From the Division of Cardiac Anesthesia, Department of Anesthesiology and
Critical Care Medicine (N.G.K., J.R.B.), and the Section of Molecular and
Cellular Cardiology, Department of Medicine, The Johns Hopkins University
School of Medicine, Baltimore, Md.
Correspondence to Jeffrey R. Balser, MD, PhD, Division of Cardiac Anesthesia, Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Carnegie 442, 600 N Wolfe St, Baltimore, MD 21287. E-mail jrbalser{at}welchlink.welch.jhu.edu
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.
© 1998 American Heart Association, Inc.
Brief Rapid Communications
Phenotypic Characterization of a Novel Long-QT Syndrome Mutation (R1623Q) in the Cardiac Sodium Channel
Key Words: arrhythmia • sodium • long-QT syndrome
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