Background: A heritable form of the long-QT syndrome (LQT3) has been linked to mutations in the cardiac sodium channel gene (SCN5A). Recently, a sporadic SCN5A mutation was identified in a Japanese girl afflicted with the long-QT syndrome. In contrast to the heritable mutations, this externally positioned domain IV, S4 mutation (R1623Q) neutralized a charged residue that is critically involved in activation-inactivation coupling.
Methods and results: We have characterized the R1623Q mutation in the human cardiac sodium channel (hH1) using both whole-cell and single-channel recordings. In contrast to the autosomal dominant LQT3 mutations, R1623Q increased the probability of long openings and caused early reopenings, producing a threefold prolongation of sodium current 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 mutations. These findings provide a biophysical explanation for this severe long-QT phenotype and extend our understanding of the mechanistic role of the S4 segment in cardiac sodium channel inactivation gating and class I antiarrhythmic drug action.