Osteogenesis imperfecta (OI) is clinically characterized by abnormal bone fragility, with most patients harboring heterozygote germline mutations in the COL1A1 or COL1A2 genes that encode the chains of type I procollagen, the major protein in bone. More than 250 mutations in both genes in OI patients have been reported, mostly missense mutations affecting glycine residues in the triple helical domains of the two chains. These mutations disrupt protein folding and structure, and their effects often can be detected by the analysis of proteins synthesized but cultured fibroblasts or, less often, osteoblasts. In this study, mutational analysis of all the COL1A1 and part of the COL1A2 was performed using exon-specific PCR amplification followed by denaturing gradient gel electrophoresis (DGGE) analysis and complemented by DNA sequencing in 57 Israeli OI patients from 55 unrelated families. Protein analysis was also performed using cultured fibroblasts obtained from a subset of these OI patients. Of 57 OI patients analyzed, 35 had OI type 1, 12 has OI type III, 8 had OI type IV, and 2 had OI type II. Fourteen different pathogenic mutations (10 novel) were identified in the COL1A1 gene: 3 missense, 5 nonsense, 3 insertion/deletion frameshift, 2 splice junction mutations, and 1 in frame deletion. We conclude that COL1A1 mutations underlie a subset of Israeli OI patients, that most commonly in OI type I, the mutations are contained within the COL1A1 gene, and that there are no predominant mutations in Jewish OI patients. Lastly, the use of protein analyses complements genetic analyses.
Copyright 2004 Wiley-Liss, Inc.