PHENOTYPIC CHARACTERIZATION OF A NOVEL LONG-QT SYNDROME MUTATION (R1623Q) IN THE CARDIAC SODIUM-CHANNEL

Background-A heritable form of the long-QT syndrome (LQT3) has been li nked to mutations in the cardiac sodium channel gene (SCN5A). Recently , a sporadic SCN5A mutation was identified in a Japanese girl afflicte d with the long-QT syndrome, In contrast to the heritable mutations, t his externally positioned domain IV, S4 mutation (R1623Q) neutralized a charged residue that is critically involved in activation-inactivati on coupling. Methods and Results-We have characterized the R1623Q muta tion in the human cardiac sodium channel (hH1) using both whole-cell a nd single-channel recordings. In contrast to the autosomal dominant LQ T3 mutations, R1623Q increased the probability of long openings and ca used early reopenings, producing a threefold prolongation of sodium cu rrent decay. Lidocaine restored rapid decay of the R1623Q macroscopic current. Conclusions-The R1623Q mutation produces inactivation gating defects that differ mechanistically from those caused by LQT3 mutation s, These findings provide a biophysical explanation for this severe lo ng-QT phenotype and extend our understanding of the mechanistic role o f the S4 segment in cardiac sodium channel inactivation gating and cla ss I antiarrhythmic drug action.