Abstract
Structurally abnormal type I collagen was identified in the dermis, bone, and cultured fibroblasts obtained from a baby with lethal perinatal osteogenesis imperfecta. Two-dimensional gel electrophoresis of the CNBr peptides demonstrated that the alpha 1(I)CB7 peptide from the alpha 1(I)-chain of type I collagen existed in a normal form and a mutant form with a more basic charge distribution. This heterozygous peptide defect was not detected in the collagens from either parent. The defect was localized to a 224-residue region at the NH2 terminus of the alpha 1(I)CB7 peptide by mammalian collagenase digestion. Analysis of unhydroxylated collagens produced in cell culture indicated that the mutant alpha 1(I)CB7 migrated faster on electrophoresis suggesting that the abnormality may be a small deletion or a mutation that alters sodium dodecyl sulfate binding. The post-translational hydroxylation of lysine residues was increased in the CB7 peptide and also in peptides CB3 and CB8 which are toward the NH2 terminus of the alpha 1(I)-chain. The COOH-terminal CB6 peptide was normally hydroxylated. These findings support the proposal that the lysine overhydroxylation resulted from a perturbation of helix propagation from the COOH to NH2 terminus of the collagen trimer caused by the structural defect in alpha 1(I)CB7.
Highlights
Abnormatlype I collagen was identified I collagen al(I)-chain inskin, bone, and cultured dermal in the dermis, bone, and cultured fibroblasts obtainedfibroblasts from a case of lethal perinatal 01
Analysis of unhydroxylacteodllagens produced in cell culture indicated that the mutant al(I)CB7migrated faster on electrophoresis suggesting that the abnormality may be a small deletion or a mutation thatalters sodium dodecylsulfate bind
The lethal perinatal form of osteogenesis imperfecta' is the clinically most severe form of the disease with gross bone fragility and perinatal death. While expressing both clinical and genetic heterogeneity (I), the general biochemical phenotype is characterized by abnormalities of type separated for analysis, and the procollagen from both fractions was precipitated with 25% saturated
Summary
The lethal perinatal form of osteogenesis imperfecta (type XI 01)' is the clinically most severe form of the disease with gross bone fragility and perinatal death While expressing both clinical and genetic heterogeneity (I), the general biochemical phenotype is characterized by abnormalities of type separated for analysis, and the procollagen from both fractions was precipitated with 25% saturated The precipitates were dissolved in 0.05 M Tris-HC1,0.15M NaC1, pH 7.5, and portions were converted to collagen by limited digestion with pepsin (Sigma) as described previously (9). In one case of lethal perinatal, shortened pro- Bone samples (femur) were washed with 0.05 M Tris-HC1, 0.15 M al(1)-chains of type I procollagen(13, 14) result from a multiexon deletion inthe al(1) collagengene (15-17). The residue was freeze-dried and sequentially extracted with 0.5 M acetic acid and 0.5 M acetic acid containing pepsin as described above.
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