Brugada syndrome and fever: genetic and molecular characterization of patients carrying SCN5A mutations.

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Serval ID
serval:BIB_D07C325F825E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Brugada syndrome and fever: genetic and molecular characterization of patients carrying SCN5A mutations.
Journal
Cardiovascular Research
Author(s)
Keller D.I., Rougier J.S., Kucera J.P., Benammar N., Fressart V., Guicheney P., Madle A., Fromer M., Schläpfer J., Abriel H.
ISSN
0008-6363
Publication state
Published
Issued date
2005
Peer-reviewed
Oui
Volume
67
Number
3
Pages
510-519
Language
english
Notes
Journal Article Research Support, Non-U.S. Gov't --- Old month value: Aug 15
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.
Keywords
Action Potentials, Adult, DNA Mutational Analysis, Death, Sudden, Cardiac, Electrocardiography, Fever, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Muscle Proteins, Mutation, Sodium Channels, Syndrome, Tachycardia, Ventricular
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 11:56
Last modification date
25/09/2019 7:10
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