title: High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations.
abstract: OBJECTIVE
  We carried out a complete screening of the SCN5A gene in 38 Japanese patients with Brugada syndrome to investigate the genotype-phenotype relationship.
  
  
  BACKGROUND
  The gene SCN5A encodes the pore-forming alpha-subunit of voltage-gated cardiac sodium (Na) channel, which plays an important role in heart excitation/contraction. Mutations of SCN5A have been identified in 15% of patients with Brugada syndrome.
  
  
  METHODS
  In 38 unrelated patients with clinically diagnosed Brugada syndrome, we screened for SCN5A gene mutations using denaturing high-performance liquid chromatography and direct sequencing, and conducted a functional assay for identified mutations using whole-cell patch-clamp in heterologous expression system.
  
  
  RESULTS
  Four heterozygous mutations were identified (T187I, D356N, K1578fs/52, and R1623X) in 4 of the 38 patients. All of them had bradyarrhythmic complications: three with sick sinus syndrome (SSS) and the other (D356N) with paroxysmal complete atrioventricular block. SCN5A-linked Brugada patients were associated with a higher incidence of bradyarrhythmia (4 of 4) than non-SCN5A-linked Brugada patients (2 of 34). Families with T187I and K1578fs/52 had widespread penetrance of SSS. Notably, the patient with K1578fs/52, who had been diagnosed as having familial SSS without any clinical signs of Brugada syndrome, showed a Brugada-type ST-segment elevation after intravenous administration of pilsicainide and programmed electrical stimulation-induced ventricular tachycardia. All of the mutations encoded non-functional Na channels, and thus were suggested to cause impulse propagation defect underlying bradyarrhythmias.
  
  
  CONCLUSIONS
  Our findings suggest that loss-of-function SCN5A mutations resulting in Brugada syndrome are distinguished by profound bradyarrhythmias.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.forename: Masaharu
authors.initials: M
authors.lastname: Akao
authors.forename: Keiko
authors.initials: K
authors.lastname: Tsuji
authors.forename: Takahiro
authors.initials: T
authors.lastname: Doi
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.forename: Kotoe
authors.initials: K
authors.lastname: Takenaka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kobori
authors.forename: Tomonori
authors.initials: T
authors.lastname: Ninomiya
authors.forename: Hidetada
authors.initials: H
authors.lastname: Yoshida
authors.forename: Makoto
authors.initials: M
authors.lastname: Takano
authors.forename: Naomasa
authors.initials: N
authors.lastname: Makita
authors.forename: Fumiko
authors.initials: F
authors.lastname: Yanagisawa
authors.forename: Yukei
authors.initials: Y
authors.lastname: Higashi
authors.forename: Youichi
authors.initials: Y
authors.lastname: Takeyama
authors.forename: Toru
authors.initials: T
authors.lastname: Kita
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D001919:Bradycardia / Q000150:complications* / Q000235:genetics*; D002037:Bundle-Branch Block / Q000150:complications* / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000235:genetics*; D013577:Syndrome
chemical_list: D018389:Codon, Nonsense; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels