3g04

Structural highlights

Disease

[TSHR_HUMAN] Note=Defects in TSHR are found in patients affected by hyperthyroidism with different etiologies. Somatic, constitutively activating TSHR mutations and/or constitutively activating G(s)alpha mutations have been identified in toxic thyroid nodules (TTNs) that are the predominant cause of hyperthyroidism in iodine deficient areas. These mutations lead to TSH independent activation of the cAMP cascade resulting in thyroid growth and hormone production. TSHR mutations are found in autonomously functioning thyroid nodules (AFTN), toxic multinodular goiter (TMNG) and hyperfunctioning thyroid adenomas (HTA). TMNG encompasses a spectrum of different clinical entities, ranging from a single hyperfunctioning nodule within an enlarged thyroid, to multiple hyperfunctioning areas scattered throughout the gland. HTA are discrete encapsulated neoplasms characterized by TSH-independent autonomous growth, hypersecretion of thyroid hormones, and TSH suppression. Defects in TSHR are also a cause of thyroid neoplasms (papillary and follicular cancers).^{[1] [2] [3]} Note=Autoantibodies against TSHR are directly responsible for the pathogenesis and hyperthyroidism of Graves disease. Antibody interaction with TSHR results in an uncontrolled receptor stimulation.^{[4] [5] [6]} Defects in TSHR are the cause of congenital hypothyroidism non-goitrous type 1 (CHNG1) [MIM:275200]; also known as congenital hypothyroidism due to TSH resistance. CHNG1 is a non-autoimmune condition characterized by resistance to thyroid-stimulating hormone (TSH) leading to increased levels of plasma TSH and low levels of thyroid hormone. CHNG1 presents variable severity depending on the completeness of the defect. Most patients are euthyroid and asymptomatic, with a normal sized thyroid gland. Only a subset of patients develop hypothyroidism and present a hypoplastic thyroid gland.^{[7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]} Defects in TSHR are the cause of familial gestational hyperthyroidism (HTFG) [MIM:603373]. HTFG is a condition characterized by abnormally high levels of serum thyroid hormones occurring during early pregnancy.^{[21] [22] [23] [24]} Defects in TSHR are the cause of hyperthyroidism non-autoimmune (HTNA) [MIM:609152]. It is a condition characterized by abnormally high levels of serum thyroid hormones, thyroid hyperplasia, goiter and lack of anti-thyroid antibodies. Typical features of Graves disease such as exophthalmia, myxedema, antibodies anti-TSH receptor and lymphocytic infiltration of the thyroid gland are absent.^{[25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43]}

Function

[TSHR_HUMAN] Receptor for thyrothropin. Plays a central role in controlling thyroid cell metabolism. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Also acts as a receptor for thyrostimulin (GPA2+GPB5).^[44]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

