Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: THRA
Cytogenetic location: 17q21.1 Genomic coordinates (GRCh38): 17:40,062,193-40,093,867 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.1 | Hypothyroidism, congenital, nongoitrous, 6 | 614450 | Autosomal dominant | 3 |
Thyroid hormone receptors (TRs) are nuclear receptors that mediate gene regulation by thyroid hormone (TH, or T3). TRs form monomers, homodimers, or heterodimers with retinoid X receptors (RXRs; see 180245) at target DNA binding sites called TH-responsive elements (TREs). Two different genes, THRA and THRB (190160), encode TRs, and both genes produce multiple TR isoforms through alternative splicing (summary by Nagaya et al., 1996).
Thompson et al. (1987) isolated a cDNA derived from rat brain messenger RNA on the basis of homology to the human thyroid receptor gene. Expression of this cDNA produced a high-affinity binding protein for thyroid hormone. Messenger RNA from this gene was expressed in tissue-specific fashion, with highest levels in the central nervous system and no expression in liver.
Nakai et al. (1988) isolated a cDNA encoding a specific form of thyroid hormone receptor expressed in human liver, kidney, placenta, and brain. Identical clones were found in human placenta. The cDNA encodes a protein of 490 amino acids with a molecular mass of 54.8 kD. Designated thyroid hormone receptor type alpha-2 (THRA2), this protein was represented by mRNAs of different sizes in liver and kidney, possibly representing tissue-specific processing of the primary transcript. Nakai et al. (1988) suggested that the thyroid hormone receptor isolated from a testis library by Benbrook and Pfahl (1987) may be identical to THRA2.
Sakurai et al. (1989) used Northern blot analysis to study the distribution and abundance of mRNAs for the 3 thyroid hormone receptors, beta, alpha-1, and alpha-2. The 3 mRNAs were expressed in all tissues examined, and the relative amounts of the 3 were roughly parallel. None of the 3 mRNAs was abundant in liver, the major thyroid hormone-responsive organ, suggesting that another thyroid hormone receptor may be present in liver.
Miyajima et al. (1989) reported that the human EAR7 generates 2 alternatively spliced forms, EAR71 and EAR72. The EAR71 protein is the human counterpart of the chicken c-erbA protein.
Koenig et al. (1989) found that alternative splicing of the rat Erba-alpha gene results in 2 proteins, Erba-alpha-1 and Erba-alpha-2, that differ at their C-terminal ends.
Laudet et al. (1991) reported that a 5-kb THRA1 mRNA encodes a predicted 410-amino acid protein, and that a 2.7-kb THRA2 mRNA encodes a 490-amino acid protein. The proteins differ at their C-terminal ends. Nagaya et al. (1996) stated that a third isoform, THRA3, is derived by alternative splicing. The proximal 39 amino acids of the THRA2-specific sequence are deleted in THRA3.
Maternal thyroid hormone is transferred to the fetus early in pregnancy and is postulated to regulate brain development. Iskaros et al. (2000) investigated the ontogeny of TR isoforms and related splice variants in 9 first-trimester fetal brains by semiquantitative RT-PCR analysis. Expression of the TR-beta-1, TR-alpha-1, and TR-alpha-2 isoforms was detected from 8.1 weeks' gestation. An additional truncated species was detected with the TR-alpha-2 primer set, consistent with the TR-alpha-3 splice variant described in rat. All TR-alpha-derived transcripts were coordinately expressed and increased approximately 8-fold between 8.1 and 13.9 weeks' gestation. A more complex ontogenic pattern was observed for TR-beta-1, suggestive of a nadir between 8.4 and 12.0 weeks' gestation. The authors concluded that these findings point to an important role for the TR-alpha-1 isoform in mediating maternal thyroid hormone action during first-trimester fetal brain development.
Laudet et al. (1991) reported that the THRA gene contains 10 exons spanning 27 kb of DNA. The last 2 exons of the gene are alternatively spliced.
Miyajima et al. (1989) reported studies on the structure and function of the EAR1 (602408) and EAR7 genes, both located on chromosome 17q21. They determined that an exon in the EAR7 coding sequence overlaps an exon of EAR1, and that the 2 genes are transcribed from opposite DNA strands.
