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Molecular Mechanism of Hypothyroidism

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 10186

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Dr. Maurizio Delvecchio

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Department of Metabolic and Genetic Diseases, Giovanni XXIII Children’s Hospital, 70126 Bari, Italy
Interests: neonatal diabetes mellitus; type 1 diabetes; celiac disease; thyroid disorders; insulin; Wolfram syndrome; Prader Villino syndrome
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Dear Colleagues,

Hypothyroidism is one of the most frequent endocrine diseases in both youths and adults. The most frequent subtypes of this disease are congenital (meaning that it is diagnosed in the first days of life), and acquired (meaning that it is usually due to autoimmunity, which is associated with the impairment of thyroid function). The second subtype is seen more frequently in childhood and adulthood, and its prevalence increases in parallel with age. Over the last few years, many studies aiming to shed light on the molecular mechanisms of hypothyroidism have been published. The most interesting field of research seems to be congenital hypothyroidism, but acquired causes of hypothyroidism are also a challenging and interesting field of research. Thyroid cancer is a less frequent cause of hypothyroidism, but knowledge of the genetics of thyroid cancer also plays a key role in the genetic counselling and follow-up of these patients and their relatives. Knowledge of the genetics of thyroid cancer is supportive of the precision medicine approach.

This Special Issue aims to collect papers about the molecular mechanisms of thyroid impairment. We welcome to submission of systematic or narrative reviews, original research, case series, and case reports for publication. We aim to publish the results of studies undertaken at the molecular level on any cause of thyroid impairment.

Dr. Maurizio Delvecchio
Guest Editor

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Keywords

congenital hypothyroidism
Hashimoto thyroiditis
thyroglobulin
dyshormonogenesis
thyroid disorders
genetics

Published Papers (5 papers)

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Research

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13 pages, 3784 KiB

Open AccessArticle

Novel Missense Variants in PAX8 and NKX2-1 Cause Congenital Hypothyroidism

by Menglin Li, Zhuo Li, Miaomiao Chen, Zhiqing Hu, Miaojin Zhou, Lingqian Wu, Chunhua Zhang and Desheng Liang

Int. J. Mol. Sci. 2023, 24(1), 786; https://doi.org/10.3390/ijms24010786 - 02 Jan 2023

Cited by 1 | Viewed by 1538

Abstract

Primary congenital hypothyroidism (CH) is a common neonatal endocrine disorder characterized by elevated concentrations of thyroid stimulating hormone (TSH) and low concentrations of free thyroxine (FT4). PAX8 and NKX2-1 are important transcription factors involved in thyroid development. In this study, we detected three novel variants in PAX8 (c.149A > C and c.329G > A) and NKX2-1 (c.706A > G) by whole exome sequencing (WES) in three unrelated CH patients with variable phenotypes. The results of Western blot and immunofluorescence analysis showed that the three variants had no effect on protein expression and subcellular localization. However, the results of the electrophoretic mobility shift assay (EMSA) and dual-luciferase reporter assay suggested that the three variants in PAX8 and NKX2-1 both affected their DNA-binding ability and reduced their transactivation capacity. Moreover, a dominant-negative effect in K236E−NKX2-1 was identified by dual-luciferase reporter assay. To sum up, our findings extend our knowledge of the current mutation spectrum of PAX8 and NKX2-1 and provide important information for diagnosing, treating, and preventing CH in these families. Full article

(This article belongs to the Special Issue Molecular Mechanism of Hypothyroidism)

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21 pages, 6042 KiB

Open AccessArticle

A Fine Regulation of the Hippocampal Thyroid Signalling Protects Hypothyroid Mice against Glial Cell Activation

by Lamis Chamas, Isabelle Seugnet, Roseline Poirier, Marie-Stéphanie Clerget-Froidevaux and Valérie Enderlin

Int. J. Mol. Sci. 2022, 23(19), 11938; https://doi.org/10.3390/ijms231911938 - 08 Oct 2022

