Department of Cardiology, the First Affiliated Hospital, Sun Yat-Sen University, and Key Laboratory on Assisted Circulation, NHC, Guangzhou, China.
J Cell Mol Med. 2018 Nov;22(11):5639-5647. doi: 10.1111/jcmm.13839. Epub 2018 Aug 30.
Abnormal cardiac ion channels current, including transient outward potassium current (I ), is associated with early repolarization syndrome (ERS). Previous studies showed that mutations in SCN1Bβ both to increase the I current and to decrease the sodium current. Yet its role in ERS remains unknown.
To determine the role of mutations in the SCN1Bβ subunits in ERS.
We screened for mutations in the SCN1B genes from four families with ERS. Wild-type and mutant SCN1Bβ genes were co-expressed with wild-type KCND3 in human embryonic kidney cells (HEK293). Whole-cell patch-clamp technique and co-immunoprecipitation were used to study the electrophysiological properties and explore the underlying mechanisms.
S248R and R250T mutations in SCN1Bβ were detected in 4 families' probands. Neither S248R nor R250T mutation had significant influence on the sodium channel current density (I ) when co-expressed with SCN5A/WT. Co-expression of KCND3/WT and SCN1Bβ/S248R or SCN1Bβ/R250T increased the transient outward potassium current I by 27.44% and 199.89%, respectively (P < 0.05 and P < 0.01, respectively) when compared with SCN1Bβ/WT. Electrophysiological properties showed that S248R and R250T mutations decreased the steady-state inactivation and recovery from inactivation of I channel. Co-immunoprecipitation study demonstrated an increased association between SCN1Bβ mutations and Kv4.3 compared with SCN1Bβ/WT (P < 0.05 and P < 0.01, respectively).
The S248R and R250T mutations of SCN1Bβ gene caused gain-of-function of I by associated with Kv4.3, which maybe underlie the ERS phenotype of the probands.
异常的心脏离子通道电流，包括瞬时外向钾电流（I ），与早期复极综合征（ERS）有关。先前的研究表明，SCN1Bβ 基因突变既增加了 I 电流，又减少了钠电流。然而，其在 ERS 中的作用尚不清楚。
确定 SCN1Bβ 亚基突变在 ERS 中的作用。
我们从四个 ERS 家族中筛选 SCN1B 基因的突变。野生型和突变型 SCN1Bβ 基因与野生型 KCND3 在人胚肾细胞（HEK293）中共表达。全细胞膜片钳技术和共免疫沉淀用于研究电生理特性并探讨潜在机制。
在 4 个家系的先证者中检测到 SCN1Bβ 的 S248R 和 R250T 突变。当与 SCN5A/WT 共表达时，S248R 或 R250T 突变对钠通道电流密度（I ）均无显著影响。与 SCN1Bβ/WT 相比，KCND3/WT 与 SCN1Bβ/S248R 或 SCN1Bβ/R250T 共表达分别增加了瞬时外向钾电流 I 27.44%和 199.89%（P < 0.05 和 P < 0.01）。电生理特性表明，S248R 和 R250T 突变降低了 I 通道的稳态失活和失活恢复。共免疫沉淀研究表明，与 SCN1Bβ/WT 相比，SCN1Bβ 突变与 Kv4.3 的结合增加（P < 0.05 和 P < 0.01）。
SCN1Bβ 基因突变 S248R 和 R250T 通过与 Kv4.3 相关引起 I 的功能获得，这可能是先证者 ERS 表型的基础。
