SCN5A(K817E), a novel Brugada syndrome-associated mutation that alters the activation gating of NaV1.5 channel
- Heart Rhythm. 2016 May;13(5):1113-1120. doi: 10.1016/j.hrthm.2016.01.008.
- 1. Department of Legal Medicine, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama, Japan.
- 2. Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama-shi, Toyama, Japan.
- 3. Clinical Research and Ethics Center, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama, Japan.
- 4. Second Department of Internal Medicine, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama, Japan.
- 5. Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, Japan.
- 6. Department of Legal Medicine, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama, Japan. Electronic address: [email protected].
Background: Brugada syndrome (BrS) is an inherited lethal arrhythmic disorder characterized by syncope and sudden cardiac death from ventricular tachyarrhythmias. Here we identified a novel K817E mutation of SCN5A gene in a man with type 1 BrS electrocardiogram pattern using next-generation Sequencing targeted for 73 cardiac disorder-related genes. SCN5A encodes the α-subunit of NaV1.5 voltage-gated Na(+) channel, and some of its mutations are linked to BrS. The proband had no mutation in any of the other arrhythmia-related genes sequenced.
Objective: We investigated whether the K817E mutation causes a functional change of NaV1.5 channel responsible for the BrS phenotype.
Methods: We compared the electrophysiological properties of the whole-cell currents mediated by wild-type and mutant channels heterologously expressed in human embryonic kidney 293 cells by using a voltage-clamp technique.
Results: The K817E mutation reduced the Na(+) current density by 39.0%-91.4% at membrane potentials from -55 to -5 mV. This reduction resulted from a ~24-mV positive shift in the voltage dependence of activation. The mutation also decelerated recovery from both fast and intermediate inactivation, whereas it had little effect on the cell surface expression, single-channel conductance, voltage-dependence of fast inactivation, entry into intermediate inactivation, use-dependent loss of channel availability, or closed-state inactivation.
Conclusion: The K817E mutation of SCN5A gene leads to loss of function of NaV1.5 channel and may underlie the BrS phenotype of the proband.