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PubMed1993

Characterization of a novel mutant human thyroid hormone receptor beta in a family with hereditary thyroid hormone resistance.

OBJECTIVE: We wished to determine the abnormality responsible for Generalized Resistance to Thyroid Hormone in a family with this syndrome. DESIGN: Molecular biological studies were performed on a mutant human thyroid hormone receptor beta (hTR beta) cloned from fibroblasts of the patient. PATIENTS: The patient is from a previously reported family with typical features of Generalized Resistance to Thyroid Hormone, demonstrating goitre, elevated thyroid hormone levels, slightly elevated TSH, and retarded bone age. MEASUREMENTS: A cDNA for hTR beta 1 was cloned using specific oligonucleotide primers from fibroblast DNA. A mutant hTR beta 1 expression vector was constructed, and an in-vitro expressed mutant receptor was tested for T3 binding. Receptor binding to DNA was studied in a DNA cellulose assay and gel mobility shift assay. RESULTS: Two mutations were found in the cloned hTR beta. One was silent but the second changed arginine 438 to histidine. The mutation was present in RNA and genomic DNA, as shown by allele-specific amplification. The mutated receptor had reduced T3 binding affinity but demonstrated normal binding in a DNA cellulose assay and in a gel mobility shift assay. The receptor did not have altered heat sensitivity. CONCLUSIONS: In the T sibship with Generalized Resistance to Thyroid Hormone, resistance to thyroid hormone is apparently produced by a substitution of a histidine for arginine at amino acid 438, which causes reduced binding of receptor to T3, although the receptor remains able to bind to DNA and, for this reason, functions as a dominant negative in affected subjects who are heterozygous with one normal and one mutated allele.

Base Sequence↗

PubMed1994

Low intelligence but not attention deficit hyperactivity disorder is associated with resistance to thyroid hormone caused by mutation R316H in the thyroid hormone receptor beta gene.

Resistance to thyroid hormone (RTH) is a syndrome of reduced responsiveness of tissues to thyroid hormone. The clinical manifestations are variable and 46-50% of children with RTH have attention deficit hyperactivity disorder (ADD). We present a new family with RTH (F120) found to have a mutation R316H in the thyroid hormone receptor beta (TR beta) gene identical for that reported in an unrelated family. Assignment of the mutant allele and haplotyping based on CA repeat polymorphism were done on 16 family members. Semistructured diagnostic interviews and psychometric testing were used to determine the psychiatric diagnosis of 12 family members by examiners blinded to the genotype. Three subjects were identified to have the R316H allele as well as mildly elevated free T4 index (168 +/- 12; normal range 77-135) and nonsuppressed TSH (4.1 +/- 1.7 mU/L). Only 2 of the subjects with RTH were found to have ADD, while one family member homozygous for the wild type TR beta and normal thyroid function tests also had ADD. Unaffected family members had higher full scale intelligence quotients (IQ) (93 +/- 7) than any of the 3 family members with RTH (77 +/- 5, p = 0.006). These data do not support the genetic linkage of ADD and RTH, but do suggest that RTH is associated with lower IQ scores that may confer a high likelihood of exhibiting ADD symptoms.

Adolescent↗

PubMed1988

Rat growth hormone gene expression. Both cell-specific and thyroid hormone response elements are required for thyroid hormone regulation.

The elements involved in mediating cell-specific and thyroid hormone stimulation of rat growth hormone gene expression have been defined by transfection studies and by nuclease footprinting. 5'-Flanking DNA extending to -104 can mediate cell-specific expression, and this is enhanced 3- to 4-fold with DNA extending to -145. Cell-specific factors, found only in rat growth hormone producing cells, bind within the -137/-107 and -95/-65 regions, and competition studies suggest that the same factor binds to both sites. The sequence A (A or T) TAAAT is found at the center of both footprints at -80 and -122, suggesting that it is a core component of the recognition sequence of the cell-specific factor. Disruption of the spatial and/or distance relationships between the two regions eliminates the enhanced level of cell-specific expression, suggesting a cooperative interaction of the proteins which bind to these elements. Sequences located between -208 and -178 can confer thyroid hormone-regulated expression when linked in either orientation in close proximity to one or both cell-specific elements. The thyroid hormone and cell-specific elements function as an enhancer-like unit and are both required to confer regulated expression to heterologous promoters. We propose that thyroid hormone acts via its receptor to enhance the function of the cell-specific element by forming a more "active" transcription complex which stimulates the level of gene expression.

