Novel Arrhythmogenic Mechanism Revealed by a Long-QT Syndrome Mutation in the Cardiac Na+ Channel

• Published in: Circulation research 2001-04, Vol.88 (7), p.740-745
• Main Authors: Abriel, Hugues, Cabo, Candido, Wehrens, Xander H.T, Rivolta, Ilaria, Motoike, Howard K, Memmi, Mirella, Napolitano, Carlo, Priori, Silvia G, Kass, Robert S
• Format: Article
• Language: English
• Subjects: Adolescent; Amino Acid Substitution; Arrhythmias, Cardiac - diagnosis; Arrhythmias, Cardiac - genetics; Biological and medical sciences; Cardiac dysrhythmias; Cardiology. Vascular system; Cell Line; Conserved Sequence; DNA Mutational Analysis; Electrocardiography; Heart; Heart - physiopathology; Humans; Ion Channel Gating - drug effects; Ion Channel Gating - genetics; Kidney - cytology; Kidney - drug effects; Kidney - metabolism; Long QT Syndrome - diagnosis; Long QT Syndrome - genetics; Long QT Syndrome - physiopathology; Male; Medical sciences; Mutation; NAV1.5 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Phenotype; Sodium - metabolism; Sodium Channels - genetics; Sodium Channels - metabolism; Tetrodotoxin - pharmacology; Transfection
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/hh0701.089668

Variant 3 of the congenital long-QT syndrome (LQTS-3) is caused by mutations in the gene encoding the α 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 (V1/2) 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.