尽管在过去的几十年中,面肩肱骨营养不良(FSHD)的病理生理学一直存在争议,近年来的进展导致了一个模型,该模型融合了这几十年的发现,并在FSHD研究界获得了普遍接受。在这里,我们回顾了多年来许多实验室的贡献如何导致对人类疾病的一种全新机制的理解。FSHD是由4号染色体上D4Z4大卫星重复序列的低效重复介导的表观遗传抑制引起的,导致DUX4逆转录基因的多样化表达,编码双同源盒转录因子,骨骼肌。通常在睾丸中表达,在体细胞组织中被表观抑制,DUX4在骨骼肌中的表达诱导许多种系的表达,干细胞,和其他可能解释FSHD病理生理学的基因。尽管在机制细节方面仍然存在一些分歧,病理生理学中心模型的合并协议代表了FSHD研究的支点,将该领域从以发现为导向的研究过渡到旨在开发基于疾病病理生理学健全模型的疗法的转化研究。
Although the pathophysiology of facioscapulohumeral dystrophy (FSHD) has been controversial over the last decades, progress in recent years has led to a model that incorporates these decades of findings and is gaining general acceptance in the FSHD research community. Here we review how the contributions from many labs over many years led to an understanding of a fundamentally new mechanism of human disease. FSHD is caused by inefficient repeat-mediated
epigenetic repression of the D4Z4 macrosatellite repeat array on chromosome 4, resulting in the variegated expression of the DUX4 retrogene, encoding a double-homeobox transcription factor, in skeletal muscle. Normally expressed in the testis and epigenetically repressed in somatic tissues, DUX4 expression in skeletal muscle induces expression of many germline, stem cell, and other genes that might account for the pathophysiology of FSHD. Although some disagreements regarding the details of mechanisms remain in the field, the coalescing agreement on a central model of pathophysiology represents a pivot-point in FSHD research, transitioning the field from discovery-oriented studies to translational studies aimed at developing therapies based on a sound model of disease pathophysiology.