MUTATION IN THE CARBOXY-TERMINAL PROPEPTIDE OF THE PRO-ALPHA-1(1) CHAIN OF TYPE-I COLLAGEN IN A CHILD WITH SEVERE OSTEOGENESIS IMPERFECTA (OI TYPE-III) - POSSIBLE IMPLICATIONS FOR PROTEIN-FOLDING

A young girl presented with severe type III osteogenesis imperfecta; h er otherwise healthy mother also had a mild connective tissue disorder with blue sclerae and recurrent joint dislocations. Skin fibroblast c ultures from the child produced both normal and post-translationally o vermodified type I collagen. The mutant collagen was poorly secreted b ut had normal thermal stability, Cyanogen bromide peptide maps of the abnormal protein indicated a C-terminal mutation, The mother's cells p roduced only normal appearing collagens,Mismatch analysis and extensiv e sequencing of cDNAs covering the suspect region did not reveal any p otentially causal changes in the triple helical domains of either the alpha 1(I) or alpha 2(I) chains, However, examination of the C-propept ide sequences revealed two heterozygous single base changes in the chi ld. One, an A-->C changing threonine to proline at residue 29 of the a lpha 2(I) C propeptide was also present in the mother and maternal gra ndfather but not in 50 unrelated control individuals. The second, a T- ->C altered the last amino acid residue of the alpha 1(I) C-propeptide from leucine to proline and had occurred de novo in the affected chil d. This mutation highlights the importance of the C-propeptides in mol ecular assembly but it is not clear how such an extreme mutation cause s the delay in triple helix formation indicated by the extensive overm odification and reduced secretion of the mutant type I collagen, It ma y inhibit intrachain disulfide bonding or possibly affect the associat ion of the procollagen chain with an intracellular ''chaperone'' prote in that normally assists the assembly of trimeric procollagen molecule s. (C) 1996 Wiley-Liss, Inc.