Dayton et al. (1984) assigned the ERBA oncogene to chromosome 17, and Spurr et al. (1984) confirmed this assignment. Both Dayton et al. (1984) and Spurr et al. (1984) showed that the ERBA locus remains on chromosome 17 in the t(15;17) translocation of acute promyelocytic leukemia (APL; 612376). The thymidine kinase (188300) locus is probably translocated to chromosome 15; study of leukemia with t(17;21) and apparently identical breakpoint showed that TK was on 21q+.
Jhanwar et al. (1985) performed in situ hybridization of a cloned DNA probe of ERBA to meiotic pachytene spreads obtained from uncultured spermatocytes. They concluded that ERBA is situated at chromosome 17q21.33-17q22, in the same region as the break that generates the t(15;17) seen in APL. Because most of the grains were seen in 17q22, they suggested that ERBA is probably in the proximal region of 17q22 or at the junction between 17q22 and 17q21.33.
By in situ hybridization, Le Beau et al. (1985) placed ERBA at chromosome 17q11-q12 and demonstrated that it remains on chromosome 17 in APL, whereas TP53 (191170), at chromosome 17q21-q22, is translocated to chromosome 15.
Ferro and San Roman (1981) discovered a constitutional t(15;17) translocation apparently identical to that of APL. Molecular genetic studies showed, however, that they are different: ERBA moves to chromosome 15 in the constitutional translocation. Mitelman et al. (1986) performed high resolution chromosome analysis on bone marrow cells from 4 patients with acute promyelocytic leukemia associated with t(15;17) and in lymphocytes from 2 unrelated phenotypically normal persons with an apparently identical constitutional translocation. In all 6 cases the breakpoints were localized to subbands 15q22.3 and 17q11.2 in prophase-prometaphase chromosomes. Thus, ERBA must be at 17q11.2 just proximal to the breakpoint in the APL translocation and just distal to it in the constitutional translocation.
By family linkage studies, Anderson et al. (1993) placed the THRA1 gene on the genetic map of 17q in relation to other genes and DNA markers.
Debuire et al. (1984) found that ERBA, which potentiates ERBB (131550), has an amino acid sequence different from that of other known oncogene products and related to those of the carbonic anhydrases. ERBA potentiates ERBB by blocking differentiation of erythroblasts at an immature stage. Carbonic anhydrases participate in the transport of carbon dioxide in erythrocytes. Sap et al. (1986) and Weinberger et al. (1986) showed that the ERBA protein is a high-affinity receptor for thyroid hormone. The cDNA sequence indicates a relationship to steroid-hormone receptors, and binding studies indicate that it is a receptor for thyroid hormones. It is located in the nucleus, where it binds to DNA and activates transcription.
Koenig et al. (1989) showed that the rat Erba-alpha-1 isoform bound T3, whereas the Erba-alpha-2 isoform did not. Erba-alpha-2 antagonized T3 binding and responsiveness by Erba-alpha-1.
Visser et al. (2010) analyzed and compared the transcriptome of fibroblasts from patients with mutations in MCT8 (300095), which result in the complex endocrine and neurologic phenotype of Allan-Herndon-Dudley syndrome (300523), with the transcriptome of normal human brain. They found that THRA2 expression closely followed MCT8 expression in human brain, much more so than the other thyroid receptor isoforms. Comparative analysis of genes differentially expressed in patient fibroblasts that were also correlated with expression of both MCT8 and THRA2 in normal brain suggested that MCT8 and THRA2 are functionally linked. Visser et al. (2010) concluded that there is a functional relationship between MCT8 and THRA2, and suggested a role for THRA2 in the (patho)physiology of thyroid hormone signaling in the brain.
Congenital Nongoitrous Hypothyroidism 6
In a 6-year-old girl with congenital nongoitrous hypothyroidism (CHNG6; 614450), Bochukova et al. (2012) performed whole-exome sequencing and identified a de novo heterozygous nonsense mutation in the THRA gene (E403X; 190120.0001) that generates a mutant protein that inhibits wildtype receptor action in a dominant-negative manner.
In a father and daughter with congenital nongoitrous hypothyroidism, van Mullem et al. (2012) identified heterozygosity for a 1-bp insertion in the THRA gene (190120.0002).
In 4 of 5 unrelated Polish children with congenital nongoitrous hypothyroidism, Tylki-Szymanska et al. (2015) identified heterozygosity for 2 nonsense mutations (190120.0001 and 190120.0003) and 2 missense mutations (190120.0004 and 190120.0005) in the THRA gene. Three mutations occurred de novo and the fourth was inherited from the patient's affected father.
