title: Novel arrhythmogenic mechanism revealed by a long-QT syndrome mutation in the cardiac Na(+) channel.
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.
authors: Department of Pharmacology, College of Physicians & Surgeons of Columbia University, New York, NY, USA.
authors: H
authors: H
authors: Abriel
authors: C
authors: C
authors: Cabo
authors: X H
authors: XH
authors: Wehrens
authors: I
authors: I
authors: Rivolta
authors: H K
authors: HK
authors: Motoike
authors: M
authors: M
authors: Memmi
authors: C
authors: C
authors: Napolitano
authors: S G
authors: SG
authors: Priori
authors: R S
authors: RS
authors: Kass
mesh_terms: D000293:Adolescent; D019943:Amino Acid Substitution; D001145:Arrhythmias, Cardiac / Q000175:diagnosis* / Q000235:genetics; D002460:Cell Line; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008133:Long QT Syndrome / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D010641:Phenotype; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D014162:Transfection
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D013779:Tetrodotoxin; D012964:Sodium