PATHOPHYSIOLOGY AND TREATMENT OF HUMAN GENETIC DISEASES

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We have continued studies to elucidate the molecular basis of heritable connective tissue disorders, and to apply this information to treatment of the disease. We have developed a system for the detection of point mutatiom in Type 1 collagen mRNA by RNase A digestion of mismatches in RNA/RNA hybrids. Anti-sense riboprobe is hybridized to the mRNA of the patient. This system allows for more rapid detection and more accurate localization of mutations than had been possible with the collagen protein system. Several mutations have been localized in patients with Osteogenesis Imperfecta and are now being sequenced. Continued work on the collagen protein of fibroblasts and Osteoblasts of Osteogenesis Imperfecta patients has allowed the delineation of the extent and direction of over modification. The effect on the osteoblast metabolism of non-collagen matrix proteins has revealed some abnormalities. We have demonstrated that chorionic villi express the same collagen defect as is expressed by the fibroblasts of OI patients; this will allow earlier prenatal diagnosis in selected cases. In clinical protocols on Osteogenesis Imperfecta, we have demonstrated abnormalities of growth hormone secretion and IGF-l stimulation associated with short stature. A pilot study of growth stimulation was encouraging. We have continued our rehabilitation and bracing protocol for children with moderately severe OI.