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Direct DNA Testing Of Collagen I Genes In Osteogenesis Imperfecta.
Darwin J. Prockop, Jarmo Korkko, Maureen Kinnarney and Leena Ala-Kokko MCP Hahnemann University, Philadelphia, Pennsylvania, USA. |
Collagen I is encoded by the COL1A1 and COL1A2 genes. Defects in these genes have been shown to be responsible for the vast majority of osteogenesis imperfecta cases. Protein analysis has been routinely used to evaluate the properties of collagen I in patients with osteogenesis imperfecta. This approach is well-documented, relatively sensitive and can be used in most, but not all, cases. We have developed a direct DNA test for the COL1A1 and COL1A2 genes for situations where collagen analysis can not be used such as when collagen I expressing cells are not available or time constraints do not allow fibroblast culturing and/or when it is practical to get a rapid mutation analysis (other affected family members, prenatal diagnosis). To date, we have analyzed the COL1A1/COL1A2 genes from 107 patients with different forms of osteogenesis imperfecta and from 23 individuals with referral of osteogenesis imperfecta versus child abuse. The genetic defect underlying the disease was detected in about 82% of the patients with osteogenesis imperfecta. The highest mutation detection rate (36 of 38, 95%) was observed in the patients with osteogenesis imperfecta type IA (multiple fractures, distinctly blue sclerae and normal or nearly normal stature), and the lowest (20 of 31, 65%), in patients with other mild or moderate forms of the disease, OI type I (excluding IA) and IV. In the severe OI forms (OI type II and III), the mutation detection rate was 82% (32/39). Of the 7 patients (OI type II and III) with no mutation detected, 5 were diagnosed with osteogenesis imperfecta based on the early prenatal ultrasound findings. The COL1A1/COL1A2 analysis of the samples with referral of osteogenesis imperfecta vs child abuse revealed a gene defect in 2 individuals of 23. Both individuals with the mutation had, in addition to fractures, other OI related findings such as blue sclerae. We conclude that COL1A1/COL1A2 DNA test detects the genetic defect in comparable or maybe in slightly higher rate than the protein analysis. The COL1A1/COL1A2 test seems to be especially sensitive in patients with osteogenesis imperfecta featuring multiple fractures, distinctly blue sclerae and normal/nearly normal stature (OI type IA). Also, COL1A1/COL1A2 gene defects do not seem to have an important role in osteogenesis imperfecta vs child abuse etiology if fractures are the only manifestation. Reference: Proceedings of the 7th International Conference on Osteogenesis Imperfecta. Montreal, Canada, 1999. |