A single base mutation in type I procollagen (COLIAI) that converts glycine alpha I-541 to aspartate in a lethal variant of osteogenesis imperfecta: Detection of the mutation with a carbodiimide reaction of DNA heteroduplexes and direct seq uencing of products of the PCR

Skin fibroblasts from a proband with a lethal variant of osteogenesis imperfecta synthesized both apparently normal type I procollagen and a type I procollagen that had slow electrophoretic mobility because of posttranslational overmodifications. The thermal unfolding of the collagen molecules as assayed by protease digestion was about 2 degree C lower than normal. It is surprising, however, that collagenase A and B fragments showed an essentially normal melting profile. Assay of cDNA heteroduplexes with a new technique involving carbodiimide modification indicated a mutation at about the codon for amino acid 550 of the alpha 1(I) chain.