Thyroid hormone action

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Ángel García-Aldea Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, Spain

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Marina Guillén-Yunta Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, Spain

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Víctor Valcárcel-Hernández Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, Spain

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Ana Montero-Pedrazuela Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, Spain

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Ana Guadaño-Ferraz Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, Spain

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Soledad Bárez-López Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, Spain

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Thyroid hormones play an important role during the development and functioning of the different sensory systems. In order to exert their actions, thyroid hormones need to access their target cells through transmembrane transporter proteins, among which the monocarboxylate transporter 8 (MCT8) stands out for its pathophysiological relevance. Mutations in the gene encoding for MCT8 lead to the Allan–Herndon–Dudley syndrome (AHDS), a rare disease characterised by severe neuromotor and cognitive impairments. The impact of MCT8 deficiency in the neurosensory capacity of AHDS patients is less clear, with only a few patients displaying visual and auditory impairments. In this review we aim to gather data from different animal models regarding thyroid hormone transport and action in the different neurosensory systems that could aid to identify potential neurosensorial alterations in MCT8-deficient patients.

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Sander Barnhoorn Department of Molecular Genetics, Erasmus Medical Center, Rotterdam, The Netherlands

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Marcel E Meima Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus Medical Center, Rotterdam, The Netherlands

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Robin P Peeters Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus Medical Center, Rotterdam, The Netherlands

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Veerle M Darras Laboratory of Comparative Endocrinology, Biology Department, KU Leuven, Leuven, Belgium

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Selmar Leeuwenburgh Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus Medical Center, Rotterdam, The Netherlands

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Jan H J Hoeijmakers Department of Molecular Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Oncode Institute, Utrecht, The Netherlands
Institute for Genome Stability in Ageing and Disease, CECAD Research Centre, Cologne, Germany

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Wilbert P Vermeij Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Oncode Institute, Utrecht, The Netherlands

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W Edward Visser Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus Medical Center, Rotterdam, The Netherlands

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Background

Thyroid hormone signaling is essential for development, metabolism, and response to stress but declines during aging, the cause of which is unknown. DNA damage accumulating with time is a main cause of aging, driving many age-related diseases. Previous studies in normal and premature aging mice, due to defective DNA repair, indicated reduced hepatic thyroid hormone signaling accompanied by decreased type 1 deiodinase (DIO1) and increased DIO3 activities. We investigated whether aging-related changes in deiodinase activity are driven by systemic signals or represent cell- or organ-autonomous changes.

Methods

We quantified liver and plasma thyroid hormone concentrations, deiodinase activities and expression of T3-responsive genes in mice with a global, liver-specific and for comparison brain-specific inactivation of Xpg, one of the endonucleases critically involved in multiple DNA repair pathways.

Results

Both in global and liver-specific Xpg knockout mice, hepatic DIO1 activity was decreased. Interestingly, hepatic DIO3 activity was increased in global, but not in liver-specific Xpg mutants. Selective Xpg deficiency and premature aging in the brain did not affect liver or systemic thyroid signaling. Concomitant with DIO1 inhibition, Xpg −/− and Alb-Xpg mice displayed reduced thyroid hormone-related gene expression changes, correlating with markers of liver damage and cellular senescence.

Conclusions

Our findings suggest that DIO1 activity during aging is predominantly modified in a tissue-autonomous manner driven by organ/cell-intrinsic accumulating DNA damage. The increase in hepatic DIO3 activity during aging largely depends on systemic signals, possibly reflecting the presence of circulating cells rather than activity in hepatocytes.

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Yalan Hu Department of Laboratory Medicine, Endocrine Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Amsterdam Gastroenterology, Endocrinology & Metabolism (AGEM) Research Institute, Amsterdam UMC, Amsterdam, the Netherlands

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Kim Falize Department of Laboratory Medicine, Endocrine Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands

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A S Paul van Trotsenburg Amsterdam Gastroenterology, Endocrinology & Metabolism (AGEM) Research Institute, Amsterdam UMC, Amsterdam, the Netherlands
Department of Pediatric Endocrinology, Emma Children’s Hospital, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands

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Raoul Hennekam Department of Pediatrics, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands

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Eric Fliers Amsterdam Gastroenterology, Endocrinology & Metabolism (AGEM) Research Institute, Amsterdam UMC, Amsterdam, the Netherlands
Department of Endocrinology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands

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Eveline Bruinstroop Amsterdam Gastroenterology, Endocrinology & Metabolism (AGEM) Research Institute, Amsterdam UMC, Amsterdam, the Netherlands
Department of Endocrinology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands

