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Gene Review

THRB  -  thyroid hormone receptor, beta

Homo sapiens

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Disease relevance of THRB

  • The SCID tumors arising after the inoculation of 10(5) cells were passaged serially in vivo and regularly showed loss of four markers; D3S1029 (3p21.3-21.2), AP20R (3p22-21.3, D3S32 (3p21.3-p21.2), and THRB (3p24) [1].
  • Heterozygosity for the orthologous human THRB(PV) mutation and other similar mutations in human THRB cause resistance to thyroid hormone (RTH), which is occasionally associated with mild sensorineural hearing impairment [2].
  • In summary, the 3p chromosome region near the D3S3 locus (3p12-p13) appears to be involved in all forms of lung cancer with additional involvement of regions close to the D3S2 (3p14-p21.1), D3F15S2 (3p21), and THRB (3p24) loci [3].
  • In addition to D3S3, the lowest frequencies of heterozygosity were seen at D3F15S2 for Ad (9%), D3S2 for large cell carcinomas (8%), and THRB for adenosquamous (0%), bronchioloalveolar (0%), and large cell (8%) carcinomas [3].
  • OBJECTIVE: We wished to ascertain whether a mutation in the thyroid hormone receptor beta gene was present in a family with generalized thyroid hormone resistance syndrome and to characterize the functional properties of this mutant receptor [4].

Psychiatry related information on THRB


High impact information on THRB

  • Generalized resistance to thyroid hormone (GRTH) is an inherited disease that is usually suspected when elevated serum thyroid hormone levels are associated with nonsuppressed thyrotropin [9].
  • This case, and the retrospective finding of high thyroxine levels in five newborns subsequently diagnosed as having GRTH, suggest that measurement of thyroxine at birth, in conjunction with thyrotropin, could allow the early detection of GRTH [9].
  • Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone. Identification of thirteen novel mutations in the thyroid hormone receptor beta gene [10].
  • 28 different point mutations in the human thyroid hormone receptor beta (TR beta) gene have been associated with GRTH [11].
  • In this family with recessively inherited GRTH, neither exon could be amplified using any combinations of primers and DNA blot revealed absence of all coding exons [12].

Chemical compound and disease context of THRB

  • Patients with GRTH and PRTH both present with elevated free thyroxine and triiodothyronine and inappropriately normal thyroid-stimulating hormone, but the former patients are clinically euthyroid, whereas the latter patients have symptoms and signs of hyperthyroidism [13].
  • Farnesol induces thyroid hormone receptor (THR) beta1 but inhibits THR-mediated signaling in MCF-7 human breast cancer cells [14].
  • Intrauterine growth restriction and postnatal undernutrition also induce striking differences in TH-receptor isoforms in functionally-distinct muscles, with critical implications for gene transcription of myosin isoforms. glucose transporters, uncoupling proteins and cation pumps [15].
  • Triiodothyroacetic acid has been used in patients showing hypermetabolism, and L-T4 treatment in high doses has been suggested in GRTH if patients have signs of clinical hypothyroidism such as growth retardation and developmental delay [16].

Biological context of THRB

  • We determined the structure of the human THRB gene, cloned seven alternately spliced 5'-untranslated region (5'-UTR) TRbeta1 mRNAs, and identified five polyadenylation position elements in the 3'-UTR [17].
  • LOH on chromosome band 3p24 was found to occur at an overall rate of 36.4% (16/44) by three markers (D3S1293, THRB, and D3S1283) [18].
  • Among the 29 tumors informative for THRB three showed loss of heterozygosity (LOH) [19].
  • We have previously shown that four markers spanning the 3p24-p21.3 region, THRB, AP20R, D3S1029, and D3S32, were regularly eliminated from three human chromosome 3 (chr3)/mouse microcell hybrids (MCHs) during tumor growth in SCID mice [20].
  • While their role in tumor generation or progression is currently unclear, both gross chromosomal and minor mutations (deletions, aberrant splicing, point mutations) and changes in the level of expression of THRA and THRB genes have been found [21].

