| Abstract: | We have examined the collagenous proteins extracted from skin and produced by skin fibroblast cultures from the members of a family with mild dominant osteogenesis imperfecta (OI type I). The two affected patients, mother and son, produce two populations of alpha 1(I) chains of type I collagen, one chain being normal, the other containing a cysteine within the triple-helical domain. Both forms can be incorporated into triple-helical molecules with an alpha 2(I) chain. When two mutant alpha (I) chains are incorporated into the same molecule, a disulfide bonded dimer is produced. We have characterized these chains by sodium dodecyl sulfate-gel electrophoresis and CNBr-peptide mapping and by measuring a number of biosynthetic and physical variables. The cysteine was localized to the COOH-terminal peptide alpha (I) CB6. Molecules containing the mutant chains are stable, have a normal denaturation temperature, are secreted normally, and have normal levels of post-translational modification of lysyl residues and intracellular degradation. We have compared and contrasted these observations with those made in a patient with lethal osteogenesis imperfecta in which there was a cysteine substitution in alpha 1(I) CB6 (Steinmann, B., Rao, V. H., Vogel, A., Bruckner, P., Gitzelmann, R., and Byers, P. H. (1984) J. Biol. Chem 259, 11129-11138) and have concluded that the mutation in the present family occurs in the X or Y position of a Gly-X-Y repeating unit of collagen and not in the glycine position shown for the previous patient (Cohn, D. H., Byers, P. H., Steinmann, B, and Gelinas, R. E. (1986) Proc. Natl. Acad. Sci. U. S. A., in press. |
