Human growth hormone (GH) deficiency has an incidence of approximately 1/4,000 to 1/10,000 births. A significant proportion of cases must be familial because up to )0% of affected individuals have an affected parent or child. The cost of replacement therapy with GH derived by recombinant DNA techniques is significant and until recombinant DNA derived GH was available replacement with human GH was associated with risk for transmitting Creutzfeldt- Jakob disease due to viral contamination of GH isolated from human pituitaries. Arginine vasopressin (AVP) deficiency causes diabetes insipidus (DI) and about 1/50 human cases are familial. DI can be associated with significant morbidity and mortality and its treatment requires careful fluid, electrolyte and AVP replacement. In previous studies I have discovered that the molecular defect responsible for one form of familial GH deficiency is deletion of the GH genes. Treatment of this severe disorder is made difficult by the frequent occurrence of immunologic intolerance to exogenous GH. Preliminary linkage studies of familial DI suggest that an autosomal dominant form may be due to alterations of the AVP gene. My overall goals are to determine the molecular basis of various familial forms of GH or AVP deficiency and to determine the contribution of GH related genes to normal fetal growth. To achieve these goals I plan the following studies: 1) Determine the basic mechanism responsible for recurrent deletions of GH genes in humans; 2) derive a genetic linkage map of human chromosomes 17 and 20 that provide insight to the loci tightly linked to GH and AVP respectively; 3) determine the molecular basis of autosomal dominant, autosomal recessive and X-linked forms of GH deficiency; 4) determine the importance of selected GH related genes to fetal growth, and 5) determine the molecular basis of familial AVP deficiency. The genetic map distances found between various loci and the fetal expression of GH related genes are of general interest. Characterization of the basic defect(s) causing familial AVP or GH deficiency would have great importance in genetic counseling and understanding the pathogenesis of these disorders. Insight to their pathophysiology could, in turn, lead to possible alternative forms of therapy. Finally, mutations affecting the AVP and GH loci should have analogies to defects in other genetic disorders and should provide insight into the functional relationships between normal gene structure and function.
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