Anatomical context of THRB


Associations of THRB with chemical compounds


Physical interactions of THRB


Regulatory relationships of THRB

  • Thus, developmental and tissue-specific expression of human thyroid hormone receptor beta1 5'-UTR mRNAs may regulate T3-responsiveness in target tissues by modulating TRbeta protein translation and thereby controlling the ratio of expressed TRalpha and -beta proteins [17].

Other interactions of THRB

  • Other 3p genes coding for receptor proteins THRB and RARB, are unlikely candidates for tumor suppression [34].
  • The following are informative cases found in a total number of patients analyzed for each locus: 13 of 26 for L-myc (1p); 9 of 23 for THRB (3p); 11 of 29 for met (7q); 27 of 50 for c-H-ras-1 (11p); 3 of 13 for TP53 (17p); 14 of 50 for D17S30 (17p); 20 of 33 for D17S4 (17q); and 13 of 33 for D18S5 (18q) [35].
  • The phenotypic manifestations of mutated THRB and THRA genes are distinct, indicating isoform-dependent actions of TR mutants in vivo [27].
  • A positive multipoint lod score of 2.9 was obtained on chromosome 3 with markers at the loci RAF1, THRB and D3S11 [36].
  • AI at one or more loci within the 3p24-26, 3p21, 3p13 and 9p21 regions or within the THRB and DCC genes was associated with reduced survival [37].

