SUBSTITUTIONS OF ASPARTIC-ACID FOR GLYCINE-220 AND OF ARGININE FOR GLYCINE-664 IN THE TRIPLE-HELIX OF THE PRO-ALPHA-1(I) CHAIN OF TYPE-I PROCOLLAGEN PRODUCE LETHAL OSTEOGENESIS IMPERFECTA AND DISRUPT THE ABILITY OF COLLAGEN FIBRILS TO INCORPORATE CRYSTALLINE HYDROXYAPATITE

We identified two infants with lethal (type II) osteogenesis imperfect a (OI) who were heterozygous for mutations in the COL1A1 gene that re sulted in substitutions of aspartic acid for glycine at position 220 a nd arginine for glycine at position 664 in the product of one COL1A1 a llele in each individual. In normal age- and site-matched bone, approx imate to 70 % (by number) of the collagen fibrils ware encrusted with plate-like crystallites of hydroxyapatite. In contrast, approximate to 5 % (by number) of the collagen fibrils in the probands' bone contain ed crystallites. In contrast with normal bone, the c-axes of hydroxyap atite crystallites were sometimes poorly aligned with the long axis of fibrils obtained from OI bone. Chemical analysis showed that the OI s amples contained normal amounts of calcium. The probands' bone samples contained type I collagen, overmodified type I collagen and elevated levels of type III and V collagens. On the basis of biochemical and mo rphological data, the fibrils in the OI samples were co-polymers of no rmal and mutant collagen. The results are consistent with a model of f ibril mineralization in which the presence of abnormal type I collagen prevents normal collagen in the same fibril from incorporating hydrox yapatite crystallites.