OSTEOGENESIS IMPERFECTA - COMPARISON OF MOLECULAR DEFECTS WITH BONE HISTOLOGICAL-CHANGES

Osteogenesis imperfecta (OI) is a group of inherited disorders charact erized by a predisposition to bone fracturing, and usually resulting f rom mutations in the genes encoding type I collagen. This report descr ibes the molecular defects in a patient with type II OI and another wi th type III OI. These patients were demonstrated to possess point muta tions resulting in glycine --> arginine substitutions within the tripl e 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 th e alpha 1(I) triple helical domain, and constitutes the most amino-ter minal lethal glycine --> arginine substitution described to date. The substitution in the type III OI patient affected residue 427 of the al pha 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 su bstitutions undergo a transition between lethal and nonlethal forms, t hereby allowing a more reliable prognosis of disease severity. The his tological examination of bone from these patients revealed striking ab normalities in the quantity and organization of mineralized bone struc tures, 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 I I and III, and that parameters external to the gene mutations might ac count for the survival differences in the 2 cases presented in this st udy.