Analytical, diagnostic and therapeutic context of THRB


  1. Nonrandom loss of human chromosome 3 fragments from mouse-human microcell hybrids following progressive growth in SCID mice. Imreh, S., Kholodnyuk, I., Allikmetts, R., Stanbridge, E.J., Zabarovsky, E.R., Klein, G. Genes Chromosomes Cancer (1994) [Pubmed]
  2. Knock-in mouse model for resistance to thyroid hormone (RTH): an RTH mutation in the thyroid hormone receptor beta gene disrupts cochlear morphogenesis. Griffith, A.J., Szymko, Y.M., Kaneshige, M., Quiñónez, R.E., Kaneshige, K., Heintz, K.A., Mastroianni, M.A., Kelley, M.W., Cheng, S.Y. J. Assoc. Res. Otolaryngol. (2002) [Pubmed]
  3. Frequent involvement of chromosome 3p alterations in lung carcinogenesis: allelotypes of 215 established cell lines at six chromosome 3p loci. Buchhagen, D.L. J. Cell. Biochem. Suppl. (1996) [Pubmed]
  4. Functional properties of a novel mutant thyroid hormone receptor in a family with generalized thyroid hormone resistance syndrome. Adams, M., Nagaya, T., Tone, Y., Jameson, J.L., Chatterjee, V.K. Clin. Endocrinol. (Oxf) (1992) [Pubmed]
  5. Resistance to thyroid hormone and its molecular basis. Refetoff, S. Acta paediatrica Japonica; Overseas edition. (1994) [Pubmed]
  6. Genetic and clinical features of 42 kindreds with resistance to thyroid hormone. The National Institutes of Health Prospective Study. Brucker-Davis, F., Skarulis, M.C., Grace, M.B., Benichou, J., Hauser, P., Wiggs, E., Weintraub, B.D. Ann. Intern. Med. (1995) [Pubmed]
  7. DNA binding affinity of hTRbeta1 mutants as heterodimers with traps from different tissues. Takeda, T., Suzuki, S., Nagasawa, T., Liu, R.T., DeGroot, L.J. Biochimie (1999) [Pubmed]
  8. Abnormalities in sustained attention and anterior cingulate metabolism in subjects with resistance to thyroid hormone. Matochik, J.A., Zametkin, A.J., Cohen, R.M., Hauser, P., Weintraub, B.D. Brain Res. (1996) [Pubmed]
  9. Neonatal detection of generalized resistance to thyroid hormone. Weiss, R.E., Balzano, S., Scherberg, N.H., Refetoff, S. JAMA (1990) [Pubmed]
  10. Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone. Identification of thirteen novel mutations in the thyroid hormone receptor beta gene. Adams, M., Matthews, C., Collingwood, T.N., Tone, Y., Beck-Peccoz, P., Chatterjee, K.K. J. Clin. Invest. (1994) [Pubmed]
  11. 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. Weiss, R.E., Weinberg, M., Refetoff, S. J. Clin. Invest. (1993) [Pubmed]
  12. Screening of nineteen unrelated families with generalized resistance to thyroid hormone for known point mutations in the thyroid hormone receptor beta gene and the detection of a new mutation. Takeda, K., Balzano, S., Sakurai, A., DeGroot, L.J., Refetoff, S. J. Clin. Invest. (1991) [Pubmed]
  13. Resistance to thyroid hormone in children. Usala, S.J. Curr. Opin. Pediatr. (1994) [Pubmed]
  14. Farnesol induces thyroid hormone receptor (THR) beta1 but inhibits THR-mediated signaling in MCF-7 human breast cancer cells. Duncan, R.E., Archer, M.C. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  15. Nutrition-hormone receptor-gene interactions: implications for development and disease. Dauncey, M.J., White, P., Burton, K.A., Katsumata, M. The Proceedings of the Nutrition Society. (2001) [Pubmed]
  16. Successful therapy with L-T4 in a 5 year-old boy with generalized thyroid hormone resistance. Dundar, B., Bober, E., Büyükgebiz, A. Journal of pediatric endocrinology & metabolism : JPEM. (2003) [Pubmed]
  17. Multiple messenger ribonucleic acid variants regulate cell-specific expression of human thyroid hormone receptor beta1. Frankton, S., Harvey, C.B., Gleason, L.M., Fadel, A., Williams, G.R. Mol. Endocrinol. (2004) [Pubmed]
  18. Lack of correlation between expression of retinoic acid receptor-beta and loss of heterozygosity on chromosome band 3p24 in esophageal cancer. Qiu, H., Lotan, R., Lippman, S.M., Xu, X.C. Genes Chromosomes Cancer (2000) [Pubmed]
  19. Submicroscopic deletions of 3p sequences in pleomorphic adenomas with t(3;8)(p21;q12). Sahlin, P., Mark, J., Stenman, G. Genes Chromosomes Cancer (1994) [Pubmed]
  20. A 3p21.3 region is preferentially eliminated from human chromosome 3/mouse microcell hybrids during tumor growth in SCID mice. Kholodnyuk, I., Kost-Alimova, M., Kashuba, V., Gizatulin, R., Szeles, A., Stanbridge, E.J., Zabarovsky, E.R., Klein, G., Imreh, S. Genes Chromosomes Cancer (1997) [Pubmed]
