Two Novel Cases of Resistance to Thyroid Hormone Due to <i>THRA</i> Mutation

Maire, Albane le; Bouhours‐Nouet, Natacha; Soamalala, Jessica; Mirebeau‐Prunier, Delphine; Paloni, Matteo; Guée, Laura; Héron, Delphine; Mignot, Cyril; Illouz, Frédéric; Joubert, Florence; Briet, Claire; Rodien, Patrice; Bourguet, William; Flamant, Frédéric; Guyot, Romain

doi:10.1089/thy.2019.0602

Cited by 22 publications

(19 citation statements)

References 6 publications

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“…We observed that the two alleles are expressed equally in P6 and P1 ( Fig. 2B, C ) as already described in peripheral blood mononuclear cells of one patient ( 8 , 12 ), but in lesions from P5 and P4, expression of the two alleles was unequal, with greater expression of receptor mRNA derived from the mut allele ( Fig. 2B, C ), this difference not being due to variation in PCR amplification efficiency ( Supplementary Fig.…”

Section: Resultssupporting

confidence: 83%

Germ Line Mutations in the Thyroid Hormone Receptor Alpha Gene Predispose to Cutaneous Tags and Melanocytic Nevi

Cicco

Moran

Visser

et al. 2021

Thyroid

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Background: Many physiological effects of thyroid hormone (TH) are mediated by its canonical action via nuclear receptors (TH receptor a and b [TRa and TRb]) to regulate transcription of target genes. Heterozygous dominant negative mutations in human TRa mediate resistance to thyroid hormone alpha (RTHa), characterized by features of hypothyroidism (e.g., skeletal dysplasia, neurodevelopmental retardation, constipation) in specific tissues, but near-normal circulating TH concentrations. Hitherto, 41 RTHa cases have been recorded worldwide. Methods: RTHa cases (n = 10) attending a single center underwent cutaneous assessment, recording skin lesions. Lesions excised from different RTHa patients were analyzed histologically and profiled for cellular markers of proliferation and oncogenic potential. Proliferative characteristics of dermal fibroblasts and inducible pluripotent stem cell (iPSC)-derived keratinocytes from patients and control subjects were analyzed. Results: Multiple skin tags and nevi were recorded in all cases, mainly in the head and neck area with a predilection for flexures. The affected patients had highly deleterious mutations (p.E403X, p.E403K, p.F397fs406X, p.A382PfsX7) involving TRa1 alone or mild/moderate loss-of-function mutations (p.A263V, p.L274P) common to TRa1 and TRa2 isoforms. In four patients, although lesions excised for cosmetic reasons were benign intradermal melanocytic nevi histologically, they significantly overexpressed markers of cell proliferation (K17, cyclin D1) and type 3 deiodinase. In addition, oncogenic markers typical of basal cell carcinoma (Gli-1, Gli-2, Ptch-1, n = 2 cases) and melanoma (c-kit, MAGE, CDK4, n = 1) were markedly upregulated in skin lesions. Cell cycle progression and proliferation of TRa mutation-containing dermal fibroblasts and iPSC-derived keratinocytes from patients were markedly increased. Conclusions: Our observations highlight frequent occurrence of skin tags and benign melanocytic nevi in RTHa, with cutaneous cells from patients being in a hyperproliferative state. Such excess of skin lesions, including nevi expressing oncogenic markers, indicates that dermatologic surveillance of RTHa patients, monitoring lesions for features that are suspicious for neoplastic change, is warranted.

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Section: Resultssupporting

confidence: 83%

Germ Line Mutations in the Thyroid Hormone Receptor Alpha Gene Predispose to Cutaneous Tags and Melanocytic Nevi

Cicco

Moran

Visser

et al. 2021

Thyroid

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“…In this setting, the addition of T3 results in the destabilization of the interaction between the two proteins. By contrast to what happens in both previous transactivation assays, T3 produced a reduction of luciferase activity, as expected from previous data ( Bochukova et al., 2012 ; le Maire et al., 2020 ). Reciprocally, supplementation with the TR antagonist 1-850 increased the luciferase activity in presence of T3 ( Figure S1 ).…”

