Two Novel Cases of Resistance to Thyroid Hormone Due to THRA Mutation
- 1 August 2020
- journal article
- research article
- Published by Mary Ann Liebert Inc in Thyroid®
- Vol. 30 (8), 1217-1221
- https://doi.org/10.1089/thy.2019.0602
Abstract
Background: Resistance to thyroid hormone alpha (RTHα) is a rare and under-recognized genetic disease caused by mutations of THRA, the gene encoding thyroid hormone receptor α1 (TRα1). We report here the discovery of two novel patients with missense mutations (M259T, T273A) causing RTHα. Methods: We combined biochemical and cellular assays with in silico modeling to assess the capacity of mutant TRα1 to bind T3, to heterodimerize with RXR, to interact with transcriptional coregulators and to transduce a T3 transcriptional response. Results: M259T, and to a lower extent T273A, reduce the affinity of TRα1 for T3. Their negative influence is only reverted by large excess of T3. Conclusions: The severity of the two novel RTHα cases originates from a reduction in the binding affinity of TRα1 mutants to T3 and thus correlates with the incapacity of corepressors to dissociate from TRα1 mutants in the presence of T3.Keywords
This publication has 6 references indexed in Scilit:
- The In Vitro Functional Impairment of Thyroid Hormone Receptor Alpha 1 Isoform Mutants Is Mainly Dictated by Reduced Ligand SensitivityThyroid®, 2019
- Metabolomic Profiling of Body Fluids in Mouse Models Demonstrates that Nuclear Magnetic Resonance Is a Putative Diagnostic Tool for the Presence of Thyroid Hormone Receptor α1 MutationsThyroid®, 2019
- Contrasting Phenotypes in Resistance to Thyroid Hormone Alpha Correlate with Divergent Properties of Thyroid Hormone Receptor α1 Mutant ProteinsThyroid®, 2017
- Resistance to Thyroid Hormone due to Heterozygous Mutations in Thyroid Hormone Receptor AlphaCurrent Topics in Developmental Biology, 2017
- Biochemical characterization of four novel mutations in the thyroid hormone receptor β gene in patients with resistance to thyroid hormoneScandinavian Journal of Clinical and Laboratory Investigation, 2008
- Structural Rearrangements in the Thyroid Hormone Receptor Hinge Domain and Their Putative Role in the Receptor FunctionJournal of Molecular Biology, 2006