Animals↗

PubMed2001

Selective thyromimetics: tissue-selective thyroid hormone analogs.

Thyroid hormone coordinates a diverse array of physiological events in development and homeostasis. Many of the actions of thyroid hormone are tissue-specific and are primarily mediated by a panel of thyroid hormone receptor isoforms that are expressed in different ratios in different tissues. Because these tissue-specific hormone signaling pathways are linked to a number of metabolic diseases, the development of synthetic thyroid hormone analogs that have tissue-selective hormone actions (i.e., selective thyromimetics) is highly desirable. There is a powerful collection of tools available today for this pursuit including efficient receptor binding and activation assays, receptor structures and a variety of thyroid hormone receptor knockout mice. The medicinal chemistry efforts in this area demonstrate that selective thyromimetics can be produced from a variety of approaches. These compounds are proving useful as probes to better define thyroid hormone actions and may one day find use in the clinic for the treatment of metabolic disorders.

Animals↗

PubMed1996

Evaluation of pituitary and peripheral tissue markers of thyroid hormone action in an Iranian family with resistance to thyroid hormone.

Resistance to thyroid hormone (RTH), an inherited syndrome of reduced sensitivity to thyroid hormone, is being detected with increased frequency. We report the first family with RTH identified in Iran. Goiter prompted thyroid evaluation, and nonsuppressed TSH associated with high free T4, suggested RTH as the etiology. The mother and all four of her children expressed the RTH phenotype associated with attention deficit and hyperactivity. Detailed clinical and laboratory studies before and following the administration of graded doses of L-T3 demonstrated relatively severe resistance to the hormone at the level of the thyrotrophs and peripheral tissues. Our data underscore the importance of evaluating the changes of various parameters of thyroid hormone action in response to thyroid hormone rather than their measurement at baseline or assessment of absolute levels.

Adolescent↗

PubMed1981

Growth hormone responses to thyroid hormone in the neonatal rat: resistance and anamnestic response.

Differences in the growth hormone (GH) responses to primary and to secondary stimulation with triiodothyronine (T3) were studied in rats deprived of thyroid hormone from birth. Neonatal hypothyroidism was induced in pups by feeding pregnant rats an iodine-deficient, propylthiouracil-containing diet. T3 stimulation was carried out in pups by subcutaneous injection of a single dose of 50 mug T3/100 g body wt. Pituitary GH content, rate of GH synthesis in vitro, and GH messenger (m)RNA activity in a cellfree translation system were measured.No significant differences in body weight and in pituitary GH content were observed between hypothyroid and normal pups at ages 1, 3, and 6 d. 10- and 28-d-old hypothyroid pups showed a significant arrest of growth, decreased pituitary GH content, and development of GH responsiveness to T3. In contrast, serum thyroxine concentration in hypothyroid pups was <0.15 mug/dl, significantly lower than normal at all ages.GH synthesis and GH mRNA activity studied in pituitaries of 28-d-old rats were expressed as percent total protein synthesis and percent mRNA activity, respectively. GH synthesis and mRNA activity were 3.0 and 2.6% in hypothyroid rats, 3.3 and 2.9% in hypothyroid rats given a single T3 injection 14 d earlier (T3-withdrawn rats), and 26.8 and 27.1% in normal rats. Administration of T3 to hypothyroid rats induced an increase in GH synthesis and GH mRNA activity, reaching 5.8 and 5.6% 12 h after primary stimulation and 12.2 and 16.1% 12 h after secondary stimulation. The response rates were linear but 2.5-fold more rapid after secondary stimulation. The latter response was similar to that observed after T3 stimulation of rats rendered hypothyroid during adulthood. The responses of GH synthesis and mRNA activity were concordant after both primary and secondary T3 stimulation. A twofold increase in both parameters was observed as early as 2 h after T3 injection. Four conclusions can be drawn from these experiments. First, during neonatal life, GH accumulation in rat pituitaries is independent of thyroid hormone and is insensitive to T3. Second, GH dependence on and sensitivity to thyroid hormone is acquired between the 6th and 10th d of neonatal life. Third, secondary T3 stimulation produces an anamnestic response manifested by an increased rate of GH synthesis and mRNA activity. Fourth, primary T3 stimulation is not associated with a lag in the endogenous translation of the newly accumulated GH mRNA.

