Molecular pathology of collagen VI-related muscular dystrophies

遗传性肌营养不良症，其特征在于进行性肌肉无力和消瘦，是身体残疾的重要原因。肌肉细胞通过一系列相互作用的蛋白质锚定在周围组织中。细胞内的蛋白质连接到细胞表面蛋白，细胞表面蛋白又连接到细胞外基质蛋白。如果任何一个链接被突变破坏，连接就会丢失，肌肉疾病就会发生。迄今为止，大多数研究都集中在细胞内和细胞表面蛋白的作用，而相对较少关注细胞外基质蛋白。在Bethlem肌病和Ullrich肌营养不良症患者中发现了细胞外基质蛋白胶原VI的突变。这些突变告诉我们VI型胶原蛋白在肌肉中起着关键作用，但我们不知道这些突变是如何破坏细胞和基质之间的联系的，也不知道它们为什么会引起肌肉疾病。我们将在我们的新Bethlem肌病和Ullrich患者组中寻找VI型胶原突变，并对突变对VI型胶原产生、结构和功能的影响进行详细研究。这些研究将使我们能够为受影响的个体提供准确的诊断和遗传咨询，并开始告诉我们突变是如何破坏细胞-基质连接的。与胶原VI相互作用的其他细胞外基质蛋白的突变也可能导致肌营养不良症。其中一种蛋白质是双糖链蛋白。我们从对小鼠的研究中得知，当双糖链蛋白聚糖缺失时，小鼠患有肌肉萎缩症，因此，一些人类肌肉萎缩症患者可能具有双糖链蛋白聚糖突变。我们将在肌营养不良症患者中寻找双糖蛋白聚糖突变，并进行详细的研究，试图了解突变对双糖蛋白聚糖蛋白的影响。该应用程序汇集了两个具有互补专业知识的团队，以进一步了解肌营养不良症的基础。

The inherited muscular dystrophies, characterised by progressive muscle weakness and wasting, are a significant cause of physical disability. Muscle cells are anchored into the surrounding tissue by a chain of interacting proteins. Proteins inside the cell link to cell surface proteins, which in turn link to extracellular matrix proteins. If any one of the links is broken by a mutation, the connection is lost and muscle disease results. Most studies to date have focused on the role of intracellular and cell surface proteins, and relatively little attention has been paid to the extracellular matrix proteins. Mutations in the extracellular matrix protein collagen VI have been found in patients with Bethlem myopathy and Ullrich muscular dystrophy. These mutations tell us that collagen VI plays a critical role in muscle but we don't know how the mutations break the link between the cell and the matrix or why they cause a muscle disease. We will look for collagen VI mutations in our group of new Bethlem myopathy and Ullrich patients, and perform detailed studies on the effect of the mutations on collagen VI production, structure and function. These studies will allow us to provide accurate diagnosis and genetic counselling for affected individuals and begin to tell us how the mutations break the cell-matrix link. Mutations in other extracellular matrix proteins that interact with collagen VI are also likely to cause muscular dystrophies. One of these proteins is biglycan. We know from studies in mice that when biglycan is missing the mice have muscular dystrophy, so it is likely that some human muscular dystrophy patients have biglycan mutations. We will look for biglycan mutations in patients with muscular dystrophies and perform detailed studies to try to understand the effect of the mutations on the biglycan protein. This application brings together two groups with complementary expertise, to further our understanding of the basis of muscular dystrophies.