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

• While goiter and thyroid test abnormalities have more often led to the suspicion of thyroid gland dysfunction, short stature, hyperactivity, learning disability and goiter in children or adolescents and recalcitrant goiter in adults, should raise the suspicion of GRTH [5].
• MEASUREMENTS: Thyroid, cardiovascular, psychometric, hearing, speech, and growth testing; thyroid tests done at baseline and after TSH-releasing hormone stimulation; and DNA analysis for detection of mutations in the thyroid hormone receptor beta (TR beta) gene (exons 9 and 10) [6].
• Patients with generalized resistance to thyroid hormone (GRTH) show various organ-specific features, for example mental retardation, growth abnormalities, liver damage, delayed bone age or cardiac disorders [7].
• Attention deficit disorders are a frequent manifestation of resistance to thyroid hormone (RTH), a disorder caused by mutations in the hormone-binding domain of the human thyroid hormone receptor beta gene [8].

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

• RESULTS: The cell lines exhibited a very low frequency of heterozygosity for the regions 3p12-3p21 (D3S3, D3S30 and D3S2) and distal 3p21-3p24 (D3F15S2 and THRB), when compared with that observed in the normal population [22].
• Although mutations of human thyroid hormone receptor beta (hTR beta) have been associated with resistance to thyroid hormone (RTH), the molecular basis by which the mutant TRs cause the various clinical symptoms is unknown [23].
• Among the informative cases, the frequency of LOH was highest in blood plasma for the markers D8S360 (18%) and D10S1765 (15%), and in BM plasma for THRB (24%) and D8S137 (22%) [24].
• Although the majority of tumours with allelic loss originated wholly, or in part, from the ciliary body, choroidal melanomas also demonstrated allelic loss of THRB [25].
• 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 [26].

Associations of THRB with chemical compounds

• Mutations of THRB cause a human genetic disease, thyroid hormone resistance syndrome (RTH) [27].
• These results indicate that partial dissociation of TR/retinoid X receptor heterodimer complex from the TRE is involved in the suppression of transcription induced by PCB [28].
• Here we describe in a patient with RTH, a new mutation in codon 426 (T426I) of the TRb gene leading to a threonine to isoleucine substitution [29].
• Previously, others have reported a kindred with GRTH, in that the same codon was subjected to proline to histidine replacement due to a mutation consisting of a cytosine to adenine replacement at nucleotide position 1643 [30].
• Because the androgen and estrogen nuclear hormone receptors are subject to acetylation, we speculated that the nuclear thyroid hormone receptor-beta1 (TRbeta1), another superfamily member, was also subject to this posttranslational modification [31].

Physical interactions of THRB

• Generalized resistance to thyroid hormones (GRTH) commonly results from mutations in the T3-binding domain of the c-erbA beta thyroid hormone receptor gene [32].
• TAF-Ibeta also binds to other nuclear receptor superfamily members and represses thyroid hormone receptor beta- induced transcription in transient transfection assays [33].

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

• We have determined the allelotypes of 215 established lung cancer cell lines by PCR analysis at six loci on the short arm of chromosome 3 (3p): D3S3 (3p12-p13), D3S30 (3p13), D3S2 (3p14-p21.1), D3S32 (3p21), D3F15S2 (3p21), and THRB (3p24) [3].
• Electrophoretic mobility shift assays revealed that the TR/retinoid X receptor heterodimer complex was partially dissociated from TRE in the presence of PCB [28].
• Cross-talk between signal transducer and activator of transcription (Stat5) and thyroid hormone receptor-beta 1 (TRbeta1) signaling pathways [38].
• The thyroid hormone receptor beta gene was amplified using the polymerase chain reaction and the receptor mutation identified by sequence analysis [4].
• 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 [39].

References