Nonfunctioning Pituitary Adenomas, Somatic Mutations
McCabe et al. (1999) hypothesized that aberrant THRA expression in nonfunctioning pituitary tumors may reflect mutations in the receptor coding and regulatory sequences. They screened THRA mRNA and THRB response elements and ligand-binding domains for sequence anomalies. Screening THRA mRNA from 23 tumors by RNase mismatch and sequencing candidate fragments identified 1 silent and 3 missense mutations, 2 in the common THRA region (S45I and K370N) and 1 that was specific for the alpha-2 isoform (S377L). No THRB response element differences were detected in 14 nonfunctioning tumors, and no THRB ligand-binding domain differences were detected in 23 nonfunctioning tumors. The authors suggested that the novel thyroid receptor mutations may be of functional significance in terms of thyroid receptor action, and that further definition of their functional properties may provide insight into the role of thyroid receptors in growth control in pituitary cells.
Papillary Thyroid Carcinoma, Somatic Mutations
Puzianowska-Kuznicka et al. (2002) tested the hypothesis that the functions of TRs could be impaired in cancer tissues by aberrant expression and/or somatic mutations. As a model system, they selected human thyroid papillary cancer. They found that the mean expression levels of THRB mRNA and THRA mRNA were significantly lower, whereas the protein levels of THRB1 and THRA1 were higher in cancer tissues than in healthy thyroid. Sequencing of THRB1 and THRA1 cDNAs, cloned from 16 papillary cancers, revealed that mutations affected receptor amino acid sequences in 93.75% and 62.5% of cases, respectively. In contrast, no mutations were found in healthy thyroid controls, and only 11.11% and 22.22% of thyroid adenomas had such THRB1 or THRA1 mutations, respectively. The majority of the mutated TRs lost their transactivation function and exhibited dominant-negative activity. The authors concluded that these findings suggest a possible role for mutated thyroid hormone receptors in the tumorigenesis of human papillary thyroid carcinoma.
To evaluate the respective contributions of THRA and THRB in the regulation of CYP7A (118455), the rate-limiting enzyme in the synthesis of bile acids, Gullberg et al. (2000) studied the responses to 2% dietary cholesterol and T3 in THRA and THRB knockout mice under hypo- and hyperthyroid conditions. Their experiments showed that the normal stimulation in CYP7A activity and mRNA level by T3 is lost in THRB -/-, but not in THRA -/-, mice, identifying THRB as the mediator of T3 action on CYP7A and, consequently, as a major regulator of cholesterol metabolism in vivo. Somewhat unexpectedly, T3-deficient THRB -/- mice showed an augmented CYP7A response after challenge with dietary cholesterol, and these animals did not develop hypercholesterolemia to the extent that wildtype controls did. The authors concluded that the latter results lend strong support to the concept that THRs may exert regulatory effects in vivo independent of T3.
Mutations in the THRB gene result in resistance to thyroid hormone. To address the question of whether mutations in the THRA gene can lead to a similar disease, Kaneshige et al. (2001) prepared mutant mice by targeting the same THRB mutation found in kindred PV, a 1-bp insertion in the THRB gene (190160.0011), into the Thra1 gene by homologous recombination. The PV mutation was derived from a patient with severe resistance to thyroid hormone who had a frameshift of the C-terminal 14 amino acids of THRB1. They compared mice heterozygous for the Thr-alpha mutation with mice heterozygous for the Thr-beta mutation. Heterozygous Thr-alpha-1 mutant mice were viable, indicating that the mutation is not an embryonic lethal. In drastic contrast to the heterozygous beta mice, which did not exhibit a growth abnormality, the heterozygous alpha mice were dwarfs. These dwarfs exhibited increased mortality and reduced fertility. In contrast to the heterozygous beta mice, which had a hyperactive thyroid, the heterozygous alpha mice exhibited mild thyroid failure. The in vivo patterns of abnormal regulation of T3 target genes in heterozygous alpha mice were different from those of heterozygous beta mice. The distinct phenotypes exhibited by the heterozygous Thr-alpha-1 and Thr-beta mice indicated that the in vivo functions of thyroid hormone receptor mutants are isoform-dependent. The heterozygous alpha mice may be useful as a tool to uncover human diseases associated with mutations in the THRA gene, and, furthermore, to understand the molecular mechanisms by which thyroid hormone receptor isoforms exert their biologic activities.
