Absence of mutations in the promoter of the COL1A1 gene of type I collagen in patients with osteogenesis imperfecta type I.

Osteogenesis imperfecta type I results from decreased production of structurally normal type I collagen as a result of a COL1A1 "null" allele. Steady state amounts of COL1A1 mRNA are reduced in both the nucleus and cytoplasm of dermal fibroblasts from most affected subjects. Mutations involving key regulatory sequences in the COL1A1 promoter, such as the TATAAA and CCAAAT boxes, could alter steady state levels of mRNA, and therefore lead to this phenotype. To determine the frequency of such mutations in OI type I cell strains, we used PCR amplified genomic DNA in conjunction with denaturing gradient gel electrophoresis (DGGE) and SSCP, to screen the 5' untranslated domain, exon 1, and a small portion of intron 1 of the COL1A1 gene. In addition, direct sequence analysis was performed on an amplified genomic DNA fragment that included the TATAAA and CCAAAT boxes. Forty unrelated probands with OI type I, in whom no causative mutation was known, were included in the study. No mutations were included in the study. No mutations were identified in either the TATAAA or CCAAAT boxes in any of the affected people. In addition, there was little evidence of sequence diversity among any of the 40 subjects. These data suggest that mutations in the COL1A1 promoter do not play a significant role in the aetiology of OI type I.