title: A lethal variant of osteogenesis imperfecta has a single base mutation that substitutes cysteine for glycine 904 of the alpha 1(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 pro alpha 1(I) and pro alpha 2(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 alpha 1(I) chains were recovered as disulfide-linked dimers. Mapping of cyanogen bromide peptides indicated that the disulfide link was contained in alpha 1-CB6, the cyanogen bromide fragment containing amino acid residues 823-1014 of the alpha 1(I) chain. Nucleotide sequencing of cDNA clones demonstrated a substitution of T for G that converted glycine 904 of the alpha 1(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 degrees 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 pro alpha 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 asymptomatic. 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Jefferson Institute of Molecular Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: C D
authors.initials: CD
authors.lastname: Constantinou
authors.forename: K B
authors.initials: KB
authors.lastname: Nielsen
authors.forename: D J
authors.initials: DJ
authors.lastname: Prockop
mesh_terms: D001483:Base Sequence; D003545:Cysteine; D005260:Female; D005313:Fetal Death / Q000235:genetics*; D005804:Genes, Lethal; D005998:Glycine; D006801:Humans; D007231:Infant, Newborn; D008969:Molecular Sequence Data; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010449:Peptide Mapping; D011247:Pregnancy; D011347:Procollagen / Q000032:analysis / Q000235:genetics*
chemical_list: D011347:Procollagen; D003545:Cysteine; D005998:Glycine