title: Altered triple helical structure of type I procollagen in lethal perinatal osteogenesis imperfecta.
abstract: Cultured dermal fibroblasts from an infant with the lethal perinatal form of osteogenesis imperfecta (type II) synthesize normal and abnormal forms of type I procollagen. The abnormal type I procollagen molecules are excessively modified during their intracellular stay, have a lower than normal melting transition temperature, are secreted at a reduced rate, and form abnormally thin collagen fibrils in the extracellular matrix in vitro. Overmodification of the abnormal type I procollagen molecules was limited to the NH2-terminal three-fourths of the triple helical domain. Two-dimensional mapping of modified and unmodified alpha chains of type I collagen demonstrated neither charge alterations nor large insertions or deletions in the region of alpha 1(I) and alpha 2(I) in which overmodification begins. Both the structure and function of type I procollagen synthesized by cells from the parents of this infant were normal. The simplest interpretation of the results of this study is that the osteogenesis imperfecta phenotype arose from a new dominant mutation in one of the genes encoding the chains of type I procollagen. Given the requirement for glycine in every third position of the triple helical domain, the mutation may represent a single amino acid substitution for a glycine residue. These findings demonstrate further heterogeneity in the biochemical basis of osteogenesis imperfecta type II and suggest that the nature and location of mutations in type I procollagen may determine phenotypic variation.
authors.forename: J
authors.initials: J
authors.lastname: Bonadio
authors.forename: K A
authors.initials: KA
authors.lastname: Holbrook
authors.forename: R E
authors.initials: RE
authors.lastname: Gelinas
authors.forename: J
authors.initials: J
authors.lastname: Jacob
authors.forename: P H
authors.initials: PH
authors.lastname: Byers
mesh_terms: D003488:Cyanogen Bromide; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D003012:Microbial Collagenase / Q000378:metabolism; D008854:Microscopy, Electron; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010434:Pepsin A / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011347:Procollagen / Q000235:genetics* / Q000378:metabolism; D011487:Protein Conformation; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D010446:Peptide Fragments; D011347:Procollagen; D012333:RNA, Messenger; D010434:Pepsin A; D003012:Microbial Collagenase; D003488:Cyanogen Bromide