Molecular mechanism for an inherited cardiac arrhythmia

IN the congenital long-QT syndrome, prolongation of the cardiac action potential occurs by an unknown mechanism 1,2 and predisposes individuals to syncope and sudden death as a result of ventricular arrhythmias 3 . Genetic heterogeneity has been demonstrated for autosomal dominant long-QT syndrome by the identification of multiple distinct loci 4,5 , and associated mutations in two candidate genes have recently been reported 6,7 . One form of hereditary long QT (LQT3) has been linked to a mutation 7 in the gene encoding the human heart voltage-gated sodium-channel α-subunit ( SCN5A on chromosome 3p21) 8 . Here we characterize this mutation using heterologous expression of recombinant human heart sodium channels. Mutant channels show a sustained inward current during membrane depolarization. Single-channel recordings indicate that mutant channels fluctuate between normal and non-inactivating gating modes. Persistent inward sodium current explains prolongation of cardiac action potentials, and provides a molecular mechanism for this form of congenital long-QT syndrome.