Variant 3 of the congenital long-QT syndrome (LQTS-3) is caused by mutations in the gene encoding the alpha subunit of the cardiac Na(+) channel. In the present study, we report a novel LQTS-3 mutation, E1295K (EK), and describe its functional consequences when expressed in HEK293 cells. The clinical phenotype of the proband indicated QT interval prolongation in the absence of T-wave morphological abnormalities and a steep QT/R-R relationship, consistent with an LQTS-3 lesion. However, biophysical analysis of mutant channels indicates that the EK mutation changes channel activity in a manner that is distinct from previously investigated LQTS-3 mutations. The EK mutation causes significant positive shifts in the half-maximal voltage (V(1/2)) of steady-state inactivation and activation (+5.2 and +3.4 mV, respectively). These gating changes shift the window of voltages over which Na(+) channels do not completely inactivate without altering the magnitude of these currents. The change in voltage dependence of window currents suggests that this alteration in the voltage dependence of Na(+) channel gating may cause marked changes in action potential duration because of the unique voltage-dependent rectifying properties of cardiac K(+) channels that underlie the plateau and terminal repolarization phases of the action potential. Na(+) channel window current is likely to have a greater effect on net membrane current at more positive potentials (EK channels) where total K(+) channel conductance is low than at more negative potentials (wild-type channels), where total K(+) channel conductance is high. These findings suggest a fundamentally distinct mechanism of arrhythmogenesis for congenital LQTS-3.

Abriel, H., Cabo, C., Wehrens, X., Rivolta, I., Motoike, H., Memmi, M., et al. (2001). Novel arrhythmogenic mechanism revealed by a long-QT syndrome mutation in the cardiac Na(+) channel. CIRCULATION RESEARCH, 88(7), 740-745 [10.1161/hh0701.089668].

Novel arrhythmogenic mechanism revealed by a long-QT syndrome mutation in the cardiac Na(+) channel

Rivolta, I;
2001

Abstract

Variant 3 of the congenital long-QT syndrome (LQTS-3) is caused by mutations in the gene encoding the alpha subunit of the cardiac Na(+) channel. In the present study, we report a novel LQTS-3 mutation, E1295K (EK), and describe its functional consequences when expressed in HEK293 cells. The clinical phenotype of the proband indicated QT interval prolongation in the absence of T-wave morphological abnormalities and a steep QT/R-R relationship, consistent with an LQTS-3 lesion. However, biophysical analysis of mutant channels indicates that the EK mutation changes channel activity in a manner that is distinct from previously investigated LQTS-3 mutations. The EK mutation causes significant positive shifts in the half-maximal voltage (V(1/2)) of steady-state inactivation and activation (+5.2 and +3.4 mV, respectively). These gating changes shift the window of voltages over which Na(+) channels do not completely inactivate without altering the magnitude of these currents. The change in voltage dependence of window currents suggests that this alteration in the voltage dependence of Na(+) channel gating may cause marked changes in action potential duration because of the unique voltage-dependent rectifying properties of cardiac K(+) channels that underlie the plateau and terminal repolarization phases of the action potential. Na(+) channel window current is likely to have a greater effect on net membrane current at more positive potentials (EK channels) where total K(+) channel conductance is low than at more negative potentials (wild-type channels), where total K(+) channel conductance is high. These findings suggest a fundamentally distinct mechanism of arrhythmogenesis for congenital LQTS-3.
Si
Articolo in rivista - Articolo scientifico
Scientifica
Heart; Ion Channel Gating; DNA Mutational Analysis; Humans; Tetrodotoxin; Sodium Channels; Sodium; Phenotype; Patch-Clamp Techniques; Conserved Sequence; Transfection; Electrocardiography; Kidney; Long QT Syndrome; Adolescent; Mutation; Amino Acid Substitution; Cell Line; Male; NAV1.5 Voltage-Gated Sodium Channel; Arrhythmias, Cardiac
English
740
745
6
Abriel, H., Cabo, C., Wehrens, X., Rivolta, I., Motoike, H., Memmi, M., et al. (2001). Novel arrhythmogenic mechanism revealed by a long-QT syndrome mutation in the cardiac Na(+) channel. CIRCULATION RESEARCH, 88(7), 740-745 [10.1161/hh0701.089668].
Abriel, H; Cabo, C; Wehrens, X; Rivolta, I; Motoike, H; Memmi, M; Napolitano, C; Priori, S; Kass, R
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/274351
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