Studies on pathophysiology and experimental therapy of Ullrich's disease and Bethlem myopathy

具有胶原VI突变的胶原病包括Ullrich先天性肌营养不良（Ullrich病）和Bethlem肌病。Ullrich病患者具有全身性肌无力、近端关节多发性挛缩和远端关节过度伸展。Bethlem肌病的特征是近端肌肉无力和手指、肘和踝关节挛缩的组合。我们发现第一次缺乏胶原VI的Ullrich病。我们发现在各种肌营养不良症的纤维结缔组织和邻近的肌膜中HSP 47过表达。然而，在Ullrich先天性肌营养不良症（UCMD）中，HSP 47的过表达仅见于结缔组织，而非肌膜。由于基底膜在受损骨骼肌再生过程中的重要性是众所周知的，因此肌肉基底膜中HSP 47的低表达也可能与Ullrich病的发病机制有关。我们发现，siRNA介导的hSMG-1或hUPF 1敲低导致突变型三螺旋胶原VI的上调，导致Ullrich病中部分功能性细胞外基质的形成。我们的结论是，无义介导的mRNA衰变（NMD）的抑制可以被用作一种治疗方法，以挽救一些人类遗传疾病加剧的NMD。

Collagenopathies with collagen VI mutations include Ullrich congenital muscular dystrophy (Ullrich's disease) and Bethlem myopathy. Patients with Ullrich's disease have generalized muscle weakness, multiple contractures of the proximal joints and hyperextensibility of the distal joints. Bethlem myopathy is characterized by the combination of proximal muscle weakness and contractures of finger, elbow, and ankle joints. We found for the first time a deficiency of collagen VI in Ullrich's disease. We found an overexpression of HSP47 in fibrous connective tissue and in the adjacent muscle membrane in various muscular dystrophies. However, in Ullrich congenital muscular dystrophy (UCMD), the overexpression of HSP47 was found only in the connective tissue, and not in the muscle membrane. Since the importance of basement membrane is well known during the regeneration of damaged skeletal muscle, the poor expression of HSP47 in the muscle basement membrane may also be related to the pathogenesis of Ullrich's disease. We show that siRNA-mediated knockdowns of hSMG-1 or hUPF1 cause up-regulation of the mutant triple helical collagen VI, resulting in the formation of partially functional extracellular matrix in Ullrich's disease. We conclude that the inhibition of nonsense-mediated mRNA decay (NMD) can be used as a therapeutic approach to rescue some human genetic diseases exacerbated by NMD.