The broad objective of this research proposal is to advance understanding of thyroid physiology through study of genetic defects at key regulatory processes. In addition to identification of new syndromes and gene defects, research centers on the mediation of thyroid hormone (TH) effects by studying syndromes of reduced sensitivity to TH due to defects in cell membrane transport, metabolism and action. These are caused, respectively, by mutations in the MCT8 (monocarboxylate transporter 8), SBP2 (selenocysteine insertion sequence-binding protein 2) and TRIl (nuclear TH receptor IJ) genes and others not yet identified. Each is studied by a triple approach, clinical (in vivo), tissue and gene expression (in-vitro) and animal models (gene altered mice that recapitulate the defect in humans). Each approach complements the other and compensates for their inherent limitations. 1. Clinical studies will serve to better characterize the phenotype, to identify tissue and organ specific defects in TH transport and metabolism. Studies will include prenatal genotyping and attempted treatment. New variants and unusual phenotypes will be sought. 2. In vitro studies using primary culture of the patients'skin fibroblasts and heterologous expression of the defective genes will serve to determine the properties of the defective molecules in isolation. In the case of SBP2 defects, in vitro studies will serve to determine the effects of various mutations on gene transcription and translation. Examination of patients'tissues by immunohistochemistry, will serve to identify the consequences of the defects at the cell level and to verify the pertinence of results generated from animal experiment. 3. Mice deficient in the substances being studied and those harboring the mutations observed in humans, will allow for better characterization of the defects under investigation and for the testing of various modalities of potential treatment. Mice deficient in the Mct8 gene have proven invaluable in the understanding of the thyroid abnormalities in humans and will now serve to characterize the consequences of Mct8 deficiency in embryonic and early postpartum life and the potentials of prenatal therapeutic intervention. The creation of inducible Sbp2K0 mice will facilitate determination of the timing of expression of selenoproteins that are crucial to survival and development, as well as the consequences of their deficiency. Massively-parallel sequencing will be applied for the identification of the gene(s) involved in resistance to TH not linked to the TRIi gene. Thus, function of such new genes will be characterized.

Public Health Relevance

The study of newlly identified congenital and inherited diseases provides not only insight into thyroid physiology but also establishes chriteria for their diagnosis, screening, and genetic counseling. Identification of mutations in women carriers of MCT8 defects allow for the provision of prenatal diagnosis particularly important since these defects produce incapacitating illness in male offspring. This also applies to the more severe forms of SBP2 and TRB gene defects. The proposed translational approach of investigation will continue to advance the clinical knowledge as well as basic consepts of inherited desease processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK015070-42
Application #
8492063
Study Section
Special Emphasis Panel (NSS)
Program Officer
Mckeon, Catherine T
Project Start
1979-07-15
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
42
Fiscal Year
2013
Total Cost
$550,931
Indirect Cost
$197,770
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Leung, Edward Ki Yun; Yi, Xin; Refetoff, Samuel et al. (2016) Diiodothyropropionic acid (DITPA) cross-reacts with thyroid function assays on different immunoassay platforms. Clin Chim Acta 453:203-4
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Ohba, Kenji; Leow, Melvin Khee-Shing; Singh, Brijesh Kumar et al. (2016) Desensitization and Incomplete Recovery of Hepatic Target Genes After Chronic Thyroid Hormone Treatment and Withdrawal in Male Adult Mice. Endocrinology 157:1660-72
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Ferrara, Alfonso Massimiliano; Liao, Xiao-Hui; Ye, Honggang et al. (2015) The Thyroid Hormone Analog DITPA Ameliorates Metabolic Parameters of Male Mice With Mct8 Deficiency. Endocrinology 156:3889-94
Tenenbaum-Rakover, Yardena; Almashanu, Shlomo; Hess, Ora et al. (2015) Long-term outcome of loss-of-function mutations in thyrotropin receptor gene. Thyroid 25:292-9
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
Ferrara, Alfonso Massimiliano; Pappa, Theodora; Fu, Jiao et al. (2015) A novel mechanism of inherited TBG deficiency: mutation in a liver-specific enhancer. J Clin Endocrinol Metab 100:E173-81

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