A Mechanism for Pituitary-Resistance to Thyroid Hormone (PRTH) Syndrome: a Loss in Cooperative Coactivator Contacts by Thyroid Hormone Receptor (TR)β2

Abstract

Thyroid hormone receptors (TR) are hormone-modulated transcription factors that regulate overall metabolic rate, lipid utilization, heart rate, and development. TR are expressed as a mix of interrelated receptor isoforms. The TRβ2 isoform is expressed in the hypothalamus and pituitary, where it plays an important role in the feedback regulation of thyroid hormone levels. TRβ2 exhibits unique transcriptional properties that parallel the ability of this isoform to bind to certain coactivators cooperatively through multiple contact surfaces. The more peripherally expressed TRβ1 isoform, in contrast, appears to recruit these coactivators through a single contact mechanism. We report here that clusters of charged amino acids in the TR hormone-binding domain are required for this enhanced mode of coactivator recruitment and that mutations in these charge clusters, by disrupting TRβ2 coactivator binding, are a molecular basis for pituitary resistance to thyroid hormone, a disease characterized by inappropriate thyroid hormone feedback regulation. We propose that the charge clusters allow wild-type TRβ2 to assume a conformation compatible with its mode of multiple contact coactivator recruitment, whereas disruption of these charge clusters disrupts normal T(3) homeostasis by reducing TRβ2 to a TRβ1-like, single contact mode of coactivator binding.

Syndromes of Reduced Sensitivity to Thyroid Hormone

“…On some occasions, mut TRβs may show greater impairment of transactivation on genes negatively rather than positively regulated by T 3 [41,54]. Recent work suggests that the mut TRβ R429Q affects predominantly the TRβ2 mediated action [55] while mut TRβ R338W, through its association with a single nucleotide polymorphism in the enhancer region, produces over expression of the mut TRβ allele [56]. These two mechanisms give credence to the existence of predominantly pituitary RTH.…”

Variable Clinical Characteristics and Molecular Spectrum of Patients with Syndromes of Reduced Sensitivity to Thyroid Hormone: Genetic Defects in the <b><i>THRB</i></b> and <b><i>SLC16A2</i></b> Genes

“…RTH has a wide phenotypic spectrum and can be classified into generalized RTH, isolated pituitary RTH, and peripheral tissue resistance [1]. Generalized RTH is characterized by failure to respond to circulating T3, resulting in a defect of negative feedback on T3 synthesis in both the hypothalamus-pituitary-thyroid axis and peripheral tissues [8]. The clinical features of generalized RTH include severe intellectual disability, growth failure, and euthyroidism or hypothyroidism despite high TSH and T3 levels [9].…”

“…The clinical features of generalized RTH include severe intellectual disability, growth failure, and euthyroidism or hypothyroidism despite high TSH and T3 levels [9]. In contrast, isolated pituitary RTH is characterized by localized symptoms, such as those associated with thyrotoxicosis, because of preserved peripheral sensitivity to thyroid hormone [8]. However, there is a wide overlap of clinical features in RTH patients [1].…”

A case of thyroid hormone resistance

“…Patients with GRTH can benefit from thyroxin administration, since it reduces TSH level and the goiter. [13] The diagnosis of RTH is confirmed if supraphysiologic doses of T 4 or T 3 are required to reduce the TSH secretion or induce the appropriate responses in peripheral tissues, such as an increase in serum sex-hormone binding globulin and reduction in cholesterol concentrations.…”