Structure, stability and interactions of type I collagen with GLY349-CYS substitution in alpha 1(I) chain in a murine Osteogenesis Imperfecta model.

Here we report the structural and functional studies of collagen from the Brtl mouse, a heterozygous knock-in model for Osteogenesis Imperfecta, which has a G349C substitution introduced in one col1a1 allele. We observed that 25+/-5% of alpha 1(I) chains in different tissues and in different extracts from matrix deposited by cultured cells were S-S-linked mutant dimers. Apparently mutant and normal molecules are equally well incorporated into the matrix and they form mature covalent crosslinks with the same efficiency. We found different extents of post-translational overmodification of mutant molecules in different tissues, but we found no consistent differences between lethal and non-lethal animals. We did not detect any changes in the thermal stability or rate of thermal denaturation of mutant collagen. We also did not detect any changes in collagen-collagen recognition and interactions except for disruption of quasi-crystalline lateral packing of molecules in tendons from some, mostly prepubertal, mutant animals. In contrast, alpha 1(I)(3) collagen from the oim mouse--the only other non-lethal murine OI model studied by similar techniques--has altered stability, fibrillogenesis, collagen-collagen interactions and produces a more consistent and more pronounced disruption of tendon crystallinity. Nevertheless, while the G349C substitution causes moderate or lethal OI, heterozygous oim mice are much less affected. Overall, our results suggest that OI symptoms and phenotype variation in G349C animals are related to abnormal interactions of mutant collagen helices with other matrix molecules or abnormal function of osteoblasts rather than to abnormal structure, physical properties or interactions between mutant collagen helices.