Ng et al. (2001) determined that a targeted mutation in the THRA gene suppresses deafness and thyroid hyperactivity in transgenic Thrb-null mice. The THRA splice variant TR-alpha-1 receptor is nonessential for hearing, and the shorter TR-alpha-2 splice variant has unknown function but neither binds thyroid hormone nor transactivates. The targeted mutation deletes TR-alpha-2 and concomitantly causes overexpression of TR-alpha-1 as a consequence of the exon structure of the gene. The Thra-null mice had normal auditory thresholds, suggesting that TR-alpha-2 is dispensable for hearing, and have only marginally reduced thyroid activity. However, a potent function for the mutated allele was revealed upon its introduction into Thrb-null mice, where it suppressed the auditory and thyroid phenotypes caused by loss of THRB. The authors proposed a modifying function for a THRA allele and suggested that increased expression of TR-alpha-1 may substitute for the absence of THRB.
Liang et al. (2021) generated knockin mice heterozygous for the E403X mutation in Thra1 (190120.0001) associated with resistance to thyroid hormone in human patients. Male and female mutant mice had slightly higher TT3 concentrations than wildtype. TT4 concentrations in male mutant mice were normal at 3 and 16 weeks of age, but were lower than wildtype at 6 weeks of age. Female mutant mice exhibited a lower TT4/TT3 ratio and lower reverse T3 (rT3) concentrations compared with wildtype. In contrast, lower TT4/TT3 ratios and lower rT3 levels were observed only for 3- and 6-week-old male mutant mice. Mutant mice were fertile, but females showed lower fertility than wildtype, with defects in placenta development. The E403X mutation resulted in postnatal growth retardation in juvenile mice, although growth retardation was largely recovered by the time mutant mice reached adulthood. Postnatal growth retardation was characterized by delayed skeletal growth and defective skeletal muscle strength. In addition, mutant mice exhibited defects in brain development, which were associated with a severe motor deficit, and defects in internal organs, such as heart and intestine, and fat tissue. Mutant mice also developed age-dependent anemia. The authors concluded that mice heterozygous for E403X recapitulated the clinical features of human patients with the E403X mutation. Mice homozygous for E403X did not survive longer than 30 days, likely due to severe growth retardation. Compared with wildtype mice at 3 weeks of age, homozygous mutant mice exhibited severe neurologic phenotypes, such as spasticity and motor ataxia, similar to those observed in endemic cretinism.
Jansson et al. (1983) demonstrated that both human and mouse DNA have 2 distantly related classes of ERBA genes and that in the human genome multiple copies of one of the classes exist.
Thompson et al. (1987) suggested that there may be as many as 5 different but related loci encoding thyroid hormone receptors. Many of the clinical and physiologic studies suggested the existence of multiple receptors. For example, patients had been identified with familial thyroid hormone resistance in which peripheral response to thyroid hormones is lost or diminished while neuronal functions are maintained (Menezes-Ferreira et al., 1984). Thyroidologists recognize a form of cretinism in which the nervous system is severely affected and another form in which the peripheral functions of thyroid hormone are more dramatically affected.
The identification of the several types of thyroid hormone receptor may explain the normal variation in thyroid hormone responsiveness of various organs and the selective tissue abnormalities found in the thyroid hormone resistance syndromes. See, for example, the sibship reported by Refetoff et al. (1972), in which several members who were resistant to thyroid hormone action had retarded growth, congenital deafness, and abnormal bones, but had normal intellect and sexual maturation, as well as augmented cardiovascular activity. In this family, Bernal et al. (1978) demonstrated abnormal T3 nuclear receptors in blood cells, and Ichikawa et al. (1987) demonstrated the same in fibroblasts. The availability of cDNAs encoding the various thyroid hormone receptors was considered useful in determining the underlying genetic defect in this family.
