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Gene Review

TSHR  -  thyroid stimulating hormone receptor

Homo sapiens

Synonyms: CHNG1, LGR3, TSH-R, Thyroid-stimulating hormone receptor, Thyrotropin receptor, ...
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Disease relevance of TSHR

  • We report two different mutations in the TSHR gene of affected members of two large pedigrees with non-autoimmune autosomal dominant hyperthyroidism (toxic thyroid hyperplasia), that involve residues in the third (Val509Ala) and seventh (Cys672Tyr) transmembrane segments [1].
  • The importance of thyrotropin receptor (TSHR) agonist antibodies in the manifestations of Graves' disease (GD) is recognized [2].
  • This pathway may be constitutively activated by mutations of the TSH receptor (TSHR) and Gsalpha in autonomous thyroid adenomas (ATAs) [3].
  • Therefore, we screened for mutations in the TSHR gene in patients with congenital hypothyroidism and hypoplasia of the gland [4].
  • To identify such reactions, we analyzed the T-cell proliferative responses of peripheral blood lymphocytes (PBMC) to human recombinant TSHR extracellular domain (hrecTSHR-ECD amino acids 19-417) expressed in Escherichia coli and to Tg [5].

Psychiatry related information on TSHR


High impact information on TSHR

  • It stimulates thyroid functions using specific membrane TSH receptor (TSHR) that belongs to the superfamily of G protein-coupled receptors (GPCRs) [8].
  • The thyrotropin receptor (TSHR), a member of the large family of G protein-coupled receptors, controls both the function and growth of thyroid cells via stimulation of adenylyl cyclase [1].
  • Evidence that the TSH receptor acts as a mitogenic antigen in Graves' disease [9].
  • In a few syndromes, tissue selectivity arises from mutation in the open reading frame of a regulatory gene (CASR, TSHR) with selective expression driven by its promoter [10].
  • Graves' hyperthyroidism can be induced in mice or hamsters by novel approaches, namely injecting cells expressing the TSH receptor (TSHR) or vaccination with TSHR-DNA in plasmid or adenoviral vectors [11].

Chemical compound and disease context of TSHR


Biological context of TSHR

  • Thus, this new potent method of antigen presentation, using autoantigen-transfected EBVL, has permitted the first unequivocal identification of TSHR T cells in GD thyroid, with distinct Th0/Th2 characteristics, unlike previously cloned TPO-responsive cells which have Th1 characteristics [2].
  • TSH and cAMP increased the tyrosine phosphorylation of TSHR and the association between TSHR and the p85alpha regulatory subunit of PI3K [17].
  • Binding and competition analyses are consistent with the presence of two binding sites on the TSHR transfected baby hamster kidney cells, one that can interact with either TSH or CGH, and another that binds CGH alone [18].
  • Thus, transfected into rat FRTL-5 cells, the activity of reporter plasmids, containing rat TSHR promoter ligated to a chloramphenicol acetyltransferase gene, was significantly suppressed in the presence of rat IFN gamma [19].
  • Germline mutations of TSHR may be associated with serum TSH values fluctuating above the upper limit of the normal range, also in the heterozygous state [20].

Anatomical context of TSHR

  • There are, however, no convincing reports of TSHR-specific T cells [2].
  • Inhibition of acquisition of N-linked oligosaccharides by tunicamycin treatment in CHO cells stably expressing TSHR produced nonglycosylated TSHR, which was totally nonfunctional [21].
  • These data demonstrate that acquisition and processing of N-linked oligosaccharides of TSHR appear to be essential for correct folding in the endoplasmic reticulum and for cell surface targeting in the Golgi apparatus [21].
  • To investigate whether this reflects an inherent difference in their oncogenic potency, we compared the effects of retrovirally-transduced mutant (A623I) TSHR or (Q227L) Galphas (GSP), using the rat thyroid cell line FRTL5 and primary human thyrocytes [22].
  • Functional expression of the mutant TSHR-R528H in COS-7 cells, however, did not result in constitutive activity of the TSHR [23].

Associations of TSHR with chemical compounds

  • In contrast, all of the TSHRs synthesized in mutant CHO-Lec1, 2, and 8 cells (mannose-rich, sialic acid-deficient, and galactose-deficient oligosaccharides, respectively) bound TSH and produced cAMP in response to TSH with an affinity and an EC50 similar to those in TSHR expressed in parental CHO cells (CHO-TSHR; sialylated oligosaccharides) [21].
  • The amino-terminal ectodomain of thyrotropin (TSH) receptor (TSHR) is heavily glycosylated with asparagine-linked (N-linked) oligosaccharides [21].
  • In this study, we sequenced the entire TSHR gene in a series of 10 unrelated patients with slight (6.6-14.9 mU/liter) to moderate (24-46 mU/liter) elevations of serum TSH, associated with definitely normal free thyroid hormone concentrations [20].
  • In the boy and his mother, an identical heterozygous TSHR mutation was identified, exchanging leucine for phenylalanine at residue 629 of the TSHR (TTG-->TTT) [24].
  • OBJECTIVES: To find whether germline and somatic gain-of-function mutations of the thyrotropin receptor (TSHR) differ in location and/or mutational mechanisms, as well as to explore the degree to which these mutations are specific to TSHR compared with pituitary glycoprotein hormone receptors [25].

