Brugada syndrome and fever: genetic and molecular characterization of patients carrying SCN5A mutations.
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.
Keller
Dagmar I
DI
Service of Cardiology, CHUV, Lausanne, Switzerland.
Rougier
Jean-Sébastien
JS
Kucera
Jan P
JP
Benammar
Nawal
N
Fressart
Véronique
V
Guicheney
Pascale
P
Madle
Alois
A
Fromer
Martin
M
Schläpfer
Jürg
J
Abriel
Hugues
H
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
D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels