Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Experimental Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Clin Genet. 2020 Jun;97(6):799-814. doi: 10.1111/cge.13726. Epub 2020 Mar 4.
Facioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is caused either by the contraction of the D4Z4 macrosatellite repeat at the distal end of chromosome 4q to a size of 1 to 10 repeat units (FSHD1) or by mutations in D4Z4 chromatin modifiers such as Structural Maintenance of Chromosomes Hinge Domain Containing 1 (FSHD2). These two genotypes share a phenotype characterized by progressive and often asymmetric muscle weakening and atrophy, and common epigenetic alterations of the D4Z4 repeat. All together, these epigenetic changes converge the two genetic forms into one disease and explain the derepression of the DUX4 gene, which is otherwise kept epigenetically silent in skeletal muscle. DUX4 is consistently transcriptionally upregulated in FSHD1 and FSHD2 skeletal muscle cells where it is believed to exercise a toxic effect. Here we provide a review of the recent literature describing the progress in understanding the complex genetic and epigenetic architecture of FSHD, with a focus on one of the consequences that these epigenetic changes inflict, the DUX4-induced immune deregulation cascade. Moreover, we review the latest therapeutic strategies, with particular attention to the potential of epigenetic correction of the FSHD locus.
面肩肱型肌营养不良症（FSHD）是一种常见的遗传性肌病，由染色体 4q 末端的 D4Z4 大片段重复收缩至 1 至 10 个重复单位（FSHD1）引起，或由 D4Z4 染色质修饰物（如结构维持染色体铰链域包含 1（FSHD2））突变引起。这两种基因型具有相同的表型特征，表现为进行性和常不对称性肌肉无力和萎缩，以及 D4Z4 重复的常见表观遗传改变。总的来说，这些表观遗传变化将两种遗传形式归结为一种疾病，并解释了 DUX4 基因的去抑制，否则 DUX4 基因在骨骼肌中保持着表观遗传沉默。在 FSHD1 和 FSHD2 骨骼肌细胞中，DUX4 始终被转录上调，人们认为它具有毒性作用。本文综述了近年来关于 FSHD 复杂遗传和表观遗传结构的研究进展，重点介绍了这些表观遗传变化造成的后果之一，即 DUX4 诱导的免疫失调级联反应。此外，我们还综述了最新的治疗策略，特别关注 FSHD 基因座的表观遗传矫正的潜力。