Physical interactions of TSHR


Regulatory relationships of TSHR


Other interactions of TSHR

  • These findings suggest that the TSHR is able to signal through JAK/STAT3 pathways [33].
  • The reactivity to Tg was less than that to TSHR-ECD in both groups [5].
  • Linkage of RTSH to TSHR and PAX8 was excluded in all five families [34].
  • By RT-PCR, increments of PDE4D and 4C messenger ribonucleic acids were found in the ATAs with mutant TSHR or Gsalpha, whereas messenger ribonucleic acids encoding other cAMP-specific PDEs were not significantly increased [3].
  • Whereas the affinity and specificity of hCG for LHR are extraordinarily high, the hormone is capable of binding to and activating both TSHR and FSHR under these conditions that mimic high ligand concentrations [35].

Analytical, diagnostic and therapeutic context of TSHR

  • Activating mutations are, however, more common in the thyrotropin receptor (TSHR) than in its downstream transducer, Galphas [22].
  • There was 100% concordance between TSHR and Tg mRNA RT-PCR results [36].
  • Genomic DNA was obtained from both siblings and parents, the TSHR amplified using pairs of intronic and/or overlapping exonic primers and the PCR products sequenced automatically [37].
  • Remarkably, only 4 of 21 TBI-positive sera (including BBI) unequivocally recognized the TSHR on flow cytometry [38].
  • In one girl detected in neonatal screening with the confirmed diagnosis of permanent congenital hypothyroidism with reduced thyroid volume, two novel mutations in the TSHR gene were identified [4].