In a 6-year-old girl of white European origin with congenital nongoitrous hypothyroidism (CHNG6; 614450), Bochukova et al. (2012) performed whole-exome sequencing and identified a de novo heterozygous 1207G-T transversion in the THRA gene, resulting in a glu403-to-ter (E403X) substitution, predicted to cause premature termination with loss of the C-terminal alpha-helix. The mutation was not found in published normal genomes and exomes or in 200 ethnically matched control alleles. Functional analysis demonstrated that the mutant receptor did not activate a thyroid hormone-responsive reporter gene and mediated substantial repression of basal promoter activity, consistent with negligible binding of radiolabeled triiodothyronine to mutant TR-alpha. Coexpression studies showed that the E403X receptor strongly inhibited transcriptional activity by wildtype TR-alpha in a dominant-negative manner. Patient peripheral blood mononuclear cells demonstrated markedly reduced basal and triiodothyronine-induced expression of the thyroid hormone-responsive target gene KLF9 (602902) compared to wildtype. Two-hybrid interaction assays revealed strong recruitment of corepressors by E403X mutant TR-alpha, with failure of their hormone-dependent dissociation, and minimal triiodothyronine-dependent association with coactivator SRC1 (602691).
In a 14-year-old Polish girl with congenital nongoitrous hypothyroidism, Tylki-Szymanska et al. (2015) identified heterozygosity a c.1207G-T transversion (c.1207G-T, NM_199334) in the THRA gene, resulting in the E403X mutation. The mutation occurred de novo in the proband.
In a father and daughter with congenital nongoitrous hypothyroidism (CHNG6; 614450), van Mullem et al. (2012) identified heterozygosity for a 1-bp insertion (1190insT) in the THRA gene, causing a frameshift predicted to result in premature termination (Phe397fs406Ter). The mutation was not found in the unaffected mother, in 300 Caucasian controls, or in public databases. Transfection studies showed that the mutant receptor does not respond to stimulation by T3, and also exerts a strong dominant-negative effect on wildtype THRA.
In an 18-year-old Polish boy with congenital nongoitrous hypothyroidism (CHNG6; 614450), Tylki-Szymanska et al. (2015) identified heterozygosity for a c.1176C-A transversion (c.1176C-A, NM_199334) in the THRA gene, resulting in a cys392-to-ter (C392X) substitution in the last exon of THRA isoform 1. The mutation occurred de novo in the proband.
In a 12-year-old Polish girl with congenital nongoitrous hypothyroidism (CHNG6; 614450), Tylki-Szymanska et al. (2015) identified heterozygosity for a c.1207G-A transition (c.1207G-A, NM_199334) in the THRA gene, resulting in a glu403-to-lys (E403K) substitution in the last exon of THRA isoform 1. The mutation was inherited from her affected father.
In an 8-year-old Polish girl with congenital nongoitrous hypothyroidism (CHNG6; 614450), Tylki-Szymanska et al. (2015) identified heterozygosity for a c.1193C-G transversion (c.1193C-G, NM_199334) in the THRA gene, resulting in a pro398-to-arg (P398R) substitution in the last exon of THRA isoform 1. The mutation occurred de novo in the proband.
Anderson, L. A., Friedman, L., Osborne-Lawrence, S., Lynch, E., Weissenbach, J., Bowcock, A., King, M.-C. High-density genetic map of the BRCA1 region of chromosome 17q12-q21. Genomics 17: 618-623, 1993. [PubMed: 8244378] [Full Text: https://doi.org/10.1006/geno.1993.1381]
Benbrook, D., Pfahl, M. A novel thyroid hormone receptor encoded by a cDNA clone from a human testis library. Science 238: 788-791, 1987. [PubMed: 3672126] [Full Text: https://doi.org/10.1126/science.3672126]
