Serine for glycine substitutions in type I collagen in two cases of type IV osteogenesis imperfecta (OI). Additional evidence for a regional model of OI pathophysiology

Serine for glycine substitutions in type I collagen have been described in seven cases of lethal type II osteogenesis imperfecta (OI), and six cases of nonlethal OI. We describe here two cases of moderately severe type IV OI with serine substitutions at alpha 1(I) Gly352 and alpha 2(I) Gly922, respectively. In both cases, G-->A point mutations were detected by RNase A cleavage of RNA/RNA and RNA/DNA hybrids. These cases extend the location for serine substitutions producing the moderately severe OI phenotype to the alpha 2(I) chain and the amino-terminal end of the alpha 1(I) chain. Their location supports a regional model of OI pathophysiology for serine substitutions. The proband with alpha 2(I) Gly922-->Ser has both normal and overmodified forms of both type I collagen chains. The overmodified form has delayed migration of all CNBr peptides. Helix thermal stability is decreased 4 degrees C. The fibroblast collagen protein and RNA of her unaffected parents are normal. However, the father was demonstrated to be a mosaic carrier using leukocyte DNA. The fibroblasts of the proband whose serine substitution is at alpha 1(I) Gly352 synthesize type I procollagen chains with delayed electrophoretic migration; normally migrating forms are difficult to detect. Only alpha 1(I) CB 8 displayed delayed migration. Helix thermal stability is reduced 2 degrees C. Parental genomic DNA was normal.