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Anita Boelen Department of Laboratory Medicine, Endocrine Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Amsterdam Gastroenterology, Endocrinology & Metabolism (AGEM) Research Institute, Amsterdam UMC, Amsterdam, the Netherlands

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Transducin β-like 1 X-linked receptor 1 (TBL1XR1) is a WD40 repeat-containing protein and part of the corepressor complex SMRT/NCoR that binds to the thyroid hormone receptor (TR). We recently described a mutation in TBL1XR1 in patients with Pierpont syndrome. A mouse model bearing this Tbl1xr1 mutation (Tbl1xr1Y446C/Y446C ) displays several aspects of the Pierpont phenotype. Although serum thyroid hormone (TH) concentrations were unremarkable in these mice, tissue TH action might be affected due to the role of TBL1XR1 in the SMRT/NCoR corepressor complex. The aim of the present study was to evaluate tissue TH metabolism and action in a variety of tissues of Tbl1xr1Y446C/Y446C mice. We studied the expression of genes involved in TH metabolism and action in tissues of naïve Tbl1xr1Y446C/Y446C mice and wild type (WT) mice. In addition, we measured deiodinase activity in liver (Dio1 and Dio3), kidney (Dio1 and Dio3) and BAT (Dio2). No striking differences were observed in the liver, hypothalamus, muscle and BAT between Tbl1xr1Y446C/Y446C and WT mice. Pituitary TRα1 mRNA expression was lower in Tbl1xr1Y446C/Y446C mice compared to WT, while the mRNA expression of Tshβ and the positively T3-regulated gene Nmb were significantly increased in mutant mice. Interestingly, Mct8 expression was markedly higher in WAT and kidney of mutants, resulting in (subtle) changes in T3-regulated gene expression in both WAT and kidney. In conclusion, mice harboring a mutation in TBL1XR1 display minor changes in cellular TH metabolism and action. TH transport via MCT8 might be affected as the expression is increased in WAT and kidney. The mechanisms involved need to be clarified.

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Zhongli Chen Department of Internal Medicine, Academic Centre for Thyroid Diseases, Erasmus University Medical Center Rotterdam, The Netherlands

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Robin P Peeters Department of Internal Medicine, Academic Centre for Thyroid Diseases, Erasmus University Medical Center Rotterdam, The Netherlands

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Wesley Flach Department of Internal Medicine, Academic Centre for Thyroid Diseases, Erasmus University Medical Center Rotterdam, The Netherlands

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Linda J de Rooij Department of Internal Medicine, Academic Centre for Thyroid Diseases, Erasmus University Medical Center Rotterdam, The Netherlands

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Sena Yildiz Department of Internal Medicine, Academic Centre for Thyroid Diseases, Erasmus University Medical Center Rotterdam, The Netherlands

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Alexander Teumer Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany

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Matthias Nauck DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Germany

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Rosalie B T M Sterenborg Department of Internal Medicine, Academic Centre for Thyroid Diseases, Erasmus University Medical Center Rotterdam, The Netherlands
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

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Joost H W Rutten Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

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Marco Medici Department of Internal Medicine, Academic Centre for Thyroid Diseases, Erasmus University Medical Center Rotterdam, The Netherlands
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

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W Edward Visser Department of Internal Medicine, Academic Centre for Thyroid Diseases, Erasmus University Medical Center Rotterdam, The Netherlands

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Marcel E Meima Department of Internal Medicine, Academic Centre for Thyroid Diseases, Erasmus University Medical Center Rotterdam, The Netherlands

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Objective

Thyroid hormone (TH) transport represents a critical first step in governing intracellular TH regulation. It is still unknown whether the full repertoire of TH transporters has been identified. Members of the solute carrier (SLC) 22 family have substrates in common with the known TH transporters of the organic anion-transporting peptide family. Therefore, we screened the SLC22 family for TH transporters

Methods

Uptake of 1 nM of iodothyronines or sulfated iodothyronines in COS1 cells expressing SLC22 proteins was performed.

Results

We first tested 25 mouse (m) SLC22 proteins for TH uptake and found that the majority of the organic anion transporter (OAT) clade were capable of 3,3’,5-triiodothyronine and/or thyroxine (T4) transport. Based on phylogenetic tree analysis of the mouse and human (h) SLC22 family, we selected eight hSLC22s that grouped with the newly identified mouse TH transporters. Of these, four tested positive for uptake of one or more substrates, particularly hSLC22A11 showed robust (3-fold over control) uptake of T4. Uptake of sulfated iodothyronines was strongly (up to 17-fold) induced by some SLC22s, most notably SLC22A8, hSLC22A9, mSLC22A27 and mSLC22A29. Finally, the zebrafish orthologues of SLC22A6/8 drOatx and drSlc22a6l also transported almost all (sulfated) iodothyronines tested. The OAT inhibitors lesinurad and probenecid inhibited most SLC22 proteins.

