Expression defect of the rare variant/Brugada mutation R1512W depends upon the SCN5A splice variant background and can be rescued by mexiletine and the common polymorphism H558R.
Expression defect of the rare variant/Brugada mutation R1512W depends upon the SCN5A splice variant background and can be rescued by mexiletine and the common polymorphism H558R.
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罕见变异/Brugada 突变 R1512W 的表达缺陷取决于 SCN5A 剪接变异背景，可以通过美西律和常见多态性 H558R 来挽救
DOI：
10.1080/19336950.2021.1875645
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Tan BH
中科院分区：
文献类型：
--
作者：
Hu RM;Song EJ;Tester DJ;Deschenes I;Ackerman MJ;Makielski JC;Tan BH
摘要背景：减少钠电流的SCN5A突变是Brugada综合征(BRS)等心律失常综合征的基础。人类的SCN5A有两个剪接变体，一个在1077位缺失谷氨酰胺(Q1077del)，另一个含有Q1077。我们研究了剪接变异背景对R1512W功能丧失和挽救的影响，R1512W是一种据报道导致BRS的突变。方法和结果：我们对两种突变体进行了突变，并在HEK-293细胞中进行了表达，用于电压钳实验。转染24小时后，R1512W在Q1077del和Q1077中的电流表达水平分别比野生型(WT)通道降低约50%。在两种剪接变异背景下，WT通道和突变通道的激活和失活中点没有差异。与WT-Q1077相比，R1512W/Q1077的恢复和中间失活时间常数较慢，而恢复和中间失活参数与WT-Q1077del相似。此外，美西律和常见的多态基因H558R都通过增加细胞表面SCN5A的表达来恢复突变通道的峰值钠电流(INa)幅度。结论：这些发现为剪接变异体影响BRS的分子表型和临床表型提供了进一步的证据，并为BRS的表达缺陷机制和潜在的治疗提供了深入的认识。
ABSTRACT Background : Mutations in SCN5A that decrease Na current underlie arrhythmia syndromes such as the Brugada syndrome (BrS). SCN5A in humans has two splice variants, one lacking a glutamine at position 1077 (Q1077del) and one containing Q1077. We investigated the effect of splice variant background on loss-of-function and rescue for R1512W, a mutation reported to cause BrS. Methods and results : We made the mutation in both variants and expressed them in HEK-293 cells for voltage-clamp study. After 24 hours of transfection, the current expression level of R1512W was reduced by ~50% in both Q1077del and Q1077 compared to the wild-type (WT) channel, respectively. The activation and inactivation midpoint were not different between WT and mutant channels in both splice variant backgrounds. However, slower time constants of recovery and enhanced intermediate inactivation were observed for R1512W/Q1077 compared with WT-Q1077, while the recovery and intermediate inactivation parameters of R1512W/Q1077del were similar to WT-Q1077del. Furthermore, both mexiletine and the common polymorphism H558R restored peak sodium current (I Na) amplitude of the mutant channel by increasing the cell surface expression of SCN5A. Conclusion : These findings provide further evidence that the splice variant affects the molecular phenotype with implications for the clinical phenotype, and they provide insight into the expression defect mechanisms and potential treatment in BrS.
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影响因子：
3.7
作者：
Hu RM;Tan BH;Tester DJ;Song C;He Y;Dovat S;Peterson BZ;Ackerman MJ;Makielski JC
通讯作者：
Makielski JC
DOI：
10.1080/19336950.2018.1475794
发表时间：
2018
期刊：
Channels (Austin, Tex.)
影响因子：
--
作者：
Hu RM;Tester DJ;Li R;Sun T;Peterson BZ;Ackerman MJ;Makielski JC;Tan BH
通讯作者：
Tan BH
影响因子：
5.5
作者：
Shinlapawittayatorn, Krekwit;Du, Xi X.;Liu, Haiyan;Ficker, Eckhard;Kaufman, Elizabeth S.;Deschenes, Isabelle
通讯作者：
Deschenes, Isabelle
影响因子：
5.5
作者：
Hu, Dan;Viskin, Sami;Antzelevitch, Chares
通讯作者：
Antzelevitch, Chares
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G