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Molecular Pathogenesis of Osteogenesis Imperfecta.
Peter H. Byers University of Washington, Seattle, WA, USA |
Despite the identification of more than 200 mutations in the type I collagen genes that give rise to the osteogenesis imperfecta (OI) phenotypes, the understanding of how these mutations produce the sometimes dramatic clinical effects remains a major challenge. Mutations in the type I collagen genes that result in OI have many different effects. OI type I results almost exclusively from mutations that result in loss of mRNA from one COL1A1 allele; these mutations usually lead, by a variety of mechanisms to premature termination codons that destabilize the mRNA. The consequence of all these mutations is the synthesis of about half the usual amount of type I procollagen but molecules that are normal. This clearly alters the relative amounts of many species of macromolecules in bone matrix, can alter fibril formation, and alters the architecture of both the cortical and cancellous bone. The physical properties of these bones differ although the overall architecture is unaltered. Other classes of mutations lead to the types of OI in which bone deformity is common. In contrast to the purely (or almost purely) quantitative alteration in OI type I, in OI types II, III, and IV the genetic alterations lead to both quantitative and qualitative abnormalities in type I collagen. Mutations may alter sequences in the C-teminal propeptide and interfere with chain assembly. Those in the triple helical domain affect helix propagation and molecular folding, or affect extracellular processing and intermolecular interactions in the matrix. Different classes of mutations may activate stress responses within the cell, lead to degradation of abnormal proteins by proteosomal systems, lead to striking intracellular accumulation, alter N-teminal cleavage, and interfere with fibrillogenesis and mineralization. Many of these mutations have dramatic effects on bone morphology and growth, and startling effects on bone integrity. It is striking that even very small amounts of an abnormal molecule can have highly deleterious effects. The phenotypic effects reflect the type of mutation in collagen genes and how those mutations alter the amount and structure of type I collagen produced by cells in bone. Although the effects of the mutations on the protein and protein processing are being identified, there remains considerable uncertainty as to the precise mechanisms in bone that lead to changes in morphology, structure, and integrity. NIH AR41223. Reference: Proceedings of the 7th International Conference on Osteogenesis Imperfecta. Montreal, Canada, 1999. |