Novel features and mechanisms of congenital myopathies

先天性肌病的新特征和机制

• 批准号: nhmrc : 321701
• 负责人: Prof Edna Hardeman
• 金额: $ 30.97万
• 依托单位: Children's Medical Research Institute
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2005
• 资助国家: 澳大利亚
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/novel-features-mechanisms-congenital-myopathies/100333
• 关键词: Novel; features; mechanisms; congenital; myopathies

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.

先天性肌病是骨骼肌的遗传性疾病，通常在出生时或幼儿期出现，其特征是肌张力差和肌无力。这组疾病包括线状体肌病、中央核疾病、先天性纤维类型不称和肌管性肌病。所有这些疾病的特征是肌节的解体，肌节是骨骼肌细胞内参与收缩的主要结构。此外，先天性肌病具有与几乎所有肌肉疾病共同的特征，例如慢纤维优势和收缩力的改变。我们使用线状体肌病作为代表性的先天性肌病，以检查肌病中的共同特征，先天性肌病的特征和线状体肌病的特异性。在线虫性肌病患者中，已发现编码肌节丝状系统蛋白质的五个基因发生突变。线虫性肌病的一个特征是肌节中存在称为线虫杆的异常结构。我们分析了大量编码细丝蛋白α-骨骼肌动蛋白和原肌球蛋白的基因发生突变的线状肌病患者。此外，我们还生成了线状肌病的小鼠模型，并建议生成具有新特征的额外模型。我们的小鼠模型揭示了一个以前认为是营养不良独有的特征，也存在于线状体肌病中。对特征良好的患者样本和小鼠模型的联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。我们将确定杆如何形成和它们的蛋白质组成。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。