2 CYSTEINE SUBSTITUTIONS IN PROCOLLAGEN-I - A GLYCINE REPLACEMENT NEAR THE N-TERMINUS OF ALPHA-1(I) CHAIN CAUSES LETHAL OSTEOGENESIS IMPERFECTA AND A GLYCINE REPLACEMENT IN THE ALPHA-2(I) CHAIN MARKEDLY DESTABILIZES THE TRIPLE HELIX

Cultured skin fibroblasts were examined from two probands with type II (lethal) osteogenesis imperfecta. One proband had a single base mutation which converted the glycine codon at position alpha1-244 in the alpha1(I) chain of procollagen I into a cysteine codon whereas the other had a similar mutation that converted the glycine codon at position alpha2-787 of the alpha2(I) chain into a cysteine codon. Both mutations produced posttranslational overmodification of procollagen I. The Cys alpha1-244 mutation, however, had a minimal effect on the thermal stability or secretion of the protein whereas the Cys alpha2-787 mutation markedly decreased the thermal stability and, apparently as a result, essentially none of the mutated protein was secreted. The results provide clear exceptions to two previous generalizations about the position-specificity of glycine substitutions in procollagen I.