2j4a

Structural highlights

Disease

[THB_HUMAN] Defects in THRB are the cause of generalized thyroid hormone resistance (GTHR) [MIM:188570]. GTHR is a disease characterized by goiter, abnormal mental functions, increased susceptibility to infections, abnormal growth and bone maturation, tachycardia and deafness. Affected individuals may also have attention deficit-hyperactivity disorders (ADHD) and language difficulties. GTHR patients also have high levels of circulating thyroid hormones (T3-T4), with normal or slightly elevated thyroid stimulating hormone (TSH).^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18]} Defects in THRB are the cause of generalized thyroid hormone resistance autosomal recessive (GTHRAR) [MIM:274300]. An autosomal recessive disorder characterized by goiter, clinical euthyroidism, end-organ unresponsiveness to thyroid hormone, abnormal growth and bone maturation, and deafness. Patients also have high levels of circulating thyroid hormones, with elevated thyroid stimulating hormone. Defects in THRB are the cause of selective pituitary thyroid hormone resistance (PRTH) [MIM:145650]; also known as familial hyperthyroidism due to inappropriate thyrotropin secretion. PRTH is a variant form of thyroid hormone resistance and is characterized by clinical hyperthyroidism, with elevated free thyroid hormones, but inappropriately normal serum TSH. Unlike GRTH, where the syndrome usually segregates with a dominant allele, the mode of inheritance in PRTH has not been established.^{[19] [20]}

Function

[THB_HUMAN] High affinity receptor for triiodothyronine.^[21]