• Human Follicle-Stimulating Hormone Complexed with its Receptor

References

1. ↑ Chistiakov DA, Savost'anov KV, Turakulov RI, Petunina N, Balabolkin MI, Nosikov VV. Further studies of genetic susceptibility to Graves' disease in a Russian population. Med Sci Monit. 2002 Mar;8(3):CR180-4. PMID:11887032
2. ↑ Ban Y, Greenberg DA, Concepcion ES, Tomer Y. A germline single nucleotide polymorphism at the intracellular domain of the human thyrotropin receptor does not have a major effect on the development of Graves' disease. Thyroid. 2002 Dec;12(12):1079-83. PMID:12593721 doi:10.1089/105072502321085171
3. ↑ Ho SC, Goh SS, Khoo DH. Association of Graves' disease with intragenic polymorphism of the thyrotropin receptor gene in a cohort of Singapore patients of multi-ethnic origins. Thyroid. 2003 Jun;13(6):523-8. PMID:12930595 doi:http://dx.doi.org/10.1089/105072503322238773
4. ↑ Chistiakov DA, Savost'anov KV, Turakulov RI, Petunina N, Balabolkin MI, Nosikov VV. Further studies of genetic susceptibility to Graves' disease in a Russian population. Med Sci Monit. 2002 Mar;8(3):CR180-4. PMID:11887032
5. ↑ Ban Y, Greenberg DA, Concepcion ES, Tomer Y. A germline single nucleotide polymorphism at the intracellular domain of the human thyrotropin receptor does not have a major effect on the development of Graves' disease. Thyroid. 2002 Dec;12(12):1079-83. PMID:12593721 doi:10.1089/105072502321085171
6. ↑ Ho SC, Goh SS, Khoo DH. Association of Graves' disease with intragenic polymorphism of the thyrotropin receptor gene in a cohort of Singapore patients of multi-ethnic origins. Thyroid. 2003 Jun;13(6):523-8. PMID:12930595 doi:http://dx.doi.org/10.1089/105072503322238773
7. ↑ Chistiakov DA, Savost'anov KV, Turakulov RI, Petunina N, Balabolkin MI, Nosikov VV. Further studies of genetic susceptibility to Graves' disease in a Russian population. Med Sci Monit. 2002 Mar;8(3):CR180-4. PMID:11887032
8. ↑ Ban Y, Greenberg DA, Concepcion ES, Tomer Y. A germline single nucleotide polymorphism at the intracellular domain of the human thyrotropin receptor does not have a major effect on the development of Graves' disease. Thyroid. 2002 Dec;12(12):1079-83. PMID:12593721 doi:10.1089/105072502321085171
9. ↑ Ho SC, Goh SS, Khoo DH. Association of Graves' disease with intragenic polymorphism of the thyrotropin receptor gene in a cohort of Singapore patients of multi-ethnic origins. Thyroid. 2003 Jun;13(6):523-8. PMID:12930595 doi:http://dx.doi.org/10.1089/105072503322238773
10. ↑ Sunthornthepvarakui T, Gottschalk ME, Hayashi Y, Refetoff S. Brief report: resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene. N Engl J Med. 1995 Jan 19;332(3):155-60. PMID:7528344 doi:http://dx.doi.org/10.1056/NEJM199501193320305
11. ↑ de Roux N, Misrahi M, Brauner R, Houang M, Carel JC, Granier M, Le Bouc Y, Ghinea N, Boumedienne A, Toublanc JE, Milgrom E. Four families with loss of function mutations of the thyrotropin receptor. J Clin Endocrinol Metab. 1996 Dec;81(12):4229-35. PMID:8954020
12. ↑ Clifton-Bligh RJ, Gregory JW, Ludgate M, John R, Persani L, Asteria C, Beck-Peccoz P, Chatterjee VK. Two novel mutations in the thyrotropin (TSH) receptor gene in a child with resistance to TSH. J Clin Endocrinol Metab. 1997 Apr;82(4):1094-100. PMID:9100579
13. ↑ Biebermann H, Schoneberg T, Krude H, Schultz G, Gudermann T, Gruters A. Mutations of the human thyrotropin receptor gene causing thyroid hypoplasia and persistent congenital hypothyroidism. J Clin Endocrinol Metab. 1997 Oct;82(10):3471-80. PMID:9329388
14. ↑ Abramowicz MJ, Duprez L, Parma J, Vassart G, Heinrichs C. Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland. J Clin Invest. 1997 Jun 15;99(12):3018-24. PMID:9185526 doi:10.1172/JCI119497
15. ↑ Tonacchera M, Agretti P, Pinchera A, Rosellini V, Perri A, Collecchi P, Vitti P, Chiovato L. Congenital hypothyroidism with impaired thyroid response to thyrotropin (TSH) and absent circulating thyroglobulin: evidence for a new inactivating mutation of the TSH receptor gene. J Clin Endocrinol Metab. 2000 Mar;85(3):1001-8. PMID:10720030
