Genetics of Thyroid-Stimulating Hormone Receptor—Relevance for Autoimmune Thyroid Disease

Stefan, Mihaela; Faustino, Larissa C.

doi:10.3389/fendo.2017.00057

Cited by 17 publications

(15 citation statements)

References 60 publications

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“…The products of these genes participate in the regulation of the immune response and have been implicated in other autoimmune diseases but do not explain why the autoimmune response focuses on the thyroid gland. Common polymorphisms have also been found in the genes specifically expressed in the thyroid [e.g., the thyrotropin receptor [ TSHR ] or thyroglobulin [ TG ] (7, 8)]; however, only the association with TSHR has been repeatedly confirmed [reviewed in (4, 5, 9, 10)]. Since the loss of tolerance to TSHR is the central mechanism for GD pathogenesis, there is a great interest in understanding how these TSHR polymorphisms contribute to the failure of tolerance.…”

Section: Introductionmentioning

confidence: 99%

Regulation of TSHR Expression in the Thyroid and Thymus May Contribute to TSHR Tolerance Failure in Graves' Disease Patients via Two Distinct Mechanisms

et al. 2019

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Graves' disease (GD) involves the presence of agonistic auto-antibodies against the thyrotropin receptor (TSHR), which are responsible for the clinical symptoms. While failure of TSHR tolerance is central to GD pathogenesis, the process leading to this failure remains poorly understood. Two mechanisms intimately linked to tolerance have been proposed to explain the association of SNPs located in TSHR intron 1 to GD: (1) differential alternative splicing in the thyroid; and (2) modulation of expression in the thymus. To elucidate the relative contribution to these two mechanisms to GD pathogenesis, we analyzed the level of full-length and ST4 and ST5 isoform expression in the thyroid ( n = 49) and thymus ( n = 39) glands, and the influence of intron 1-associated SNPs on such expression. The results show that: (1) the level of flTSHR and ST4 expression in the thymus was unexpectedly high (20% that of the thyroid); (2) while flTSHR is the predominant isoform, the levels are similar to ST4 (ratio flTSHR/ST4 = 1.34 in the thyroid and ratio flTSHR/ST4 in the thymus = 1.93); (3) next-generation sequencing confirmed the effect of the TSHR intron 1 polymorphism on TSHR expression in the thymus with a bias of 1.5 ± 0.2 overexpression of the protective allele in the thymus compared to the thyroid; (4) GD-associated intron 1 SNPs did not influence TSHR alternative splicing of ST4 and ST5 in the thyroid and thymus; and (5) three-color confocal imaging showed that TSHR is associated with both thymocytes, macrophages, and dendritic cells in the thymus. Our findings confirm the effect of intron 1 polymorphisms on thymic TSHR expression and we present evidence against an effect on the relative expression of isoforms. The high level of ST4 expression in the thymus and its distribution within the tissue suggest that this would most likely be the isoform that induces central tolerance to TSHR thus omitting most of the hinge and transmembrane portion. The lack of central tolerance to a large portion of TSHR may explain the relatively high frequency of autoimmunity related to TSHR and its clinical consequence, GD.

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Section: Introductionmentioning

confidence: 99%

Regulation of TSHR Expression in the Thyroid and Thymus May Contribute to TSHR Tolerance Failure in Graves' Disease Patients via Two Distinct Mechanisms

et al. 2019

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“…Однако при сравнении распространенности мутаций среди здоровых людей и пациентов с БГ не было выявлено каких-либо различий. Это послужило поводом к исключению мутантного гена TSHR из списка возможных причин БГ [16,51]. На основании этого большинство авторов считают, что первичный дефект при БГ кроется именно в механизмах регуляции иммунной системы, а не в особенностях аутоантигенов, против которых направлена иммунная система человека [31].…”

