Resistance to Thyroid Hormone Alpha in an 18-Month-Old Girl: Clinical, Therapeutic, and Molecular Characteristics

Gucht, Anja L M van; Meima, Marcel E; Zwaveling-Soonawala, Nitash; Visser, Willy; Fliers, Eric; Wennink, J. M. B.; Henny, Civile; Visser, Theo J.; Peeters, Robin P.; Trotsenburg, A S Paul van

doi:10.1089/thy.2015.0463

Cited by 55 publications

(63 citation statements)

References 32 publications

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“…JEG3-cell culture and transfection were performed as previously described (van Gucht et al, 2016). Briefly, FLAG-tagged human TRα1 was overexpressed in JEG3 cells together with a DR4-TRE luciferase reporter construct and pMaxGFP as a transfection control.…”

Section: Methodsmentioning

confidence: 99%

The pyriproxyfen metabolite 4'OH- pyriproxyfen disrupts thyroid hormone signaling and enhances Musashi-1 levels in neuroprogenitors.

Špirhanzlová

Wejaphikul

et al. 2018

Preprint

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12Epidemiological and experimental studies have raised questions as to whether the insecticide 13 pyriproxyfen (PPF) could be implicated in the increased incidence of microcephaly associated 14 with ZIKA infection during pregnancy. This pesticide is documented as a thyroid hormone (TH) 15 disrupting chemical. We investigated whether environmentally relevant amounts of its main 16 metabolite, 4'-OH-pyriproxyfen (4'-OH-PPF), modified TH signaling and early neuronal 17 development. First, an in silico study revealed strong affinity of 4'-OH-PPF to fit the ligand 18 binding pocket of TH receptors (TRs). Further, in vitro assays on human cell lines showed 4'OH-19 PPF (> 3 mg/L ) to act as a TR antagonist. Next, using a transgenic Xenopus TH-sensitive 20 reporter system, Tg(thibz:GFP) tadpoles showed that 4'OH-PPF (> 10 -7 mg/L) displayed TH-21 disruptive activity and reduced tadpole mobility (> 10 -1 mg/L). Exposure to 4'OH-PPF 22 significantly reduced Xenopus head size at levels equivalent to the maximum recommended daily 23 intake of PPF (3x 10 -1 mg/L). Most strikingly, in both the Xenopus system in vivo and in mouse 24 neurosphere cultures, environmentally relevant concentrations of 4'OH-PPF increased expression 25 of the gene encoding an RNA-binding protein that enables ZIKA replication: Musashi-1 (msi1) in 26 neurogenic brain areas. We conclude that first, the PPF metabolite, 4'OH-PPF, disrupts thyroid 27 signaling, neuronal development and behavior in Xenopus embryos, and second, that it increases 28 Musashi-1 levels in neurogenic zones of both mouse and Xenopus, creating the potential to 29 enhance viral replication. As PPF is used in areas with high microcephaly incidence and is 30 readily broken down to 4'OH-PPF, these findings provide a plausible mechanism whereby PPF 31 could, through modulating expression of Musashi-1, exacerbate the effects of ZIKA virus 32 infection. 33

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Section: Methodsmentioning

confidence: 99%

The pyriproxyfen metabolite 4'OH- pyriproxyfen disrupts thyroid hormone signaling and enhances Musashi-1 levels in neuroprogenitors.

Špirhanzlová

Wejaphikul

et al. 2018

Preprint

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“…No. 92120308, RRID:CVCL_ 0363; Sigma-Aldrich) were cultured in 24-well plates using the growth medium (Dulbecco's Modified Eagle Medium (DMEM)/F12 supplemented with 9% fetal bovine serum (FBS), 100 nM Na 2 SeO 3 , 100 U/mL penicillin, and 100 lg/mL streptomycin) and transfected as previously described (19,26). Briefly, 20 ng of FLAG-TRa1 plasmid was cotransfected with 120 ng TRE-tkLuc reporter construct for transcriptional activity assays.…”

