Thyroid hormone receptors and resistance to thyroid hormone disorders - PubMed (original) (raw)

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Thyroid hormone receptors and resistance to thyroid hormone disorders

Tânia M Ortiga-Carvalho et al. Nat Rev Endocrinol. 2014 Oct.

Abstract

Thyroid hormone action is predominantly mediated by thyroid hormone receptors (THRs), which are encoded by the thyroid hormone receptor α (THRA) and thyroid hormone receptor β (THRB) genes. Patients with mutations in THRB present with resistance to thyroid hormone β (RTHβ), which is a disorder characterized by elevated levels of thyroid hormone, normal or elevated levels of TSH and goitre. Mechanistic insights about the contributions of THRβ to various processes, including colour vision, development of the cochlea and the cerebellum, and normal functioning of the adult liver and heart, have been obtained by either introducing human THRB mutations into mice or by deletion of the mouse Thrb gene. The introduction of the same mutations that mimic human THRβ alterations into the mouse Thra and Thrb genes resulted in distinct phenotypes, which suggests that THRA and THRB might have non-overlapping functions in human physiology. These studies also suggested that THRA mutations might not be lethal. Seven patients with mutations in THRα have since been described. These patients have RTHα and presented with major abnormalities in growth and gastrointestinal function. The hypothalamic-pituitary-thyroid axis in these individuals is minimally affected, which suggests that the central T3 feedback loop is not impaired in patients with RTHα, in stark contrast to patients with RTHβ.

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Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

Figure 1

Figure 1

Overview of thyroid hormone action. T3 enters the cell via thyroid hormone transporters, or is generated locally by cytoplasmic deiodinases (not shown). In the nucleus T3 binds to THR-containing dimers, which bind to genomic TREs to regulate gene transcription. Abbreviations: RXR, retinoic acid receptor; THR, thyroid hormone receptor; TRE, thyroid-hormone responsive element.

Figure 2

Figure 2

The THRα and THRβ isoforms have considerable homology. The DBDs of all THR isoforms are highly homologous and each of these proteins can form heterodimers and homodimers. Alternative splicing and use of alternative transcription sites results in the generation of four THR isoforms that able to bind T3 (THRα1 and THRβ1-3). The AF-1 and AF-2 regions of the proteins have some sequence variability across the isoforms; the THRα2 and THRα3 isoforms are truncated and, as a result of having no AF-2 domains, they are unable to bind T3. Abbreviations: AF-1, activation function 1; AF-2, activation function 2; DBD, DNA-binding domain; LBD, ligand-binding domain.

Figure 3

Figure 3

Model of gene regulation by thyroid hormones. In the absence of T3, a co-repressor is bound to the RXR–THR heterodimer at the positive TRE, thereby actively repressing target gene expression. When T3 binds to the THR dimer, the o-repressor is released and co-activators are recruited, which results in activation of gene transcription. Abbreviations: CoA, co-activator; CoR, co-repressor; RXR, retinoid X receptor; THR, thyroid hormone receptor; TRE, thyroid-hormone responsive element.

Figure 4

Figure 4

Overview of tissues and homeostatic functions affected in RTHβ. Patients with mutations in THRB can present with different phenotypes that affect a number of tissues and functions. These effects include increased levels of circulating thyroid hormones, goitre, impaired negative feedback of the HPT axis, affected vision and hearing, heart defects and abnormal neuronal development. Abbreviations: HPT, hypothalamic–pituitary–thyroid; RTHβ, resistance to thyroid hormone β; TRH, thyrotropin-releasing hormone.

Figure 5

Figure 5

Overview of tissues and homeostatic functions affected in RTHα. In patients with mutations in THRA the levels of circulating thyroid hormones are mildly affected. Additionally, these patients have delayed bone development, heart defects, chronic constipation and impaired neuronal development. Abbreviation: RTHα, resistance to thyroid hormone α.

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