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 
alpha-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 degrees 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.