title: Brugada syndrome and fever: genetic and molecular characterization of patients carrying SCN5A mutations.
abstract: OBJECTIVE
  Brugada syndrome (BrS) is characterized by ventricular tachyarrhythmias leading to sudden cardiac death and is caused, in part, by mutations in the SCN5A gene encoding the sodium channel Na(v)1.5. Fever can trigger or exacerbate the clinical manifestations of BrS. The aim of this work was to characterize the genetic and molecular determinants of fever-dependent BrS.
  
  
  METHODS
  Four male patients with typical BrS ST-segment elevation in V1-V3 or ventricular arrhythmias during fever were screened for mutations in the SCN5A gene. Wild-type (WT) and mutant Na(v)1.5 channels were expressed in HEK293 cells. The sodium currents (I(Na)) were analysed using the whole-cell patch clamp technique at various temperatures. Protein expression of WT and mutant channels was studied by Western blot experiments.
  
  
  RESULTS
  Two mutations in SCN5A, L325R and R535X, were identified. Expression of the two mutant Na(v)1.5 channels in HEK293 cells revealed in each case a severe loss-of-function. Upon the increase of temperature up to 42 degrees C, we observed a pronounced acceleration of Na(v)1.5 activation and fast inactivation kinetics. Cardiac action potential modelling experiments suggest that in patients with reduced I(Na), fever could prematurely shorten the action potential by virtue of its effect on WT channels. Further experiments revealed that L325R channels are likely misfolded, since their function could be partially rescued by mexiletine or curcumin. In co-expression experiments, L325R channels interfered with the proper function of WT channels, suggesting that a dominant negative phenomenon may underlie BrS triggered by fever.
  
  
  CONCLUSIONS
  The genetic background of BrS patients sensitive to fever is heterogeneous. Our experimental data suggest that the clinical manifestations of fever-exacerbated BrS may not be mutation specific.
authors.affiliation: Service of Cardiology, CHUV, Lausanne, Switzerland.
authors.forename: Dagmar I
authors.initials: DI
authors.lastname: Keller
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Rougier
authors.forename: Jan P
authors.initials: JP
authors.lastname: Kucera
authors.forename: Nawal
authors.initials: N
authors.lastname: Benammar
authors.forename: Véronique
authors.initials: V
authors.lastname: Fressart
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
authors.forename: Alois
authors.initials: A
authors.lastname: Madle
authors.forename: Martin
authors.initials: M
authors.lastname: Fromer
authors.forename: Jürg
authors.initials: J
authors.lastname: Schläpfer
authors.forename: Hugues
authors.initials: H
authors.lastname: Abriel
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000328:Adult; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D004562:Electrocardiography; D005334:Fever / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome; D017180:Tachycardia, Ventricular / Q000235:genetics* / Q000378:metabolism
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels