Sasaki-Honda Mitsuru, Kishimoto Takumi, Sakurai Hidetoshi
Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.
Institute of Biomedicine and Biotechnology of Cantabria, CSIC/University of Cantabria, Santander, Spain.
J Hum Genet. 2025 Sep 16. doi: 10.1038/s10038-025-01401-6.
Facioscapulohumeral muscular dystrophy (FSHD) is a rare genetic disease with an estimated prevalence of no more than 1 in 8000; however, it is among the most common myopathies affecting global populations. This condition is classically categorised into two genetic types, FSHD1 (MIM: 158900) and FSHD2 (MIM: 158901), which, although have different genetic causes, are phenotypically indistinguishable, manifesting as progressive muscle weakness primarily affecting the face and periscapular muscles, as well as other muscle groups in later stages. The intense efforts of clinical and basic studies to understand this disease have revealed the critical necessity for disease manifestation: ectopic activation of the embryogenic and germline gene DUX4 (double homeobox 4, MIM: 606009) in skeletal muscles and the genetic and epigenetic backgrounds allowing DUX4 expression. Thus, the potential target therapies of FSHD include silencing DUX4 transcription or blocking its translation. Although the central role of DUX4 in FSHD pathology has almost reached a consensus, the mechanism of its activation remains largely unclear. Notably, the clinical dissection of genotype-epigenotype-phenotype observations, including non-penetrant and asymptomatic carriers of permissive genetic backgrounds, highlights the yet unsolved clinical diversity with potential additional layers of DUX4 regulation or other disease-modifying factors. This review provides an overview of essential findings with potential implications for further understanding the mechanisms underlying diverse clinical cases of FSHD and endogenous DUX4 activation in FSHD pathology.
面肩肱型肌营养不良症（FSHD）是一种罕见的遗传病，估计患病率不超过八千分之一；然而，它是影响全球人群的最常见的肌病之一。这种疾病传统上分为两种遗传类型，即FSHD1（MIM：158900）和FSHD2（MIM：158901），尽管它们有不同的遗传原因，但在表型上无法区分，表现为进行性肌肉无力，主要影响面部和肩胛周围肌肉，后期也会影响其他肌肉群。临床和基础研究为了解这种疾病付出了巨大努力，揭示了疾病表现的关键必要条件：胚胎发生和种系基因DUX4（双同源盒4，MIM：606009）在骨骼肌中的异位激活以及允许DUX4表达的遗传和表观遗传背景。因此，FSHD的潜在靶向治疗包括使DUX4转录沉默或阻断其翻译。尽管DUX4在FSHD病理中的核心作用几乎已达成共识，但其激活机制仍 largely不清楚。值得注意的是，对基因型 - 表观基因型 - 表型观察的临床剖析，包括具有允许遗传背景的非 penetrant和无症状携带者，突出了尚未解决的临床多样性，可能存在DUX4调节的其他层面或其他疾病修饰因素。本综述概述了一些重要发现，这些发现可能有助于进一步理解FSHD不同临床病例背后的机制以及FSHD病理中内源性DUX4激活的机制。
