外显子 52 至 55 缺失的贝克尔肌肉营养不良症新型小鼠模型的生成和特征描述。

IF 4 3区 医学 Q2 CELL BIOLOGY
Lucie O M Perillat, Tatianna W Y Wong, Eleonora Maino, Abdalla Ahmed, Ori Scott, Elzbieta Hyatt, Paul Delgado-Olguin, Shagana Visuvanathan, Evgueni A Ivakine, Ronald D Cohn
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引用次数: 0

摘要

贝克尔肌肉萎缩症(BMD)是一种罕见的 X 连锁隐性神经肌肉疾病,常因 DMD 基因中的框架内缺失导致产生截短但功能正常的肌营养不良蛋白而引起。导致 BMD 的框架内缺失对机体的影响很难预测,尤其是在长期预后方面。在这里,我们采用 CRISPR-Cas9 技术,通过缺失 52-55 号外显子产生了一种新的 Dmd del52-55 小鼠模型,从而导致类似 BMD 的框架内缺失。为了明确这种缺失的长期影响,我们对这些小鼠进行了长达 52 周的研究,包括进行组织学和超声心动图分析以及评估运动功能。我们的研究结果表明,在幼年小鼠体内,截短的肌营养不良蛋白足以维持野生型的肌肉和心脏组织学及功能。然而,截短蛋白似乎不足以维持正常的肌肉稳态,也不足以在52周时保护小鼠免受运动引起的损伤。为了进一步阐明这种外显子52-55框内缺失的影响,我们在运动前和运动后进行了RNA-Seq分析,发现了几种不同的表达途径,它们反映了在BMD模型中52周时观察到的异常肌肉表型。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Generation and characterization of a novel mouse model of Becker Muscular Dystrophy with a deletion of exons 52 to 55.

Becker Muscular Dystrophy (BMD) is a rare X-linked recessive neuromuscular disorder frequently caused by in-frame deletions in the DMD gene that result in the production of a truncated, yet functional, dystrophin protein. The consequences of BMD-causing in-frame deletions on the organism are difficult to predict, especially in regard to long-term prognosis. Here, we employed CRISPR-Cas9 to generate a new Dmd del52-55 mouse model by deleting exons 52-55, resulting in a BMD-like in-frame deletion. To delineate the long-term effects of this deletion, we studied these mice over 52 weeks by performing histology and echocardiography analyses and assessing motor functions. Our results suggest that a truncated dystrophin is sufficient to maintain wildtype-like muscle and heart histology and functions in young mice. However, the truncated protein appears insufficient to maintain normal muscle homeostasis and protect against exercise-induced damage at 52 weeks. To further delineate the effects of this exon52-55 in-frame deletion, we performed RNA-Seq pre- and post-exercise and identified several differentially expressed pathways that reflect the abnormal muscle phenotype observed at 52 weeks in the BMD model.

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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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