Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria.
Division of Medical Genetics, Department of Specialized Medicine, McGill University Hospital Centre, Montreal, QC, Canada.
Genet Med. 2019 Nov;21(11):2521-2531. doi: 10.1038/s41436-019-0532-z. Epub 2019 May 16.
Skeletal muscle growth and regeneration rely on muscle stem cells, called satellite cells. Specific transcription factors, particularly PAX7, are key regulators of the function of these cells. Knockout of this factor in mice leads to poor postnatal survival; however, the consequences of a lack of PAX7 in humans have not been established.
Here, we study five individuals with myopathy of variable severity from four unrelated consanguineous couples. Exome sequencing identified pathogenic variants in the PAX7 gene. Clinical examination, laboratory tests, and muscle biopsies were performed to characterize the disease.
The disease was characterized by hypotonia, ptosis, muscular atrophy, scoliosis, and mildly dysmorphic facial features. The disease spectrum ranged from mild to severe and appears to be progressive. Muscle biopsies showed the presence of atrophic fibers and fibroadipose tissue replacement, with the absence of myofiber necrosis. A lack of PAX7 expression was associated with satellite cell pool exhaustion; however, the presence of residual myoblasts together with regenerating myofibers suggest that a population of PAX7-independent myogenic cells partially contributes to muscle regeneration.
These findings show that biallelic variants in the master transcription factor PAX7 cause a new type of myopathy that specifically affects satellite cell survival.
骨骼肌的生长和再生依赖于肌肉干细胞，也被称为卫星细胞。特定的转录因子，特别是 PAX7，是这些细胞功能的关键调节因子。在小鼠中敲除该因子会导致出生后存活率下降；然而，PAX7 缺乏对人类的影响尚未确定。
在这里，我们研究了来自四个无关近亲家庭的五名具有不同严重程度的肌病患者。外显子组测序鉴定了 PAX7 基因中的致病性变异。进行了临床检查、实验室检查和肌肉活检，以表征该疾病。
该疾病的特征是张力减退、上睑下垂、肌肉萎缩、脊柱侧凸和轻度畸形的面部特征。疾病谱从轻度到重度不等，且似乎呈进行性发展。肌肉活检显示存在萎缩纤维和纤维脂肪组织替代，无肌纤维坏死。缺乏 PAX7 表达与卫星细胞池耗竭有关；然而，存在残余成肌细胞以及再生肌纤维表明，PAX7 非依赖性成肌细胞群体部分有助于肌肉再生。
这些发现表明，主转录因子 PAX7 的双等位基因变异会导致一种新的肌病，该肌病专门影响卫星细胞的存活。