16. ↑ Russo D, Betterle C, Arturi F, Chiefari E, Girelli ME, Filetti S. A novel mutation in the thyrotropin (TSH) receptor gene causing loss of TSH binding but constitutive receptor activation in a family with resistance to TSH. J Clin Endocrinol Metab. 2000 Nov;85(11):4238-42. PMID:11095460
17. ↑ Nagashima T, Murakami M, Onigata K, Morimura T, Nagashima K, Mori M, Morikawa A. Novel inactivating missense mutations in the thyrotropin receptor gene in Japanese children with resistance to thyrotropin. Thyroid. 2001 Jun;11(6):551-9. PMID:11442002 doi:10.1089/105072501750302859
18. ↑ Alberti L, Proverbio MC, Costagliola S, Romoli R, Boldrighini B, Vigone MC, Weber G, Chiumello G, Beck-Peccoz P, Persani L. Germline mutations of TSH receptor gene as cause of nonautoimmune subclinical hypothyroidism. J Clin Endocrinol Metab. 2002 Jun;87(6):2549-55. PMID:12050212
19. ↑ Park SM, Clifton-Bligh RJ, Betts P, Chatterjee VK. Congenital hypothyroidism and apparent athyreosis with compound heterozygosity or compensated hypothyroidism with probable hemizygosity for inactivating mutations of the TSH receptor. Clin Endocrinol (Oxf). 2004 Feb;60(2):220-7. PMID:14725684
20. ↑ Tonacchera M, Perri A, De Marco G, Agretti P, Banco ME, Di Cosmo C, Grasso L, Vitti P, Chiovato L, Pinchera A. Low prevalence of thyrotropin receptor mutations in a large series of subjects with sporadic and familial nonautoimmune subclinical hypothyroidism. J Clin Endocrinol Metab. 2004 Nov;89(11):5787-93. PMID:15531543 doi:89/11/5787
21. ↑ Chistiakov DA, Savost'anov KV, Turakulov RI, Petunina N, Balabolkin MI, Nosikov VV. Further studies of genetic susceptibility to Graves' disease in a Russian population. Med Sci Monit. 2002 Mar;8(3):CR180-4. PMID:11887032
22. ↑ Ban Y, Greenberg DA, Concepcion ES, Tomer Y. A germline single nucleotide polymorphism at the intracellular domain of the human thyrotropin receptor does not have a major effect on the development of Graves' disease. Thyroid. 2002 Dec;12(12):1079-83. PMID:12593721 doi:10.1089/105072502321085171
23. ↑ Ho SC, Goh SS, Khoo DH. Association of Graves' disease with intragenic polymorphism of the thyrotropin receptor gene in a cohort of Singapore patients of multi-ethnic origins. Thyroid. 2003 Jun;13(6):523-8. PMID:12930595 doi:http://dx.doi.org/10.1089/105072503322238773
24. ↑ Rodien P, Bremont C, Sanson ML, Parma J, Van Sande J, Costagliola S, Luton JP, Vassart G, Duprez L. Familial gestational hyperthyroidism caused by a mutant thyrotropin receptor hypersensitive to human chorionic gonadotropin. N Engl J Med. 1998 Dec 17;339(25):1823-6. PMID:9854118 doi:10.1056/NEJM199812173392505
25. ↑ Chistiakov DA, Savost'anov KV, Turakulov RI, Petunina N, Balabolkin MI, Nosikov VV. Further studies of genetic susceptibility to Graves' disease in a Russian population. Med Sci Monit. 2002 Mar;8(3):CR180-4. PMID:11887032
26. ↑ Ban Y, Greenberg DA, Concepcion ES, Tomer Y. A germline single nucleotide polymorphism at the intracellular domain of the human thyrotropin receptor does not have a major effect on the development of Graves' disease. Thyroid. 2002 Dec;12(12):1079-83. PMID:12593721 doi:10.1089/105072502321085171
27. ↑ Ho SC, Goh SS, Khoo DH. Association of Graves' disease with intragenic polymorphism of the thyrotropin receptor gene in a cohort of Singapore patients of multi-ethnic origins. Thyroid. 2003 Jun;13(6):523-8. PMID:12930595 doi:http://dx.doi.org/10.1089/105072503322238773
28. ↑ Duprez L, Parma J, Van Sande J, Allgeier A, Leclere J, Schvartz C, Delisle MJ, Decoulx M, Orgiazzi J, Dumont J, et al.. Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism. Nat Genet. 1994 Jul;7(3):396-401. PMID:7920658 doi:http://dx.doi.org/10.1038/ng0794-396
29. ↑ Kopp P, van Sande J, Parma J, Duprez L, Gerber H, Joss E, Jameson JL, Dumont JE, Vassart G. Brief report: congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene. N Engl J Med. 1995 Jan 19;332(3):150-4. PMID:7800007 doi:http://dx.doi.org/10.1056/NEJM199501193320304
30. ↑ Tonacchera M, Van Sande J, Cetani F, Swillens S, Schvartz C, Winiszewski P, Portmann L, Dumont JE, Vassart G, Parma J. Functional characteristics of three new germline mutations of the thyrotropin receptor gene causing autosomal dominant toxic thyroid hyperplasia. J Clin Endocrinol Metab. 1996 Feb;81(2):547-54. PMID:8636266
