title: A Novel SCN5A Mutation Associated with Drug Induced Brugada Type ECG.
abstract: BACKGROUND
  Class IC antiarrhythmic agents may induce acquired forms of Brugada Syndrome. We have identified a novel mutation in SCN5A, the gene that encodes the α-subunit of the human cardiac sodium channel (hNav1.5), in a patient who exhibited Brugada- type ECG changes during pharmacotherapy of atrial arrhythmias.
  
  
  OBJECTIVE
  To assess whether the novel mutation p.V1328M can cause drug induced Brugada Syndrome.
  
  
  METHODS
  Administration of pilsicainide, a class IC antiarrhythmic agent, caused Brugada- type ST elevation in a 66-year-old Japanese male who presented with paroxysmal atrial fibrillation (PAF), type I atrial flutter and inducible ventricular fibrillation (VF) during electrophysiological study. Genetic screening using direct sequencing identified a novel SCN5A variant, p.V1328M. Electrophysiological parameters of WT and p.V1328M and their effects on drug pharmacokinetics were studied using the patch-clamp method.
  
  
  RESULTS
  Whole-cell sodium current densities were similar for WT and p.V1328M channels. While p.V1328M mutation did not affect the voltage-dependence of the activation kinetics, it caused a positive shift of voltage-dependent steady-state inactivation by 7 mV. The tonic block in the presence of pilsicainide was similar in WT and p.V1328M, when sodium currents were induced by a low frequency pulse protocol (q15s). On the contrary, p.V1328M mutation enhanced pilsicainide induced use-dependent block at 2 Hz. (Ki: WT, 35.8 μM; V1328M, 19.3 μM).
  
  
  CONCLUSIONS
  Our study suggests that a subclinical SCN5A mutation, p.V1328M, might predispose individuals harboring it to drug-induced Brugada Syndrome.
authors: Krannert Institute of Cardiology, Indiana University, Indianapolis, IN, United States of America.
authors: Isik
authors: I
authors: Turker
authors: Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Takeru
authors: T
authors: Makiyama
authors: Department of Cardiovascular Genetics, Indiana University, Indianapolis, IN, United States of America.
authors: Matteo
authors: M
authors: Vatta
authors: Cardiovascular and Respiratory Medicine, Shiga Univ. School of Medicine, Otsu, Japan.
authors: Hideki
authors: H
authors: Itoh
authors: Cardiology, Yamaguchi University School of Medicine, Yamaguchi, Japan.
authors: Takeshi
authors: T
authors: Ueyama
authors: Cardiology, Yamaguchi University School of Medicine, Yamaguchi, Japan.
authors: Akihiko
authors: A
authors: Shimizu
authors: Krannert Institute of Cardiology, Indiana University, Indianapolis, IN, United States of America.|Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Tomohiko
authors: T
authors: Ai
authors: Cardiovascular and Respiratory Medicine, Shiga Univ. School of Medicine, Otsu, Japan.
authors: Minoru
authors: M
authors: Horie
mesh_terms: D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000503:physiopathology; D001282:Atrial Flutter / Q000188:drug therapy / Q000503:physiopathology; D001483:Base Sequence; D053840:Brugada Syndrome / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D057809:HEK293 Cells; D006801:Humans; D008012:Lidocaine / Q000009:adverse effects / Q000031:analogs & derivatives; D008297:Male; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*
chemical_list: D000889:Anti-Arrhythmia Agents; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D008012:Lidocaine; C042288:pilsicainide