变种内置增强器控制SCN10A-short表达和心脏传导
Joyce C K Man1,2, Fernanda M Bosada1,2, Koen T Scholman1,2
1Department of Medical Biology (J.C.K.M., F.M.B., K.T.S., K.v.D., V.W.W.v.E., A.O.V., B.J.B., P.B., V.M.C.), Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands.
Circulation
|April 29, 2021
概括
在SCN10A的基因变异通过改变心脏特异性的短转录影响心律. 这会影响通道功能,影响心房导电和心律失常.
科学领域:
- 心血管遗传学
- 分子心脏病学
- 离子通道生理学
背景情况:
- SCN10A基因变异与心律失常,如心房动和布鲁加达综合征有关.
- SCN10A及其相关通道NaV1. 8的精确心脏功能尚不清楚.
- 本研究研究心脏SCN10A表达和调控增强剂元素的作用.
研究的目的:
- 确定SCN10A的心脏表达模式.
- 阐明调节SCN10A的变异敏感内基增强剂的功能.
- 了解这种增强剂的遗传变异如何影响心脏功能和节律.
主要方法:
- 在小鼠和人类心脏组织中研究了SCN10A表达.
- 使用CRISPR/Cas9来破坏小鼠的内部增强剂,随后进行转录和电生理分析.
- 进行全基因组关联研究和表达定量特征位置分析,以将遗传变异与基因表达联系起来.
主要成果:
- 在心房和结节心肌细胞中鉴定出一种心脏特异性的短SCN10A转录 (Scn10a-short),转录来自内置增强剂促进剂.
- 在小鼠中,增强剂的干扰减少了Scn10a短表达,导致心房导电受损,心律失常以及流变化.
- 增强了NaV1. 5介导的电流,而Scn5a表达没有受到影响.
结论:
- 在SCN10A附近的基因变异调节增强剂活性,控制心脏特异性SCN10A短转录的表达.
- 这种非编码变异影响NaV1.5功能和心电生理学,影响心律失常的易感性.
- 这项研究揭示了一种新的机制,SCN10A变体通过调节心肌细胞中NaV1.8的功能部分来影响心律.
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