Background: COL6 gene mutations are associated with Ullrich congenital muscular dystrophy (UCMD), which is clinically characterized by muscle weakness from early infancy, hyperlaxity of distal joints, and multiple proximal joint contractures. We previously reported that the majority of patients with UCMD have sarcolemma-specific collagen VI deficiency (SSCD). More recently, we found heterozygous COL6A1 glycine substitutions in patients with UCMD with SSCD.
Objective: To elucidate how COL6A1 glycine mutation leads to SSCD.
Methods: We evaluated the synthesis, formation, and binding of collagen VI to the extracellular matrix in fibroblasts with p.G284R mutation in COL6A1.
Results: Collagen VI was normally secreted into the cultured medium in fibroblasts harboring p.G284R mutation. When the medium with normal collagen VI was added to collagen VI-deficient fibroblast culture, collagen VI bound surrounding the cells, while collagen VI with p.G284R mutation did not. Cell adhesion of fibroblasts with p.G284R mutation was markedly reduced similarly to that of collagen VI-deficient cells. Interestingly, this reduction in adhesion of the cells with p.G284R mutation was recovered by the addition of the medium with normal collagen VI, which would suggest a therapeutic strategy for a replacement therapy.
Conclusion: Heterozygous glycine substitution in COL6A1 may cause decreased binding of collagen VI microfibrils to the extracellular matrix resulting in sarcolemma-specific collagen VI deficiency.