Cited by 2 | Viewed by 1923

Abstract

Adult-onset hypothyroidism is associated with learning and cognitive dysfunctions, which may be related to alterations in synaptic plasticity. Local reduced levels of thyroid hormones (THs) may impair glia morphology and activity, and promote the increase of pro-inflammatory cytokine levels mainly in the hippocampus. Given that neuroinflammation induces memory impairments, hypothyroidism-related glia dysfunction may participate in brain disorders. Thus, we investigated the mechanisms linking hypothyroidism and neuroinflammation, from a protective perspective. We induced hypothyroidism in adult C57BL/6J and wild-derived WSB/EiJ male mice by a seven-week propylthiouracil (PTU) treatment. We previously showed that WSB/EiJ mice were resistant to high-fat diet (HFD)-induced obesity, showing no neuroinflammatory response through adaptive abilities, unlike C57BL/6J. As PTU and HFD treatments are known to induce comparable inflammatory responses, we hypothesized that WSB/EiJ mice might also be protected against hypothyroidism-induced neuroinflammation. We showed that hypothyroid WSB/EiJ mice depicted no hippocampal neuroinflammatory response and were able to maintain their hippocampal thyroid signalling despite low circulatisng TH levels. In contrast, C57BL/6J mice exhibited disturbed hippocampal TH signalling, accompanied by neuroinflammation and memory impairment. Our results reinforce the preponderance of the hippocampal TH regulatory system over TH circulating levels in the hippocampal glial reactivity. Full article

(This article belongs to the Special Issue Molecular Mechanism of Hypothyroidism)

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14 pages, 1656 KiB

Open AccessArticle

Targeted Next-Generation Sequencing of Congenital Hypothyroidism-Causative Genes Reveals Unexpected Thyroglobulin Gene Variants in Patients with Iodide Transport Defect

by Carlos Eduardo Bernal Barquero, Romina Celeste Geysels, Virginie Jacques, Gerardo Hernán Carro, Mariano Martín, Victoria Peyret, María Celeste Abregú, Patricia Papendieck, Ana María Masini-Repiso, Frédérique Savagner, Ana Elena Chiesa, Cintia E. Citterio and Juan Pablo Nicola

Int. J. Mol. Sci. 2022, 23(16), 9251; https://doi.org/10.3390/ijms23169251 - 17 Aug 2022

Viewed by 1973

Abstract

Congenital iodide transport defect is an uncommon autosomal recessive disorder caused by loss-of-function variants in the sodium iodide symporter (NIS)-coding SLC5A5 gene and leading to dyshormonogenic congenital hypothyroidism. Here, we conducted a targeted next-generation sequencing assessment of congenital hypothyroidism-causative genes in a cohort of nine unrelated pediatric patients suspected of having a congenital iodide transport defect based on the absence of ^99mTc-pertechnetate accumulation in a eutopic thyroid gland. Although, unexpectedly, we could not detect pathogenic SLC5A5 gene variants, we identified two novel compound heterozygous TG gene variants (p.Q29* and c.177-2A>C), three novel heterozygous TG gene variants (p.F1542Vfs*20, p.Y2563C, and p.S523P), and a novel heterozygous DUOX2 gene variant (p.E1496Dfs*51). Splicing minigene reporter-based in vitro assays revealed that the variant c.177-2A>C affected normal TG pre-mRNA splicing, leading to the frameshift variant p.T59Sfs*17. The frameshift TG variants p.T59Sfs*17 and p.F1542Vfs*20, but not the DUOX2 variant p.E1496Dfs*51, were predicted to undergo nonsense-mediated decay. Moreover, functional in vitro expression assays revealed that the variant p.Y2563C reduced the secretion of the TG protein. Our investigation revealed unexpected findings regarding the genetics of congenital iodide transport defects, supporting the existence of yet to be discovered mechanisms involved in thyroid hormonogenesis. Full article

(This article belongs to the Special Issue Molecular Mechanism of Hypothyroidism)

