Mutations near amino end of alpha1(I) collagen cause combined osteogenesis imperfecta/Ehlers-Danlos syndrome by interference with N-propeptide processing

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Peer Reviewed


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NLM Title Abbreviation

J Biol Chem

Journal/Book/Conference Title

The Journal of biological chemistry

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Patients with OI/EDS form a distinct subset of osteogenesis imperfecta (OI) patients. In addition to skeletal fragility, they have characteristics of Ehlers-Danlos syndrome (EDS). We identified 7 children with types III or IV OI, plus severe large and small joint laxity and early progressive scoliosis. In each child with OI/EDS, we identified a mutation in the first 90 residues of the helical region of alpha1(I) collagen. These mutations prevent or delay removal of the procollagen N-propeptide by purified N-proteinase (ADAMTS-2) in vitro and in pericellular assays. The mutant pN-collagen which results is efficiently incorporated into matrix by cultured fibroblasts and osteoblasts and is prominently present in newly incorporated and immaturely cross-linked collagen. Dermal collagen fibrils have significantly reduced cross-sectional diameters, corroborating incorporation of pN-collagen into fibrils in vivo. Differential scanning calorimetry revealed that these mutant collagens are less stable than the corresponding procollagens, which is not seen with other type I collagen helical mutations. These mutations disrupt a distinct folding region of high thermal stability in the first 90 residues at the amino end of type I collagen and alter the secondary structure of the adjacent N-proteinase cleavage site. Thus, these OI/EDS collagen mutations are directly responsible for the bone fragility of OI and indirectly responsible for EDS symptoms, by interference with N-propeptide removal.


ADAM Proteins, Adolescent, Adult, Amino Acid Sequence, Calorimetry, Differential Scanning, Cells, Cultured, Child, Preschool, Collagen/metabolism, Collagen Type I/genetics, Cross-Linking Reagents/pharmacology, DNA Mutational Analysis, Ehlers-Danlos Syndrome/genetics, Electrophoresis, Polyacrylamide Gel, Extracellular Matrix/metabolism, Female, Fibroblasts/cytology, Hot Temperature, Humans, Infant, Male, Microscopy, Electron, Transmission, Molecular Sequence Data, Mutation, Osteoblasts/metabolism, Osteogenesis Imperfecta/genetics, Peptides/chemistry, Phenotype, Procollagen N-Endopeptidase/metabolism, Protein Binding, Protein Conformation, Protein Folding, Protein Structure, Secondary, Protein Structure, Tertiary, Sequence Homology, Amino Acid, Skin/cytology/metabolism, Time Factors

Published Article/Book Citation

The Journal of biological chemistry, 280:19 (2005) pp.19259-19269. DOI:10.1074/jbc.M414698200.

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