HERITABLE DISORDERS OF CONNECTIVE TISSUE

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The section has continued its studies aimed at elucidating the molecular mechanisms of heritable disorders of connective tissue, specifically osteogenesis imperfecta OI) and Ehlers-Danlos syndrome (EDS), and to apply this information to the treatment of these disorders. One of the primary goals of the Section is to determine the relationship between the type and location of the type I collagen mutation and the severity of the bone disease. To this end, we have applied our collagen protein and RNA hybrid methodology to four cases of OI with a range of severities. We have demonstrated serine for glycine substitutions at different positions along the two collagen chains. We have proposed a regional model of OI pathophysiology in which there is an alternation along the chains of clusters of lethal and non-lethal mutations. In this model, the functional significance of the regions resides in higher order fibrils, secondary effects on osteoblast metabolism or interactions with no-collagenous matrix molecules. We have studied seven cases of mild-moderate EDS, and find that the collagen results in these cases converge with the OI studies. That is, the EDS cases have abnormalities of collagen protein similar to OI cases. Since the symptoms of EDS and OI overlap, except that EDS patients do not have brittle bone disease and osteoporosis, these cases provide important insight into regions of collagen which are non-crucial for bone structure. We are pursuing the molecular description of these cases using SSCP analysis. In clinical studies, we initiated a treatment trial of growth hormone in short children with OI and will determine its effects on linear growth, bone density and bone morphometric properties. We are concluding a collaborative cross-over protocol for weaning OI children from braces. We are exploring new carbon and polymer rodding materials.