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10 pages, 19304 KiB

Open AccessCommunication

NKX2-5 Variant in Two Siblings with Thyroid Hemiagenesis

by Ewelina Szczepanek-Parulska, Bartłomiej Budny, Martyna Borowczyk, Igor Zhukov, Kosma Szutkowski, Katarzyna Zawadzka, Raiha Tahir, Andrzej Minczykowski, Marek Niedziela and Marek Ruchała

Int. J. Mol. Sci. 2022, 23(6), 3414; https://doi.org/10.3390/ijms23063414 - 21 Mar 2022

Viewed by 2337

Abstract

Thyroid hemiagenesis (THA) is an inborn absence of one thyroid lobe of largely unknown etiopathogenesis. The aim of the study was to reveal genetic factors responsible for thyroid maldevelopment in two siblings with THA. None of the family members presented with congenital heart defect. The samples were subjected to whole-exome sequencing (WES) (Illumina, TruSeq Exome Enrichment Kit, San Diego, CA 92121, USA). An ultra-rare variant c.839C>T (p.Pro280Leu) in NKX2-5 gene (NM_004387.4) was identified in both affected children and an unaffected father. In the mother, the variant was not present. This variant is reported in population databases with 0.0000655 MAF (GnomAD v3, dbSNP rs761596254). The affected amino acid position is moderately conserved (positive scores in PhyloP: 1.364 and phastCons: 0.398). Functional prediction algorithms showed deleterious impact (dbNSFP v4.1, FATHMM, SIFT) or benign (CADD, PolyPhen-2, Mutation Assessor). According to ACMG criteria, variant is classified as having uncertain clinical significance. For the first time, NKX2-5 gene variants were found in two siblings with THA, providing evidence for its potential contribution to the pathogenesis of this type of thyroid dysgenesis. The presence of the variant in an unaffected parent, carrier of p.Pro280Leu variant, suggests potential contribution of yet unidentified additional factors determining the final penetrance and expression. Full article

(This article belongs to the Special Issue Molecular Mechanism of Hypothyroidism)

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Review

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12 pages, 1491 KiB

Open AccessReview

Defective Thyroglobulin: Cell Biology of Disease

by Xiaohan Zhang, Crystal Young, Yoshiaki Morishita, Kookjoo Kim, Omer O. Kabil, Oliver B. Clarke, Bruno Di Jeso and Peter Arvan

Int. J. Mol. Sci. 2022, 23(21), 13605; https://doi.org/10.3390/ijms232113605 - 06 Nov 2022

Cited by 2 | Viewed by 1568

Abstract

The primary functional units of the thyroid gland are follicles of various sizes comprised of a monolayer of epithelial cells (thyrocytes) surrounding an apical extracellular cavity known as the follicle lumen. In the normal thyroid gland, the follicle lumen is filled with secreted protein (referred to as colloid), comprised nearly exclusively of thyroglobulin with a half-life ranging from days to weeks. At the cellular boundary of the follicle lumen, secreted thyroglobulin becomes iodinated, resulting from the coordinated activities of enzymes localized to the thyrocyte apical plasma membrane. Thyroglobulin appearance in evolution is essentially synchronous with the appearance of the follicular architecture of the vertebrate thyroid gland. Thyroglobulin is the most highly expressed thyroid gene and represents the most abundantly expressed thyroid protein. Wildtype thyroglobulin protein is a large and complex glycoprotein that folds in the endoplasmic reticulum, leading to homodimerization and export via the classical secretory pathway to the follicle lumen. However, of the hundreds of human thyroglobulin genetic variants, most exhibit increased susceptibility to misfolding with defective export from the endoplasmic reticulum, triggering hypothyroidism as well as thyroidal endoplasmic reticulum stress. The human disease of hypothyroidism with defective thyroglobulin (either homozygous, or compound heterozygous) can be experimentally modeled in thyrocyte cell culture, or in whole animals, such as mice that are readily amenable to genetic manipulation. From a combination of approaches, it can be demonstrated that in the setting of thyroglobulin misfolding, thyrocytes under chronic continuous ER stress exhibit increased susceptibility to cell death, with interesting cell biological and pathophysiological consequences. Full article

(This article belongs to the Special Issue Molecular Mechanism of Hypothyroidism)

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