Molecular mechanism for an inherited cardiac arrhythmia

PB Bennett, K Yazawa, N Makita, AL George Jr - Nature, 1995 - nature.com
PB Bennett, K Yazawa, N Makita, AL George Jr
Nature, 1995nature.com
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 …
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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