The molecular defect in a nonlethal variant of osteogenesis imperfecta. Synthesis of pro-alpha 2(I) chains which are not incorporated into trimers of type I procollagen.
Cultured fibroblasts were examined from a patient with a nonlethal form of osteogenesis imperfecta. As reported previously (Nicholls, A. C., Pope, F. M., and Schloon, H. (1979) Lancet 1, 1193), the cells synthesized and secreted a type I procollagen which lacked pro-alpha 2(I) chains and consisted of a trimer of pro-alpha 1(I) chains. No pro-alpha 2(I) chains were recovered from the medium under conditions in which nonhelical pro-alpha 1(I) and pro-alpha 2(I) chains were readily detected in the medium of normal fibroblasts incubated with the hydroxylase inhibitor, alpha, alpha'-dipyridyl. Examination of cellular proteins demonstrated that the fibroblasts synthesized both pro-alpha 1(I) and pro-alpha 2(I) chains. The cellular pro-alpha 2(I) chains did not, however, become disulfide-linked into dimers or trimers of pro-alpha chains. Since the association of pro-alpha chains during the biosynthesis of type I procollagen is directed by the conformation of the COOH-terminal propeptides, the data suggest that the pro-alpha 2(I) chains synthesized by the fibroblasts have a mutated structure in the COOH-terminal propeptides which markedly reduces their affinity for pro-alpha 1(I) chains. A further observation was that the ratio of newly synthesized pro-alpha (I):pro-alpha 2(I) chains in the patient's fibroblasts was 7.18 +/- 0.58 S.E. instead of the value of 2.25 +/- 0.16 S.E. seen in control fibroblasts. One possible explanation for the high ratio is that the proband is homozygous for a mutation altering the structure of the pro-alpha 2(I) chain and that a secondary effect of the structural mutation is a decreased rate of synthesis of pro-alpha 2(I) chains.
D015082:2,2'-Dipyridyl / Q000494:pharmacology; D003488:Cyanogen Bromide; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010434:Pepsin A / Q000378:metabolism; D010446:Peptide Fragments / Q000032:analysis; D011347:Procollagen / Q000096:biosynthesis* / Q000235:genetics
D046911:Macromolecular Substances; D010446:Peptide Fragments; D011347:Procollagen; D015082:2,2'-Dipyridyl; D010434:Pepsin A; D003488:Cyanogen Bromide