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

We describe a new dominant mutation of type I collagen responsible for a recurrent lethal osteogenesis imperfecta. Dermal cultured fibroblas ts of the proband produced both normal and overmodified type I collage n chains. Previous results (Cohen-Solal, L., Bonaventure, J., and Maro teaux, P. (1991) Hum. Genet. 87, 297-301) and cyanogen bromide peptide mapping after non-equilibrium pH gradient gel electrophoresis indicat ed that the anomaly was a charge mutation localized in the alpha 2CB3- 5(A). 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 cha in. 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 synthes ized collagen. To understand more directly the tissue defect in osteog enesis imperfecta, skin and especially bone were studied with biochemi cal and transmission electron microscopy techniques. Collagen matrix o f both tissues was dramatically decreased and presented a retarded mig ration, showing that abnormal molecules were incorporated during the f ibrillogenesis. The abnormal collagen mostly remained within the fibro blasts and osteoblasts, which presented typical features of intracellu lar retention. We observed the presence of spheritic aggregates of min eral, unrelated to the scarse and thin collagen fibrils, in bone. Such abnormal mineralization could be the consequence not only of the decr ease of the collagen content but more importantly of the inability of the abnormal molecules to form an organized network necessary to the d eposition of apatite crystallites.