Showing papers by "Joan C. Marini published in 2006"
TL;DR: Three of 10 children with lethal or severe osteogenesis imperfecta were found to have a recessive condition resulting in CRTAP deficiency, suggesting that prolyl 3-hydroxylation of type I collagen is important for bone formation.
Abstract: Classic osteogenesis imperfecta, an autosomal dominant disorder associated with osteoporosis and bone fragility, is caused by mutations in the genes for type I collagen. A recessive form of the disorder has long been suspected. Since the loss of cartilage-associated protein (CRTAP), which is required for post-translational prolyl 3-hydroxylation of collagen, causes severe osteoporosis in mice, we investigated whether CRTAP deficiency is associated with recessive osteogenesis imperfecta. Three of 10 children with lethal or severe osteogenesis imperfecta, who did not have a primary collagen defect yet had excess post-translational modification of collagen, were found to have a recessive condition resulting in CRTAP deficiency, suggesting that prolyl 3-hydroxylation of type I collagen is important for bone formation.
302 citations
TL;DR: As in Ehlers-Danlos syndrome (EDS) VIIA/B, fibrils containing pN-collagen are thinner and weaker causing EDS-like laxity of large and small joints and paraspinal ligaments, however, distinct structural consequences of N-anchor destabilization result in a distinct alpha1(I)-osteogenesis imperfecta (OI)/EDS phenotype.
79 citations
TL;DR: Mutation detection in OI is important for counselling, reproductive decisions, exclusion of child abuse, and genotype-phenotype correlations and requires supplementation by molecular analysis of cDNA or gDNA in the amino third of α1(I) and amino half of α2(I).
Abstract: Background: The biochemical test for osteogenesis imperfecta (OI) detects structural abnormalities in the helical region of type I collagen as delayed electrophoretic migration of alpha chains on SDS-urea-PAGE. Sensitivity of this test is based on overmodification of alpha chains in helices with a glycine substitution or other structural defect. The limits of detectability have not been reported. Methods: We compared the collagen electrophoretic migration of 30 probands (types III or IV OI) with known mutations in the amino half of the α1(I) and α2(I) chains. Differences in sensitivity were examined by 5% and 6% SDS-urea-PAGE, and with respect to alpha chain, location along the chain, and substituting amino acid. Results: Sensitivity was enhanced on 5% gels, and by examination of intracellular and secreted collagen. In α1(I), substitutions in the first 100 residues were not detectable; 7% of cases in the current Mutation Consortium database are in this region. α1(I) substitutions between residues 100 and 230 were variably detectable, while those after residue 232 were all detected. In α2(I), variability of electrophoretic detection extended through residue 436. About a third of cases in the Consortium database are located in the combined variable detection region. Biochemical sensitivity did not correlate with substituting residue. Conclusions: Complete testing of probands with normal type I collagen biochemical results requires supplementation by molecular analysis of cDNA or gDNA in the amino third of α1(I) and amino half of α2(I). Mutation detection in OI is important for counselling, reproductive decisions, exclusion of child abuse, and genotype-phenotype correlations.
21 citations
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