The broad objective of this research proposal is to improve our understanding of thyroid physiology through the detailed study of patients with genetic defects at key regulatory processes, in combination with complementary studies in animal models. More specifically, a dual clinical and laboratory approach is proposed to study two hormone resistance syndromes, resistance to thyroid hormone (RTH) and resistance to thyrotropin (RTSH), for which the etiologies of important subtypes remain unknown. The etiology of RTH without TH receptor (TR) gene mutations (nonTR-RTH) will be determined. Th hypothesis, based on preliminary data, that nonTR-RTH involves a cofactor common to other nuclear receptors will be examined. 1) Clinical studies will search for resistance to glucocorticoid and sex hormone. 2) Fibroblasts from RTH subjects with and without TR gene mutations will be examined for phenotypic differences in their responses to TH and dexamethasone, using microarrays. 3) Families with nonTR-RTH will be examined for linkage to candidate genes. 4) Cofactors isolated from the fibroblasts of nonTR-RTH subjects by pull down techniques will be analyzed. Furthermore, the involvement of cofactors in the variability of the RTH phenotype will be studied by: 1) Analysis of large families with the same TRB gene mutation, for linkage of the RTH phenotype to candidate cofactor genes. 2) Crossing of mice with a targeted TRJ3 gene mutation with mice Strains of different TH sensitivity in order to identify putative modifiers of the RTH phenotype. RTSH is characterized by an elevated serum TSH level in the presence of a normal or hypoplastic thyroid gland. In the USA and in Europe only 20 percent of subjects with RTSH have loss-of-function mutations in the TSH receptor gene. Five large families with dominantly inherited RTSH, in which the involvement of 5 other candidate genes (TSH receptor, Pax8, TTF-1, TTF-2 and GSa) has been ruled out, will be analyzed by genome-wide screening. In the endemic iodine deficient region of the Ubangui (Africa), RTSH manifests as myxedematous agoitrous cretinism despite the presence of a thyroid gland in the normal location and very high serum TSH levels. In contrast, euthyroid subjects have goiters of variable sizes. The cause of this endemic form of RTSH will be determined. The TSH receptor gene will be examined for possible mutations. The possibility for a gain-of-function mutation in the H202 generating-THOX gene will be explored, based on its selection for iodide retention in the heterozygous state that could cause gland destruction in homozygotes.
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