Section: злокачественное новообразование и бгunclassified

“…В последнее время в связи с рутинным применением генетических исследований и накоплением новых данных, полученных на животных моделях, исследователи вновь заговорили о первичных изменениях в самой ЩЖ как о пусковом механизме БГ [43,51]. В 3 недавних метаанализах определен однонуклеотидный полиморфизм гена TSHR (точечные мутации гена в интроне 1 -rs179247, rs12101255), который имеет сильную корреляцию с БГ [51]. Таким образом, в представленном клиническом наблюдении можно предположить наличие в клетках новообразования активизирующей мутации TSHR, которая нарушила периферическую иммунологическую толерантность организма, привела к появлению антител к рецепторам к ТТГ и перекрестной реакции со здоровой тканью ЩЖ.…”

Section: злокачественное новообразование и бгunclassified

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Graves’ disease with hyperfunctioning thyroid nodule harboring thyroid carcinoma. Case report and literature review

Александрович¹,

Malyuga

Македонская³

et al. 2020

Opuholi golovy i šei

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According to the American Thyroid Association’s 2015 guidelines: “Since hyperfunctioning nodules rarely harbor malignancy, if one is found that corresponds to the nodule in question, no cytologic evaluation is necessary”. These findings are based on numerous studies proving the rareness of the combination of functional autonomy and thyroid cancer, and when such casuistry is detected, the non-aggressive course of the malignant process is observed.Rare revealing of malignant nodules functional autonomy can be attributed to several fundamental bases of non-medullary thyroid carcinoma pathogenesis. According to one of the hypotheses of carcinogenesis, dedifferentiation of thyrocytes occurs initially with the loss of the possibility of the sodium-iodine symporter synthesis, and later of the thyroid-stimulating hormone receptor synthesis by the cell, which reduces the hormone production by tumor cells. In addition, hyperthyroidism has a protective feature. It reduces the level of thyroid-stimulating hormone (which causes hypertrophy, hyperplasia of thyrocytes and has an antiapoptotic effect). This protective function is used in practice for suppressive therapy in the postoperative period, which reduces the progression, recurrence and mortality from thyroid cancer. The above circumstances prove the rareness of the clinical observation described below, which deserves additional attention and subsequent discussion.

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“…Since we wrote a similar review on genetics of Graves' disease for Hormone and Metabolic Research 3 years ago [1], the association of thyrotropin receptor gene (TSHR) variations to Graves' Disease (GD) has been further confirmed and additional comprehensive reviews have been published including extensive meta-analyses [2][3][4][5]. It is well established that a 30 Kb region at the 5′ end of the intron 1 (a large intron of 106 Kb) of the TSHR is linked to GD predisposition.…”

Section: Introductionmentioning

confidence: 99%

Central Tolerance Mechanisms to TSHR in Graves’ Disease: Contributions to Understand the Genetic Association

et al. 2018

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In the last 3 years, the association of thyrotropin receptor gene (TSHR) variations to Graves’ disease (GD) has been confirmed. It is now well established that a 30 Kb region of intron 1 of the TSHR gene is linked to GD predisposition. Elucidating the mechanism(s) by which these polymorphisms confer susceptibility is difficult but would constitute an important advance in endocrine autoimmunity in general. Two hypotheses, both postulating TSHR gene regulatory mechanisms, are discussed. One postulates differential level of expression in the thymus, involving central tolerance. The other postulates a shift in TSHR differential splicing leading to the production of soluble proteins that will have easy access to antigen presenting cells, so it is focused in peripheral tolerance. A combination of the 2 hypothesis is feasible, especially under the light of recent evidence that have identified epigenetic factors acting on TSHR intron 1.

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Genetics of Thyroid-Stimulating Hormone Receptor—Relevance for Autoimmune Thyroid Disease

Cited by 17 publications

References 60 publications

Regulation of TSHR Expression in the Thyroid and Thymus May Contribute to TSHR Tolerance Failure in Graves' Disease Patients via Two Distinct Mechanisms

Regulation of TSHR Expression in the Thyroid and Thymus May Contribute to TSHR Tolerance Failure in Graves' Disease Patients via Two Distinct Mechanisms

Graves’ disease with hyperfunctioning thyroid nodule harboring thyroid carcinoma. Case report and literature review

Central Tolerance Mechanisms to TSHR in Graves’ Disease: Contributions to Understand the Genetic Association

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