Department of Human Genetics Leiden University Medical Centre, Leiden, The Netherlands.
Department of Neurology Leiden University Medical Centre, Leiden, The Netherlands.
PLoS One. 2018 May 15;13(5):e0197388. doi: 10.1371/journal.pone.0197388. eCollection 2018.
Merosin deficient congenital muscular dystrophy 1A (MDC1A) is a very rare autosomal recessive disorder caused by mutations in the LAMA2 gene leading to severe and progressive muscle weakness and atrophy. Although over 350 causative mutations have been identified for MDC1A, no treatment is yet available. There are many therapeutic approaches in development, but the lack of natural history data of the mouse model and standardized outcome measures makes it difficult to transit these pre-clinical findings to clinical trials. Therefore, in the present study, we collected natural history data and assessed pre-clinical outcome measures for the dy2J/dy2J mouse model using standardized operating procedures available from the TREAT-NMD Alliance. Wild type and dy2J/dy2J mice were subjected to five different functional tests from the age of four to 32 weeks. Non-tested control groups were taken along to assess whether the functional test regime interfered with muscle pathology. Respiratory function, body weights and creatine kinase levels were recorded. Lastly, skeletal muscles were collected for further histopathological and gene expression analyses. Muscle function of dy2J/dy2J mice was severely impaired at four weeks of age and all mice lost the ability to use their hind limbs. Moreover, respiratory function was altered in dy2J/dy2J mice. Interestingly, the respiration rate was decreased and declined with age, whereas the respiration amplitude was increased in dy2J/dy2J mice when compared to wild type mice. Creatine kinase levels were comparable to wild type mice. Muscle histopathology and gene expression analysis revealed that there was a specific regional distribution pattern of muscle damage in dy2J/dy2J mice. Gastrocnemius appeared to be the most severely affected muscle with a high proportion of atrophic fibers, increased fibrosis and inflammation. By contrast, triceps was affected moderately and diaphragm only mildly. Our study presents a complete natural history dataset which can be used in setting up standardized studies in dy2J/dy2J mice.
先天性肌营养不良症 1A（MDC1A）是一种非常罕见的常染色体隐性疾病，由 LAMA2 基因突变引起，导致严重且进行性的肌肉无力和萎缩。尽管已经确定了超过 350 种导致 MDC1A 的致病突变，但目前尚无治疗方法。有许多治疗方法正在开发中，但由于缺乏小鼠模型的自然病史数据和标准化的结果测量方法，使得这些临床前发现难以转化为临床试验。因此，在本研究中，我们收集了自然病史数据，并使用 TREAT-NMD 联盟提供的标准化操作程序评估了 dy2J/dy2J 小鼠模型的临床前结果测量方法。野生型和 dy2J/dy2J 小鼠从 4 到 32 周龄时接受了五种不同的功能测试。同时设立了非测试对照组，以评估功能测试方案是否会干扰肌肉病理学。记录了呼吸功能、体重和肌酸激酶水平。最后，收集了骨骼肌进行进一步的组织病理学和基因表达分析。dy2J/dy2J 小鼠的肌肉功能在 4 周龄时严重受损，所有小鼠都丧失了使用后腿的能力。此外，dy2J/dy2J 小鼠的呼吸功能也发生了改变。有趣的是，与野生型小鼠相比，dy2J/dy2J 小鼠的呼吸频率降低且随年龄增长而下降，而呼吸幅度增加。肌酸激酶水平与野生型小鼠相当。肌肉组织病理学和基因表达分析显示，dy2J/dy2J 小鼠的肌肉损伤具有特定的区域性分布模式。比目鱼肌似乎是受影响最严重的肌肉，存在大量萎缩纤维、纤维化和炎症增加。相比之下，三头肌中度受累，膈肌仅轻度受累。我们的研究提供了一个完整的自然病史数据集，可用于在 dy2J/dy2J 小鼠中建立标准化研究。
