Thyroid hormone receptor (THR) belongs to the nuclear receptor (NR) superfamily that facilitates thyroid hormone (TH) signaling to regulate various physiological and developmental processes of the body [1,2]. THR in its two subtypes, THRα and THRβ, is encoded by separate genes, THRA and THRB, having overlapping and distinct properties of tissue-specific distribution, hormone binding, and biological function [3]. THRα is primarily present in the heart, brain, skeletal muscle, and adipose tissues. In contrast, THRβ is widely expressed in the liver, kidney, brain, hypothalamus, and pituitary [4,5]. The THRβ isoform significantly regulates the metabolism and feedback mechanism of the hypothalamus-pituitary-thyroid (HPT) axis and acts as a tumor suppressor in various solid malignancies [6].

Like the other members of the NR superfamily, THR has an N-terminal activation domain (AF-1), a central conserved DNA-binding domain (DBD), a flexible hinge region, and a ligand binding domain (LBD) that has a second activation domain (AF-2). The hinge region acts as a bridge between DBD and LBD, providing structural flexibility to the receptor. The C-terminal region of LBD comprises several contact surfaces critical for dimerization with its heterodimeric partner Retinoid X receptor (RXR), as well as interaction with co-repressors and co-activators [1,2,7]. The unliganded THR is associated with co-repressors, such as nuclear CoR (NCoR) and silencing mediators for retinoid and thyroid hormone receptors (SMRT) to form a complex that inhibits the target gene expression at thyroid hormone response element (TRE). Ligand-receptor interaction leads to the dissociation of co-repressors and is replaced by co-activators that enhance target gene expression [8].

The synonymous and non-synonymous mutations occurring in the THRB gene are often linked to the occurrence of diverse disease conditions. While the former does not change the amino acid sequence of the protein, the non-synonymous mutations result in an altered protein sequence [9,10]. Many of these non-synonymous variants are benign, having little or no apparent influence on protein/receptor function; nevertheless, others have been coupled to different disease states [10]. Around 11.5% of all inherited diseases in humans are caused by nonsense mutations that result in an in-frame premature stop codon [11]. This incorporation prematurely shortens the protein that may have impaired physiological functions [12]. The receptor variants that have premature stop codons are called ‘truncated variants’ hereafter. Several studies have shown the association of truncated variants of THRβ inflicting various health conditions, including resistance to thyroid hormone (RTH), cancers, autoimmune diseases, etc. [7].

The truncated THRβ variants are considered biologically significant in determining the pathogenesis of several associated diseases [[13], [14], [15], [16]]. Therefore, we attempt to address the effects of naturally occurring disease-associated truncated variants of THRβ by studying in silico and cellular properties of the receptor, including 1) molecular dynamics simulation analysis, 2) subcellular localization of the THRβ-truncated variants, 3) response to cognate ligand T3, 4) transcriptional regulation, 5) heterodimeric interaction with its partner, RXR and 6) receptor-chromatin interaction. Recent studies have shown that NRs associate to the chromatin during mitosis, a property known as ‘mitotic genome bookmarking’ (also known as mitotic bookmarking) [17]. In this state, the cell chooses a strategy to retain a blueprint of the active cellular state and relay the transcriptional memory to subsequent generations [18]. It has been suggested that the phenomenon of mitotic bookmarking plays an integral role in the maintenance of the cellular proteome, traits, and phenotypes, along with perturbed occurrences in several disease states [17,19]. Our study indicates that the appearance of truncated receptor variants has a detrimental effect on the structural, functional, and physiological behavior of the receptor at multiple cellular and molecular levels, that may result in the pathogenicity of disease states. This study also reveals that THRβ exhibits the receptor-chromatin interaction, showing mitotic bookmarking property similar to a few other NRs (AR, PXR, VDR) [17]. By taking cues from the current observations, personalized genomic tests may be applied to treat patients at disease risk.