title: Mutations near amino end of alpha1(I) collagen cause combined osteogenesis imperfecta/Ehlers-Danlos syndrome by interference with N-propeptide processing.
abstract: 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.
authors.affiliation: Bone and Extracellular Matrix Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Cabral
authors.forename: Elena
authors.initials: E
authors.lastname: Makareeva
authors.forename: Alain
authors.initials: A
authors.lastname: Colige
authors.forename: Anne D
authors.initials: AD
authors.lastname: Letocha
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Ty
authors.forename: Heather N
authors.initials: HN
authors.lastname: Yeowell
authors.forename: Gerard
authors.initials: G
authors.lastname: Pals
authors.forename: Sergey
authors.initials: S
authors.lastname: Leikin
authors.forename: Joan C
authors.initials: JC
authors.lastname: Marini
mesh_terms: D051722:ADAM Proteins; D000071096:ADAMTS Proteins; D000071121:ADAMTS4 Protein; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002152:Calorimetry, Differential Scanning; D002478:Cells, Cultured; D002675:Child, Preschool; D003094:Collagen / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004252:DNA Mutational Analysis; D004535:Ehlers-Danlos Syndrome / Q000235:genetics*; D004591:Electrophoresis, Polyacrylamide Gel; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D006358:Hot Temperature; D006801:Humans; D007223:Infant; D008297:Male; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D009154:Mutation; D010006:Osteoblasts / Q000378:metabolism; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D011348:Procollagen N-Endopeptidase / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D012867:Skin / Q000166:cytology / Q000378:metabolism; D013997:Time Factors
chemical_list: D024042:Collagen Type I; D003432:Cross-Linking Reagents; D010455:Peptides; D003094:Collagen; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C000609307:ADAMTS2 protein, human; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein