Studies on pathophysiology and experimental therapy of Ullrich's disease with collagen VI deficiency.

具有VI型胶原突变的胶原病包括Ulirich先天性肌营养不良症(Ullrich‘s病)和Bethlem肌病。乌尔里希病的患者有全身肌肉无力、近端关节多发性痉挛和远端关节高度伸展。Bethlem肌病的特征是近端肌肉无力和手指、肘部和脚踝关节的痉挛。我们首次在乌尔里奇病中发现了VI型胶原的缺乏。此外，我们还发现乌尔里希病存在细胞黏附异常和再生或成熟异常。COL6A1、COL6A2、COL6A3基因突变与乌尔里希病和白纹肌病有关。Bethlem肌病以常染色体显性方式遗传，Ullrich病通常以常染色体隐性方式遗传。最近，在乌尔里希病中发现了新的显性突变。我们评估了无义介导的信使核糖核酸衰变(NMD)在乌尔里奇病中的作用。乌尔里希病具有COL6A2基因提前终止密码子的移码突变，导致VI型胶原的丢失。NMD的药理阻断导致突变的VI型胶原上调和部分功能性细胞外基质形成。我们的结果表明，NMD抑制剂可以作为一种治疗工具来拯救一些因NMD而加剧的人类遗传病。

Collagenopathies with collagen VI mutations include Ulirich 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. Furthermore, we found an abnormality of cell adhesion and abnormal regeneration or maturation in Ullrich's disease. Mutations in the genes COL6A1, COL6A2, COL6A3 are associated with Ullrich's disease and Bethlem myopathy. Bethlem myopathy is inherited in an autosomal dominant manner and Ullrich's disease usually in an autosomal recessive manner. Recently, de novo dominant mutations are reported in Ullrich's disease. We evaluated the role of nonsense-mediated mRNA decay (NMD) in Ullrich's disease that has a frameshift mutation with a premature termination codon in the COL6A2 gene causing the loss of collagen VI. The pharmacological block of NMD caused upregulation of the mutant collagen VI and partially functional extracellular matrix formation. Our results suggest that NMD inhibitors can be used as a therapeutic tool to rescue some human genetic diseases exacerbated by NMD.