Strukturelle und funktionelle Untersuchungen von Basalmembranen und ihren Rezeptoren in der Pathogenese hereditärer Muskelerkrankungen

在横纹肌细胞中，肌营养不良蛋白-糖蛋白复合物（DGC）充当细胞外基质中的层粘连蛋白与F-肌动蛋白细胞骨架之间的连接。最近的研究将与影响DGC组分的原发性突变相关的肌营养不良症的数量扩展到六种遗传上不同的疾病。复合物的关键分子是基底膜受体肌营养不良蛋白聚糖，由细胞外α-和跨膜β-亚基组成。已显示肌营养不良聚糖在基底膜的组装和形成中以及在DGC相关肌营养不良症的发病机制中起重要作用。我们鉴定了4种不同的遗传性肌肉疾病，其具有α-肌营养不良蛋白聚糖缺陷、基底膜组分的改变的表达模式和细胞外基质的病理学，其不同于已知的DGC相关的肌营养不良症。到目前为止，这4种疾病中没有一种的主要遗传缺陷被确定。我们项目的目的是进一步描述受影响患者的临床和生化表型，并确定其潜在的生化和遗传缺陷。总的来说，该项目应有助于阐明基底膜及其受体在遗传性肌肉疾病发病机制中的作用。

In striated muscle cells the dystrophin-glycoprotein complex (DGC), serves as a link between laminin in the extracellular matrix and the F-actin cytoskeleton. Recent studies extended the numbers of muscular dystrophies associated with primary mutations affecting components of the DGC to six genetically distinct diseases. A key molecule of the complex is the basement membrane receptor dystroglycan, consisting of an extracellular a- and a transmembrane ß-subunit. Dystroglycan has been shown to play an important role in the assembly and formation of basement membranes and in the pathogenesis of DGC associated muscular dystrophies. We identified 4 distinct hereditary muscle diseases with a-dystroglycan deficiency, an altered expression pattern of basement membrane components, and pathology of the extracellular matrix which are different from the known DGC associated muscular dystrophies. The primary genetic defect in none of the 4 diseases has so far been identified. The aim of our project is to further characterize the clinical and biochemical phenotype of the affected patients and to identify their underlying biochemical and genetic defects. Overall the project should contribute to elucidate the role of basement membranes and their receptors in the pathogenesis of hereditary muscle diseases.