Bernal, J., Refetoff, S., DeGroot, L. J. Abnormalities of triiodothyronine binding to lymphocyte and fibroblast nuclei from a patient with peripheral tissue resistance to thyroid hormone action. J. Clin. Endocr. Metab. 47: 1266-1272, 1978. [PubMed: 233694] [Full Text: https://doi.org/10.1210/jcem-47-6-1266]
Bochukova, E., Schoenmakers, N., Agostini, M., Schoenmakers, E., Rajanayagam, O., Keogh, J. M., Henning, E., Reinemund, J., Gevers, E., Sarri, M., Downes, K., Offiah, A., and 11 others. A mutation in the thyroid hormone receptor alpha gene. New Eng. J. Med. 366: 243-249, 2012. Note: Erratum: New Eng. J. Med. 367: 1474 only, 2012. [PubMed: 22168587] [Full Text: https://doi.org/10.1056/NEJMoa1110296]
Dayton, A. I., Selden, J. R., Laws, G., Dorney, D. J., Finan, J., Tripputi, P., Emanuel, B. S., Rovera, G., Nowell, P. C., Croce, C. M. A human c-erbA oncogene homologue is closely proximal to the chromosome 17 breakpoint in acute promyelocytic leukemia. Proc. Nat. Acad. Sci. 81: 4495-4499, 1984. [PubMed: 6589608] [Full Text: https://doi.org/10.1073/pnas.81.14.4495]
Debuire, B., Henry, C., Benaissa, M., Biserte, G., Claverie, J. M., Saule, S., Martin, P., Stehelin, D. Sequencing the erbA gene of avian erythroblastosis virus reveals a new type of oncogene. Science 224: 1456-1459, 1984. [PubMed: 6328658] [Full Text: https://doi.org/10.1126/science.6328658]
Ferro, M. T., San Roman, C. Constitutional t(15;17). Cancer Genet. Cytogenet. 4: 89-91, 1981. [PubMed: 6456810] [Full Text: https://doi.org/10.1016/0165-4608(81)90011-x]
Gullberg, H., Rudling, M., Forrest, D., Angelin, B., Vennstrom, B. Thyroid hormone receptor beta-deficient mice show complete loss of the normal cholesterol 7-alpha-hydroxylase (CYP7A) response to thyroid hormone but display enhanced resistance to dietary cholesterol. Molec. Endocr. 14: 1739-1749, 2000. [PubMed: 11075809] [Full Text: https://doi.org/10.1210/mend.14.11.0548]
Ichikawa, K., Hughes, I. A., Horwitz, A. L., DeGroot, L. J. Characterization of nuclear thyroid hormone receptors of cultured skin fibroblasts from patients with resistance to thyroid hormone. Metabolism 36: 392-399, 1987. [PubMed: 3561254] [Full Text: https://doi.org/10.1016/0026-0495(87)90214-9]
Iskaros, J., Pickard, M., Evans, I., Sinha, A., Hardiman, P., Ekins, R. Thyroid hormone receptor gene expression in first trimester human fetal brain. J. Clin. Endocr. Metab. 85: 2620-2623, 2000. [PubMed: 10902817] [Full Text: https://doi.org/10.1210/jcem.85.7.6766]
Jansson, M., Philipson, L., Vennstrom, B. Isolation and characterization of multiple human genes homologous to the oncogenes of avian erythroblastosis virus. EMBO J. 2: 561-565, 1983. [PubMed: 6313346] [Full Text: https://doi.org/10.1002/j.1460-2075.1983.tb01463.x]
Jhanwar, S. C., Chaganti, R. S. K., Croce, C. M. Germ-line chromosomal localization of human c-erb-A oncogene. Somat. Cell Molec. Genet. 11: 99-102, 1985. [PubMed: 3856334] [Full Text: https://doi.org/10.1007/BF01534740]
Kaneshige, M., Suzuki, H., Kaneshige, K., Cheng, J., Wimbrow, H., Barlow, C., Willingham, M. C., Cheng, S. A targeted dominant negative mutation of the thyroid hormone alpha-1 receptor causes increased mortality, infertility, and dwarfism in mice. Proc. Nat. Acad. Sci. 98: 15095-15100, 2001. [PubMed: 11734632] [Full Text: https://doi.org/10.1073/pnas.261565798]
Koenig, R. J., Lazar, M. A., Hodin, R. A., Brent, G. A., Larsen, P. R., Chin, W. W., Moore, D. D. Inhibition of thyroid hormone action by a non-hormone binding c-erbA protein generated by alternative mRNA splicing. Nature 337: 659-661, 1989. [PubMed: 2537467] [Full Text: https://doi.org/10.1038/337659a0]
