GENETIC ANALYSIS--PEPTIDE HORMONE AND COLLAGEN DISORDER

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Human growth hormone deficiency (GHD) has an incidence of approximately 1/4,000 to 1/110,000 births. An unknown but significant proportion of cases are familial because up to 30% of those affected have an affected parent or child. Replacement therapy with GH derived by recombinant DNA techniques is expensive but necessary to avoid Creutzfeldt-Jakob disease caused by viral contamination of GH isolated from cadaver pituitaries. Arginine vasopressin (AVP) deficiency causes diabetes insipidus (DI) of which 1/50 human cases are familial. DI has significant associated morbidity and mortality and its treatment requires careful water, electrolyte and AVP replacement. In previous studies I have discovered the molecular basis of a variety of familial forms of GHD including gene deletions that arise through recombination, developed a PCR method to detect GH deletions and detected recessive and "dominant-negative" mutations that affect alternative splicing of GH. I have mapped the locus for DI due to AVP deficiency and detected recurring "dominant-negative" mutations that affect cleavage of AVP's signal peptide or AVP expression. My overall goals are to explore the five concepts that "dominant-negative" mutations of AVP and GH1 are heterogeneous and probably have their effect at the protein level; alternative splicing differs qualitatively and quantitatively between normal and abnormal GH1 alleles due, in some cases, to mutations in stem loops in IVSs that are not splicing consensus sequences; analysis of mutant products should give insights to intracellular trafficking and secretion mechanisms, and less severe mutations may contribute to normal variations in growth. To achieve these goals I plan to determine the: 1) gene alterations causing autosomal recessive, autosomal dominant, X-linked and sporadic forms of isolated GHD, 2) mechanism(s) by which various gene alterations cause GHD, and 3) molecular basis of familial forms of DI that are associated with AVP deficiency. Characterization of the molecular basis of GH and AVP deficiency will provide insight to the 1) mechanisms of how derangement of genes for monomeric hormones cause autosomal recessive or dominant phenotypes, 2) pathogenesis of analogous "dominant-recessive" endocrine disorders, 3) mechanisms of molecular and protein trafficking within cells, and 4) functional relationships between normal gene structure, function and homeostasis.