The main isoforms of thyroid hormone receptors, THRα1, THRβ1 and THRβ2, are predominantly responsible for mediating thyroid hormone action, which is critical for normal development, growth and metabolism
Patients with mutations in either THRA or THRB have been described and have strikingly different clinical phenotypes known as resistance to thyroid hormone (RTH)α and RTHβ, respectively
Patients with RTHβ frequently present with elevated thyroid hormone levels, normal or elevated TSH levels and goitre, which suggests a critical role for THRB in negative-feedback regulation
Currently only seven patients with RTHα have been described; these individuals have near-normal levels of thyroid hormones and TSH but display hypothyroidism, delayed growth and constipation
Studies of mutations associated with RTH disorders using transgenic mouse models have provided novel insights into the divergent roles of THRA and THRB in physiology
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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T.M.O.-C.'s research is supported by Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ, CNE 102.873/2012) and Conselho Nacional de Pesquisa e Desenvolvimento (CNPq, #303,734/2012-4) and the Bill and Melinda Gates Foundation. F.E.W.'s research is supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant R01 DK49126 and the Johns Hopkins–University of Maryland Diabetes Research Center NIDDK grant P30DK79637.
The authors declare no competing financial interests.
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Ortiga-Carvalho, T., Sidhaye, A. & Wondisford, F. Thyroid hormone receptors and resistance to thyroid hormone disorders. Nat Rev Endocrinol 10, 582–591 (2014). https://doi.org/10.1038/nrendo.2014.143
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