Laudet, V., Begue, A., Henry-Duthoit, C., Joubel, A., Martin, P., Stehelin, D., Saule, S. Genomic organization of the human thyroid hormone receptor alpha (c-erbA-1) gene. Nucleic Acids Res. 19: 1105-1112, 1991. [PubMed: 1850510] [Full Text: https://doi.org/10.1093/nar/19.5.1105]
Le Beau, M. M., Westbrook, C. A., Diaz, M. O., Rowley, J. D., Oren, M. Translocation of the p53 gene in t(15;17) in acute promyelocytic leukaemia. Nature 316: 826-828, 1985. [PubMed: 3929142] [Full Text: https://doi.org/10.1038/316826a0]
Liang, Y., Zhao, D., Wang, R., Dang, P., Xi, Y., Zhang, D., Wang, W., Shan, Z., Teng, X., Teng, W. Generation and characterization of a new resistance to thyroid hormone mouse model with thyroid hormone receptor alpha gene mutation. Thyroid 31: 678-691, 2021. [PubMed: 32924834] [Full Text: https://doi.org/10.1089/thy.2019.0733]
Mathieu-Mahul, D., Xu, D. Q., Saule, S., Lidereau, R., Galibert, F., Berger, R., Mauchauffe, M., Larsen, C. J. An EcoRI restriction fragment length polymorphism (RFLP) in the human c-erb A locus. Hum. Genet. 71: 41-44, 1985. [PubMed: 2993156] [Full Text: https://doi.org/10.1007/BF00295666]
McCabe, C. J., Gittoes, N. J., Sheppard, M. C., Franklyn, J. A. Thyroid receptor alpha-1 and alpha-2 mutations in nonfunctioning pituitary tumors. J. Clin. Endocr. Metab. 84: 649-653, 1999. [PubMed: 10022432] [Full Text: https://doi.org/10.1210/jcem.84.2.5469]
Menezes-Ferreira, M. M., Eil, C., Wortsman, J., Weintraub, B. D. Decreased nuclear uptake of [125-I]triiodo-L-thyronine in fibroblasts from patients with peripheral thyroid hormone resistance. J. Clin. Endocr. Metab. 59: 1081-1087, 1984. [PubMed: 6092406] [Full Text: https://doi.org/10.1210/jcem-59-6-1081]
Mitelman, F., Manolov, G., Manolova, Y., Billstrom, R., Heim, S., Kristoffersson, U., Mandahl, N., Ferro, M. T., San Roman, C. High resolution chromosome analysis of constitutional and acquired t(15;17) maps c-erbA to subband 17q11.2. Cancer Genet. Cytogenet. 22: 95-98, 1986. [PubMed: 3458521] [Full Text: https://doi.org/10.1016/0165-4608(86)90168-8]
Miyajima, N., Horiuchi, R., Shibuya, Y., Fukushige, S., Matsubara, K., Toyoshima, K., Yamamoto, T. Two erbA homologs encoding proteins with different T(3) binding capacities are transcribed from opposite DNA strands of the same genetic locus. Cell 57: 31-39, 1989. [PubMed: 2539258] [Full Text: https://doi.org/10.1016/0092-8674(89)90169-4]
Nagaya, T., Nomura, Y., Fujieda, M., Seo, H. Heterodimerization preferences of thyroid hormone receptor alpha isoforms. Biochem. Biophys. Res. Commun. 226: 426-430, 1996. [PubMed: 8806651] [Full Text: https://doi.org/10.1006/bbrc.1996.1372]
Nakai, A., Seino, S., Sakurai, A., Szilak, I., Bell, G. I., DeGroot, L. J. Characterization of a thyroid hormone receptor expressed in human kidney and other tissues. Proc. Nat. Acad. Sci. 85: 2781-2785, 1988. [PubMed: 3357890] [Full Text: https://doi.org/10.1073/pnas.85.8.2781]
Ng, L., Rusch, A., Amma, L. L., Nordstrom, K., Erway, L. C., Vennstrom, B., Forrest, D. Suppression of the deafness and thyroid dysfunction in Thrb-null mice by an independent mutation in the Thra thyroid hormone receptor gene. Hum. Molec. Genet. 10: 2701-2708, 2001. [PubMed: 11726557] [Full Text: https://doi.org/10.1093/hmg/10.23.2701]
Puzianowska-Kuznicka, M., Krystyniak, A., Madej, A., Cheng, S.-Y., Nauman, J. Functionally impaired TR mutants are present in thyroid papillary cancer. J. Clin. Endocr. Metab. 87: 1120-1128, 2002. [PubMed: 11889175] [Full Text: https://doi.org/10.1210/jcem.87.3.8296]
