Physiol. Genomics AJP: Regulatory, Integrative and Comparative Physiology
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Physiol. Genomics 10: 191-197, 2002. First published July 16, 2002; doi:10.1152/physiolgenomics.00039.2002
1094-8341/02 $5.00
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Received 9 April 2002; accepted in final form 12 July 2002.
Physiological Genomics 10:191-197 (2002)
1094-8341/02 $5.00 © 2002 American Physiological Society

A novel SCN5A mutation associated with long QT-3: altered inactivation kinetics and channel dysfunction

Ilaria Rivolta1, Colleen E. Clancy1, Michihiro Tateyama1, Huajun Liu1, Silvia G. Priori2 and Robert S. Kass1

1 Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York 10032
2 University of Pavia and Molecular Cardiology Laboratory, Fondazione Salvatore Maugeri, Instituto di Ricovero e Cura a Carattere Scientifico, Pavia 27100, Italy

Mutations in the gene (SCN5A) encoding the {alpha}-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.

long QT syndrome; sodium channel; electrophysiology; genetics; arrhythmias




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