与家族性室上性心动过速和沃尔夫-帕金森-怀特综合征有关的 MRC2 罕见变体

IF 6 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Adam S Potter, Christina Y Miyake, Claudia Gonzaga-Jauregui, Yuriana Aguilar-Sanchez, Mohit M Hulsurkar, Satadru K Lahiri, Lucia M Moreira, Neelam Mehta, Mahshid S Azamian, James R Lupski, Svetlana Reilly, Seema R Lalani, Xander H T Wehrens
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引用次数: 0

摘要

背景:辅助通路是室上性心动过速(SVT)的常见病因,当与沃尔夫-帕金森-怀特综合征(Wolff-Parkinson-White syndrome)并发时,可导致原本健康的儿童和成人发生心脏性猝死。本研究的目的是在一个受 SVT 和沃尔夫-帕金森-怀特综合征影响的心脏结构正常的大家族中鉴定基因变异,并在相应的小鼠模型中确定基因缺失的因果关系:在一个三代同堂的家族中,有多名成员受 SVT 或心电图上的 Wolff-Parkinson-White 模式(预激)影响,对该家族的两名远亲进行了全外显子组测序,发现 MRC2 是一个候选基因。对Mrc2突变小鼠和WT(野生型)小鼠进行了连续心电图、心内电生理学研究、超声心动图、光学图谱研究和组织学研究:结果:MRC2 中的一个罕见的 HET(杂合子)错义变异 c.2969A>G;p.Glu990Gly (E990G) 被确定为主要的候选基因变异,该变异与心脏表型的分离遵循常染色体显性孟德尔性状分离模式,具有不同的表达性。体内电生理学研究显示,E990G 小鼠存在再发性室上性心动过速。在 E990G 小鼠体内进行的光学图谱研究显示,逆行传导异常,表明存在一条辅助通路。对 E990G 小鼠心脏的组织学分析表明,纤维环的 ECM(细胞外基质)紊乱。最后,人心脏成纤维细胞中的Mrc2基因敲除增强了细胞的加速迁移:本研究发现,在家族性再发性室上性心动过速、沃尔夫-帕金森-怀特心电图模式和心脏结构正常的个体中,MRC2 基因存在罕见的非同义变异。此外,MRC2基因敲入小鼠显示,在心脏结构和功能保留的情况下,再发性室上性心动过速和旁路束形成的发生率增加。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Rare Variant in MRC2 Associated With Familial Supraventricular Tachycardia and Wolff-Parkinson-White Syndrome.

Background: Accessory pathways are a common cause of supraventricular tachycardia (SVT) and can lead to sudden cardiac death in otherwise healthy children and adults when associated with Wolff-Parkinson-White syndrome. The goal of this study was to identify genetic variants within a large family with structurally normal hearts affected by SVT and Wolff-Parkinson-White syndrome and determine causality of the gene deficit in a corresponding mouse model.

Methods: Whole exome sequencing performed on 2 distant members of a 3-generation family in which multiple members were affected by SVT or Wolff-Parkinson-White pattern (preexcitation) on ECG identified MRC2 as a candidate gene. Serial electrocardiograms, intracardiac electrophysiology studies, echocardiography, optical mapping studies, and histology were performed on both Mrc2 mutant and WT (wild-type) mice.

Results: A rare HET (heterozygous) missense variant c.2969A>G;p.Glu990Gly (E990G) in MRC2 was identified as the leading candidate gene variant segregating with the cardiac phenotype following an autosomal-dominant Mendelian trait segregation pattern with variable expressivity. In vivo electrophysiology studies revealed reentrant SVT in E990G mice. Optical mapping studies in E990G mice demonstrated abnormal retrograde conduction, suggesting the presence of an accessory pathway. Histological analysis of E990G mouse hearts showed a disordered ECM (extracellular matrix) in the annulus fibrosus. Finally, Mrc2 knockdown in human cardiac fibroblasts enhanced accelerated cell migration.

Conclusions: This study identified a rare nonsynonymous variant in the MRC2 gene in individuals with familial reentrant SVT, Wolff-Parkinson-White ECG pattern, and structurally normal hearts. Furthermore, Mrc2 knock-in mice revealed an increased incidence of reentrant SVT and bypass tract formation in the setting of preserved cardiac structure and function.

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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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