Deletion of a Gly-Pro-Pro repeat in the proα2(I) chain of procollagen I in a family with dominant osteogenesis imperfecta type IV

Abstract

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 1, 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 α2(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 lower molecular weight band confirmed the deletion of the nine base pairs involving codons 1003–1006 of COL1A2. The deletion introduced aSfiI 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.