Section: Resultssupporting

confidence: 82%

“…The assay was performed in HEK293 cells transfected for the transient expression of several constructs, as described before ( le Maire et al., 2020 ). The pBKGal4NcoR construct encodes a Gal4NcoR hybrid protein, which normally acts as a transcription repressor on expression vectors driven by the UAS DNA binding elements.…”

Section: Methodsmentioning

confidence: 99%

In vitro assessment of pesticides capacity to act as agonists/antagonists of the thyroid hormone nuclear receptors

Zekri

Agnol²,

Flamant³

et al. 2021

iScience

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Summary Chemicals acting as thyroid hormone disruptors (THDs) are of a particular concern for public health, considering the importance of this hormone in neurodevelopment and metabolic processes. They might either alter the circulating level of thyroid hormone (TH) or interfere with the cellular response to the hormonal stimulation. In order to assess this later possibility we selected 39 pesticides and combined several in vitro tests. Reporter assays respectively addressed the transactivation capacity of the full-length TH nuclear receptor TRα1, the transactivation capacity of its C-terminal ligand binding domain, or the ability of the hormone to destabilize the interaction between TRα1 and the transcriptional corepressor NcoR. Although some pesticides elicit a cellular response, which sometimes interferes with TH signaling, RNA-seq analysis provided no evidence that they can act as TRα1 agonists or antagonists. Their neurodevelopmental toxicity in mammals cannot be explained by an alteration of the response to TH.

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“…The pathophysiology of all so-far reported disease-associated THRA variants was mediated through a loss-of-T3-function, leading to a dominant negative effect of the mutant THRA on the wild-type THRA in heterodimers. Thus, the variant is inherited in a dominant mode and heterozygous patients are affected [ 23 , 25 ]. Here, we describe a new pathomechanism for a THRA variant that does not interfere with T3-binding but rather with further receptor features such as dimerization and DNA-binding.…”

Section: Discussionmentioning

confidence: 99%

A New Mechanism in THRA Resistance: The First Disease-Associated Variant Leading to an Increased Inhibitory Function of THRA2

Paisdzior

Knierim

Kleinau³

et al. 2021

IJMS

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The nuclear thyroid hormone receptors (THRs) are key mediators of thyroid hormone function on the cellular level via modulation of gene expression. Two different genes encode THRs (THRA and THRB), and are pleiotropically involved in development, metabolism, and growth. The THRA1 and THRA2 isoforms, which result from alternative splicing of THRA, differ in their C-terminal ligand-binding domain (LBD). Most published disease-associated THRA variants are located in the LBD of THRA1 and impede triiodothyronine (T3) binding. This keeps the nuclear receptor in an inactive state and inhibits target gene expression. Here, we investigated a new dominant THRA variant (chr17:g.38,241,010A > G, GRCh37.13 | c.518A > G, NM_199334 | p.(E173G), NP_955366), which is located between the DNA- and ligand-binding domains and affects both splicing isoforms. Patients presented partially with hypothyroid (intellectual disability, motor developmental delay, brain atrophy, and constipation) and partially with hyperthyroid symptoms (tachycardia and behavioral abnormalities) to varying degrees. Functional characterization of THRA1p.(E173G) by reporter gene assays revealed increased transcriptional activity in contrast to THRA1(WT), unexpectedly revealing the first gain-of-function mutation found in THRA1. The THRA2 isoform does not bind T3 and antagonizes THRA1 action. Introduction of p.(E173G) into THRA2 increased its inhibitory effect on THRA1, which helps to explain the hypothyroid symptoms seen in our patients. We used protein structure models to investigate possible underlying pathomechanisms of this variant with a gain-of-antagonistic function and suggest that the p.(E173G) variant may have an influence on the dimerization domain of the nuclear receptor.

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Two Novel Cases of Resistance to Thyroid Hormone Due to THRA Mutation

Cited by 22 publications

References 6 publications

Germ Line Mutations in the Thyroid Hormone Receptor Alpha Gene Predispose to Cutaneous Tags and Melanocytic Nevi

Germ Line Mutations in the Thyroid Hormone Receptor Alpha Gene Predispose to Cutaneous Tags and Melanocytic Nevi

In vitro assessment of pesticides capacity to act as agonists/antagonists of the thyroid hormone nuclear receptors

A New Mechanism in THRA Resistance: The First Disease-Associated Variant Leading to an Increased Inhibitory Function of THRA2

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