A clinician's guide to understanding resistance to thyroid hormone due to receptor mutations in the TRα and TRβ isoforms

Abstract

There are two genes that express the major thyroid hormone receptor isoforms. Mutations in both these genes have given rise to Resistance to Thyroid Hormone (RTH) syndromes (RTHβ, RTHα) that can have variable phenotypes for mutations of the same receptor isoform as well as between the two receptor isoforms. In general, the relative tissue-specific distribution of TRβ and TRα determine RTH in different tissues for each form of RTH. These differences highlight some of the isoform-specific roles of each TR isoform. The diagnosis of RTH is challenging for the clinician but should be considered whenever a patient presents with unexplained elevated serum free T₄ (fT₄) and unsuppressed TSH levels, as well as decreased serum free T₄/T₃ ratio. Here we provide a guide for the clinician to diagnose and treat both types of RTH.

Keywords: Dominant negative activity; Human mutation; Resistance to thyroid hormone; Thyroid hormone receptors; Thyroid stimulating hormone.

Fig. 1

Alternative splicing and translation give rise to multiple TRα (a) and TRβ (b) isoforms

Fig. 2

Role of co-activator and co-repressor recruitment in positively-regulated target genes. a For positively-regulated target genes, in the presence of T₃, co-activators (Co-A) and histone acetyl transferases (HAT) are recruited by the T₃-bound TR/RXR heterodimer sitting on the thyroid hormone response element (TRE). This leads to histone acetylation and chromatin nearby changes to a more open conformation to facilitate recruitment of RNA pol II to the TATA box region. Subsequently another co-activator complex, TH receptor-associated protein/vitamin D receptor interacting protein complex (TRAP/DRIP comp), is recruited by ligand-bound TR/RXR and RNA polymerase II complex to activate transcription. b For positively-regulated target genes in the absence of T₃, TR/RXR has a different conformation than its T₃-bound state, and has poor affinity for co-activator complexes. Instead, it recruits a co-repressor complex (Co-R) with histone deacetylase activity (HDAC). This leads to histone deacetylation and formation of a more closed chromatin conformation that does not allow RNA pol II binding to the promoter and thus “represses” transcription. c In some negatively-regulated target genes, in the presence of ligand, co-repressor and HDAC are recruited by TR/RXR sitting on the TRE. This leads to decreased histone acetylation and a more closed chromatin conformation that prevents RNA pol II binding to the promoter of the target gene, and thus negatively regulates transcription in the presence of T₃. Please see text for more details

Fig. 3

Models for RTHβ and RTHα. a RTHβ occurs in tissues expressing TRβ and causes a rise in serum T₃ and T₄ levels due to impaired negative feedback of the hypothalamic/pituitary/thyroid axis. b RTHα occurs in tissues expressing predominantly TRα (bone, gut, and heart) and causes symptoms shown in Table 1. In contrast to RTHβ, there is no defect in the negative feedback of the HPT axis by TH. However, patients have increased serum T₄/ T₃ ratios suggesting that a downstream effect such as increased deiodinase 1 (Dio 1) activity may occur

Fig. 4

Model for resistance to thyroid hormone in RTHβ patients. a In both normal and RTH patients, wild-type TRβ and TRα isoforms derived from normal THRB and THRA alleles bind as TR/RXR heterodimers to the TRE and are able to activate transcription. b The mutant TRβ encoded by the abnormal THRB allele in RTH patients bind to the TRE constitutively in both the presence and absence of T₃. Since it has decreased ligand-binding affinity, its ability to recruit co-activators and activate transcription is impaired. The unliganded mutant TR/RXR heterodimer thus competes with T₃-bound wild type TR/RXR heterodimer for binding to the TRE