Human SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome

Background: Primary dysrhythmias other than those associated with the long QT syndrome, are increasingly recognized. One of these are represented by p atients with a history of resuscitation from cardiac arrest but without any structural heart disease. These patients exhibit a distinct electrocardiog raphic (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 mo rtality rate and has been shown to display familial occurrence. Methods and results: Pharmacological sodium channel blockade elicits or worsens the el ectrocardiographic features associated with this syndrome. Hence, a candida te gene approach directed towards SCN5A, the gene encoding the a-subunit of the cardiac sodium channel, was followed in six affected individuals. In t wo patients missense mutations were identified in the coding region of the gene: R1512W in the DIII-DIV cytoplasmic linker and A1924T in the C-termina l cytoplasmic domain. In two other patients mutations were detected near in tron/exon junctions. To assess the functional consequences of the R1512W an d A1924T mutations, wild-type and mutant sodium channel proteins were expre ssed in Xenopus oocytes. Both missense mutations affected channel function, most notably a 4-5 mV negative voltage shift of the steady-state activatio n and inactivation curves in R1512W and a 9 mV negative voltage shift of th e steady-state activation curve in A1924T, measured at 22 degrees C. Recove ry from inactivation was slightly prolonged for R1512W channels. The time d ependent kinetics of activation and inactivation at -20 mV were not signifi cantly affected by either mutation. Conclusions: Two SCN5A mutations associ ated 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. (C) 1999 Elsev ier Science B.V. All rights reserved.