Lamin variants cause cardiac arrhythmogenicity in Drosophila.

IF 3.3 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2025-07-01 Epub Date: 2025-07-25 DOI:10.1242/dmm.052424
Stan W van Wijk, Puck Vree, Fabries G Huiskes, Reinier L van der Palen, Aiste Liutkute, Niels Voigt, Lori L Wallrath, Bianca J J M Brundel
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引用次数: 0

Abstract

Atrial fibrillation (AF), the most common progressive cardiac arrhythmia, is associated with serious complications such as stroke and heart failure. Although common risk factors underlie AF onset, in 15% of the affected population, AF may have a genetic cause. Here, we investigated how LMNA variants cause cardiac arrhythmicity. Drosophila melanogaster strains were generated possessing the analogous variants in the Drosophila orthologue of human lamin A/C (LMNA), Lamin C (LamC). Heart wall movements in prepupae were recorded before (BTP) and after (ATP) tachypacing. ATP, flies expressing wild-type LamC, and the variants ΔN and p.R205W showed a significant reduction in heart rate (HR), but the arrhythmia index (AI) was not affected, compared to BTP. By contrast, those expressing p.N210K and p.R264Q showed a significant reduction in HR and increased AI, compared to BTP. p.N210K- and p.R264Q-expressing prepupae showed contrasting effects after pharmacological intervention with microtubule stabilizer taxol. Taxol attenuated the arrhythmogenicity in p.N210K-expressing prepupae, but aggravated it in p.R264Q-expressing prepupae. These findings suggest that different lamin variants trigger distinct molecular pathways that drive arrhythmogenic effects in Drosophila.

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纤层蛋白变异引起果蝇心律失常。
房颤(AF)是最常见的进行性心律失常,与中风和心力衰竭等严重并发症有关。虽然共同的危险因素是房颤发病的基础,但在15%的受影响人群中,房颤可能有遗传原因。在这里,我们研究LMNA变异是如何引起心律失常的。由此产生的黑腹果蝇菌株具有与人类LMNA同源的果蝇类似的变体,称为Lamin C (LamC)。分别记录速搏前(BTP)和速搏后(ATP)预蛹的心壁运动。与BTP相比,表达野生型LamC (WT)、ΔN和p.R205W的果蝇心率(HR)ATP显著降低,但心律失常指数(AI)ATP不受影响。与BTP相比,LamC p.N210K和p.R264Q显著降低HRATP,增加AIATP。LamC p.N210K和LamC p.R264Q在微管稳定剂紫杉醇的药物干预后显示出相互矛盾的作用。紫杉醇可减弱LamC p.N210K的致心律失常作用,但可加重p.R264Q的致心律失常作用。研究结果表明,不同的纤层蛋白变体触发不同的分子途径,驱动果蝇的心律失常效应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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