THYROID PHYSIOLOGY STUDIES OF INHERITED DISORDERS

描述：（由申请人提供）本研究的广泛目标 我们的建议是，通过以下方法来提高我们对甲状腺生理学的理解： 详细研究在关键调控过程中存在遗传缺陷的患者， 与动物模型中的互补研究相结合。更具体地称为 提出了临床和实验室双重方法来研究两种激素 抵抗综合征、甲状腺激素抵抗（RTH）和 促甲状腺激素（RTSH），其重要亚型的病因仍然存在 未知 无TH受体（TR）基因突变的RTH（nonTR-RTH）的病因将是 测定根据初步数据，非TR-RTH涉及一种 将检测与其他核受体共同的辅因子。1)临床 研究将寻找对糖皮质激素和性激素的抗性。（二） 来自具有和不具有TR基因突变的RTH受试者的成纤维细胞将被 检查它们对TH和地塞米松反应的表型差异， 使用微阵列。3)将检查非TR-RTH家族与以下疾病的联系： 候选基因4)从非TR-RTH的成纤维细胞分离的辅因子 将分析通过下拉技术的受试者。此外，参与 将通过以下方法研究RTH表型变异性中的辅助因子：1） 分析具有相同TRB基因突变的大家族，以寻找TRB基因突变的连锁关系。 RTH表型与候选辅因子基因。2)小鼠与靶向的 TRJ 3基因突变与不同TH敏感性小鼠品系， 鉴定RTH表型的推定修饰物。 RTSH的特征在于在存在促甲状腺激素的情况下血清TSH水平升高。 正常或发育不良的甲状腺。在美国和欧洲， 的RTSH受试者在TSH受体基因中存在功能缺失突变。 五个显性遗传RTSH的大家庭，其中参与 其他5个候选基因（TSH受体、Pax 8、TTF-1、TTF-2和GSa）已被 排除后，将通过全基因组筛查进行分析。在地方性碘 缺乏地区的乌班吉（非洲），RTSH表现为粘液水肿 尽管在正常甲状腺组织中存在甲状腺， 位置和非常高的血清TSH水平。相反，甲状腺功能正常的受试者 大小不一的甲状腺肿。这种地方性RTSH的原因将是 测定检查TSH受体基因是否存在可能的突变。的 H202生成THOX基因中功能获得性突变的可能性 将探讨，根据其选择的碘化物保留在 杂合子状态，可能导致纯合子腺体破坏。

DESCRIPTION: (provided by applicant) 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.