Copyright © 2006, European Society of Cardiology
A novel SCN5A mutation, F1344S, identified in a patient with Brugada syndrome and fever-induced ventricular fibrillation
aCardiology Department, University Hospital Basel, Switzerland
bCardiobiology Research Group, University Hospital Basel, Switzerland
cLaval Hospital, Québec Heart Institute, Research Centre, 2725, Chemin Sainte-Foy, Sainte-Foy, Québec, Canada G1V 4G5
dCardiology Department, Tiefenau Hospital, Bern, Switzerland
eSwiss Cardiovascular Center, Bern, Switzerland
* Corresponding author. Tel.: +1 418 656 8711x5447; fax: +1 418 656 4509. Email address: mohamed.chahine{at}phc.ulaval.ca
Objective Brugada syndrome (BS) is an inherited electrical cardiac disorder characterized by right bundle branch block pattern and ST segment elevation in leads V1 to V3 on surface electrocardiogram that can potentially lead to malignant ventricular tachycardia and sudden cardiac death. About 20% of patients have mutations in the only so far identified gene, SCN5A, which encodes the 
-subunit of the human cardiac voltage-dependent sodium channel (hNav1.5). Fever has been shown to unmask or trigger the BS phenotype, but the associated molecular and the biophysical mechanisms are still poorly understood. We report on the identification and biophysical characterization of a novel heterozygous missense mutation in SCN5A, F1344S, in a 42-year-old male patient showing the BS phenotype leading to ventricular fibrillation during fever.
Methods The mutation was reproduced in vitro using site-directed mutagenesis and characterized using the patch clamp technique in the whole-cell configuration.
Results The biophysical characterization of the channels carrying the F1344S mutation revealed a 10mV mid-point shift of the G/V curve toward more positive voltages during activation. Raising the temperature to 40.5°C further shifted the mid-point activation by 18mV and significantly changed the slope factor in Nav1.5/F1344S mutant channels from – 6.49 to – 10.27mV.
Conclusions Our findings indicate for the first time that the shift in activation and change in the slope factor at a higher temperature mimicking fever could reduce sodium currents' amplitude and trigger the manifestation of the BS phenotype.
KEYWORDS Brugada syndrome; Sudden cardiac death; Genetics; SCN5A; Sodium channel; Nav1.5; Fever; Ventricular fibrillation
1 These authors contributed equally to this work.
Time for primary review 14 days
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Burashnikov, W. Shimizu, and C. Antzelevitch Fever Accentuates Transmural Dispersion of Repolarization and Facilitates Development of Early Afterdepolarizations and Torsade de Pointes Under Long-QT Conditions Circ Arrhythm Electrophysiol, August 1, 2008; 1(3): 202 - 208. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ahmad, L. Dahllund, A. B. Eriksson, D. Hellgren, U. Karlsson, P.-E. Lund, I. A. Meijer, L. Meury, T. Mills, A. Moody, et al. A stop codon mutation in SCN9A causes lack of pain sensation Hum. Mol. Genet., September 1, 2007; 16(17): 2114 - 2121. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Skinner, S.-K. Chung, C.-A. Nel, A. N. Shelling, J. R. Crawford, N. McKenzie, R. Pinnock, J. K. French, and M. I. Rees Brugada Syndrome Masquerading as Febrile Seizures Pediatrics, May 1, 2007; 119(5): e1206 - e1211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. P. Harty, S. D. Dib-Hajj, L. Tyrrell, R. Blackman, F. M. Hisama, J. B. Rose, and S. G. Waxman Nav1.7 Mutant A863P in Erythromelalgia: Effects of Altered Activation and Steady-State Inactivation on Excitability of Nociceptive Dorsal Root Ganglion Neurons J. Neurosci., November 29, 2006; 26(48): 12566 - 12575. [Abstract] [Full Text] [PDF]
|
|