Disease-associated SNP variants of THRβ: Insights into the molecular determinants of aberrant receptor function

Abstract

Thyroid hormone receptor beta (THRβ) is a ligand-modulated transcription factor that regulates thyroid hormone (T₃)-mediated genomic actions. It regulates the hypothalamus-pituitary-thyroid axis and various metabolic processes, primarily in the liver and kidney. Research has shown that genetic variations, mainly single nucleotide polymorphism (SNP) in the THRB gene, may be linked to diseases like resistance to thyroid hormone, thyroid-related cancers, neurological and mental disorders. Despite this revelation, a significant gap remains in understanding the impact of SNPs on THRβ cellular function and disease etiology. Thus, the present study investigated the disease-associated missense THRβ-SNPs using both in silico analysis and cell-based assays. The study was initiated with computational analysis of disease-associated THRβ variants to predict the effects of SNPs on receptor conformation, structure, stability, and function. The molecular docking and simulation approach then evaluated the impact of these variants on interactions with T₃ and RXR. Following this, an extensive investigation was conducted into the dynamics and functioning of these receptor variants to address the underlying deviations in their cellular functioning by assessing receptor-subcellular localization, response to T₃ hormone, transcriptional functions, interaction with heterodimeric partner RXR, and receptor-chromatin interactions encountered in healthy and disease states. The study emphasizes that the structural and conformational integrity of THRβ is essential for its normal function, and critical deviations are associated with several metabolic/endocrine disease states. A comprehensive analysis of these disease-associated THRβ variants suggests the prospects of personalized medicine and the development of SNP-based genomic tests. The findings may also facilitate the discovery of novel small-molecule modulators to treat thyroid-related diseases linked to THRβ dysfunction, improving diagnosis and management of disease conditions.