Animals↗

PubMed1999

A novel point mutation in cluster 3 of the thyroid hormone receptor beta gene (P247L) causing mild resistance to thyroid hormone.

Resistance to thyroid hormone (RTH), a syndrome characterized by variable tissue hyposensitivity to thyroid hormone (TH), is linked to mutations in the thyroid hormone receptor (TR) beta gene. We report a new family with a heretofore unreported mutation, P247L. The proposita, a 31-year-old female, presented with goiter and palpitations. RTH was suspected because of elevated serum free thyroxine (FT4) level with a normal thyrotropin (TSH). Sequencing the TRbeta gene revealed a mutation causing replacement of a proline at position 247 with leucine. Seven family members were heterozygous for the mutation, two of whom also had evidence of autoimmune thyroid disease. The mutant TRbeta had a Ka for triiodothyronine (T3) 30% that of the wild-type TRbeta, approximately a threefold reduction in T3-induced transactivation and a low level dominant negative activity when tested with a positively regulated reporter gene. In vivo sensitivity to TH was evaluated in three affected subjects by measurement of the responses to graded doses of levotriiodothyronine (LT3). Peak TSH responses to TRH were reduced and were not completely suppressed at even the highest dose of LT3, (0.9, 0.2, and 0.2, compared to < 0.01 microU/mL in unaffected controls), confirming pituitary resistance to TH in all three subjects. In contrast, peripheral tissues responded variably to LT3: serum cholesterol decreased in all by 15%-25%, serum creatine kinase decreased by 15% in two subjects and increased 35% in another, but serum ferritin and sex hormone-binding globulin increased in only one of the three affected individuals that were tested. Basal metabolic rate and sleeping pulse did not change in three and two individuals, respectively. Hyporesponsiveness to exogenous TH established the clinical diagnosis of RTH in one member of the family with a mutant TRbeta but normal tests of thyroid function at baseline. Three affected subjects had an axis I diagnosis of major depression but had Wechsler Intelligence Scale for Children, III (WISC-III) full-scale IQs (FSIQs) in the normal range. This novel TRbeta mutation is associated with a realtively mild RTH. Results of responses to LT3 underscore the variable phenotype of RTH.

Adolescent↗

PubMed1991

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.

Generalized resistance to thyroid hormone (GRTH) is a syndrome characterized by impaired tissue responsiveness to thyroid hormone. Two distinct point mutations in the hormone binding domain of the thyroid hormone receptor (TR) beta have recently been identified in two unrelated families with GRTH. One, Mf, involves a replacement of the normal glycine-345 for arginine in exon 7 and another, Mh, replaces the normal proline-453 for histidine in exon 8. To probe for the presence of the Mf and Mh defect in 19 unrelated families with GRTH, we applied separate polymerase chain reactions using allele-specific oligonucleotide primers containing the normal and each of the two mutant nucleotides at the 3'-position. A total of 24 affected subjects and 13 normal family members were studied. The mode of inheritance was dominant in 13 families, was unknown in 5 families, and was clearly recessive in 1 family in which only the consanguineous subjects were affected. Primers containing the substitutions specific for Mf and Mh amplified exons 7 and 8, respectively, only in affected members of each of the two index families. Primers containing the normal sequences amplified exons 7 and 8 of the TR beta gene in all subjects except affected members of one family. 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. These results indicate a major deletion of the TR beta gene, including both DNA and hormone binding domains. Since heterozygous members of this family are not affected, the presence of a single normal allele is sufficient for normal function of the TR beta. These data also support the hypothesis that in the dominant mode of GRTH inheritance the presence of an abnormal TR beta interferes with the function of the normal TR beta. Distinct mutations are probably responsible for GRTH in unrelated families.

Alleles↗

PubMed2005

Transthyretin is not necessary for thyroid hormone metabolism in conditions of increased hormone demand.

