My overall objective is to contribute to the understanding of why expression of specific genes is deranged in different human genetic diseases. Using restriction mapping, cloning and nucleotide suquencing, I will study the mutations, rearrangements, and altered modification states of polypeptide hormone or collagen genes that are associated with clinical symptoms. Specific objectives of these studies include determining (1) the molecular basis of growth hormone (GH) gene deletions and familial types of GH deficiency; (2) the origin of a spcific GH gene polymorphism; (3) the contributions of alterations in the parathyroid hormone (PTH) gene, its copy number or methylation state to different types of hyperparathyroidism; (4) the contribution of pro Alpha1(1) or pro Alpha2(1) collagen gene alterations to osteogenesis imperfecta (OI), OI associated with GH deficiency, or the Marfan syndrome; (5) the chromosomal assignment of the arginine vasopressin (AVP) gene, its copy number, and allelic forms seen in individuals with familial diabetes insipidus due to AVP deficiency and (6) the contribution of insulin gene alterations in certain mandelian types of diabetes mellitus. Alterations found in the polypeptide hormone or collagen genes which are associated with familial disorders affecting the expression of these genes should have similarities to defects in other inborn errors of metabolism and should provide insight into the functional relationship between normal gene structure and expression.
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