A lethal variant of osteogenesis imperfecta has a single base mutation that substitutes cysteine for glycine 904 of the α1(I) chain of type I procollagen. The asymptomatic mother has an unidentified mutation producing an overmodified and unstable type I procollagen

Abstract

A fraction of the proα1(I) and proα2(I) chains in type I procollagen synthesized by the fibroblasts from a proband with a lethal variant of osteogenesis imperfecta were overmodified by posttranslational reactions. After digestion with pepsin, some of the α1(I) chains were recovered as disulfide-linked dimers. Mapping of cyanogen bromide peptides indicated that the disulfide link was contained in α1-CB6, the cyanogen bromide fragment containing amino acid residues 823-1014 of the α1(I) chain. Nucleotide sequencing of cDNA clones demonstrated a substitution of T for G that converted glycine 904 of the α1(I) chain to cysteine. A large fraction of the type I procollagen synthesized by the proband's fibroblasts, had a thermostability that was 3-4°C lower than the normal type I procollagen as assayed by brief proteinase digestion. In addition, the type I procollagen synthesized by the proband's fibroblasts was secreted with an abnormal kinetic pattern in that there was a lag period of about 30 min in pulse-chase experiments. The mutation of glycine to cysteine was not found in type I procollagen synthesized by fibroblasts from the proband's parents. Therefore, the mutation was a sporadic one. However, the mother's fibroblasts synthesized a type I procollagen in which part of the proα chains were overmodified and had a lower thermostability. Therefore, the proband may have inherited a mutated allele for type I procollagen from her mother that contributed to the lethal phenotype. The mother was assymptomatic. She was somewhat short and had slightly blue sclerae but no definitive signs of a connective tissue abnormality. The observations on the mother indicated, therefore, that a mutation that causes synthesis of a type I procollagen with a lowered thermal stability does not necessarily produce a heritable disorder of connective tissue.