Mutations in osteogenesis imperfecta leading to the synthesis of abnormal type I procollagens.
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abstract
What are the conclusions one can draw at this stage about these mutations that lead to the synthesis of structurally abnormal procollagens? One is that mutations that cause the synthesis of a shortened pro-1(I) or a shortened pro-2(I) chain appear to be relatively prevalent in the population of patients with osteogenesis imperfecta. The total number of patients who have been examined in detail is still small and the techniques that are being used to study cultured fibroblasts are far more sensitive to changes in size of the pro- chains than any other structural change. Therefore this conclusion may have to be modified as further data are developed. However, the results at the moment strongly suggest that collagen genes may be unusually prone to mutations that shorten or lengthen the genes. Detailed examination of the precise nucleotide changes in these mutated genes should provide interesting information about the specific vulnerabilities of collagen genes to mutations and perhaps about the specific role of the large number of intervening sequences in the genes. A second conclusion is that synthesis of a structurally abnormal pro- chain is, in many of the variants, more deleterious than decreased synthesis of the same normal pro- chain. As discussed above, in-phase deletions in one allele can cause biological inactivation of normal pro- chains synthesized in the same cell from normal alleles. Therefore such in-phase deletions can reduce the synthesis of biologically active procollagen to a greater extent than a mutation which makes a gene inactive. A third conclusion is that some of the structural features of the procollagen molecule are essential for the normal function of some tissues but less important in other tissues. In some variants of osteogenesis imperfecta, synthesis of a structurally abnormal type I procollagen clearly explains the increased brittleness of bones. In the same patients, however, tissues such as skin and ligaments shown no gross abnormalities. Conversely, one variant of EDS type VII B synthesizes structurally abnormal type I procollagen which causes increased joint laxity but apparently has no effect on the structure and function of bone.