Conclusions

Our results demonstrated that members of the OAT clade of the SLC22 family constitute a novel, evolutionary conserved group of transporters for (sulfated) iodothyronines. Future studies should reveal the relevance of these transporters in TH homeostasis and physiology.

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Sepehr Torabinejad Department of Clinical Medicine and Surgery, University of Naples ’Federico II’, Naples, Italy

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Caterina Miro Department of Clinical Medicine and Surgery, University of Naples ’Federico II’, Naples, Italy

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Biagio Barone Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II

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Ciro Imbimbo Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II

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Felice Crocetto Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II

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Monica Dentice Department of Clinical Medicine and Surgery, University of Naples ’Federico II’, Naples, Italy
CEINGE – Biotecnologie Avanzate Scarl, Naples, Italy

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There is increasing evidence that thyroid hormones (THs) work in an integrative fashion with androgen receptors (ARs) to regulate gonadal differentiation and reproductive function. Studies reveal that THs have interactions with the AR promoter region and increase AR expression. THs also have a role in the regulation of enzymes involved in the biosynthesis of androgens, such as 5α-reductase, which is essential in the conversion of testosterone into its active form, 5α-dihydrotestosterone. Additionally, the presence of androgen response elements in the promoter regions of TH-related genes, such as deiodinases and TH receptor isoforms, has been identified in some vertebrates, indicating a mutual interaction between THs and ARs. Since the androgen signaling pathway, mediated by ARs, plays a key role in the formation and progression of prostate cancer (PCa), the existence of crosstalk between THs and ARs supports the epidemiologic and experimental evidence indicating a relationship between the high incidence of PCa and hyperthyroidism. This article aims to review the role of androgen-TH crosstalk in PCa and its implication in clinical management. As life expectancy is growing these days, it can increase the number of patients with PCa and the critical relevance of the disease. In order to gain better knowledge about PCa and to improve clinical management, it is essential to get better insight into the key factors related to the formation and progression of this cancer.

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Eveline Bruinstroop Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands

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Anne H van der Spek Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands

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Anita Boelen Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
Department of Laboratory Medicine, Endocrine Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Amsterdam Reproduction & Development Research Institute, Amsterdam, the Netherlands

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Thyroid hormones play an essential role in regulating whole-body homeostasis. Deiodinases are known to convert thyroid hormone from the prohormone thyroxine (T4) to the bioactive hormone tri-iodothyronine (T3) and convert both T4 and T3 toward their inactive metabolites 3,3’,5’-tri-iodothyronine (rT3) and 3,3’-di-iodothyronine (3,3’-T2). Deiodinases are thus important for the regulation of intracellular thyroid hormone concentrations. This is known to be crucial both during development and adult life in regulating thyroid hormone-related gene transcription. This review discusses the importance of liver deiodinases in determining serum and liver thyroid hormone concentrations, liver metabolism and liver disease.

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Juan Ren ENS de Lyon, INRAE, CNRS, Institut de Génomique Fonctionnelle de Lyon, Lyon, France

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Frédéric Flamant ENS de Lyon, INRAE, CNRS, Institut de Génomique Fonctionnelle de Lyon, Lyon, France

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Thyroid hormones are known to trigger metamorphosis in an amphibian. This review discusses the hypothesis according to which they act in a similar manner to synchronize the post-natal development of mice, using brain, brown adipose tissue, and heart as examples.

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Yingxin Fang Department of Endocrinology and Metabolism, Institute of Endocrine, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, People’s Republic of China

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Pingping Dang Department of Endocrinology and Metabolism, Institute of Endocrine, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, People’s Republic of China

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Yue Liang Department of Endocrinology and Metabolism, Institute of Endocrine, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, People’s Republic of China

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Defa Zhao Department of Endocrinology and Metabolism, Institute of Endocrine, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, People’s Republic of China

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Ranran Wang Department of Endocrinology and Metabolism, Institute of Endocrine, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, People’s Republic of China

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Yue Xi Department of Endocrinology and Metabolism, Institute of Endocrine, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, People’s Republic of China
Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, People’s Republic of China

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Dan Zhang Department of Endocrinology and Metabolism, Institute of Endocrine, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, People’s Republic of China
Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, People’s Republic of China

