Cardiovascular Research Advance Access first published online on December 7, 2007
This version [Corrected Proof] published online on January 16, 2008
Cardiovascular Research, doi:10.1093/cvr/cvm096
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Combination of cardiac conduction disease and long QT syndrome caused by mutation T1620K in the cardiac sodium channel
1 Department of Internal Medicine I, Friedrich Schiller University Jena, 07740 Jena, Germany
2 Institute of Physiology II, Friedrich Schiller University Jena, Kollegiengasse 9, 07743 Jena, Germany
* Corresponding author. Tel: +49 3641 934372; fax: +49 3641 933202. E-mail address: thomas.zimmer{at}mti.uni-jena.de
Aims: The aim of the present study was to elucidate the molecular mechanism underlying the concomitant occurrence of cardiac conduction disease and long QT syndrome (LQT3), two SCN5A channelopathies that are explained by loss-of-function and gain-of-function, respectively, in the cardiac Na+ channel.
Methods and results: A Caucasian family with prolonged QT interval, intermittent bundle-branch block, sudden cardiac death, and syncope was investigated. Lidocaine (1 mg/kg i.v.) normalized the prolonged QT interval and rescued bundle-branch block. An SCN5A mutation analysis was performed that revealed a C-to-A mutation at position 4859 (exon 28), predicted to change a highly conserved threonine for a lysine at position 1620. Mutant channels were characterized both in Xenopus oocytes and HEK293 cells. The T1620K mutation remarkably altered the properties of Nav1.5 channels. In particular, the voltage-dependence of the current decay time constants was largely lost. As a consequence, mutant channels inactivated faster than wild-type channels at potentials negative to –30 mV, resulting in less Na+ inward current (loss-of-function), but significantly slower at potentials positive to –30 mV, resulting in an increased Na+ inward current (gain-of-function). Moreover, we found a hyperpolarized shift of steady-state activation and an accelerated recovery from inactivation (gain-of-function). At the same time, channel availability was significantly reduced at the resting membrane potential (loss-of-function).
Conclusion: We conclude that lysine at position 1620 leads to both loss-of-function and gain-of-function properties in hNav1.5 channels, which may consequently cause in the same individuals impaired impulse propagation in the conduction system and prolonged QTc intervals, respectively.
KEYWORDS Conduction block; Ion channels; Long QT syndrome; Na+ channels
Time for primary review: 21 days
These authors contributed equally to this work.