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| THYROID HORMONE RECEPTOR, ALPHA-1; THRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| THYROID HORMONE RECEPTOR, CENTRAL NERVOUS SYSTEM FORM; THRA1 ERBA-ALPHA ONCOGENE ERBA; ERBA ERBA-RELATED 7; EAR7 V-ERB-A AVIAN ERYTHROBLASTIC LEUKEMIA VIRAL ONCOGENE HOMOLOG 1; ERBA1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other entities represented in this entry: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| THYROID HORMONE RECEPTOR, ALPHA-2, INCLUDED; THRA2, INCLUDED | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| THYROID HORMONE RECEPTOR, ALPHA-3, INCLUDED; THRA3, INCLUDED | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: THRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 17q21.1 Genomic coordinates (GRCh37): 17:38,218,445 - 38,250,119 (from NCBI) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Cloning | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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) 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 hormones. Messenger RNA from this gene was expressed in tissue-specific fashion, with highest levels in the central nervous system and no expression in the liver. An increasing body of evidence indicated the presence of multiple thyroid hormone receptors. Thompson et al. (1987) suggested that there may be as many as 5 different but related loci. 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. 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 and molecular mass of 54,824. Designated thyroid hormone receptor type alpha-2 (THRA2), this protein is represented by mRNAs of different size in liver and kidney, which may represent 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Structure | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. A 5-kb THRA1 mRNA encodes a predicted 410-amino acid protein; a 2.7-kb THRA2 mRNA encodes a 490-amino acid protein. Nagaya et al. (1996) stated that a third isoform, TR-alpha-3, is derived by alternative splicing. The proximal 39 amino acids of the TH-alpha-2 specific sequences are deleted in TR-alpha-3. A second gene, THRB (190160), on chromosome 3, encodes 2 isoforms of TR-beta by alternative splicing. Miyajima et al. (1989) reported studies on the structure and function of the EAR1 (602408) and EAR7 genes, both located on 17q21. They determined that one of the exons in the EAR7 coding sequence overlaps an exon of EAR1, and that the 2 genes are transcribed from opposite DNA strands. In addition, the EAR7 mRNA generates 2 alternatively spliced isoforms, referred to as EAR71 and EAR72, of which the EAR71 protein is the human counterpart of the chicken c-erbA protein. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Function | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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, which is the major thyroid hormone-responsive organ. This led Sakurai et al. (1989) to suggest that another thyroid hormone receptor may be present in liver. 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. 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 the 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. 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dayton et al. (1984) assigned the ERBA oncogene to chromosome 17. Spurr et al. (1984) confirmed this assignment. 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 c-erb-A to meiotic pachytene spreads obtained from uncultured spermatocytes. They concluded that ERBA is situated at 17q21.33-17q22, in the same region as the break that generated 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 17q11-q12 and demonstrated that it remains on chromosome 17 in APL, whereas TP53 (191170), at 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Table View | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0001 HYPOTHYROIDISM, CONGENITAL, NONGOITROUS 6 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| THRA, GLU403TER | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 truncation 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). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mathieu-Mahul et al. (1985); Rider et al. (1987); Sheer et al. (1985); Spurr et al. (1984); Zabel et al. (1984) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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