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

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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.