© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Human SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome*
aDepartment of Medical Physiology, Utrecht University, Utrecht, The Netherlands
bDepartment of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands
cDepartment of Experimental and Molecular Cardiology, Academic Medical Center, Amsterdam, The Netherlands
dDepartment of Physiology, Academic Medical Center, Amsterdam, The Netherlands
eHeart Lung Institute, University Hospital Utrecht, Utrecht, The Netherlands
fDepartment of Cardiology, University Hospital Groningen, Groningen, The Netherlands
gLaboratory of Molecular Genetics, Department of Pathology, The Medical School, University of Malta, Msida, Malta
hThe Interuniversity Cardiology Institute of The Netherlands
* Corresponding author. Academic Medical Center, University of Amsterdam, Department of Clinical and Experimental Cardiology, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. Tel.: +31-20-566-3265; fax: +31-20-697-5458 c.alshinawi{at}amc.uva.nl
Background: Primary dysrhythmias other than those associated with the long QT syndrome, are increasingly recognized. One of these are represented by patients with a history of resuscitation from cardiac arrest but without any structural heart disease. These patients exhibit a distinct electrocardiographic (ECG) pattern consisting of a persistent ST-segment elevation in the right precordial leads often but not always accompanied by a right bundle branch block (Brugada syndrome). This syndrome is associated with a high mortality rate and has been shown to display familial occurrence. Methods and results: Pharmacological sodium channel blockade elicits or worsens the electrocardiographic features associated with this syndrome. Hence, a candidate gene approach directed towards SCN5A, the gene encoding the 
-subunit of the cardiac sodium channel, was followed in six affected individuals. In two patients missense mutations were identified in the coding region of the gene: R1512W in the DIII–DIV cytoplasmic linker and A1924T in the C-terminal cytoplasmic domain. In two other patients mutations were detected near intron/exon junctions. To assess the functional consequences of the R1512W and A1924T mutations, wild-type and mutant sodium channel proteins were expressed in Xenopus oocytes. Both missense mutations affected channel function, most notably a 4–5 mV negative voltage shift of the steady-state activation and inactivation curves in R1512W and a 9 mV negative voltage shift of the steady-state activation curve in A1924T, measured at 22°C. Recovery from inactivation was slightly prolonged for R1512W channels. The time dependent kinetics of activation and inactivation at –20 mV were not significantly affected by either mutation. Conclusions: Two SCN5A mutations associated with the Brugada syndrome, significantly affect cardiac sodium channel characteristics. The alterations seem to be associated with an increase in inward sodium current during the action potential upstroke.
KEYWORDS Ventricular arrhythmias; Sudden death; Ion channels; Genetic code