Thyroid hormones circulate in blood mainly bound to plasma proteins. Transthyretin is the major thyroxine plasma carrier in mice. Studies in transthyretin-null mice revealed that the absence of transthyretin results in euthyroid hypothyroxinemia and normal thyroid hormone tissue distribution, with the exception of the choroid plexus in the brain. Therefore, transthyretin does not influence normal thyroid hormone homeostasis under standard laboratory conditions. To investigate if transthyretin has a buffer/storage role we challenged transthyretin-null and wild-type mice with conditions of increased hormone demand: (i) exposure to cold, which elicits thermogenesis, a process that requires thyroid hormones; and (ii) thyroidectomy, which abolishes thyroid hormone synthesis and secretion and induces severe hypothyroidism. Transthyretin-null mice responded as the wild-type both to changes induced by stressful events, namely in body weight, food intake and thyroid hormone tissue content, and in the mRNA levels of genes whose expression is altered in such conditions. These results clearly exclude a role for transthyretin in thyroid hormone homeostasis even under conditions of increased hormone demand.

Animals↗

PubMed1992

Thyroid hormone alters the DNA binding properties of chicken thyroid hormone receptors alpha and beta.

The effects of thyroid hormone agonists on thyroid hormone receptor (TR)/DNA complex formation was investigated to elucidate the mechanism by which TRs transactivate genes in response to ligand. The data, obtained from gel shift experiments, indicate that thyroid hormones alter the conformation of TRs bound to DNA, irrespective of if the element is occupied by monomeric TR, homodimeric TR/TR, or heterodimeric complexes with the retinoid receptors RAR or RXR. Furthermore, triiodo-thyronine (T3) prevents 2 TR molecules from binding to oligonucleotides containing direct repeats or inverted palindromes of the consensus AGGTCA motif, an effect that was not detected with palindromic elements. Heterodimers bound to direct repeats were less affected: RXR/TR were fully and RAR/TR complexes partially resistant to thyroid hormone. The data suggest that a ligand-induced conformational change in TR prevents double TR occupancy of a response element containing 2 direct repeats of the consensus binding motif, possibly by steric hindrance, whereas such an event does not prevent TR/RXR heterodimers from binding to DNA. Finally, our data show that a monomeric, liganded TR bound preferentially to the second half site in a AGGTCActcaAGGTCA element, and therefore indicate that nucleotides adjacent to the consensus half site contribute to binding specificity.

Animals↗

PubMed2001

Increased sensitivity to thyroid hormone in mice with complete deficiency of thyroid hormone receptor alpha.

Only three of the four thyroid hormone receptor (TR) isoforms, alpha1, beta1, and beta2, bind thyroid hormone (TH) and are considered to be true TRs. TRalpha2 binds to TH response elements on DNA, but its role in vivo is still unknown. We produced mice completely deficient in TRalpha (TRalpha(o/o)) that maintain normal serum thyroid-stimulating hormone (TSH) concentration despite low serum thyroxine (T(4)), suggesting increased sensitivity to TH. We therefore examined the effects of TH (L-3,3',5-triiodothyronine, L-T3) given to TH-deprived and to intact TRalpha(o/o) mice. Controls were wild-type (WT) mice of the same strain and mice resistant to TH due to deficiency in TRbeta (TRbeta(-/-)). In liver, T3 produced significantly greater responses in TRalpha(o/o) and smaller responses in TRbeta(-/-) as compared with WT mice. In contrast, cardiac responses to L-T3 were absent or reduced in TRalpha(o/o), whereas they were similar in WT and TRbeta(-/-) mice, supporting the notion that TRalpha1 is the dominant TH-dependent TR isoform in heart. 5-Triiodothyronine (L-T3) given to intact mice produced a greater suppression of serum T(4) in TRalpha(o/o) than it did in WT mice and reduced by a greater amount the TSH response to TSH-releasing hormone. This is an in vivo demonstration that a TR deficiency can enhance sensitivity to TH. This effect is likely due to the abrogation of the constitutive "silencing" effect of TRalpha2 in tissues expressing the TRbeta isoforms.

Animals↗

PubMed2003

Positive predictive value of serum thyroglobulin levels, measured during the first year of follow-up after thyroid hormone withdrawal, in thyroid cancer patients.

