Osteogenesis imperfecta: phenotypic heterogeneity, protein suicide, short and long collagen.
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Recent experimental work has demonstrated that mutations that alter the synthesis or structure of type I collagen, or of its precursor type I procollagen, are the cause of the brittleness of bones seen in many variants of osteogenesis imperfecta (OI). They also account for the hyperextensibility of skin, tendons, and ligaments seen in some variants of Ehlers-Danlos syndrome (EDS). Many of the recent findings are not particularly surprising. Type I collagen is the principal protein of bone; it accounts for about half of the dry weight of the bone and as much as 85% of the demineralized dry weight of the tissue. Three aspects of recent discoveries, have been surprising. One surprise has been that a mutation that alters the structure of one region of the type I procollagan can produce a disease that primarily affects skin, tendons, and ligaments, whereas a mutation that makes a very similar change in another part of the same molecule produces a disease that primarily affects bone. A second surprise in the recent work on molecular defects in OI and EDS has been the discovery of a phenomenon that can be referred to as 'protein suicide'. One variant of OI is produced by a deletion of about 500 base pairs (bp) in about the middle of one allele for the pro1(I) chain. The deletion leaves coding sequences on either side of the deletion in register. As a result, the allele is expressed and half the pro1 chains synthesized by fibroblasts from the patient are shortened by about 80 amino acids. The other allele for pro1 chains is normal, and half the pro1 chains synthesized are normal. However, because the structure of the pro1(I) chain beyond the deletion is normal, the shortened pro1 chains associate with and become disulfide-linked to normal pro1 and pro2 chains synthesized by the same fibroblasts. Three-fourths of the procollagen trimers synthesized by fibroblasts contain either one or two shortened pro chains. The shortening of the pro1(I) chain in this variant is so great that the presence of even one shortened pro1 chain in this variant is so great that the presence of even one shortened pro1 chain in a procollagen molecule prevents it from folding into a triple-helical conformation. Therefore, trimers containing either one or two shortened pro1 chains cannot be used to form collagen fibers. Instead, they are rapidly degraded. The third surprise from recent work on OI and EDS has been the discovery that mutations that shortened or lengthened the pro chains of type I procollagen are relatively common. Of the first 15 variants of OI we have examined in our own laboratory, three involved synthesis of a shortened pro1 or pro1 chain. Two others may possibly involve synthesis of a lengthened pro1 chain. Byers et al. reported on another variant of OI with a shortened pro2(I) chain and a variant of the Marfan syndrome with a lengthened pro2(I) chain. The reasons for the high frequency of such mutations in procollagen genes is not clear. In the best studied example, a shortened pro1 chain is synthesized because of a partial deletion of the allele. Procollagen genes may be particularly prone to such mutations because the coding sequences are highly repetitive with frequent sequences of -GGN-CCN-CCN- coding for -Gly-Pro-Hyp- in the -chain domains of the protein. The repetitive DNA sequences may well predispose the genes to unequal cross-over mutations during meiosis.
