Mutations in the carboxyl-terminal propeptide of the pro alpha 1(I) chain of type I collagen result in defective chain association and produce lethal osteogenesis imperfecta.

Fibroblast cell strains from three infants with perinatal lethal osteogenesis imperfecta (OI) carry unique mutations in COL1A1 (the gene encoding the pro alpha 1(I) chain of type I procollagen) that impair chain association. The three mutations are: substitution of arginine for leucine at position 170 in the carboxyl-terminal propeptide, substitution of histidine for aspartic acid at position 59 of the propeptide, and a 6-base pair deletion that results in loss of 2 amino acid residues, glutamic acid and tyrosine, at positions 119 and 120 of the propeptide. In each cell strain the rate of association of the abnormal chain into molecules is slowed and formation of interchain disulfide bonds is impaired. The substitution at residue 59 alters the most highly conserved region of the propeptide and has a much greater effect on the incorporation of pro alpha 2(I) chains into disulfide-bonded trimers than the other two mutations. The molecules that contain the abnormal chains are extensively overmodified by post-translational modifying enzymes, yet have a normal thermal stability. These findings extend the range of lethal mutations in the type I collagen genes and help to identify regions of the carboxyl-terminal propeptide that may be important for chain-chain recognition and molecular assembly.