  1. Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism. Duprez, L., Parma, J., Van Sande, J., Allgeier, A., Leclère, J., Schvartz, C., Delisle, M.J., Decoulx, M., Orgiazzi, J., Dumont, J. Nat. Genet. (1994) [Pubmed]
  2. Identification of thyroid stimulating hormone receptor-specific T cells in Graves' disease thyroid using autoantigen-transfected Epstein-Barr virus-transformed B cell lines. Mullins, R.J., Cohen, S.B., Webb, L.M., Chernajovsky, Y., Dayan, C.M., Londei, M., Feldmann, M. J. Clin. Invest. (1995) [Pubmed]
  3. Induction of specific phosphodiesterase isoforms by constitutive activation of the cAMP pathway in autonomous thyroid adenomas. Persani, L., Lania, A., Alberti, L., Romoli, R., Mantovani, G., Filetti, S., Spada, A., Conti, M. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  4. Mutations of the human thyrotropin receptor gene causing thyroid hypoplasia and persistent congenital hypothyroidism. Biebermann, H., Schöneberg, T., Krude, H., Schultz, G., Gudermann, T., Grüters, A. J. Clin. Endocrinol. Metab. (1997) [Pubmed]
  5. T-cell reactivity to recombinant human thyrotropin receptor extracellular domain and thyroglobulin in patients with autoimmune and nonautoimmune thyroid diseases. Soliman, M., Kaplan, E., Fisfalen, M.E., Okamoto, Y., DeGroot, L.J. J. Clin. Endocrinol. Metab. (1995) [Pubmed]
  6. Polymorphisms in the TSHR (thyrotropin receptor) gene on chromosome 14q31 are not associated with mental retardation in the iodine-deficient areas of China. Guo, T.W., Zhang, F.C., Gao, J.J., Bian, L., Gao, X.C., Ma, J., Yang, M., Ji, Q., Duan, S.W., Zheng, Z.J., Li, R.L., Feng, G.Y., St Clair, D., He, L. Neurosci. Lett. (2005) [Pubmed]
  7. Thyroid stimulating hormone-receptor overexpression in brain of patients with Down syndrome and Alzheimer's disease. Labudova, O., Cairns, N., Koeck, T., Kitzmueller, E., Rink, H., Lubec, G. Life Sci. (1999) [Pubmed]
  8. Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships. Szkudlinski, M.W., Fremont, V., Ronin, C., Weintraub, B.D. Physiol. Rev. (2002) [Pubmed]
  9. Evidence that the TSH receptor acts as a mitogenic antigen in Graves' disease. Mäkinen, T., Wägar, G., Apter, L., von Willebrand, E., Pekonen, F. Nature (1978) [Pubmed]
  10. Hereditary hormone excess: genes, molecular pathways, and syndromes. Marx, S.J., Simonds, W.F. Endocr. Rev. (2005) [Pubmed]
  11. Insight into Graves' hyperthyroidism from animal models. McLachlan, S.M., Nagayama, Y., Rapoport, B. Endocr. Rev. (2005) [Pubmed]
  12. Adipose thyrotrophin receptor expression is elevated in Graves' and thyroid eye diseases ex vivo and indicates adipogenesis in progress in vivo. Starkey, K.J., Janezic, A., Jones, G., Jordan, N., Baker, G., Ludgate, M. J. Mol. Endocrinol. (2003) [Pubmed]
  13. Premature birth and low birth weight associated with nonautoimmune hyperthyroidism due to an activating thyrotropin receptor gene mutation. Vaidya, B., Campbell, V., Tripp, J.H., Spyer, G., Hattersley, A.T., Ellard, S. Clin. Endocrinol. (Oxf) (2004) [Pubmed]
  14. Detection of an activating mutation of the thyrotropin receptor in a case of an autonomously hyperfunctioning thyroid insular carcinoma. Russo, D., Tumino, S., Arturi, F., Vigneri, P., Grasso, G., Pontecorvi, A., Filetti, S., Belfiore, A. J. Clin. Endocrinol. Metab. (1997) [Pubmed]
  15. Analysis of the genetic variability of the 1st (CCC/ACC, P52T) and the 10th exons (bp 1012-1704) of the TSH receptor gene in Graves' disease. Kaczur, V., Takács, M., Szalai, C., Falus, A., Nagy, Z., Berencsi, G., Balázs, C. Eur. J. Immunogenet. (2000) [Pubmed]
  16. Thyroid disorders associated with pregnancy: etiology, diagnosis, and management. Lazarus, J.H. Treatments in endocrinology. (2005) [Pubmed]
  17. Regulation of the phosphatidylinositol 3-kinase, Akt/protein kinase B, FRAP/mammalian target of rapamycin, and ribosomal S6 kinase 1 signaling pathways by thyroid-stimulating hormone (TSH) and stimulating type TSH receptor antibodies in the thyroid gland. Suh, J.M., Song, J.H., Kim, D.W., Kim, H., Chung, H.K., Hwang, J.H., Kim, J.M., Hwang, E.S., Chung, J., Han, J.H., Cho, B.Y., Ro, H.K., Shong, M. J. Biol. Chem. (2003) [Pubmed]
  18. A glycoprotein hormone expressed in corticotrophs exhibits unique binding properties on thyroid-stimulating hormone receptor. Okada, S.L., Ellsworth, J.L., Durnam, D.M., Haugen, H.S., Holloway, J.L., Kelley, M.L., Lewis, K.E., Ren, H., Sheppard, P.O., Storey, H.M., Waggie, K.S., Wolf, A.C., Yao, L.Y., Webster, P.J. Mol. Endocrinol. (2006) [Pubmed]
  19. Interferon-gamma suppresses thyrotropin receptor promoter activity by reducing thyroid transcription factor-1 (TTF-1) binding to its recognition site. Ohe, K., Ikuyama, S., Takayanagi, R., Kohn, L.D., Nawata, H. Mol. Endocrinol. (1996) [Pubmed]
  20. Germline mutations of TSH receptor gene as cause of nonautoimmune subclinical hypothyroidism. Alberti, L., Proverbio, M.C., Costagliola, S., Romoli, R., Boldrighini, B., Vigone, M.C., Weber, G., Chiumello, G., Beck-Peccoz, P., Persani, L. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  21. Role of asparagine-linked oligosaccharides in protein folding, membrane targeting, and thyrotropin and autoantibody binding of the human thyrotropin receptor. Nagayama, Y., Namba, H., Yokoyama, N., Yamashita, S., Niwa, M. J. Biol. Chem. (1998) [Pubmed]
