Phenotypic characterization of a novel long-QT syndrome mutation (R1623Q) in the cardiac sodium channel

Nicholas G. Kambouris, H. Bradley Nuss, David C. Johns, Gordon F. Tomaselli, Eduardo Marban, Jeffrey R. Balser

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Abstract

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 gift 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.

Original languageEnglish (US)
Pages (from-to)640-644
Number of pages5
JournalCirculation
Volume97
Issue number7
Publication statusPublished - Feb 24 1998
Externally publishedYes

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Keywords

  • Arrhythmia
  • Long-QT syndrome
  • Sodium

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Kambouris, N. G., Nuss, H. B., Johns, D. C., Tomaselli, G. F., Marban, E., & Balser, J. R. (1998). Phenotypic characterization of a novel long-QT syndrome mutation (R1623Q) in the cardiac sodium channel. Circulation, 97(7), 640-644.