Substitution of serine for glycine 883 in the triple helix of the pro alpha 1 (I) chain of type I procollagen produces osteogenesis imperfecta type IV and introduces a structural change in the triple helix that does not alter cleavage of the molecule by procollagen N-proteinase.

Type I procollagen secreted by dermal fibroblasts from an individual with osteogenesis imperfecta type IV was a mixture of normal molecules and molecules that were post-translationally overmodified. The individual was heterozygous for a G to A transition in the COL1A1 gene that resulted in the substitution of serine for glycine 883 in one or both of the pro alpha 1 (I) chains. The thermal stability of molecules containing overmodified chains was lower by 2 degrees C than that of normal molecules. However, following cleavage of the molecules with vertebrate collagenase, the temperature of denaturation of the overmodified A fragments (residues 1-775 of the helix did not contain the substitution) was 2 degrees C greater than that of A fragments from normal molecules. The rates of cleavage by procollogen N-proteinase (EC 3.4.214.14) (N-proteinase) of procollagen molecules in normal and osteogenesis imperfecta samples were not significantly different. The procollagen molecules in the osteogenesis imperfecta sample were also indistinguishable from those in control samples by rotary shadowing electron microscopy. The results suggest that this substitution of serine for glycine in the alpha 1 (I) chain of procollagen, like the substitution of aspartate for the same glycine previously described (Lightfoot, S. J., Holmes, D. F., Brass, A., Grant, M. E., Byers, P. H., and Kadler, K. E. (1992) J. Biol. Chem. 267, 25521-25528), can alter the structure of the triple helix N-terminal to the site of the substitution. However, in contrast to the aspartate for glycine substitution, the structural change is insufficient to delay the cleavage of the procollagen by N-proteinase and results in a mild rather than lethal phenotype.