  21. Thyroid hormone receptors/THR genes in human cancer. González-Sancho, J.M., García, V., Bonilla, F., Muñoz, A. Cancer Lett. (2003) [Pubmed]
  22. Two regions of homozygosity on chromosome 3p in squamous cell carcinoma of the head and neck: comparison with cytogenetic analysis. Buchhagen, D.L., Worsham, M.J., Dyke, D.L., Carey, T.E. Head & neck. (1996) [Pubmed]
  23. A mutant thyroid hormone receptor beta 1 identified in a patient with resistance to thyroid hormone inhibits the activities of not only the wild-type TRs, but also other nuclear receptors. Miyoshi, Y., Nakao, K. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  24. Detection of tumor-specific DNA in blood and bone marrow plasma from patients with prostate cancer. Schwarzenbach, H., Chun, F.K., Lange, I., Carpenter, S., Gottberg, M., Erbersdobler, A., Friedrich, M.G., Huland, H., Pantel, K. Int. J. Cancer (2007) [Pubmed]
  25. Loss of heterozygosity of the thyroid hormone receptor B in posterior uveal melanoma. Sisley, K., Curtis, D., Rennie, I.G., Rees, R.C. Melanoma Res. (1993) [Pubmed]
  26. Enhanced levels of wild-type versus mutant thyroid hormone receptor beta 1 messenger RNA in fibroblasts from heterozygotes of kindred S with thyroid hormone resistance. Bercu, B.B., Usala, S.J., Klann, R.C., Root, A.W., Nguyen, U.K., Torres, B., Holbrook, C.T. Thyroid (1996) [Pubmed]
  27. Thyroid hormone receptor mutations and disease: beyond thyroid hormone resistance. Cheng, S.Y. Trends Endocrinol. Metab. (2005) [Pubmed]
  28. Polychlorinated biphenyls suppress thyroid hormone receptor-mediated transcription through a novel mechanism. Miyazaki, W., Iwasaki, T., Takeshita, A., Kuroda, Y., Koibuchi, N. J. Biol. Chem. (2004) [Pubmed]
  29. 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. Menzaghi, C., Di Paola, R., Corrias, A., Einaudi, S., Trischitta, V., De Sanctis, C., De Filippis, V. Hum. Mutat. (1998) [Pubmed]
  30. 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. Shuto, Y., Wakabayashi, I., Amuro, N., Minami, S., Okazaki, T. J. Clin. Endocrinol. Metab. (1992) [Pubmed]
  31. Acetylation of nuclear hormone receptor superfamily members: thyroid hormone causes acetylation of its own receptor by a mitogen-activated protein kinase-dependent mechanism. Lin, H.Y., Hopkins, R., Cao, H.J., Tang, H.Y., Alexander, C., Davis, F.B., Davis, P.J. Steroids (2005) [Pubmed]
  32. Homozygosity for a dominant negative thyroid hormone receptor gene responsible for generalized resistance to thyroid hormone. Ono, S., Schwartz, I.D., Mueller, O.T., Root, A.W., Usala, S.J., Bercu, B.B. J. Clin. Endocrinol. Metab. (1991) [Pubmed]
  33. A novel estrogen receptor alpha-associated protein, template-activating factor Ibeta, inhibits acetylation and transactivation. Loven, M.A., Muster, N., Yates, J.R., Nardulli, A.M. Mol. Endocrinol. (2003) [Pubmed]
  34. Deletions of the short arm of chromosome 3 in solid tumors and the search for suppressor genes. Kok, K., Naylor, S.L., Buys, C.H. Adv. Cancer Res. (1997) [Pubmed]
  35. Benign breast disease: absence of genetic alterations at several loci implicated in breast cancer malignancy. Lizard-Nacol, S., Lidereau, R., Collin, F., Arnal, M., Hahnel, L., Roignot, P., Cuisenier, J., Guerrin, J. Cancer Res. (1995) [Pubmed]
  36. Linkage analysis and exclusion of regions of chromosomes 3 and 8 in Gilles de la Tourette syndrome following the identification of a balanced reciprocal translocation 46 XY, t(3:8)(p21.3 q24.1) in a case of Tourette syndrome. Brett, P.M., Curtis, D., Robertson, M.M., Dahlitz, M., Gurling, H.M. Psychiatr. Genet. (1996) [Pubmed]
  37. The prognostic significance of allelic imbalance at key chromosomal loci in oral cancer. Partridge, M., Emilion, G., Pateromichelakis, S., A'Hern, R., Lee, G., Phillips, E., Langdon, J. Br. J. Cancer (1999) [Pubmed]
  38. Cross-talk between signal transducer and activator of transcription (Stat5) and thyroid hormone receptor-beta 1 (TRbeta1) signaling pathways. Favre-Young, H., Dif, F., Roussille, F., Demeneix, B.A., Kelly, P.A., Edery, M., de Luze, A. Mol. Endocrinol. (2000) [Pubmed]
  39. A pulsed-field gel electrophoresis map locates the polymorphic probes for ERBA2 and ErbA beta within 120 kb of each other, confirming that THRB (formerly ERBA2) maps to chromosome 3. Douglas, J.B., Daly, M.C., Rabbitts, P.H. Genomics (1991) [Pubmed]
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