A Novel Thyroid Hormone Receptor-β Mutation That Fails to Bind Nuclear Receptor Corepressor in a Patient as an Apparent Cause of Severe, Predominantly Pituitary Resistance to Thyroid Hormone

Wu, Sharon Y.; Cohen, Ronald N.; Şimşek, Enver; Senses, Dursun Alí; Yar, Nese E.; Grasberger, Helmut; Noel, Janet; Refetoff, Samuel; Weiss, Roy E.

doi:10.1210/jc.2005-2428

Cited by 41 publications

(24 citation statements)

References 21 publications

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“…Astapova et al (41) recently found that negative hepatic TH target genes were regulated normally in mice expressing in the liver a mutant NCoR protein (L-NCoR⌬ID) that cannot interact with the TR, suggesting that NCoR does not mediate negative gene regulation by TH. Others have reported that the R429Q mutant TR is impaired for silencing mediator of retinoid and thyroid receptors (SMRT) release in vitro (42), a functional property that has recently been reported in conjunction with deficient NCoR binding in another TR-␤ mutant (Mkar) discovered in a patient with predominantly central RTH (43). However, it is unlikely that the observed specific defect in TH negative regulation with the R429Q mutant is due to defective SMRT release, given that (i) NCoR is the corepressor preferentially recruited by TR-␤ (44,45), (ii) we were unable to detect R429Q TR binding to SMRT in EMSA (data not shown), and (iii) Mkar had defective TH function on both positive and negative TH response elements.…”

Section: Discussionmentioning

confidence: 99%

A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo

Machado

Sabet

Santiago

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Resistance to thyroid hormone (RTH) is most often due to point mutations in the ␤-isoform of the thyroid hormone (TH) receptor (TR-␤). The majority of mutations involve the ligand-binding domain, where they block TH binding and receptor function on both stimulatory and inhibitory TH response elements. In contrast, a few mutations in the ligand-binding domain are reported to maintain TH binding and yet cause RTH in certain tissues. We introduced one such naturally occurring human RTH mutation (R429Q) into the germline of mice at the TR-␤ locus. R429Q knock-in (KI) mice demonstrated elevated serum TH and inappropriately normal thyroid-stimulating hormone (TSH) levels, consistent with hypothalamic-pituitary RTH. In contrast, 3 hepatic genes positively regulated by TH (Dio1, Gpd1, and Thrsp) were increased in R429Q KI animals. Mice were then rendered hypothyroid, followed by graded T 3 replacement. Hypothyroid R429Q KI mice displayed elevated TSH subunit mRNA levels, and T 3 treatment failed to normally suppress these levels. T3 treatment, however, stimulated pituitary Gh levels to a greater degree in R429Q KI than in control mice. Gsta, a hepatic gene negatively regulated by TH, was not suppressed in R429Q KI mice after T 3 treatment, but hepatic Dio1 and Thrsp mRNA levels increased in response to TH. Cardiac myosin heavy chain isoform gene expression also showed a specific defect in TH inhibition. In summary, the R429Q mutation is associated with selective impairment of TH-mediated gene repression, suggesting that the affected domain, necessary for TR homodimerization and corepressor binding, has a critical role in negative gene regulation by TH.corepressor ͉ homodimer ͉ negative regulation ͉ resistance to thyroid hormone T hyroid-stimulating hormone (thyrotropin or TSH) is a heterodimeric glycoprotein consisting of 2 non-covalently linked protein subunits (TSH-␣ and TSH-␤), synthesized in the pituitary thyrotroph, which regulates the thyroid. TSH-releasing hormone (TRH) is synthesized in the paraventricular nucleus of the hypothalamus and released into the portal circulation, where it regulates the synthesis and glycosylation pattern (bioactivity) of pituitary TSH. The hypothalamic-pituitary-thyroid (HPT) axis is regulated by negative feedback involving thyroid hormones (THs) (T 4 and T 3 ), which are produced by the thyroid gland. The major negative regulator of TSH secretion is T 3 , which directly inhibits the transcription of the TSH-␣ and -␤ subunit genes (1-5) and TRH (6-8).TH action is mediated by different isoforms of the TH receptor (TR), which are members of the nuclear receptor superfamily of ligand-modulated transcription factors. Two genes, by alternative splicing and transcriptional start site utilization, express the known ligand-binding TR isoforms, TR-␣1, TR-␤1, TR-␤2, and TR-␤3. Negative regulation of the HPT axis is principally mediated by the ␤ isoform of the TR (9-13).On genes with a positive TH response element, TR interacts with corepressor proteins (CoRs) in the absence of ligand, and this...

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Section: Discussionmentioning

confidence: 99%

A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo

Machado

Sabet

Santiago

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…In a subgroup of RTHβ patients, TA 3 is able to decrease TSH and consequently the high serum T 4 and T 3 levels. Since the thyromimetic effects of TA 3 itself do not fully compensate the reduction in endogenous TH levels, it alleviates the thyrotoxic symptoms including tachycardia, goiter, excessive sweating and behavioral problems (BeckPeccoz et al 1983, Lind & Eber 1986, Faglia et al 1987, Salmela et al 1988, Kunitake et al 1989, Smallridge et al 1989, Beck-Peccoz et al 1990, Aguilar Diosdado et al 1991 Crino et al 1992, Dulgeroff et al 1992, Ueda et al 1996, Darendeliler & Basx 1997, Radetti et al 1997, CliftonBligh et al 1998, Persani et al 1998, Asteria et al 1999, Kong et al 2005, Torre et al 2005, Wu et al 2006, Gurgel et al 2008, Santos et al 2008, Guran et al 2009, Anzai et al 2012, Ferrara et al 2012, Ramos-Prol et al 2013, Stagi et al 2014, Chatzitomaris et al 2015, Xue et al 2015. However, some patients do not respond to TA 3 treatment, which is assumed to depend on the type or location of the mutation (Hamon et al 1988, Persani et al 1998.…”

Section: Rthβmentioning

confidence: 99%

Triiodothyroacetic acid in health and disease

Groeneweg

Peeters

Visser

et al. 2017

Journal of Endocrinology

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Thyroid hormone (TH) is crucial for development and metabolism of many tissues. The physiological relevance and therapeutic potential of TH analogs have gained attention in the field for many years. In particular, the relevance and use of 3,3′,5-triiodothyroacetic acid (Triac, TA 3 ) has been explored over the last decades. Although TA 3 closely resembles the bioactive hormone T 3 , differences in transmembrane transport and receptor isoformspecific transcriptional activation potency exist. For these reasons, the application of TA 3 as a treatment for resistance to TH (RTH) syndromes, especially MCT8 deficiency, is topic of ongoing research. This review is a summary of all currently available literature about the formation, metabolism, action and therapeutic applications of TA 3 .

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“…This has been observed with frameshift mutations producing a TRβ with an extended nonsense carboxylterminal sequence [126]. In such instances, temporary reduction of the TH level with somatostatin, and if ineffective, the judicious administration of antithyroid drugs could be tried.…”

Section: Rthmentioning

confidence: 99%