Lethal perinatal osteogenesis imperfecta due to the substitution of arginine for glycine at residue 391 of the α1(I) chain of type I collagen

Abstract

A baby with the lethal perinatal form of osteogenesis imperfecta was shown to have a structural defect in the α1(I) chain of type I procollagen. Normal and mutant α1(I) CB8 cyanogen bromide peptides, from the helical part of the α1(I) chains, were purified from bone. Amino acid sequencing of tryptic peptides derived from the mutant α1(I) CB8 peptide showed that the glycine residue at position 391 of the α1(I) chain had been replaced by an arginine residue. This substitution accounted for the more basic charged form of this peptide that was observed on two-dimensional electrophoresis of the collagen peptides obtained from the tissues. The substitution was associated with increased enzymatic hydroxylation of lysine residues in the α1(I) CB8 and the adjoining CB3 peptides but not in the carboxyl-terminal CB6 and CB7 peptides. This finding suggested that the sequence abnormality had interfered with the propagation of the triple helix across the mutant region. The abnormal collagen was not incorporated into the more insoluble fraction of bone collagen. The baby appeared to be heterozygous for the sequence abnormality and as the parents did not show any evidence of the defect it is likely that the baby had a new mutation of one allele of the pro-α1(I) gene. The amino acid substitution could result from a single nucleotide mutation in the codon GGC (glycine) to produce the codon CGC (arginine).