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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Leschek, Ellen W
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University of Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Refetoff, Samuel; Bassett, J H Duncan; Beck-Peccoz, Paolo et al. (2014) Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism. J Clin Endocrinol Metab 99:768-70
Greenberg, Solomon Maximo; Ferrara, Alfonso Massimiliano; Nicholas, Everton S et al. (2014) A novel mutation in the Albumin gene (R218S) causing familial dysalbuminemic hyperthyroxinemia in a family of Bangladeshi extraction. Thyroid 24:945-50
Refetoff, Samuel; Bassett, J H Duncan; Beck-Peccoz, Paolo et al. (2014) Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism. Thyroid 24:407-9
Champa, Devora; Russo, Marika A; Liao, Xiao-Hui et al. (2014) Obatoclax overcomes resistance to cell death in aggressive thyroid carcinomas by countering Bcl2a1 and Mcl1 overexpression. Endocr Relat Cancer 21:755-67
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
Bianco, Antonio C; Anderson, Grant; Forrest, Douglas et al. (2014) American Thyroid Association Guide to investigating thyroid hormone economy and action in rodent and cell models. Thyroid 24:88-168
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Hermanns, Pia; Grasberger, Helmut; Cohen, Ronald et al. (2013) Two cases of thyroid dysgenesis caused by different novel PAX8 mutations in the DNA-binding region: in vitro studies reveal different pathogenic mechanisms. Thyroid 23:791-6
Hermanns, Pia; Refetoff, Samuel; Sriphrapradang, Chutintorn et al. (2013) A clinically euthyroid child with a large goiter due to a thyroglobulin gene defect: clinical features and genetic studies. J Pediatr Endocrinol Metab 26:119-23
Fu, Jiao; Refetoff, Samuel; Dumitrescu, Alexandra M (2013) Inherited defects of thyroid hormone-cell-membrane transport: review of recent findings. Curr Opin Endocrinol Diabetes Obes 20:434-40

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