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 b...

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Bibliographic Details
Published in:Nature (London) 1995-08, Vol.376 (6542), p.683-685
Main Authors: Bennett, Paul B, Yazawa, Kazuto, Makita, Naomasa, George, Alfred L
Format: Article
Language:English
Subjects:
Action Potentials
Animals
Biological and medical sciences
Cardiac arrhythmia
Cardiac dysrhythmias
Cardiology. Vascular system
Cells, Cultured
Computer Simulation
Genes
Heart
Heterogeneity
Humanities and Social Sciences
Humans
Ion Channel Gating - genetics
letter
Long QT Syndrome - genetics
Long QT Syndrome - metabolism
Medical research
Medical sciences
Membranes
multidisciplinary
Mutation
Myocardium - metabolism
Oocytes
Patch-Clamp Techniques
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Science
Science (multidisciplinary)
Sodium
Sodium Channels - genetics
Sodium Channels - metabolism
Xenopus laevis
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Summary: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.
ISSN:0028-0836
1476-4687
DOI:10.1038/376683a0