Disruption of one intra-chain disulphide bond in the carboxyl-terminal propeptide of the pro alpha 1(I) chain of type I procollagen permits slow assembly and secretion of overmodified, but stable procollagen trimers and results in mild osteogenesis imperfecta

Type I procollagen is a heterotrimer comprised of two proal(I) chains and o ne pro alpha2(I) chain. Chain recognition, association, and alignment of pr o alpha chains into correct registration are thought to occur through inter actions between the C-terminal propeptide domains of the three chains. The C-propeptide of each chain contains a series of cysteine residues (eight in pro alpha1(I) and seven in pro alpha2(I)), the last four of which form int ra-chain disulphide bonds. The remaining cysteine residues participate in i nter-chain stabilisation. Because these residues are conserved, they are th ought to be important for folding and assembly of procollagen. We identifie d a mutation (3897C -->G) that substituted tryptophan for the cysteine at p osition 1299 in proal(I) (C1299W, the first cysteine that participates in i ntra-chain bonds) and resulted in mild osteogenesis imperfecta. The patient was born with a fractured clavicle and four rib fractures. By 18 months of age he had had no other fractures and was on the 50th centile for length a nd weight. The proband's mother, maternal aunt, and grandfather had the sam e mutation and had few fractures, white sclerae, and discoloured teeth, but their heights were within the normal range. In the patient's cells the def ective chains remained as monomers for over 80 minutes (about four times no rmal) and were overmodified. Some secreted procollagens were also overmodif ied but had normal thermal stability, consistent with delayed, but normal h elix formation. This intra-chain bond may stabilise the C-propeptide and pr omote rapid chain association. Other regions of the C-propeptide thus play more prominent roles in chain registration and triple helix nucleation.