. The broad objective of this research proposal is to gain knowledge about the molecular mechanisms of thyroid physiology through the identification and characterization of human genetic errors causing defects of thyroid hormone regulation, synthesis, transport and action. Abnormal gene products will be characterized at the molecular level, and animal models will be generated for in-depth phenotype analysis. Five areas of study are proposed: (1) Subjects expressing the phenotype of thyrotropin resistance will be studied, in order to identify a putative thyrotropin-beta with reduced bioactivity, as well as thyrotropin receptor defects. The mechanism whereby in some families resistance to thyrotropin is inherited in an apparent dominant fashion, will also be included. (2) The sodium/iodide symporter will be sequenced in two families with iodide trapping defect and the nature of the functional defect will be characterized by in vitro expression. In addition, a genome-wide homozygosity screen will be used to identify the gene locus in a large Amish kindred with an apparent iodide organification defect. (3) The molecular basis of defects of thyroxine-binding globulin, transthyretin and albumin, will be identified and characterized. (4) The etiology of resistance to thyroid hormone in the absence of thyroid hormone receptor beta or alpha defects will be investigated, and the possibility of a defective corepressor or coactivator will be explored. In addition, a clinical protocol will be used to identify new families with thyroid hormone hypersensitivity and laboratory studies will be carried out to determine the molecular basis of this syndrome. (5) Finally, the role of genetic background on the variable clinical severity of the syndrome of thyroid hormone resistance will be explored, using mice strains with differing sensitivity to thyroid hormone. Somatic gene transfer of mutant thyroid hormone receptors will be performed, and the transgenic mice outbred to examine the effects on phenotypicexpression of the thyroid hormone resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK015070-27
Application #
2733959
Study Section
Endocrinology Study Section (END)
Program Officer
Linder, Barbara
Project Start
1979-07-15
Project End
2001-06-30
Budget Start
1998-07-05
Budget End
1999-06-30
Support Year
27
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Bellelli, Roberto; Vitagliano, Donata; Federico, Giorgia et al. (2018) Oncogene-induced senescence and its evasion in a mouse model of thyroid neoplasia. Mol Cell Endocrinol 460:24-35
Watanabe, Y; Sharwood, E; Goodwin, B et al. (2018) A novel mutation in the TG gene (G2322S) causing congenital hypothyroidism in a Sudanese family: a case report. BMC Med Genet 19:69
Berger, Hara Rosen; Creech, Matthew K; Hannoush, Zeina et al. (2017) A NOVEL MUTATION CAUSING COMPLETE THYROID BINDING GLOBULIN DEFICIENCY (TBG-CD MIA) IN A MALE WITH COEXISTING GRAVES DISEASE. AACE Clin Case Rep 3:e134-e139
Grasberger, Helmut; Refetoff, Samuel (2017) Resistance to thyrotropin. Best Pract Res Clin Endocrinol Metab 31:183-194
Srichomkwun, Panudda; Admoni, Osnat; Refetoff, Samuel et al. (2016) A Novel Mutation (S54C) of the PAX8 Gene in a Family with Congenital Hypothyroidism and a High Proportion of Affected Individuals. Horm Res Paediatr 86:137-142
Villacorte, Mylah; Delmarcelle, Anne-Sophie; Lernoux, Manon et al. (2016) Thyroid follicle development requires Smad1/5- and endothelial cell-dependent basement membrane assembly. Development 143:1958-70
Choudhary, Abha; Sriphrapradang, Chutintorn; Refetoff, Samuel et al. (2015) Familial dysalbuminemic hyperthyroxinemia in a 4-year-old girl with hyperactivity, palpitations and advanced dental age: how gold standard assays may be misleading. J Pediatr Endocrinol Metab 28:241-5
Larsen, Cæcilie C; Karaviti, Lefkothea P; Seghers, Victor et al. (2014) A new family with an activating mutation (G431S) in the TSH receptor gene: a phenotype discussion and review of the literature. Int J Pediatr Endocrinol 2014:23
Ikegami, Keisuke; Liao, Xiao-Hui; Hoshino, Yuta et al. (2014) Tissue-specific posttranslational modification allows functional targeting of thyrotropin. Cell Rep 9:801-10
Ferrara, Alfonso Massimiliano; Liao, Xiao-Hui; Gil-Ibáñez, Pilar et al. (2014) Placenta passage of the thyroid hormone analog DITPA to male wild-type and Mct8-deficient mice. Endocrinology 155:4088-93

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