Osteogenesis imperfecta: comparison of molecular defects with bone histological changes.

Osteogenesis imperfecta (OI) is a group of inherited disorders characterized by a predisposition to bone fracturing, and usually resulting from mutations in the genes encoding type I collagen. This report describes the molecular defects in a patient with type II OI and another with type III OI. These patients were demonstrated to possess point mutations resulting in glycine-->arginine substitutions within the triple helical domain of the alpha 1(I) or alpha 2(I) collagen polypeptide chain. The defect in the type II OI patient affected residue 211 of the alpha 1(I) triple helical domain, and constitutes the most amino-terminal lethal glycine-->arginine substitution described to date. The substitution in the type III OI patient affected residue 427 of the alpha 2(I) triple helical domain. Both defects were informative in that they identified the regions of the alpha 1(I) and alpha 2(I) collagen chains in which the phenotypes associated with glycine-->arginine substitutions undergo a transition between lethal and nonlethal forms, thereby allowing a more reliable prognosis of disease severity. The histological examination of bone from these patients revealed striking abnormalities in the quantity and organization of mineralized bone structures, compared with age-matched controls. Although the patients were differently classified, no major differences in the magnitude of bone architectural changes could be perceived, consistent with the presence of their defects near a common phenotypic transition. The results are compatible with there being a gradient in severity between OI types II and III, and that parameters external to the gene mutations might account for the survival differences in the 2 cases presented in this study.