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.

中文翻译：

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面肩肱型肌营养不良症的细胞和动物模型。

面肩肱型肌营养不良症 (FSHD) 是肌营养不良症最常见的形式之一，表现为面部、肩胛骨和肱骨肌肉无力，经常发展到下肢和躯干区域，导致严重残疾。肌病是由4 号染色体上D4Z4微卫星重复阵列的表观遗传去抑制引起的，这允许发育调节的DUX4基因的错误表达。DUX4 在骨骼肌中错误表达时会产生毒性，并会破坏多种细胞通路，包括肌源性分化和融合，这可能是病理学的基础。DUX4和D4Z4阵列仅在灵长类动物中高度保守，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镶嵌表达模式进一步使体外和体内的产生复杂化。FSHD 模型。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，很难设计一个准确概括人类疾病各个方面的系统。尽管如此，在过去的几年里，出现了许多新的疾病模型，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，我们回顾了广泛的 FSHD 模型，包括几个体外细胞模型，以及一系列体内转基因和异种移植 模型，特别关注新开发的系统以及如何使用它们来加深我们对 FSHD 病理学的理解并测试候选药物的功效。