Characterization of human cardiac Na+ channel mutations in the congenital long QT syndrome

Dao W. Wang, Kazuto Yazawa, Alfred L. George, Paul B. Bennett*

*Corresponding author for this work

Research output: Contribution to journalArticle

210 Scopus citations

Abstract

The congenital long QT syndrome (LQTS) is an inherited disorder characterized by a prolonged cardiac action potential. This delay in cellular repolarization can lead to potentially fatal arrhythmias. One form of LQTS (LQT3) has been linked to the human cardiac voltage-gated sodium channel gene (SCN5A). Three distinct mutations have been identified in the sodium channel gene. The biophysical and functional characteristics of each of these mutant channels were determined by heterologous expression of a recombinant human heart sodium channel in a mammalian cell line. Each mutation caused a sustained, non-inactivating sodium current amounting to a few percent of the peak inward sodium current, observable during long (>50 msec) depolarizations. The voltage dependence and rate of inactivation were altered, and the rate of recovery from inactivation was changed compared with wild-type channels. These mutations in diverse regions of the ion channel protein, all produced a common defect in channel gating that can cause the long QT phenotype. The sustained inward current caused by these mutations will prolong the action potential. Furthermore, they may create conditions that promote arrhythmias due to prolonged depolarization and the altered recovery from inactivation. These results provide insights for successful intervention in the disease.

Original languageEnglish (US)
Pages (from-to)13200-13205
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number23
DOIs
StatePublished - Nov 12 1996

Keywords

  • LQT3
  • SCN5A
  • hH1
  • heart
  • sodium channel

ASJC Scopus subject areas

  • General

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