The follow-up of patients with papillary and follicular thyroid carcinoma after thyroidectomy and radioiodine ablation is mainly based on serum thyroglobulin (Tg) level deter-mination. The positive predictive value (PPV) of serum Tg level after thyroid hormone withdrawal, measured during the first 6-12 months of follow-up (initial off L-T(4) Tg), was studied in 256 consecutive differentiated thyroid cancer patients. All underwent a total thyroidectomy and 3.7 GBq (131)I ablation; 37 patients had an elevated initial off L-T(4) Tg level. This study focuses on these 37 patients, 9 of whom had a clinical recurrence. The present data confirm that in this selected cohort of patients, 74-185 MBq (131)I-total body scan (TBS) has no clinical interest in the initial work-up and during the subsequent follow-up because it was negative in all patients, except in one with recurrent disease. The PPV of initial serum off L-T(4) Tg level above 5 ng/ml and 10 ng/ml was 42% and 53%, respectively; this PPV was only 50% at the time of recurrence or subsequent control. This relatively low PPV is related to the low recurrence rate in this series of patients, despite a prolonged follow-up, and to the subsequent decrease of serum Tg level in 14 of 37 (38%) patients in the absence of any further treatment. In contrast, the PPV of the increasing slope of serum Tg levels obtained after thyroid hormone withdrawal (83%) was excellent. In conclusion, we confirm that (131)I-TBS has a limited interest for the follow-up of thyroid cancer patients. Follow-up should rely on serum Tg level and prognostic parameters; however, initial serum Tg may be produced by thyroid tissues of various significance, an increase at two consecutive determinations indicating disease progression and a decrease being related to late effects of therapy. The best PPV is brought by the slope of serum Tg levels.

Adenocarcinoma, Follicular↗

PubMed1997

A novel point mutation of thyroid hormone receptor beta gene in a family with resistance to thyroid hormone.

Resistance to thyroid hormone (RTH) is characterized by variable tissue hyporesponsiveness to thyroid hormone caused by mutations of thyroid hormone receptor beta (TRbeta) gene. We found a novel point mutation of the TRbeta gene in a family (F123) with RTH, a transition of a guanine to adenine at nucleotide 1215, which replaced the normal Met-310 with Ile. This substitution was found in only one allele of affected family members. In vitro transcription and translation of this mutant TRbeta demonstrated a 12-fold reduction of the affinity for triiodothyronine (T3) compared with the wild type TRbeta. Thyroid function tests were similar to a previously reported RTH family (F99) who had a different mutation in the same codon (Thr 310).

Adolescent↗

PubMed1996

Negative regulation of the gene for the preprothyrotropin-releasing hormone from the mouse by thyroid hormone requires additional factors in conjunction with thyroid hormone receptors.

To gain additional insights into the negative gene regulatory action by triiodothyronine (T3), we isolated a 2-kilobase pair 5'-flanking region of the mouse preprothyrotropin-releasing hormone (ppTRH) gene and characterized the DNA elements mediating inhibitory regulation by T3 in the promoter region. In GH4C1 cells, the expression of the 2-kilobase pair mouse ppTRH 5'-flanking region fused to the luciferase reporter gene occurred by transfection and was significantly suppressed by T3. In contrast, T3 suppression was not observed in T3 receptor (T3R)-deficient CV-1 cells, suggesting that T3Rs were required for the negative regulation. Cotransfected mouse T3R alpha1, beta1, and beta2 possessed indistinguishable potency for the negative regulation. Deletion analysis localized the element mediating the negative regulation to the region between -83 and +46, and the sequence downstream of the transcription start site (TSS) between +12 and +46 was found to be essential for the inhibitory regulation. In mobility shift assays, only T3R monomers bound to the element containing a T3 response element half-site at -57. No apparent T3R binding was observed to the element downstream of TSS. Neither the T3 response element half-site nor the element downstream of the TSS confer T3 suppression individually in heterologous promoters. These results indicate that the negative regulation of murine ppTRH gene by T3 might be mediated by the cooperation of T3R monomers with unknown factor(s) interacting with the element downstream of the TSS.

Animals↗

PubMed1991

Homozygosity for a dominant negative thyroid hormone receptor gene responsible for generalized resistance to thyroid hormone.

Generalized resistance to thyroid hormones (GRTH) commonly results from mutations in the T3-binding domain of the c-erbA beta thyroid hormone receptor gene. We have reported on a novel deletion mutation in c-erbA beta in a kindred, S, with GRTH. One patient from this kindred was the product of a consanguineous union from two affected members and was homozygous for the beta-receptor defect. This patient at 3.5 weeks of age had unprecedented elevations of TSH, free T4, and free T3 (TSH, 389 mU/L; free T4, 330.8 pmol/L; free T3, 82,719 fmol/L). He displayed a complex mixture of tissue-specific hyperthyroidism and hypothyroidism. He had delayed growth (height age, 1 3/12 yr at chronological age 2 9/12 yr) and skeletal maturation (bone age, 4 months), and developmental delay (developmental age, 8 months), but he was quite tachycardic. The homozygous patient of kindred S is markedly different from a recently reported patient with no c-erbA beta-receptor. This difference indicates that a dominant negative form of c-erbA beta in man can inhibit at least some thyroid hormone action mediated by the c-erbA alpha-receptors.

