Cellular and animal models for facioscapulohumeral muscular dystrophy.
Cellular and animal models for facioscapulohumeral muscular dystrophy.
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DOI：
10.1242/dmm.046904
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发表时间：
2020-10-28
影响因子：
4.3
通讯作者：
Lek A
中科院分区：
文献类型：
--
作者：
DeSimone AM;Cohen J;Lek M;Lek A
面肩肱骨肌营养不良症（FSHD）是最常见的肌肉营养不良症之一，表现为面部、肩胛骨和肱骨肌肉无力，经常进展到下肢和躯干区域，造成严重的残疾。肌病是由4号染色体上D4Z4微卫星重复序列的表观遗传去抑制引起的，这使得发育调节的DUX4基因错误表达。当DUX4在骨骼肌中错误表达时是有毒的，并破坏几种细胞通路，包括肌源性分化和融合，这可能是病理学的基础。DUX4和D4Z4序列仅在灵长类动物中是强保守的，这使得非灵长类动物的FSHD建模变得困难。此外，其细胞毒性和不寻常的马赛克表达模式进一步复杂化了FSHD体外和体内模型的生成。然而，迫切需要开发系统来测试治疗方法，这导致了多种工程FSHD模型的创建。由于FSHD背后复杂的遗传、表观遗传和分子因素，很难设计出一个准确概括人类疾病各个方面的系统。然而，在过去的几年里，我们看到了许多新的疾病模型的发展，每个模型都有自己的相关优势，强调疾病的不同方面。在这里，我们回顾了各种各样的FSHD模型，包括几种体外细胞模型，以及一系列转基因和异种移植体内模型，特别关注新开发的系统，以及它们如何用于加深我们对FSHD病理的理解和测试候选药物的功效。摘要：由于其复杂的病因和DUX4的毒性，面部肩胛肱肌营养不良（FSHD）的建模具有独特的挑战性。在这里，我们回顾了克服这些困难来开发高度相关的FSHD模型的方法。
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy and presents with weakness of the facial, scapular and humeral muscles, which frequently progresses to the lower limbs and truncal areas, causing profound disability. Myopathy results from epigenetic de-repression of the D4Z4 microsatellite repeat array on chromosome 4, which allows misexpression of the developmentally regulated DUX4 gene. DUX4 is toxic when misexpressed in skeletal muscle and disrupts several cellular pathways, including myogenic differentiation and fusion, which likely underpins pathology. DUX4 and the D4Z4 array are strongly conserved only in primates, making FSHD modeling in non-primate animals difficult. Additionally, its cytotoxicity and unusual mosaic expression pattern further complicate the generation of in vitro and in vivo models of FSHD. However, the pressing need to develop systems to test therapeutic approaches has led to the creation of multiple engineered FSHD models. Owing to the complex genetic, epigenetic and molecular factors underlying FSHD, it is difficult to engineer a system that accurately recapitulates every aspect of the human disease. Nevertheless, the past several years have seen the development of many new disease models, each with their own associated strengths that emphasize different aspects of the disease. Here, we review the wide range of FSHD models, including several in vitro cellular models, and an array of transgenic and xenograft in vivo models, with particular attention to newly developed systems and how they are being used to deepen our understanding of FSHD pathology and to test the efficacy of drug candidates. Summary: Owing to its complex etiology and the toxicity of DUX4, modeling facioscapulohumeral muscular dystrophy (FSHD) is uniquely challenging. Here, we review the approaches that overcame these difficulties to develop highly relevant FSHD models.
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DOI：
10.1038/mt.2016.111
发表时间：
2016-08
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
通讯作者：
--
影响因子：
16.6
作者：
Banerji CRS;Panamarova M;Hebaishi H;White RB;Relaix F;Severini S;Zammit PS
通讯作者：
Zammit PS
影响因子：
3.4
作者：
Celegato, Barbara;Capitanio, Daniele;Gelfi, Cecilia
通讯作者：
Gelfi, Cecilia
影响因子：
3.9
作者：
Banerji, Christopher R. S.;Knopp, Paul;Zammit, Peter S.
通讯作者：
Zammit, Peter S.
影响因子：
3.7
作者：
Chen, Steven C.;Frett, Ellie;Kennedy, Brian K.
通讯作者：
Kennedy, Brian K.