COL6A3 Protein Deficiency in Mice Leads to Muscle and Tendon Defects Similar to Human Collagen VI Congenital Muscular Dystrophy

Collagen VI is a ubiquitously expressed extracellular microfibrillar protein. Its most common molecular form is composed of the alpha 1(VI), alpha 2(VI), and alpha 3(VI) collagen alpha chains encoded by the COL6A1, COL6A2, and COL6A3 genes, respectively. Mutations in any of the three collagen VI genes cause congenital muscular dystrophy types Bethlem and Ullrich as well as intermediate phenotypes characterized by muscle weakness and connective tissue abnormalities. The alpha 3(VI) collagen alpha chain has much larger N- and C-globular domains than the other two chains. Its most C-terminal domain can be cleaved off after assembly into microfibrils, and the cleavage product has been implicated in tumor angiogenesis and progression. Here we characterize a Col6a3 mutant mouse that expresses a very low level of a nonfunctional alpha 3(VI) collagen chain. The mutant mice are deficient in extracellular collagen VI microfibrils and exhibit myopathic features, including decreased muscle mass and contractile force. Ultrastructurally abnormal collagen fibrils were observed in tendon, but not cornea, of the mutant mice, indicating a distinct tissue-specific effect of collagen VI on collagen I fibrillogenesis. Overall, the mice lacking normal alpha 3(VI) collagen chains displayed mild musculoskeletal phenotypes similar to mice deficient in the alpha 1(VI) collagen alpha chain, suggesting that the cleavage product of the alpha 3(VI) collagen does not elicit essential functions in normal growth and development. The Col6a3 mouse mutant lacking functional alpha 3(VI) collagen chains thus serves as an animal model for COL6A3-related muscular dystrophy.