch-clamp technique. A novel mutation, W1191X, was identified in a family with BS. Expression of the WT or the mutant channel (Na(v)1.5/W1191X) co-transfected with the beta(1)-subunit in tsA201 cells resulted in a loss of function of Na(v)1.5 channels. While voltage-clamp recordings of the WT channel showed a distinct acceleration of Na(v)1.5 activation and fast inactivation kinetics, the Na(v)1.5/W1191X mutant failed to generate any currents. Co-expression of the WT channel and the mutant channel resulted in a 50% reduction in I(Na). No effect on activation and inactivation were observed with this heterozygous expression. The W1191X mutation is associated with BS and resulted in the loss of function of the cardiac sodium channel.
authors.affiliation: Cardiovascular Genome Center, Yonsei University Medical Center, Seoul, Republic of Korea.
authors.forename: Dong-Jik
authors.initials: DJ
authors.lastname: Shin
authors.forename: Eunmin
authors.initials: E
authors.lastname: Kim
authors.forename: Sang-Bum
authors.initials: SB
authors.lastname: Park
authors.forename: Won-Cheoul
authors.initials: WC
authors.lastname: Jang
authors.forename: Yoonsun
authors.initials: Y
authors.lastname: Bae
authors.forename: Jihye
authors.initials: J
authors.lastname: Han
authors.forename: Yangsoo
authors.initials: Y
authors.lastname: Jang
authors.forename: Boyoung
authors.initials: B
authors.lastname: Joung
authors.forename: Moon Hyoung
authors.initials: MH
authors.lastname: Lee
authors.forename: Sung Soon
authors.initials: SS
authors.lastname: Kim
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.forename: Mohamed
authors.initials: M
authors.lastname: Chahine
authors.forename: Sungjoo Kim
authors.initials: SK
authors.lastname: Yoon
mesh_terms: D000328:Adult; D000368:Aged; D053840:Brugada Syndrome / Q000175:diagnosis / Q000235:genetics*; D002460:Cell Line; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D010375:Pedigree; D016133:Polymerase Chain Reaction; D015222:Sodium Channels / Q000235:genetics*; D014162:Transfection
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels