A novel SCN5A mutation associated with long QT-3

Altered inactivation kinetics and channel dysfunction

Ilaria Rivolta, Colleen E. Clancy, Michihiro Tateyama, Huajun Liu, Silvia G. Priori, Robert S. Kass

Research output: Contribution to journalArticle

Abstract

Mutations in the gene (SCN5A) encoding the α-subunit of the cardiac Na+ channel cause congenital long QT syndrome (LQT-3). Here we describe a novel LQT-3 mutation I1768V (I1768V) located in the sixth transmembrane spanning segment of domain IV. This mutation is unusual in that it is located within a transmembrane spanning domain and does not promote the typically observed sustained inward current corresponding to a gain of channel function (bursting). Rather, I1768V increases the rate of recovery from inactivation and increases the channel availability, observed as a positive shift of the steady-state inactivation curve (+7.6 mV). Using a Markovian model of the cardiac Na+ channel, we simulated these changes in gating behavior and demonstrated that a small increase in the rate of recovery from inactivation is sufficient to explain all of the experimentally observed current changes. The effect of these alterations in channel gating results in an increase in window current that may act to disrupt cardiac repolarization.

Original languageEnglish
Pages (from-to)191-197
Number of pages7
JournalPhysiol Genomics
Volume2002
Issue number10
Publication statusPublished - Oct 2002

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Mutation
Genes
Long QT syndrome type 3

Keywords

  • Arrhythmias
  • Electrophysiology
  • Genetics
  • Long QT syndrome
  • Sodium channel

ASJC Scopus subject areas

  • Genetics
  • Physiology

Cite this

Rivolta, I., Clancy, C. E., Tateyama, M., Liu, H., Priori, S. G., & Kass, R. S. (2002). A novel SCN5A mutation associated with long QT-3: Altered inactivation kinetics and channel dysfunction. Physiol Genomics, 2002(10), 191-197.

A novel SCN5A mutation associated with long QT-3 : Altered inactivation kinetics and channel dysfunction. / Rivolta, Ilaria; Clancy, Colleen E.; Tateyama, Michihiro; Liu, Huajun; Priori, Silvia G.; Kass, Robert S.

In: Physiol Genomics, Vol. 2002, No. 10, 10.2002, p. 191-197.

Research output: Contribution to journalArticle

Rivolta, I, Clancy, CE, Tateyama, M, Liu, H, Priori, SG & Kass, RS 2002, 'A novel SCN5A mutation associated with long QT-3: Altered inactivation kinetics and channel dysfunction', Physiol Genomics, vol. 2002, no. 10, pp. 191-197.
Rivolta, Ilaria ; Clancy, Colleen E. ; Tateyama, Michihiro ; Liu, Huajun ; Priori, Silvia G. ; Kass, Robert S. / A novel SCN5A mutation associated with long QT-3 : Altered inactivation kinetics and channel dysfunction. In: Physiol Genomics. 2002 ; Vol. 2002, No. 10. pp. 191-197.
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