Abstract
IN the congenital long-QT syndrome, prolongation of the cardiac action potential occurs by an unknown mechanism1,2 and predisposes individuals to syncope and sudden death as a result of ventricular arrhythmias3. Genetic heterogeneity has been demonstrated for autosomal dominant long-QT syndrome by the identification of multiple distinct loci4,5, and associated mutations in two candidate genes have recently been reported6,7. One form of hereditary long QT (LQT3) has been linked to a mutation7 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.
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Bennett, P., Yazawa, K., Makita, N. et al. Molecular mechanism for an inherited cardiac arrhythmia. Nature 376, 683–685 (1995). https://doi.org/10.1038/376683a0
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DOI: https://doi.org/10.1038/376683a0