title: Enhanced fast-inactivated state stability of cardiac sodium channels by a novel voltage sensor SCN5A mutation, R1632C, as a cause of atypical Brugada syndrome.
abstract: BACKGROUND
  Mutations in SCN5A, which encodes the cardiac voltage-gated sodium channels, can be associated with multiple electrophysiological phenotypes. A novel SCN5A R1632C mutation, located in the domain IV-segment 4 voltage sensor, was identified in a young male patient who had a syncopal episode during exercise and presented with atrial tachycardia, sinus node dysfunction, and Brugada syndrome.
  
  
  OBJECTIVE
  We sought to elucidate the functional consequences of the R1632C mutation.
  
  
  METHODS
  The wild-type (WT) or R1632C SCN5A mutation was coexpressed with β1 subunit in tsA201 cells, and whole-cell sodium currents (INa) were recorded using patch-clamp methods.
  
  
  RESULTS
  INa density, measured at -20 mV from a holding potential of -120 mV, for R1632C was significantly lower than that for WT (R1632C: -433 ± 52 pA/pF, n = 14; WT: -672 ± 90 pA/pF, n = 15; P < .05); however, no significant changes were observed in the steady-state activation and fast inactivation rate. The steady-state inactivation curve for R1632C was remarkably shifted to hyperpolarizing potentials compared with that for WT (R1632C: V1/2 = -110.7 ± 0.8 mV, n = 16; WT: V1/2 = -85.9 ± 2.5 mV, n = 17; P < .01). The steady-state fast inactivation curve for R1632C was also shifted to the same degree. Recovery from fast inactivation after a 20-ms depolarizing pulse for R1632C was remarkably delayed compared with that for WT (R1632C: τ = 246.7 ± 14.3 ms, n = 8; WT: τ = 3.7 ± 0.3 ms, n = 8; P < .01). Repetitive depolarizing pulses at various cycle lengths greatly attenuated INa for R1632C than that for WT.
  
  
  CONCLUSIONS
  R1632C showed a loss of function of INa by an enhanced fast-inactivated state stability because of a pronounced impairment of recovery from fast inactivation, which may explain the phenotypic manifestation observed in our patient.
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Japan. Electronic address: tnakajim@gunma-u.ac.jp.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kaneko
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Saito
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ota
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Iijima
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kurabayashi
mesh_terms: D000293:Adolescent; D053840:Brugada Syndrome / Q000175:diagnosis / Q000235:genetics*; D054849:Cardiac Electrophysiology; D004252:DNA Mutational Analysis; D004562:Electrocardiography / Q000379:methods; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D018408:Patch-Clamp Techniques; D010641:Phenotype; D016133:Polymerase Chain Reaction / Q000379:methods; D011379:Prognosis; D035583:Rare Diseases; D012720:Severity of Illness Index
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel
keywords: Atrial tachycardia; Brugada syndrome; Mutation; SCN5A; Sinus node dysfunction; Sodium currents; Voltage sensor