MUTATIONS IN TYPE-1 PROCOLLAGEN THAT CAUSE OSTEOGENESIS IMPERFECTA - EFFECTS OF THE MUTATIONS ON THE ASSEMBLY OF COLLAGEN INTO FIBRILS, THEBASIS OF PHENOTYPIC VARIATIONS, AND POTENTIAL ANTISENSE THERAPIES

Work by a large number of investigators over the last decade has estab lished that over 90% of patients with osteogenesis imperfecta have mut ations in one of the two genes for type I procollagen, that most unrel ated probands have different mutations in the genes, and that the muta tions found in most of the serious variants of the disease cause synth esis of abnormal proalpha chains of the protein. The results have demo nstrated that synthesis of structurally abnormal but partially functio nal proalpha chains can interfere with folding of the central region o f the protein into a triple-helical conformation, prevent processing o f the N-terminal propeptides of procollagen, or produce subtle alterat ions in conformation that interfere with the self-assembly of the prot ein into collagen fibrils. One of the unsolved mysteries about the dis ease is why some mutations produce severe phenotypes, whereas very sim ilar mutations produce mild phenotypes. Recent studies in transgenic m ice suggest that nongenetic factors, such as stochastic events during development, may determine the severity of the phenotype produced by a specific mutation. Also, recent results raised the possibility that s trategies of antisense gene therapy may be effective in treating the d isease some time in the future. Specific inhibition of expression of a mutated collagen gene has been obtained with antisense oligonucleotid es in cell culture experiments. However, there is no means of selectiv e delivery of antisense oligonucleotides to the appropriate tissues.