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Resistance to Thyroid Hormone α (RTHα), a reduced sensitivity to thyroid hormone (T3) in peripheral tissues, is caused by mutations in thyroid hormone receptor α (TRα), a nuclear receptor that mediates T3-responsive gene expression. All mutations characterized in RTHα, to date, are in the ligand binding domain (LBD), resulting in reduced affinity for T3. In addition, some mutations result in truncated proteins lacking all or part of helix 12. Previously, we have used fluorescence recovery after photobleaching (FRAP) to examine the effects of select RTHα mutations on the intracellular trafficking of TRα. After transfecting HeLa cells with expression plasmids for green fluorescent protein (GFP)-tagged wild-type TRα and each of the mutants, we first assessed their intracellular distribution and initial intranuclear mobility. Although wild-type TRα is known to shuttle between the nucleus and cytoplasm, it is primarily localized to the nucleus at a steady state. We showed that TR-E403X, Ala382ProfsX7, and F397fs406X are also primarily localized to the nucleus, and FRAP revealed that wild-type TRα and the RTHα mutants are highly dynamic within the nucleus, indicating that the receptors rapidly dissociate and reassociate with DNA binding sites and/or other nuclear binding sites, independent of T3 (1). Some studies have shown that Nuclear Receptor Corepressor 1 (NCoR1), which interacts with the hinge region of TRα (the region between the DNA-binding domain and LBD) has a higher affinity for RTHα mutants compared to wild-type TRα, supporting the hypothesis that helix 12 of the LBD also functions to disassociate NCoR1 from TRα when it is bound to T3 (2). We proposed that this increased affinity for NCoR1 alters the mobility of TRα in the nucleus, impacting its function. Here, we show that NCoR1 has slower FRAP recovery kinetics compared with TRα, and we evaluate the intranuclear dynamics of RTH TRα1 mutants ΤR-E403X, Ala382ProfsX7, and F397fs406X in response to increased levels of NCoR1. Investigation of the effects of overexpression of NCoR1 will provide further insight into the impact of altered binding affinity for NCoR1 on the intranuclear dynamics of RTHα mutants. References: (1) Femia et al., Journal of Cellular Biochemistry, 2020 2020 Apr; 121(4), 2909-2926.(2) Bochukova et al., New England Journal of Medicine, 2012 Jan. 19; 366(3), 243–249.

Altered Intracellular Trafficking of Mutant Thyroid Hormone Receptors in Resistance to Thyroid Hormone Syndrome