Substitution of cysteine for glycine at residue 415 of one allele of the α1(I) chain of type I procollagen in type III/IV osteogenesis imperfecta

Abstract

We have examined the type I collagen in a patient with type III/IV osteogenesis imperfecta. Two forms of al(I) chain were produced, one normal and the other containing a cysteine residue within the triple helical domain of the molecule. Cysteine is not normally present in this domain of type I collagen. Peptide mapping experiments localised the mutation to peptide al(I)CB3 which spans residues 403 to 551 of the triple helix. Subsequent PCR amplification of cDNA covering this region followed by sequencing showed a G to T single base change in the GGC codon for glycine 415 generating TGC, the codon for cysteine. The effect of the mutation on the protein is to delay secretion from the cell, reduce the thermal stability of the molecule by 2'C, and cause excessive post-translational modification of all chains in molecules containing one or more mutant ael(I) chains. The clinical phenotype observed in this patient and the position of the mutation conform to the recent prediction of Starman et a) that Gly-+Cys mutations in the al(I) chain have a gradient of severity decreasing from the C-terminus to the N-terminus.