2016年5月
SCN5A(K817E), a novel Brugada syndrome-associated mutation that alters the activation gating of NaV1.5 channel.
Heart Rhythm
- 巻
- 13
- 号
- 5
- 開始ページ
- 1113
- 終了ページ
- 1120
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1016/j.hrthm.2016.01.008
- 出版者・発行元
- ELSEVIER SCIENCE INC
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.
- リンク情報
- ID情報
-
- DOI : 10.1016/j.hrthm.2016.01.008
- ISSN : 1547-5271
- eISSN : 1556-3871
- PubMed ID : 26776555
- Web of Science ID : WOS:000375466200022