Novel features and mechanisms of congenital myopathies

先天性肌病是骨骼肌的遗传性疾病，通常在出生时或儿童早期出现，其特征是肌肉紧张度差和肌肉无力。这组疾病包括线状肌病、中央核心病、先天性纤维型失调和肌小管肌病。所有这些疾病的特征都是骨骼肌细胞内参与收缩的主要结构——肌节的紊乱。此外，先天性肌病具有与几乎所有肌肉疾病共同的特征，如慢纤维优势和收缩力的改变。我们使用线状肌病作为代表性的先天性肌病来检查肌病之间的共同特征，先天性肌病的特征和线状肌病的特异性。在线状肌病患者中，在编码肌节丝状系统蛋白的五个基因中发现了突变。线状肌病特有的特征是存在称为线状棒的异常肌节结构。我们分析了大量线状肌病患者，这些患者编码纤维蛋白α -骨骼肌动蛋白和原肌球蛋白的基因发生了突变。此外，我们已经建立了线虫性肌病的小鼠模型，并建议建立一个具有新特征的小鼠模型。我们的小鼠模型揭示了一种以前被认为是营养不良症独有的特征，也存在于线状肌病中。对特征良好的患者样本和小鼠模型的综合分析将使我们能够解决关于这种特殊的先天性肌病和一般肌病的长期问题。我们将确定杆状体是如何形成的以及它们的蛋白质组成。特别是我们的小鼠模型将使我们能够解决支持慢肌纤维增加的分子机制以及特定突变对肌肉功能的影响。

Congenital myopathies are inherited diseases of skeletal muscle that typically present at birth or in early childhood and are characterised by poor muscle tone and muscle weakness. This group of disorders includes nemaline myopathy, central core disease, congenital fiber type disproportion, and myotubular myopathy. All of these disorders are characterised by disorganisation of the sarcomere, the major structure within skeletal muscle cells that is involved in contraction. In addition, the congenital myopathies have features in common with virtually all muscle diseases such as slow fibre predominance and alterations in contractile force. We are using nemaline myopathy as a representative congenital myopathy to examine features in common amongst the myopathies, characteristic of the congenital myopathies and specific to nemaline myopathy. In nemaline myopathy patients, mutations have been found in five genes that encode proteins of the filamentous systems of the sarcomere. A feature specific to nemaline myopathy is the presence of abnormal structures of the sarcomere called nemaline rods. We have analysed a large number of nemaline myopathy patients that have mutations in the genes that encode the filament proteins alpha-skeletal actin and tropomyosin. In addition, we have generated mouse models for nemaline myopathy and propose to generate an additional one with novel features. Our mouse model has revealed that a feature previously thought exclusive to dystrophies, is also present in nemaline myopathy. The combined analysis of well-characterised patient samples and mouse models will allow us to address longstanding questions about this particular congenital myopathy and myopathies in general. We will determine how rods form and their protein composition. Our mouse models in particular will allow us to address the molecular mechanisms that underpin the increase in slow twitch fibres and the effects that a particular mutation has on muscle function.