Osteogenesis imperfecta. The position of substitution for glycine by cysteine in the triple helical domain of the Proα1(I) chains of type I collagen determines the clinical phenotype
Abstract
Skin fibroblasts grown from three individuals with osteogenesis imperfecta (OI) each synthesized a population of normal type I collagen molecules and additional molecules that had one or two α1(I) chains that contained a cysteine residue within the triple-helical domain, a region from which cysteine normally is excluded. The patients had very different phenotypes. One patient with OI type I had a population of α1(I) chains in which glycine at position 94 of the triple helix was substituted by cysteine; a patient with OI type III had a population of α1(I) chains in which glycine at position 526 of the triple helix was substituted by cysteine; and the third patient, with OI type II, had a cysteine for glycine substitution at position 718 of the α1(I) chain. From all three patients, molecules that contained two mutant chains formed interchain, intramolecular disulfide bonds, and although less stable to thermal denaturation than normal molecules, they were more stable than molecules that contained only a single mutant chain. These findings indicate that substitutions for glycine within the triple-helical domain of the α1(I) chain are not invariably lethal and that their phenotypic effect largely depends on the nature of the substituting residue and its location in the chain.
Publication Title
Journal of Clinical Investigation
Recommended Citation
Starman, B., Eyre, D., Charbonneau, H., Harrylock, M., Weis, M., Weiss, L., Graham, J., & Byers, P. (1989). Osteogenesis imperfecta. The position of substitution for glycine by cysteine in the triple helical domain of the Proα1(I) chains of type I collagen determines the clinical phenotype. Journal of Clinical Investigation, 84 (4), 1206-1214. https://doi.org/10.1172/JCI114286