31. ↑ de Roux N, Polak M, Couet J, Leger J, Czernichow P, Milgrom E, Misrahi M. A neomutation of the thyroid-stimulating hormone receptor in a severe neonatal hyperthyroidism. J Clin Endocrinol Metab. 1996 Jun;81(6):2023-6. PMID:8964822
32. ↑ Holzapfel HP, Wonerow P, von Petrykowski W, Henschen M, Scherbaum WA, Paschke R. Sporadic congenital hyperthyroidism due to a spontaneous germline mutation in the thyrotropin receptor gene. J Clin Endocrinol Metab. 1997 Nov;82(11):3879-84. PMID:9360555
33. ↑ Fuhrer D, Wonerow P, Willgerodt H, Paschke R. Identification of a new thyrotropin receptor germline mutation (Leu629Phe) in a family with neonatal onset of autosomal dominant nonautoimmune hyperthyroidism. J Clin Endocrinol Metab. 1997 Dec;82(12):4234-8. PMID:9398746
34. ↑ Kopp P, Jameson JL, Roe TF. Congenital nonautoimmune hyperthyroidism in a nonidentical twin caused by a sporadic germline mutation in the thyrotropin receptor gene. Thyroid. 1997 Oct;7(5):765-70. PMID:9349581
35. ↑ Gruters A, Schoneberg T, Biebermann H, Krude H, Krohn HP, Dralle H, Gudermann T. Severe congenital hyperthyroidism caused by a germ-line neo mutation in the extracellular portion of the thyrotropin receptor. J Clin Endocrinol Metab. 1998 May;83(5):1431-6. PMID:9589634
36. ↑ Khoo DH, Parma J, Rajasoorya C, Ho SC, Vassart G. A germline mutation of the thyrotropin receptor gene associated with thyrotoxicosis and mitral valve prolapse in a Chinese family. J Clin Endocrinol Metab. 1999 Apr;84(4):1459-62. PMID:10199795
37. ↑ Tonacchera M, Agretti P, Chiovato L, Rosellini V, Ceccarini G, Perri A, Viacava P, Naccarato AG, Miccoli P, Pinchera A, Vitti P. Activating thyrotropin receptor mutations are present in nonadenomatous hyperfunctioning nodules of toxic or autonomous multinodular goiter. J Clin Endocrinol Metab. 2000 Jun;85(6):2270-4. PMID:10852462
38. ↑ Biebermann H, Schoneberg T, Krude H, Gudermann T, Gruters A. Constitutively activating TSH-receptor mutations as a molecular cause of non-autoimmune hyperthyroidism in childhood. Langenbecks Arch Surg. 2000 Oct;385(6):390-2. PMID:11127522
39. ↑ Tonacchera M, Agretti P, Rosellini V, Ceccarini G, Perri A, Zampolli M, Longhi R, Larizza D, Pinchera A, Vitti P, Chiovato L. Sporadic nonautoimmune congenital hyperthyroidism due to a strong activating mutation of the thyrotropin receptor gene. Thyroid. 2000 Oct;10(10):859-63. PMID:11081252
40. ↑ Fuhrer D, Warner J, Sequeira M, Paschke R, Gregory J, Ludgate M. Novel TSHR germline mutation (Met463Val) masquerading as Graves' disease in a large Welsh kindred with hyperthyroidism. Thyroid. 2000 Dec;10(12):1035-41. PMID:11201847
41. ↑ Alberti L, Proverbio MC, Costagliola S, Weber G, Beck-Peccoz P, Chiumello G, Persani L. A novel germline mutation in the TSH receptor gene causes non-autoimmune autosomal dominant hyperthyroidism. Eur J Endocrinol. 2001 Sep;145(3):249-54. PMID:11517004
42. ↑ Biebermann H, Schoneberg T, Hess C, Germak J, Gudermann T, Gruters A. The first activating TSH receptor mutation in transmembrane domain 1 identified in a family with nonautoimmune hyperthyroidism. J Clin Endocrinol Metab. 2001 Sep;86(9):4429-33. PMID:11549687
43. ↑ Vaidya B, Campbell V, Tripp JH, Spyer G, Hattersley AT, Ellard S. Premature birth and low birth weight associated with nonautoimmune hyperthyroidism due to an activating thyrotropin receptor gene mutation. Clin Endocrinol (Oxf). 2004 Jun;60(6):711-8. PMID:15163335 doi:10.1111/j.1365-2265.2004.02040.x
44. ↑ Nakabayashi K, Matsumi H, Bhalla A, Bae J, Mosselman S, Hsu SY, Hsueh AJ. Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor. J Clin Invest. 2002 Jun;109(11):1445-52. PMID:12045258 doi:10.1172/JCI14340
45. ↑ Sanders J, Chirgadze DY, Sanders P, Baker S, Sullivan A, Bhardwaja A, Bolton J, Reeve M, Nakatake N, Evans M, Richards T, Powell M, Miguel RN, Blundell TL, Furmaniak J, Smith BR. Crystal structure of the TSH receptor in complex with a thyroid-stimulating autoantibody. Thyroid. 2007 May;17(5):395-410. PMID:17542669 doi:10.1089/thy.2007.0034