Centre for Medical Research, The University of Western Australia, Western Australian Institute for Medical Research, Nedlands, Australia.
PLoS One. 2011;6(12):e28699. doi: 10.1371/journal.pone.0028699. Epub 2011 Dec 9.
Mutations in the skeletal muscle α-actin gene (ACTA1) cause congenital myopathies including nemaline myopathy, actin aggregate myopathy and rod-core disease. The majority of patients with ACTA1 mutations have severe hypotonia and do not survive beyond the age of one. A transgenic mouse model was generated expressing an autosomal dominant mutant (D286G) of ACTA1 (identified in a severe nemaline myopathy patient) fused with EGFP. Nemaline bodies were observed in multiple skeletal muscles, with serial sections showing these correlated to aggregates of the mutant skeletal muscle α-actin-EGFP. Isolated extensor digitorum longus and soleus muscles were significantly weaker than wild-type (WT) muscle at 4 weeks of age, coinciding with the peak in structural lesions. These 4 week-old mice were ~30% less active on voluntary running wheels than WT mice. The α-actin-EGFP protein clearly demonstrated that the transgene was expressed equally in all myosin heavy chain (MHC) fibre types during the early postnatal period, but subsequently became largely confined to MHCIIB fibres. Ringbinden fibres, internal nuclei and myofibrillar myopathy pathologies, not typical features in nemaline myopathy or patients with ACTA1 mutations, were frequently observed. Ringbinden were found in fast fibre predominant muscles of adult mice and were exclusively MHCIIB-positive fibres. Thus, this mouse model presents a reliable model for the investigation of the pathobiology of nemaline body formation and muscle weakness and for evaluation of potential therapeutic interventions. The occurrence of core-like regions, internal nuclei and ringbinden will allow analysis of the mechanisms underlying these lesions. The occurrence of ringbinden and features of myofibrillar myopathy in this mouse model of ACTA1 disease suggests that patients with these pathologies and no genetic explanation should be screened for ACTA1 mutations.
骨骼肌α-肌动蛋白基因（ACTA1）突变可导致先天性肌病，包括杆状体肌病、肌动蛋白聚集性肌病和杆-核病。大多数 ACTA1 突变患者存在严重的低张力，且无法存活至 1 岁以上。本研究构建了一个表达常染色体显性突变（在严重杆状体肌病患者中发现的 D286G）的转基因小鼠模型，突变的骨骼肌α-肌动蛋白与 EGFP 融合表达。在多种骨骼肌中观察到杆状体，连续切片显示这些杆状体与突变的骨骼肌α-肌动蛋白-EGFP 聚集有关。在 4 周龄时，与野生型（WT）肌肉相比，分离的趾长伸肌和比目鱼肌明显较弱，这与结构病变的高峰期一致。这些 4 周龄的小鼠在自愿跑轮上的活动量比 WT 小鼠低约 30%。α-肌动蛋白-EGFP 蛋白清楚地表明，在出生后早期，转基因在所有肌球蛋白重链（MHC）纤维类型中表达均等，但随后主要局限于 MHCIIB 纤维。环状纤维、内部核和肌原纤维肌病病理学，这些不是杆状体肌病或 ACTA1 突变患者的典型特征，经常被观察到。在成年小鼠的快肌纤维占主导的肌肉中发现了环状纤维，且这些纤维均为 MHCIIB 阳性纤维。因此，该小鼠模型为研究杆状体形成和肌肉无力的病理生物学以及评估潜在治疗干预措施提供了一个可靠的模型。核心样区域、内部核和环状纤维的出现将允许分析这些病变的潜在机制。在 ACTA1 疾病的小鼠模型中，环状纤维和肌原纤维肌病的出现表明，具有这些病变且无遗传解释的患者应筛查 ACTA1 突变。
