Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor beta.

Sakurai, Akihiro; Takeda, Kyoko; Ain, Kenneth B.; Ceccarelli, P.; Nakai, Asami; Seino, Susumu; Bell, Graeme I.; Refetoff, Samuel; DeGroot, Leslie J.

doi:10.1073/pnas.86.22.8977

Cited by 253 publications

(113 citation statements)

References 34 publications

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“…So far, no mutation has been identified in the TR␣ gene in humans, whereas mutations in the TR␤ gene result in the syndrome of resistance to THs (27,28). Presumably, if mutations of TR␣ do exist in humans, their symptoms might be quite different from those of resistance to THs.…”

Section: Resultsmentioning

confidence: 99%

Thyroid hormone receptor α is a molecular switch of cardiac function between fetal and postnatal life

Maï

Janier

Allioli

et al. 2004

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

112

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Thyroid hormones are involved in the regulation of many physiological processes and regulate gene transcription by binding to their nuclear receptors TR␣ and TR␤. In the absence of triiodothyronine (T3), the unliganded receptors (aporeceptors) do bind DNA and repress the transcription of target genes. The role of thyroid hormone aporeceptors as repressors was observed in hypothyroid adult mice, but its physiological relevance in nonpathological hypothyroid conditions remained to be determined. Here we show that, in the normal mouse fetus, TR␣ aporeceptors repress heart rate as well as the expression of TR␤ and several genes encoding ion channels involved in cardiac contractile activity. Right after birth, when T3 concentration sharply increases, liganded TR␣ (holoreceptors) turn on the expression of some of these same genes concomitantly with heart rate increase. These data describe a physiological situation under which conversion of TR␣ from apo-receptors into holo-receptors, upon changes in T3 availability, plays a determinant role in a developmental process.

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Section: Resultsmentioning

confidence: 99%

Thyroid hormone receptor α is a molecular switch of cardiac function between fetal and postnatal life

Maï

Janier

Allioli

et al. 2004

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

112

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“…The identification of other cases supported the concept of RTH though proof had to await the cloning of the TH receptors (TRs) [3,4]. In fact, 22 years later, a mutation in the TRβ gene (also known as THRB) was found in a subject with RTH [5] closing the circle of hypothesis and proof.…”

Section: Introductionmentioning

confidence: 90%

Syndromes of Reduced Sensitivity to Thyroid Hormone

Weiss

Dumitrescu

Refetoff

2010

Genetic Diagnosis of Endocrine Disorders

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“…The syndrome of resistance to thyroid hormone (RTH), caused by mutations within the C terminus of TR-␤, is characterized by resistance to TH negative feedback at the pituitary and hypothalamus, with resulting TSH and TH elevation (20)(21)(22)(23)(24). Acting in a dominant negative fashion, TR-␤ mutants cause RTH by interfering with the function of normal TRs (25)(26)(27)(28).…”

mentioning

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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Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor beta.

Cited by 253 publications

References 34 publications

Thyroid hormone receptor α is a molecular switch of cardiac function between fetal and postnatal life

Thyroid hormone receptor α is a molecular switch of cardiac function between fetal and postnatal life

Syndromes of Reduced Sensitivity to Thyroid Hormone

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

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