Refetoff, S., DeGroot, L. J., Benard, B., DeWind, L. T. Studies of a sibship with apparent hereditary resistance to the intracellular action of thyroid hormone. Metabolism 21: 723-756, 1972. [PubMed: 5047916] [Full Text: https://doi.org/10.1016/0026-0495(72)90121-7]
Rider, S. H., Bailey, C. J., Voss, R., Sheer, D., Hiorns, L. R., Solomon, E. RFLP for the human erb-A1 gene. Nucleic Acids Res. 15: 863 only, 1987. [PubMed: 2881264] [Full Text: https://doi.org/10.1093/nar/15.2.863]
Sakurai, A., Nakai, A., DeGroot, L. J. Expression of three forms of thyroid hormone receptor in human tissues. Molec. Endocr. 3: 392-399, 1989. [PubMed: 2710139] [Full Text: https://doi.org/10.1210/mend-3-2-392]
Sap, J., Munoz, A., Damm, K., Goldberg, Y., Ghysdael, J., Leutz, A., Beug, H., Vennstrom, B. The c-erb-A protein is a high-affinity receptor for thyroid hormone. Nature 324: 635-640, 1986. [PubMed: 2879242] [Full Text: https://doi.org/10.1038/324635a0]
Sheer, D., Sheppard, D. M., Le Beau, M., Rowley, J. D., San Roman, C., Solomon, E. Localization of the oncogene c-erbA1 immediately proximal to the acute promyelocytic leukaemia breakpoint on chromosome 17. Ann. Hum. Genet. 49: 167-171, 1985. [PubMed: 3865620] [Full Text: https://doi.org/10.1111/j.1469-1809.1985.tb01690.x]
Spurr, N. K., Goodfellow, P. N., Sheer, D., Bodmer, W. F., Vennstrom, B. Mapping of cellular oncogenes: ERBA1 is on chromosome 17. (Abstract) Cytogenet. Cell Genet. 37: 591 only, 1984.
Spurr, N. K., Solomon, E., Jansson, M., Sheer, D., Goodfellow, P. N., Bodmer, W. F., Vennstrom, B. Chromosomal localisation of the human homologues to the oncogenes erbA and B. EMBO J. 3: 159-163, 1984. [PubMed: 6323162] [Full Text: https://doi.org/10.1002/j.1460-2075.1984.tb01777.x]
Thompson, C. C., Weinberger, C., Lebo, R., Evans, R. M. Identification of a novel thyroid hormone receptor expressed in the mammalian central nervous system. Science 237: 1610-1614, 1987. [PubMed: 3629259] [Full Text: https://doi.org/10.1126/science.3629259]
Tylki-Szymanska, A., Acuna-Hidalgo, R., Krajewska-Walasek, M., Lecka-Ambroziak, A., Steehouwer, M., Gilissen, C., Brunner, H. G., Jurecka, A., Rozdzynska-Swiatkowska, A., Hoischen, A., Chrzanowska, K. H. Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor alpha-gene (THRA). J. Med. Genet. 52: 312-316, 2015. [PubMed: 25670821] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102936]
van Mullem, A., van Heerebeek, R., Chrysis, D., Visser, E., Medici, M., Andrikoula, M., Tsatsoulis, A., Peeters, R., Visser, T. J. Clinical phenotype and mutant TR-alpha-1. (Letter) New Eng. J. Med. 366: 1451-1453, 2012. [PubMed: 22494134] [Full Text: https://doi.org/10.1056/NEJMc1113940]
Visser, W. E., Swagemakers, S. M. A., Ozgur, Z., Schot, R., Verheijen, F. W., van Ijcken, W. F. J., van der Spek, P. J., Visser, T. J. Transcriptional profiling of fibroblasts from patients with mutations in MCT8 and comparative analysis with the human brain transcriptome. Hum. Molec. Genet. 19: 4189-4200, 2010. [PubMed: 20705735] [Full Text: https://doi.org/10.1093/hmg/ddq337]
Weinberger, C., Thompson, C. C., Ong, E. S., Lebo, R., Gruol, D. J., Evans, R. M. The c-erb-A gene encodes a thyroid hormone receptor. Nature 324: 641-646, 1986. [PubMed: 2879243] [Full Text: https://doi.org/10.1038/324641a0]
Zabel, B. U., Fournier, R. E. K., Lalley, P. A., Naylor, S. L., Sakaguchi, A. Y. Cellular homologs of the avian erythroblastosis virus erb-A and erb-B genes are syntenic in mouse but asyntenic in man. Proc. Nat. Acad. Sci. 81: 4874-4878, 1984. [PubMed: 6087351] [Full Text: https://doi.org/10.1073/pnas.81.15.4874]