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

Research output: Contribution to journalArticle

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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
DOIs
StatePublished - Feb 24 1998
Externally publishedYes

Fingerprint

Long QT Syndrome
Sodium Channels
Mutation
Gift Giving
Anti-Arrhythmia Agents
Lidocaine
Sodium
Phenotype

Keywords

  • Arrhythmia
  • Long-QT syndrome
  • Sodium

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Phenotypic characterization of a novel long-QT syndrome mutation (R1623Q) in the cardiac sodium channel. / Kambouris, Nicholas G.; Nuss, H. Bradley; Johns, David C.; Tomaselli, Gordon F.; Marban, Eduardo; Balser, Jeffrey R.

In: Circulation, Vol. 97, No. 7, 24.02.1998, p. 640-644.

Research output: Contribution to journalArticle

Kambouris, Nicholas G. ; Nuss, H. Bradley ; Johns, David C. ; Tomaselli, Gordon F. ; Marban, Eduardo ; Balser, Jeffrey R. / Phenotypic characterization of a novel long-QT syndrome mutation (R1623Q) in the cardiac sodium channel. In: Circulation. 1998 ; Vol. 97, No. 7. pp. 640-644.
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