In affected members of a family with Brugada syndrome (BRGDA1; 601144), a distinct form of idiopathic ventricular fibrillation, Chen et al. (1998) found an arg1232-to-trp (R1232W) and a thr1620-to-met (T1620M) mutation on the same chromosome with no mutation in the other chromosome, suggesting to them that IVF in this family was inherited as an autosomal dominant trait. The presence of both normal and mutated sodium channels in the same tissue would promote heterogeneity of the refractory period, a well established mechanism in arrhythmogenesis, and therefore may be the underlying molecular defect that causes re-entrant arrhythmia in this family. The potential contribution of R1232W and T1620M mutations to the mechanism of IVF was determined by heterologous expression in Xenopus oocytes. They found that sodium channels with the missense mutation recovered from inactivation more rapidly than normal, indicating that IVF with right bundle branch block (RBBB) and ST segment elevation is a defect distinct from long QT syndrome. When studied alone, the R1232W mutant behaved most like normal channels, whereas the T1620M mutant closely followed the kinetic pattern of the double mutant. This indicated that T1620M is the mutation probably responsible for the IVF phenotype in this kindred and that R1232W could be a rare polymorphism. In summary, biophysical analysis of the 2 missense mutations in SCN5A showed a shift in the voltage dependence of steady-state inactivation toward more positive potentials associated with a 25 to 30% acceleration in recovery time from inactivation at potentials near -80mV.
Commenting that studies of the thr1620-to-met mutant by Chen et al. (1998) revealed an abnormal electrophysiologic profile at room temperature that did not adequately explain the ECG signature of Brugada syndrome, Dumaine et al. (1999) undertook a more detailed electrophysiologic study of the thr1620-to-met mutant protein. Dumaine et al. (1999) expressed the mutant protein in a mammalian cell line and employed a patch-clamp technique to study current kinetics at 32 degrees C. The results indicated that current decay kinetics were faster in mutant than in wildtype channels at this temperature and that recovery from inactivation was slower, with a significant shift in steady-state activation. These findings provided an explanation for the ECG features of Brugada syndrome and represented the first illustration of a cardiac sodium channel mutation in which arrhythmogenicity is revealed only at temperatures approaching the physiologic range.
Voltage-gated sodium channels are multimeric structures consisting of a large, heavily glycosylated alpha subunit and 1 or 2 smaller beta subunits. The beta subunits are thought necessary for normal gating function. In brain and skeletal muscle, the beta-1 subunit (600235) accelerates sodium channel inactivation. Makita et al. (2000) characterized the functional roles of the auxiliary beta subunit by coexpression of the beta subunit with either wildtype SCN5A or SCN5A carrying the heterologously expressed T1620M mutation in Xenopus oocytes. The midpoint of steady-state inactivation was significantly shifted to positive potentials in the T1620M alpha/beta-1 channel, with an acceleration in recovery from inactivation when compared to other channels. Makita et al. (2000) therefore suggested that coexpression of T1620M alpha/beta-1 subunits exposed a significant electrophysiologic deficit that may predispose to ventricular fibrillation. Expression of both normal and mutant channels, as in the hearts of patients with Brugada syndrome, would promote heterogeneity of the refractory period in their myocardium, which serves as an ideal electrical substrate for reentrant arrhythmia.
