ETA2024 Oral Presentations Oral Session 11: Molecular Thyroidology (7 abstracts)
Molecular mechanisms of triac in the treatment of resistance to thyroid hormone beta (RTHβ)
Wenjun Liao 1 , Ferdy van Geest 1 , Federica Marelli 2 , Irene Campi 2 , Carla Moran 3 , Greta Lyons 3 , Maura Agostini 3 , Robin Peeters 1 , Krishna Chatterjee 3 , Luca Persani 2 , Marcel Meima 1 & W. Edward Visser 1
1Erasmus Medical Center, Department of Internal Medicine, Academic Center for Thyroid Diseases, Rotterdam, Netherlands; 2Irccs Istituto Auxologico Italiano, Milan, Italy; 3Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
Background: Resistance to thyroid hormone (TH) beta (RTHβ), caused by mutations in the THRB gene, 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 and from thyrotoxic effects in tissues expressing TRα1, most notably the heart. A recent clinical study showed a 3-times higher risk of cardiovascular morbidity and mortality for RTHβ patients, indicating the necessity of effective treatment options. For some symptomatic patients, the T3-analogue TRIAC has been employed successfully to suppress TSH, thereby lower circulating TH concentrations. However, the exact mechanism by which TRIAC works in RTHβ, is as yet unclear. Here, we linked biochemical data from patients with molecular studies to investigate whether TRIAC exerts its effects through activation of mutant TRβ or by stimulating residual wild-type TRβ.
Methods: We collected biochemical data from 18 RTHβ patients treated with TRIAC in 3 centres. Receptor function for TRβ mutants, including 16 missense mutations and two indel mutations, was studied in the TRβ2 pituitary isoform background. Transcriptional activity was measured using two TRE-luciferase reporters for respectively a positively and negatively T3-regulated gene DR+4-TRE, TSHα-TRE).
Results: TRIAC substantially reduced TSH and concomitantly FT4 concentrations in all patients. In contrast, our in vitro studies showed that the indel mutants ΔG432- and R438fsx445-TRβ2 mediated no transcriptional responses on either TRE. All missense TRβ2 mutants displayed impaired T3-dependent receptor activity with similar EC50 and IC50 values for T3 and TRIAC, except for R316H-TRβ2 which showed a 5-fold lower EC50/IC50 value for TRIAC compared to T3.
Conclusion: TRIAC has beneficial effects in vivo, even though most TRβ2 mutants are insensitive to TRIAC or equally sensitive compared to T3 in vitro. These results suggest that the main mechanism of TRIAC in lowering TSH in RTHβ patients is increased activation of the remaining wild-type receptor rather than engagement of the mutant receptor. However, some mutants, as exemplified by R316H-TRβ2 in our panel, may have preference for TRIAC and hence patients carrying these mutations may respond particularly well to TRIAC therapy. Our studies may provide insights into mechanisms of action of TRIAC in RTHβ and may shape future studies developing therapies for RTH syndromes.
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more