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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
19
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pubmed:dateCreated |
2005-5-9
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
13
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pubmed:volume |
280
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
19259-69
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:15728585-ADAM Proteins,
pubmed-meshheading:15728585-Adolescent,
pubmed-meshheading:15728585-Adult,
pubmed-meshheading:15728585-Amino Acid Sequence,
pubmed-meshheading:15728585-Calorimetry, Differential Scanning,
pubmed-meshheading:15728585-Cells, Cultured,
pubmed-meshheading:15728585-Child, Preschool,
pubmed-meshheading:15728585-Collagen,
pubmed-meshheading:15728585-Collagen Type I,
pubmed-meshheading:15728585-Cross-Linking Reagents,
pubmed-meshheading:15728585-DNA Mutational Analysis,
pubmed-meshheading:15728585-Ehlers-Danlos Syndrome,
pubmed-meshheading:15728585-Electrophoresis, Polyacrylamide Gel,
pubmed-meshheading:15728585-Extracellular Matrix,
pubmed-meshheading:15728585-Female,
pubmed-meshheading:15728585-Fibroblasts,
pubmed-meshheading:15728585-Hot Temperature,
pubmed-meshheading:15728585-Humans,
pubmed-meshheading:15728585-Infant,
pubmed-meshheading:15728585-Male,
pubmed-meshheading:15728585-Microscopy, Electron, Transmission,
pubmed-meshheading:15728585-Molecular Sequence Data,
pubmed-meshheading:15728585-Mutation,
pubmed-meshheading:15728585-Osteoblasts,
pubmed-meshheading:15728585-Osteogenesis Imperfecta,
pubmed-meshheading:15728585-Peptides,
pubmed-meshheading:15728585-Phenotype,
pubmed-meshheading:15728585-Procollagen N-Endopeptidase,
pubmed-meshheading:15728585-Protein Binding,
pubmed-meshheading:15728585-Protein Conformation,
pubmed-meshheading:15728585-Protein Folding,
pubmed-meshheading:15728585-Protein Structure, Secondary,
pubmed-meshheading:15728585-Protein Structure, Tertiary,
pubmed-meshheading:15728585-Sequence Homology, Amino Acid,
pubmed-meshheading:15728585-Skin,
pubmed-meshheading:15728585-Time Factors
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pubmed:year |
2005
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pubmed:articleTitle |
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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pubmed:affiliation |
Bone and Extracellular Matrix Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892, USA.
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pubmed:publicationType |
Journal Article
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