Deletion of a Gly-Pro-Pro repeat in the pro alpha2(I) chain of procollagen I in a family with dominant osteogenesis imperfecta type IV.

We have investigated one member of a family with dominant osteogenesis imperfecta type IV through three generations. In protein-chemical studies of cultured fibroblasts derived from the proband, collagen I was overmodified, with normal processing of procollagen I, normal thermal stability, and a cyanogen bromide peptide map that suggested a C-terminal location of the structural abnormality in the collagen triple helix. Sequencing of the gene encoding the alpha2(I) chain of collagen I (COL1A2) indicated a nine base-pair deletion of nucleotides 3418-3426. When a polymerase chain reaction product containing the nucleotides in question was electrophoresed in a 12% polyacrylamide gel, two bands with a difference in size of nine base pairs could be shown. Sequencing of the molecular weight band confirmed the deletion of the nine base pairs involving codons 1003-1006 of COL1A2. The deletion introduced a SfiI restriction site that was used for confirmation of the deletion in genomic DNA from the proband. The deletion resulted in the removal of three amino acids (Gly-Pro-Pro), but this did not disrupt the Gly-X-Y sequence of the collagen triple helix, as is often the case in the more common glycine substitutions. We discuss the ways in which this deletion could result in osteogenesis imperfecta.