Randall Centre for Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, United Kingdom.
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525 GA, The Netherlands.
Hum Mol Genet. 2024 Jan 7;33(2):182-197. doi: 10.1093/hmg/ddad175.
Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable myopathy. FSHD is highly heterogeneous, with patients following a variety of clinical trajectories, complicating clinical trials. Skeletal muscle in FSHD undergoes fibrosis and fatty replacement that can be accelerated by inflammation, adding to heterogeneity. Well controlled molecular studies are thus essential to both categorize FSHD patients into distinct subtypes and understand pathomechanisms. Here, we further analyzed RNA-sequencing data from 24 FSHD patients, each of whom donated a biopsy from both a non-inflamed (TIRM-) and inflamed (TIRM+) muscle, and 15 FSHD patients who donated peripheral blood mononucleated cells (PBMCs), alongside non-affected control individuals. Differential gene expression analysis identified suppression of mitochondrial biogenesis and up-regulation of fibroadipogenic progenitor (FAP) gene expression in FSHD muscle, which was particularly marked on inflamed samples. PBMCs demonstrated suppression of antigen presentation in FSHD. Gene expression deconvolution revealed FAP expansion as a consistent feature of FSHD muscle, via meta-analysis of 7 independent transcriptomic datasets. Clustering of muscle biopsies separated patients in an unbiased manner into clinically mild and severe subtypes, independently of known disease modifiers (age, sex, D4Z4 repeat length). Lastly, the first genome-wide analysis of alternative splicing in FSHD muscle revealed perturbation of autophagy, BMP2 and HMGB1 signalling. Overall, our findings reveal molecular subtypes of FSHD with clinical relevance and identify novel pathomechanisms for this highly heterogeneous condition.
面肩肱型肌营养不良症（FSHD）是一种常见的、无法治愈的肌病。FSHD 高度异质性，患者具有多种临床轨迹，使临床试验复杂化。FSHD 中的骨骼肌发生纤维化和脂肪替代，炎症可加速这一过程，增加异质性。因此，进行严格控制的分子研究对于将 FSHD 患者分为不同亚型以及了解病理机制至关重要。在这里，我们进一步分析了 24 名 FSHD 患者的 RNA 测序数据，每位患者都捐赠了非炎症（TIRM-）和炎症（TIRM+）肌肉的活检，以及 15 名 FSHD 患者的外周血单核细胞（PBMC），以及非受影响的对照个体。差异基因表达分析确定了 FSHD 肌肉中线粒体生物发生的抑制和纤维脂肪祖细胞（FAP）基因表达的上调，在炎症样本中尤为明显。FSHD 的 PBMC 表现出抗原呈递的抑制。通过对 7 个独立转录组数据集的荟萃分析，发现基因表达去卷积揭示了 FAP 的扩张是 FSHD 肌肉的一个一致特征。肌肉活检的聚类以无偏倚的方式将患者分为临床轻度和重度亚型，与已知的疾病修饰因子（年龄、性别、D4Z4 重复长度）无关。最后，对 FSHD 肌肉中可变剪接的全基因组分析揭示了自噬、BMP2 和 HMGB1 信号通路的扰动。总的来说，我们的研究结果揭示了具有临床相关性的 FSHD 分子亚型，并确定了这种高度异质性疾病的新病理机制。
