A CYSTEINE FOR GLYCINE SUBSTITUTION AT POSITION-175 IN AN ALPHA-1-(I)CHAIN OF TYPE-I COLLAGEN PRODUCES A CLINICALLY HETEROGENEOUS FORM OF OSTEOGENESIS-IMPERFECTA

The molecular basis for Osteogenesis Imperfecta in a large kindred wit h a highly variable phenotype was identified by sequencing the mutant pro alpha 1 (I) protein, cDNA and genomic DNA from the proband. Fibrob lasts from different affected individuals all synthesize both normal T ype I procollagen molecules and abnormal Type I procollagen molecules in which one or both pro alpha 1 (I) chain(s) contain a cysteine resid ue within the triple helical domain. Protein studies of the proband lo calized the mutant cysteine residue to the alpha 1 (I) CB 8 peptide.(1 ) We now report that cysteine has replaced glycine at triple helical r esidue 175 disrupting the invariant Gly-X-Y structural motif required for perfect triple helix formation. The consequences include post-tran slational overmodification, decreased thermal stability, and delayed s ecretion of mutant molecules.(2) The highly variable phenotype in the present kindred cannot be explained solely on the basis of the cystein e for glycine substitution but will require further exploration.