Section: In Silico Model Predictionmentioning

confidence: 99%

“…The expression of FLAG-and VP16-TRa1 proteins in cells was verified by immunoblotting nuclear extracts of JEG-3 cells transfected with WT or mutant TR expression constructs as previously described (19,26). The receptors were probed with 1:1000 dilution of FLAG-M2 antibody (#F1804; Sigma-Aldrich) or 1:1000 dilution of VP16 antibody (sc-7545; Santa Cruz Biotechnology).…”

Section: Immunoblottingmentioning

confidence: 99%

“…We tested seven TRa1 mutants, of which four were derived from RTHa patients [D211G (19), M256T (20), A263S, and R384H (14)]. These mutations covered the three CpG-rich regions of the LBD of TRa1 that are equivalent to the mutation-prone hotspots of the TRb1 receptor, namely R384H in cluster 1, M256T and A263S in cluster 2, and D211G in cluster 3.…”

Section: Selection Of Mutantsmentioning

confidence: 99%

“…This structural alteration completely abolishes T3 affinity and T3-induced transcriptional activity of TRa1. The second group consists of missense mutations that result in single amino acid substitutions in the LBD (10,(13)(14)(15)(16)(17)(18)(19)(20). These mutant receptors can still bind T3, but with a lower affinity than wild-type (WT) receptors.…”

Section: Introductionmentioning

confidence: 99%

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The In Vitro Functional Impairment of Thyroid Hormone Receptor Alpha 1 Isoform Mutants Is Mainly Dictated by Reduced Ligand Sensitivity

Wejaphikul

Gucht

Groeneweg

et al. 2019

Thyroid

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Background: Thyroid hormone (TH) acts on TH receptors (TRs) and regulates gene transcription by binding of TRs to TH response elements (TREs) in target gene promoters. The transcriptional activity of TRs is modulated by interactions with TR-coregulatory proteins. Mutations in TRa cause resistance to thyroid hormone alpha (RTHa). In this study, we analyzed if, beyond reduced triiodothyronine (T3) affinity, altered interactions with cofactors or different TREs could account for the differential impaired transcriptional activity of different mutants. Methods: We evaluated four mutants derived from patients (D211G, M256T, A263S, and R384H) and three artificial mutants at equivalent positions in patients with RTHb (T223A, L287V, and P398H). The in vitro transcriptional activity was evaluated on TRE-luciferase reporters (DR4, IR0, and ER6). The affinity for T3 and interaction with coregulatory proteins (nuclear receptor corepressor 1 [NCoR1] and steroid receptor coactivator 1 [SRC1]) were also determined. Results: We found that the affinity for T3 was significantly reduced for all mutants, except for TRa1-T223A. The reduction in the T3 sensitivity of the transcriptional activity on three TREs, the dissociation of the corepressor NCoR1, and the association of the coactivator SRC1 recruitment for each mutant correlated with the reduced affinity for T3. We did not observe mutation-specific alterations in interactions with cofactors or TREs. Conclusions: In summary, the degree of impaired transcriptional activity of mutants is mainly determined by their reduced affinity for T3.

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The Thyroid Gland

Peters

Schoenmakers

2019

Brook's Clinical Pediatric Endocrinology

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Resistance to Thyroid Hormone Alpha in an 18-Month-Old Girl: Clinical, Therapeutic, and Molecular Characteristics

Abstract: This report describes the phenotype of a young RTHα patient with a mild TRα mutation before and during early LT4 treatment. Treatment had beneficial effects on her muscle tone, motor development, and growth.

Cited by 55 publications

References 32 publications

The pyriproxyfen metabolite 4'OH- pyriproxyfen disrupts thyroid hormone signaling and enhances Musashi-1 levels in neuroprogenitors.

The pyriproxyfen metabolite 4'OH- pyriproxyfen disrupts thyroid hormone signaling and enhances Musashi-1 levels in neuroprogenitors.

The In Vitro Functional Impairment of Thyroid Hormone Receptor Alpha 1 Isoform Mutants Is Mainly Dictated by Reduced Ligand Sensitivity

The Thyroid Gland

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