ETA2022 Poster Presentations Thyroid Hormone ACTION (10 abstracts)
Molecular mechanisms underlying action of triac in resistance to thyroid hormone BETA (RTHβ)
Wenjun Liao 1 , Ferdy van Geest 2 , Federica Marelli 3 , Irene Campi 3 , Carla Moran 4 , Greta Lyons 5 , Maura Agostini 6 , Robin Peeters 7 , Krishna Chatterjee 8 , Luca Persani 9 , Marcel Meima 10 & W. Edward Visser 11
1Erasmus Medical Center, Department of Internal Medicine, Academic Center for Thyroid Diseases, Rotterdam, Netherlands; 2Erasmus MC, Academic Center for Thyroid Disease, Department of Internal Medicine, Rotterdam, Netherlands; 3Irccs Istituto Auxologico Italiano, Division of Endocrine and Metabolic Diseases, Milan, Italy; 4Endocrine Dept, Endocrine, Ucd School of Medicine, Dublin, Ireland; 5Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United Kingdom; 6Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom; 7Academic Center for Thyroid Diseases, Department of Endocrinology, Erasmus, Department of Internal Medicine,, Rotterdam, Netherlands; 8University of Cambridge, Wellcome-Mrc Institute of Metabolic Science, Cambridge, United Kingdom; 9University of Milan, Irccs Istituto Auxologico Italiano, Ospedale San Luca, Milan, Italy; 10Dept of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus MC, Rotterdam, Rotterdam, Netherlands; 11Erasmus Medical Center, Academic Center for Thyroid Diseases, Department of Internal Medicine, Academic Center for Thyroid Diseases, Rotterdam, Netherlands
Background: Resistance to thyroid hormone (TH) beta (RTHβ), caused by mutations in THRB, is characterized by elevated serum (F)T4 accompanied by non-suppressed TSH concentrations. Disease features arise from variable resistance to TH action in tissues expressing Thyroid Hormone Receptor (TR) β (hypothalamus, pituitary, liver) and from thyrotoxic effects in tissues expressing TRα (heart, bone, brain). In symptomatic patients, treatment mainly involves beta blockade to ameliorate tachycardia. In a subgroup of patients, the T3-analogue TRIAC has been employed to alleviate thyrotoxic symptoms. TRIAC preferentially activates TRβ rather than TRα, and has been proven to suppress TSH, thereby lower circulating TH concentrations. Despite its clinical use for decades, the exact mechanism by which TRIAC works in RTHβ, is as yet unclear. Here, by linking clinical observations with molecular studies, we investigated whether TRIAC exerts its effects through activation of mutant TRβ or by stimulating residual wild-type TRβ.
Methods: We collected clinical and biochemical data from 17 RTHβ patients treated with TRIAC in 3 centres. A proof-of-concept study was done with two TRβ mutants (G432del and R438fsx445). G432del and R438fsx445 were studied in the TRβ2 pituitary isoform background. Transcriptional activity was measured using two TRE-luciferase reporters (DR+4-TRE, TSHα-TRE) and interaction with cofactors (NCoR1 and SRC1) tested in mammalian two-hybrid assays with increasing doses of T3 or TRIAC (0 to 10000 nM).
Results: All patients showed clear clinical and biochemical responses to TRIAC treatment. In contrast, our in vitro studies showed that G432del and R438fsx445 TRβ mutants mediated no transcriptional responses on either TRE at any concentration of TRIAC and T3 tested. In addition, TRIAC did not induce co-repressor (NCoR1) release or promote co-activator (SRC1) recruitment for the G432del mutant. Data from thirteen other receptor mutants in TRIAC-treated patients, will be included in the presentation.
Conclusion: Despite beneficial effects in vivo, our preliminary results, utilizing a battery of functional assays, indicate that TRIAC does not activate mutant TRβ2 in vitro. We are currently testing in vitro and in vivo in a zebrafish model the expanded panel of mutant receptors, found in patients that responded favourably to TRIAC. Our studies will provide insights into mechanisms of action of TRIAC in RTHβ and may shape future studies developing therapies for RTH syndromes.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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