Type I procollagen in the severe non-lethal form of osteogenesis imperfecta. Defective pro-alpha 1(I) chains in a patient with abnormal proteoglycan metabolism and mineral deposits in the dermis.
We have screened type I procollagen synthesized in vitro by skin fibroblasts from several patients with the severe non-lethal form of osteogenesis imperfecta. Cells from one patient synthesized and secreted both normal and a larger amount of abnormal type I procollagen. The abnormal alpha chains are larger in size due to post-translational overmodifications involving the whole triple helical domain. Abnormal collagen heterotrimers had a melting temperature 2.5 degrees-3 degrees C lower than normal ones or from controls. Chemical analysis of collagen in the medium showed a greater degree of both lysyl hydroxylation and hydroxylysyl glycosylation, the major increase in molecular mass of overmodified alpha chains being due to the higher hydroxylysine-bound hexose content. The proband's cells modify proteoglycan metabolism and mineral crystals form in the dermis, possibly a response to abnormal collagen-proteoglycan interactions. These findings can be explained by a small defect in the product of one allele for pro-alpha 1(I) chains: three-quarters of the synthesized type I procollagen molecules are composed of trimers containing one or two chains defective near the C-terminus of the triple helix or in the C-propeptide. The data obtained for this patient confirmed that the severity of clinical manifestations in osteogenesis imperfecta strongly depends on the location and nature of the mutations, and that the phenotype could be a consequence of a collagen defect(s) and its influence on collagen-collagen interactions and collagen interactions with other connective tissue components.
Tenni
R
R
Dipartimento di Biochimica, University of Pavia, Italy.
Cetta
G
G
Dyne
K
K
Rossi
A
A
Quacci
D
D
Lenzi
L
L
Castellani
A A
AA
D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003488:Cyanogen Bromide; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D008297:Male; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010449:Peptide Mapping; D011347:Procollagen / Q000235:genetics* / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism*; D012016:Reference Values; D012867:Skin / Q000378:metabolism* / Q000473:pathology
D046911:Macromolecular Substances; D011347:Procollagen; D011509:Proteoglycans; D003488:Cyanogen Bromide