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Wei Wang Department of Endocrinology and Metabolism, Institute of Endocrine, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, People’s Republic of China

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Zhongyan Shan Department of Endocrinology and Metabolism, Institute of Endocrine, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, People’s Republic of China

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Weiping Teng Department of Endocrinology and Metabolism, Institute of Endocrine, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, People’s Republic of China

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Xiaochun Teng Department of Endocrinology and Metabolism, Institute of Endocrine, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Hospital of China Medical University, Shenyang, People’s Republic of China

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Background

Proper thyroid hormone signaling via the TRα1 nuclear receptor is required for normal neurodevelopmental processes. The specific downstream mechanisms mediated by TRα1 that impact brain development remain to be investigated.

Methods

In this study, the structure, function and transcriptome of hippocampal tissue in a mouse model expressing the first RTHα mutation discovered in a patient, THRA E403X, were analyzed. RNAscope was used to visualize the spatial and temporal expression of Thra1 mRNA in the hippocampus of WT mice, which is corresponding to THRA1 mRNA in humans. The morphological structure was analyzed by Nissl staining, and the synaptic transmission was analyzed on the basis of long-term potentiation. The Morris water maze test and the zero maze test were used to evaluate the behavior. RNA-seq and quantitative real-time PCR were used to analyze the differentially expressed genes (DEGs) of the hippocampal tissues in the mouse model expressing the Thra E403X mutation.

Results

The juvenile mutant Thra E403X mice presented with delayed neuronal migration, disordered neuronal distribution, and decreased synaptic plasticity. A total of 754 DEGs, including 361 upregulated genes and 393 downregulated genes, were identified by RNA-seq. DEG-enriched Gene Ontology (GO) and KEGG pathways were associated with PI3K-Akt signaling, ECM−receptor interaction, neuroactive ligand−receptor interaction, and a range of immune-related pathways. 25 DEGs were validated by qPCR.

Conclusions

The Thra E403X mutation results in histological and functional abnormalities, as well as transcriptomic alterations in the juvenile mouse hippocampus. This study of the Thra E403X mutant offers new insights into the biological cause of RTHα-associated neurological diseases.

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Giorgio Radetti Marienklinik, Bolzano, Italy

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Franco Rigon Department of Paediatrics, University of Padua, Padua, Italy

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Alessandro Salvatoni Department of Medicine and Surgery, University of Insubria, Varese, Italy

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Irene Campi Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, IRCCS, Milan, Italy

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Tiziana De Filippis Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, IRCCS, Milan, Italy

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Valentina Cirello Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, IRCCS, Milan, Italy

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Silvia Longhi Department of Paediatrics, Regional Hospital of Bolzano, Bolzano, Italy

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Fabiana Guizzardi Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, IRCCS, Milan, Italy

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Marco Bonomi Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, IRCCS, Milan, Italy
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Luca Persani Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, IRCCS, Milan, Italy
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Introduction

Patients with congenital hypothyroidism (CH) may transiently show a certain degree of pituitary resistance to levothyroxine (LT4) which, however, normalizes subsequently. However, in some individuals, thyroid-stimulating hormone (TSH) fails to normalize despite adequate LT4 treatment.

Methods

Nine patients with CH followed in three Academic Centre who developed over time resistance to thyroid hormones underwent extensive biochemical and genetic analyses. These latter were performed by Sanger sequence or targeted next-generation sequencing technique including a panel of candidate genes involved in thyroid hormone actions and congenital hypothyroidism (CH): THRA, THRB, DIO1, DIO2, SLC16A2, SECISBP2, DUOX2, DUOXA2, FOXE1, GLIS3, IYD, JAG1, NKX2-1, NKX2- 5, PAX8, SLC26A4, SLC5A5, TG, TPO, TSHR.

Results

All patients displayed a normal sensitivity to thyroid hormone (TH) in the first years of life but developed variable degrees of resistance to LT4 treatment at later stages. In all cases, TSH normalized only in the presence of high free thyroxine levels. Tri-iodothyronine suppression test followed by thyrotrophin-releasing hormone stimulation was performed in two cases and was compatible with central resistance to THs. This biochemical feature was present independently on the cause of CH, being observed either in patients with an ectopic (n = 2) or eutopic gland (n = 3) or in case of athyreosis (n = 1). None of the patients had genetic variants in genes involved in the regulation of TH actions, while in two cases, we found two double heterozygous missense variants in TSHR and GLIS3 or in DUOX2 and SLC26A4 genes, respectively.

Conclusions

We report CH patients who showed an acquired and unexplainable pituitary refractoriness to TH action.

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