DELETION OF A GLY-PRO-PRO REPEAT IN THE PRO-ALPHA-2(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 stu dies 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-termi nal location of the structural abnormality in the collagen triple heli x. Sequencing of the gene encoding the alpha 2(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 i n question was electrophoresed in a 12% polyacrylamide gel, two bands with a difference in size of nine base pairs could be shown. Sequencin g of the lower molecular weight band confirmed the deletion of the nin e base pairs involving codons 1003-1006 of COL1A2. The deletion introd uced a SfiI restriction site that was used for confirmation of the del etion in genomic DNA from the proband. The deletion resulted in the re moval 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 i n the more common glycine substitutions. We discuss the ways in which this deletion could result in osteogenesis imperfecta.