Adolescent↗

PubMed2002

Knock-in mouse model for resistance to thyroid hormone (RTH): an RTH mutation in the thyroid hormone receptor beta gene disrupts cochlear morphogenesis.

Thyroid hormone and the beta isoform of its receptor, Trb, are essential for normal development of the mammalian auditory system. We have analyzed auditory system function and structure in a mouse strain with a targeted Thrb mutation, Thrb(PV), which leads to the loss of binding of thyroid hormone (T3) to the Trb protein. 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. Auditory brainstem response analysis of heterozygous Thrb(PV)/+ mice demonstrates that they develop normal hearing. In contrast, Thrb(PV)/Thrb(PV) mice have severe hearing impairment that is already present at 3 weeks of age. This hearing loss is associated with disruption of postnatal morphogenesis of the tectorial membrane and organ of Corti. Comparison with the previously described phenotype of a Thrb -/- knockout strain suggests that Thrb(PV) disrupts the function of other genes that are critical for development and/or maintenance of these structures.

Amino Acid Sequence↗

PubMed2003

Differential effects of triiodothyronine and the thyroid hormone receptor beta-specific agonist GC-1 on thyroid hormone target genes in the b ain.

The availability of synthetic thyroid hormone receptor agonists provides a valuable tool to analyze whether specific receptor isoforms mediate specific physiological responses to thyroid hormone. GC-1 is a thyroid hormone analog displaying selectivity for thyroid hormone receptor beta. We have analyzed the effect of GC-1 on expression of thyroid hormone target genes in the cerebrum and cerebellum. Congenitally hypothyroid rats were treated with single daily doses of either T3 or GC-1. Both compounds similarly induced Purkinje cell protein-2 (PCP-2) in the cerebellum. Expression of RC3 and Rhes in the caudate, and hairless, neurotrophin-3, Reelin, and Rev-ErbAalpha in the cerebellum, was analyzed by in situ hybridization on postnatal d 16. Hypothyroidism strongly decreased expression of RC3 and Rhes in the caudate, and hairless, Rev-ErbAalpha, and neurotrophin-3 in the cerebellum, and increased Reelin. T3 treatment normalized the expression of all genes. However, GC-1 effectively normalized expression of Rhes and Reelin only. The lack of a GC-1 effect on most cerebellar genes can be explained by the known distribution of thyroid hormone receptor alpha and beta isoforms. However, in the caudate, RC3 and Rhes are expressed in the same cells, and therefore, they may represent specific gene responses linked to specific thyroid hormone receptor isoforms.

Acetates↗

PubMed1997

A unique role of the beta-2 thyroid hormone receptor isoform in negative regulation by thyroid hormone. Mapping of a novel amino-terminal domain important for ligand-independent activation.

Negative regulation by thyroid hormone is mediated by nuclear thyroid hormone receptors (TRs) acting on thyroid hormone response elements (TREs). We examine here the role of human TR-beta2, a TR isoform with central nervous system-restricted expression, in the regulation of target genes whose expression are decreased by triiodothyronine (T3). Using transient transfection studies, we found that TR-beta2 achieved significantly greater ligand-independent activation on the thyrotropin-releasing hormone (TRH) and common glycoprotein alpha-subunit genes than either TR-beta1 or TR-alpha1. A chimeric TR-beta isoform containing the TR-beta2 amino terminus linked to the TR-alpha1 DNA- and ligand-binding domains functioned like the TR-beta2 isoform on these promoters, confirming that the amino terminus of TR-beta2 was both necessary and sufficient to mediate this effect. By constructing deletion mutants of the TR-beta2 amino terminus, we demonstrate that amino acids 89-116 mediate this function. This domain, important in ligand-independent activation on negative TREs, is discrete from a previously described activation domain in the amino-terminal portion of TR-beta2. We conclude that the central nervous system-restricted TR-beta2 isoform has a unique effect on negative regulation by T3 that can be mapped to amino acids 89-116 of the amino terminus of the human TR-beta2.

Amino Acid Sequence↗