Evolutionary Conservation

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

References

1. ↑ Sakurai A, Takeda K, Ain K, Ceccarelli P, Nakai A, Seino S, Bell GI, Refetoff S, DeGroot LJ. Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor beta. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8977-81. PMID:2510172
2. ↑ Usala SJ, Tennyson GE, Bale AE, Lash RW, Gesundheit N, Wondisford FE, Accili D, Hauser P, Weintraub BD. A base mutation of the C-erbA beta thyroid hormone receptor in a kindred with generalized thyroid hormone resistance. Molecular heterogeneity in two other kindreds. J Clin Invest. 1990 Jan;85(1):93-100. PMID:2153155 doi:http://dx.doi.org/10.1172/JCI114438
3. ↑ Usala SJ, Menke JB, Watson TL, Berard WE, Bradley C, Bale AE, Lash RW, Weintraub BD. A new point mutation in the 3,5,3'-triiodothyronine-binding domain of the c-erbA beta thyroid hormone receptor is tightly linked to generalized thyroid hormone resistance. J Clin Endocrinol Metab. 1991 Jan;72(1):32-8. PMID:1846005
4. ↑ Parrilla R, Mixson AJ, McPherson JA, McClaskey JH, Weintraub BD. Characterization of seven novel mutations of the c-erbA beta gene in unrelated kindreds with generalized thyroid hormone resistance. Evidence for two "hot spot" regions of the ligand binding domain. J Clin Invest. 1991 Dec;88(6):2123-30. PMID:1661299 doi:http://dx.doi.org/10.1172/JCI115542
5. ↑ Usala SJ, Menke JB, Watson TL, Wondisford FE, Weintraub BD, Berard J, Bradley WE, Ono S, Mueller OT, Bercu BB. A homozygous deletion in the c-erbA beta thyroid hormone receptor gene in a patient with generalized thyroid hormone resistance: isolation and characterization of the mutant receptor. Mol Endocrinol. 1991 Mar;5(3):327-35. PMID:1653889
6. ↑ Adams M, Nagaya T, Tone Y, Jameson JL, Chatterjee VK. Functional properties of a novel mutant thyroid hormone receptor in a family with generalized thyroid hormone resistance syndrome. Clin Endocrinol (Oxf). 1992 Mar;36(3):281-9. PMID:1563081
7. ↑ Cugini CD Jr, Leidy JW Jr, Chertow BS, Berard J, Bradley WE, Menke JB, Hao EH, Usala SJ. An arginine to histidine mutation in codon 315 of the c-erbA beta thyroid hormone receptor in a kindred with generalized resistance to thyroid hormones results in a receptor with significant 3,5,3'-triiodothyronine binding activity. J Clin Endocrinol Metab. 1992 May;74(5):1164-70. PMID:1314846
8. ↑ Shuto Y, Wakabayashi I, Amuro N, Minami S, Okazaki T. A point mutation in the 3,5,3'-triiodothyronine-binding domain of thyroid hormone receptor-beta associated with a family with generalized resistance to thyroid hormone. J Clin Endocrinol Metab. 1992 Jul;75(1):213-7. PMID:1619012
9. ↑ Sasaki S, Nakamura H, Tagami T, Miyoshi Y, Tanaka K, Imura H. A point mutation of the T3 receptor beta 1 gene in a kindred of generalized resistance to thyroid hormone. Mol Cell Endocrinol. 1992 Apr;84(3):159-66. PMID:1587388
10. ↑ Behr M, Loos U. A point mutation (Ala229 to Thr) in the hinge domain of the c-erbA beta thyroid hormone receptor gene in a family with generalized thyroid hormone resistance. Mol Endocrinol. 1992 Jul;6(7):1119-26. PMID:1324420
11. ↑ Weiss RE, Weinberg M, Refetoff S. Identical mutations in unrelated families with generalized resistance to thyroid hormone occur in cytosine-guanine-rich areas of the thyroid hormone receptor beta gene. Analysis of 15 families. J Clin Invest. 1993 Jun;91(6):2408-15. PMID:8514853 doi:http://dx.doi.org/10.1172/JCI116474
12. ↑ Weiss RE, Chyna B, Duell PB, Hayashi Y, Sunthornthepvarakul T, Refetoff S. A new point mutation (C446R) in the thyroid hormone receptor-beta gene of a family with resistance to thyroid hormone. J Clin Endocrinol Metab. 1994 May;78(5):1253-6. PMID:8175986
13. ↑ Refetoff S, Weiss RE, Wing JR, Sarne D, Chyna B, Hayashi Y. Resistance to thyroid hormone in subjects from two unrelated families is associated with a point mutation in the thyroid hormone receptor beta gene resulting in the replacement of the normal proline 453 with serine. Thyroid. 1994 Fall;4(3):249-54. PMID:7833659
14. ↑ Pohlenz J, Schonberger W, Wemme H, Winterpacht A, Wirth S, Zabel B. New point mutation (R243W) in the hormone binding domain of the c-erbA beta 1 gene in a family with generalized resistance to thyroid hormone. Hum Mutat. 1996;7(1):79-81. PMID:8664910 doi:<79::AID-HUMU15>3.0.CO;2-P 10.1002/(SICI)1098-1004(1996)7:1<79::AID-HUMU15>3.0.CO;2-P
15. ↑ Seto D, Weintraub BD. Rapid molecular diagnosis of mutations associated with generalized thyroid hormone resistance by PCR-coupled automated direct sequencing of genomic DNA: detection of two novel mutations. Hum Mutat. 1996;8(3):247-57. PMID:8889584 doi:<247::AID-HUMU8>3.0.CO;2-6 10.1002/(SICI)1098-1004(1996)8:3<247::AID-HUMU8>3.0.CO;2-6
16. ↑ Menzaghi C, Di Paola R, Corrias A, Einaudi S, Trischitta V, De Sanctis C, De Filippis V. T426I a new mutation in the thyroid hormone receptor beta gene in a sporadic patient with resistance to thyroid hormone and dysmorphism. Mutations in brief no. 192. Online. Hum Mutat. 1998;12(4):289. PMID:10660344
17. ↑ Mamanasiri S, Yesil S, Dumitrescu AM, Liao XH, Demir T, Weiss RE, Refetoff S. Mosaicism of a thyroid hormone receptor-beta gene mutation in resistance to thyroid hormone. J Clin Endocrinol Metab. 2006 Sep;91(9):3471-7. Epub 2006 Jun 27. PMID:16804041 doi:10.1210/jc.2006-0727
18. ↑ Rivolta CM, Olcese MC, Belforte FS, Chiesa A, Gruneiro-Papendieck L, Iorcansky S, Herzovich V, Cassorla F, Gauna A, Gonzalez-Sarmiento R, Targovnik HM. Genotyping of resistance to thyroid hormone in South American population. Identification of seven novel missense mutations in the human thyroid hormone receptor beta gene. Mol Cell Probes. 2009 Jun-Aug;23(3-4):148-53. doi: 10.1016/j.mcp.2009.02.002., Epub 2009 Mar 4. PMID:19268523 doi:10.1016/j.mcp.2009.02.002
19. ↑ Flynn TR, Hollenberg AN, Cohen O, Menke JB, Usala SJ, Tollin S, Hegarty MK, Wondisford FE. A novel C-terminal domain in the thyroid hormone receptor selectively mediates thyroid hormone inhibition. J Biol Chem. 1994 Dec 30;269(52):32713-6. PMID:7528740
20. ↑ Geffner ME, Su F, Ross NS, Hershman JM, Van Dop C, Menke JB, Hao E, Stanzak RK, Eaton T, Samuels HH, et al.. An arginine to histidine mutation in codon 311 of the C-erbA beta gene results in a mutant thyroid hormone receptor that does not mediate a dominant negative phenotype. J Clin Invest. 1993 Feb;91(2):538-46. PMID:8381821 doi:http://dx.doi.org/10.1172/JCI116233
21. ↑ Chou WY, Cheng YS, Ho CL, Liu ST, Liu PY, Kuo CC, Chang HP, Chen YH, Chang GG, Huang SM. Human spot 14 protein interacts physically and functionally with the thyroid receptor. Biochem Biophys Res Commun. 2007 May 25;357(1):133-8. Epub 2007 Mar 26. PMID:17418816 doi:10.1016/j.bbrc.2007.03.103
22. ↑ Koehler K, Gordon S, Brandt P, Carlsson B, Backsbro-Saeidi A, Apelqvist T, Agback P, Grover GJ, Nelson W, Grynfarb M, Farnegardh M, Rehnmark S, Malm J. Thyroid receptor ligands. 6. A high affinity "direct antagonist" selective for the thyroid hormone receptor. J Med Chem. 2006 Nov 16;49(23):6635-7. PMID:17154490 doi:10.1021/jm060521i