  22. Contrasting effects of activating mutations of GalphaS and the thyrotropin receptor on proliferation and differentiation of thyroid follicular cells. Ludgate, M., Gire, V., Crisp, M., Ajjan, R., Weetman, A., Ivan, M., Wynford-Thomas, D. Oncogene (1999) [Pubmed]
  23. Severe congenital hyperthyroidism caused by a germ-line neo mutation in the extracellular portion of the thyrotropin receptor. Grüters, A., Schöneberg, T., Biebermann, H., Krude, H., Krohn, H.P., Dralle, H., Gudermann, T. J. Clin. Endocrinol. Metab. (1998) [Pubmed]
  24. Identification of a new thyrotropin receptor germline mutation (Leu629Phe) in a family with neonatal onset of autosomal dominant nonautoimmune hyperthyroidism. Führer, D., Wonerow, P., Willgerodt, H., Paschke, R. J. Clin. Endocrinol. Metab. (1997) [Pubmed]
  25. The human thyrotropin receptor is highly mutable: a review of gain-of-function mutations. Farid, N.R., Kascur, V., Balazs, C. Eur. J. Endocrinol. (2000) [Pubmed]
  26. Evaluation of small-molecule modulators of the luteinizing hormone/choriogonadotropin and thyroid stimulating hormone receptors: structure-activity relationships and selective binding patterns. Moore, S., Jaeschke, H., Kleinau, G., Neumann, S., Costanzi, S., Jiang, J.K., Childress, J., Raaka, B.M., Colson, A., Paschke, R., Krause, G., Thomas, C.J., Gershengorn, M.C. J. Med. Chem. (2006) [Pubmed]
  27. Expression of the FSH receptor in the testis. Heckert, L., Griswold, M.D. Recent Prog. Horm. Res. (1993) [Pubmed]
  28. Interferon-gamma inhibition of human thyrotropin receptor gene expression. Nishikawa, T., Yamashita, S., Namba, H., Usa, T., Tominaga, T., Kimura, H., Izumi, M., Nagataki, S. J. Clin. Endocrinol. Metab. (1993) [Pubmed]
  29. The thyrotropin receptor. Kohn, L.D., Shimura, H., Shimura, Y., Hidaka, A., Giuliani, C., Napolitano, G., Ohmori, M., Laglia, G., Saji, M. Vitam. Horm. (1995) [Pubmed]
  30. Detection of thyrotropin-receptor messenger ribonucleic acid (mRNA) and thyroglobulin mRNA transcripts in peripheral blood of patients with thyroid disease: sensitive and specific markers for thyroid cancer. Chinnappa, P., Taguba, L., Arciaga, R., Faiman, C., Siperstein, A., Mehta, A.E., Reddy, S.K., Nasr, C., Gupta, M.K. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  31. Relationship between CTLA-4 and CD28 molecule expression on T lymphocytes and stimulating and blocking autoantibodies to the TSH-receptor in children with Graves' disease. Bossowski, A., Stasiak-Barmuta, A., Urban, M. Horm. Res. (2005) [Pubmed]
  32. Expression of hypothalamic-pituitary-thyroid axis related genes in the human skin. Slominski, A., Wortsman, J., Kohn, L., Ain, K.B., Venkataraman, G.M., Pisarchik, A., Chung, J.H., Giuliani, C., Thornton, M., Slugocki, G., Tobin, D.J. J. Invest. Dermatol. (2002) [Pubmed]
  33. Involvement of JAK/STAT (Janus kinase/signal transducer and activator of transcription) in the thyrotropin signaling pathway. Park, E.S., Kim, H., Suh, J.M., Park, S.J., You, S.H., Chung, H.K., Lee, K.W., Kwon, O.Y., Cho, B.Y., Kim, Y.K., Ro, H.K., Chung, J., Shong, M. Mol. Endocrinol. (2000) [Pubmed]
  34. Autosomal dominant resistance to thyrotropin as a distinct entity in five multigenerational kindreds: clinical characterization and exclusion of candidate loci. Grasberger, H., Mimouni-Bloch, A., Vantyghem, M.C., van Vliet, G., Abramowicz, M., Metzger, D.L., Abdullatif, H., Rydlewski, C., Macchia, P.E., Scherberg, N.H., van Sande, J., Mimouni, M., Weiss, R.E., Vassart, G., Refetoff, S. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  35. Specificity of cognate ligand-receptor interactions: fusion proteins of human chorionic gonadotropin and the heptahelical receptors for human luteinizing hormone, thyroid-stimulating hormone, and follicle-stimulating hormone. Schubert, R.L., Narayan, P., Puett, D. Endocrinology (2003) [Pubmed]
  36. Thyrotropin receptor/thyroglobulin messenger ribonucleic acid in peripheral blood and fine-needle aspiration cytology: diagnostic synergy for detecting thyroid cancer. Wagner, K., Arciaga, R., Siperstein, A., Milas, M., Warshawsky, I., Sethu, S., Reddy, K., Gupta, M.K. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  37. The W546X mutation of the thyrotropin receptor gene: potential major contributor to thyroid dysfunction in a Caucasian population. Jordan, N., Williams, N., Gregory, J.W., Evans, C., Owen, M., Ludgate, M. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  38. Thyrotropin receptor autoantibodies in serum are present at much lower levels than thyroid peroxidase autoantibodies: analysis by flow cytometry. Jaume, J.C., Kakinuma, A., Chazenbalk, G.D., Rapoport, B., McLachlan, S.M. J. Clin. Endocrinol. Metab. (1997) [Pubmed]
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