Facioscapulohumeral Muscular Dystrophy
Facioscapulohumeral Muscular Dystrophy
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DOI：
10.1002/cphy.c160039
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发表时间：
2017-10-01
影响因子：
5.8
通讯作者：
Emerson, Charles P., Jr.
中科院分区：
文献类型：
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作者：
DeSimone, Alec M.;Pakula, Anna;Emerson, Charles P., Jr.
面肩肱骨肌营养不良症是一种常见的肌营养不良症，临床表现为面部、肩胛骨和肱骨肌进行性无力，随后累及躯干和下肢。面肩肱骨肌营养不良症（FSHD）通常为常染色体显性遗传，但其复杂的遗传和表观遗传病因直到最近才被很好地描述。这种疾病最常见的形式是FSHD1，它与位于容许性4qA染色体上的D4Z4微卫星重复序列的收缩有关。D4Z4收缩允许阵列以及周围4q35区域的表观遗传抑制，从而导致骨骼肌中D4Z4末端重复序列编码的有毒DUX4转录因子的错误表达。FSHD2是一种不太常见的疾病，它是由携带一个允许的4qA等位基因的个体的SMCHD1基因单倍不足引起的，也导致DUX4的抑制，进一步支持DUX4的核心作用。DUX4错误表达如何导致FSHD肌肉病理是当前研究的主要焦点。在4q35位点的其他基因（包括FRG1和FAT1）和非连锁基因（如SMCHD1）的错误表达也被认为是疾病修饰因子，导致几种相互竞争的疾病模型。在这篇综述中，我们描述了FSHD病理生理学的最新进展，包括MRI作为研究和诊断工具的应用，与该疾病相关的遗传和表观遗传破坏，以及FSHD的分子基础。我们讨论了这些进展如何导致新方法的出现，从而使FSHD治疗方法的发展成为可能。(C) 2017年美国生理学会。
Facioscapulohumeral Muscular Dystrophy is a common form of muscular dystrophy that presents clinically with progressive weakness of the facial, scapular, and humeral muscles, with later involvement of the trunk and lower extremities. While typically inherited as autosomal dominant, facioscapulohumeral muscular dystrophy (FSHD) has a complex genetic and epigenetic etiology that has only recently been well described. The most prevalent form of the disease, FSHD1, is associated with the contraction of the D4Z4 microsatellite repeat array located on a permissive 4qA chromosome. D4Z4 contraction allows epigenetic derepression of the array, and possibly the surrounding 4q35 region, allowing misexpression of the toxic DUX4 transcription factor encoded within the terminal D4Z4 repeat in skeletal muscles. The less common form of the disease, FSHD2, results from haploinsufficiency of the SMCHD1 gene in individuals carrying a permissive 4qA allele, also leading to the derepression of DUX4, further supporting a central role for DUX4. How DUX4 misexpression contributes to FSHD muscle pathology is a major focus of current investigation. Misexpression of other genes at the 4q35 locus, including FRG1 and FAT1, and unlinked genes, such as SMCHD1, has also been implicated as disease modifiers, leading to several competing disease models. In this review, we describe recent advances in understanding the pathophysiology of FSHD, including the application of MRI as a research and diagnostic tool, the genetic and epigenetic disruptions associated with the disease, and the molecular basis of FSHD. We discuss how these advances are leading to the emergence of new approaches to enable development of FSHD therapeutics. (C) 2017 American Physiological Society.