Substitution of an aspartic acid for glycine 700 in the alpha 2(I) chain of type I collagen in a recurrent lethal type II osteogenesis imperfecta dramatically affects the mineralization of bone.

Abstract

We describe a new dominant mutation of type I collagen responsible for a recurrent lethal osteogenesis imperfecta. Dermal cultured fibroblasts of the proband produced both normal and overmodified type I collagen chains. Previous results (Cohen-Solal, L., Bonaventure, J., and Maroteaux, P. (1991) Hum. Genet. 87, 297-301) and cyanogen bromide peptide mapping after non-equilibrium pH gradient gel electrophoresis indicated that the anomaly was a charge mutation localized in the alpha 2CB3-5A. The mutation was identified as a G to A transition in the COL1A2 gene, which converts glycine 700 to aspartic acid in the alpha 2I chain. This mutation caused the abolition of a ScrFI site, which was also absent in the suspected mosaic father. Pulse-chase experiment showed intracellular retention and increase of the degradation of the synthesized collagen. To understand more directly the tissue defect in osteogenesis imperfecta, skin and especially bone were studied with biochemical and transmission electron microscopy techniques. Collagen matrix of both tissues was dramatically decreased and presented a retarded migration, showing that abnormal molecules were incorporated during the fibrillogenesis. The abnormal collagen mostly remained within the fibroblasts and osteoblasts, which presented typical features of intracellular retention. We observed the presence of spheritic aggregates of mineral, unrelated to the scarce and thin collagen fibrils, in bone. Such abnormal mineralization could be the consequence not only of the decrease of the collagen content but more importantly of the inability of the abnormal molecules to form an organized network necessary to the deposition of apatite crystallites.