Common SYNE2 Genetic Variant Associated With Atrial Fibrillation Lowers Expression of Nesprin-2α1 With Downstream Effects on Nuclear and Electrophysiological Traits.

IF 6 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation: Genomic and Precision Medicine Pub Date : 2024-10-01 Epub Date: 2024-10-02 DOI:10.1161/CIRCGEN.124.004750
Nana Liu, Jeffrey Hsu, Gautam Mahajan, Han Sun, Kenneth R Laurita, Sathyamangla V Naga Prasad, John Barnard, David R Van Wagoner, Chandrasekhar R Kothapalli, Mina K Chung, Jonathan D Smith
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Abstract

Background: Atrial fibrillation GWAS (genome-wide association studies) identified significant associations for rs1152591 and linked variants in the SYNE2 gene encoding Nesprin-2, which connects the nuclear membrane with the cytoskeleton.

Methods: Reporter gene vector transfection and CRISPR-Cas9 editing were used to identify the causal variant regulating the expression of SYNE2α1. After SYNE2 knockdown or SYNE2α1 overexpression in human stem cell-derived cardiomyocytes, nuclear phenotypes were assessed by imaging and atomic force microscopy. Gene expression was assessed by RNAseq and gene set enrichment analysis. Fura-2 AM staining assessed calcium transients. Optical mapping assessed action potential duration and conduction velocity.

Results: The risk allele of rs1152591 had lower promoter and enhancer activity and was significantly associated with lower expression of the short SYNE2α1 isoform in human stem cell-derived cardiomyocytes, without an effect on the expression of the full-length SYNE2 mRNA. SYNE2α1 overexpression had dominant negative effects on the nucleus with its overexpression or SYNE2 knockdown leading to increased nuclear area and decreased nuclear stiffness. Gene expression results from SYNE2α1 overexpression demonstrated both concordant and nonconcordant effects with SYNE2 knockdown. SYNE2α1 overexpression had a gain of function on electrophysiology, leading to significantly faster calcium reuptake and decreased assessed action potential duration, while SYNE2 knockdown showed both shortened assessed action potential duration and decreased conduction velocity.

Conclusions: rs1152591 was identified as a causal atrial fibrillation variant, with the risk allele decreasing SYNE2α1 expression. Downstream effects of SYNE2α1 overexpression include changes in nuclear stiffness and electrophysiology, which may contribute to the mechanism for the risk allele's association with AF.

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与心房颤动有关的常见 SYNE2 基因变异会降低 Nesprin-2α1 的表达,并对核和电生理特征产生下游影响。
背景:心房颤动全基因组关联研究(GWAS)发现rs1152591与编码Nesprin-2的SYNE2基因中的相关变异有显著关联,Nesprin-2连接核膜与细胞骨架:方法:利用报告基因载体转染和CRISPR-Cas9编辑来确定调节SYNE2α1表达的因果变异。在人类干细胞衍生的心肌细胞中敲除SYNE2或过表达SYNE2α1后,通过成像和原子力显微镜评估核表型。基因表达通过 RNAseq 和基因组富集分析进行评估。Fura-2 AM 染色评估钙瞬态。光学绘图评估了动作电位持续时间和传导速度:结果:rs1152591的风险等位基因具有较低的启动子和增强子活性,与人干细胞衍生心肌细胞中较低的短SYNE2α1异构体表达显著相关,但对全长SYNE2 mRNA的表达没有影响。SYNE2α1的过表达对细胞核有显性负效应,其过表达或SYNE2基因敲除会导致核面积增加和核硬度降低。SYNE2α1过表达的基因表达结果表明,与SYNE2基因敲除的效应既有一致的,也有不一致的。SYNE2α1过表达对电生理学有增益作用,导致钙再摄取明显加快,评估的动作电位持续时间缩短,而SYNE2敲除则显示评估的动作电位持续时间缩短,传导速度降低。SYNE2α1过表达的下游效应包括核僵化和电生理学的变化,这可能是风险等位基因与心房颤动相关的机制。
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来源期刊
Circulation: Genomic and Precision Medicine
Circulation: Genomic and Precision Medicine Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
9.20
自引率
5.40%
发文量
144
期刊介绍: Circulation: Genomic and Precision Medicine is a distinguished journal dedicated to advancing the frontiers of cardiovascular genomics and precision medicine. It publishes a diverse array of original research articles that delve into the genetic and molecular underpinnings of cardiovascular diseases. The journal's scope is broad, encompassing studies from human subjects to laboratory models, and from in vitro experiments to computational simulations. Circulation: Genomic and Precision Medicine is committed to publishing studies that have direct relevance to human cardiovascular biology and disease, with the ultimate goal of improving patient care and outcomes. The journal serves as a platform for researchers to share their groundbreaking work, fostering collaboration and innovation in the field of cardiovascular genomics and precision medicine.
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