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Biomedical subjects

V K Chatterjee

Publications and source records attributed to V K Chatterjee.

At least 37 records · Page 2Linked to original sources
PubMed1999

Three novel mutations at serine 314 in the thyroid hormone beta receptor differentially impair ligand binding in the syndrome of resistance to thyroid hormone.

The syndrome of resistance to thyroid hormone is associated with diverse mutations in the ligand-binding domain of the thyroid hormone beta receptor, localizing to three clusters around the hormone binding cavity. Here, we report three novel resistance to thyroid hormone mutations (S314C, S314F, and S314Y), due to different nucleotide substitutions in the same codon, occurring in six separate families. Functional characterization of these mutant receptors showed marked differences in their properties. S314F and S314Y receptor mutants exhibited significant transcriptional impairment in keeping with negligible ligand binding and were potent dominant negative inhibitors of wild-type receptor action. In contrast, the S314C mutant bound ligand with reduced affinity, such that its functional impairment and dominant negative activity manifest at low concentrations of thyroid hormone, but are more reversible at higher T3 concentrations. The degree of functional impairment of mutant receptors in vitro may correlate with the magnitude of thyroid dysfunction in vivo. Modelling these mutations using the crystal structure of thyroid hormone receptor beta shows why ligand binding is perturbed and why the phenylalanine/tyrosine mutations are more deleterious than cysteine.

Adolescent↗
PubMed1999

Development of a luminescent bioassay for thyroid stimulating antibodies.

The hyperthyroidism of Graves Disease (GD) is due to thyroid stimulating antibodies (TSAb) which are thyrotropin (TSH) agonists. They are detected routinely by measuring their ability to inhibit TSH binding to the receptor (TBII), which does not reflect their true biological activity. Current bioassays which measure cAMP by RIA, are not suitable for routine use. We have developed a luminescent bioassay for TSAb, by introducing a cAMP responsive luciferase construct into CHO cells stably expressing the human TSH receptor (TSHR). Clone lulul displays dose dependent TSH response detectable from 10 microU/ml and maximal at 10 mU/ml when a >25 fold increase in light output is obtained. 34 euthyroid sera were tested to determine a reference range, with values >1.5 relative light units (R.L.U.) being considered positive. An international TSAb standard responded in a dose dependent manner with 10 mIU/ml giving an R.L.U. of >10. The assay was adapted to a 96 well format for automatic readout and 100 treated GD samples (50 TBII negative and 50 TBII positive) were tested, 73% being positive. In contrast only 4% of 79 control sera from individuals with Hashimoto's, non-thyroid autoimmunity or multinodular goitre produced R.L.U. >1.5. When 44 of the GD sera were compared in a traditional salt-free bioassay, 61% were positive compared with 75% in the new luminescent assay. In conclusion, we have developed a luminescent bioassay for TSAb, using unfractionated serum which is capable of high throughput suitable for routine use.

Animals↗
PubMed1999

Prenatal diagnosis of thyroid hormone resistance.

A 29-yr-old woman with pituitary resistance to thyroid hormones (PRTH) was found to harbor a novel point mutation (T337A) on exon 9 of the thyroid hormone receptor beta (TRbeta) gene. She presented with symptoms and signs of hyperthyroidism and was successfully treated with 3,5,3'-triiodothyroacetic acid (TRIAC) until the onset of pregnancy. This therapy was then discontinued in order to prevent TRIAC, a compound that crosses the placental barrier, from exerting adverse effects on normal fetal development. However, as the patient showed a recurrence of thyrotoxic features after TRIAC withdrawal, we sought to verify, by means of genetic analysis and hormone measurements, whether the fetus was also affected by RTH, in order to rapidly reinstitute TRIAC therapy, which could potentially be beneficial to both the mother and fetus. At 17 weeks gestation, fetal DNA was extracted from chorionic villi and was used as a template for PCR and restriction analysis together with direct sequencing of the TRbeta gene. The results indicated that the fetus was also heterozygous for the T337A mutation. Accordingly, TRIAC treatment at a dose of 2.1 mg/day was restarted at 20 weeks gestation. The mother rapidly became euthyroid, and the fetus grew normally up to 24 weeks gestation. At 29 weeks gestation mild growth retardation and fetal goiter were observed, prompting cordocentesis. Circulating fetal TSH was very high (287 mU/L) with a markedly reduced TSH bioactivity (B/I: 1.1 +/- 0.4 vs 12.7 +/- 1.2), while fetal FT4 concentrations were normal (8.7 pmol/L; normal values in age-matched fetuses: 5-22 pmol/L). Fetal FT3 levels were raised (7.1 pmol/L; normal values in age-matched fetuses: <4 pmol/L), as a consequence of 100% cross-reactivity of TRIAC in the FT3 assay method. To reduce the extremely high circulating TSH levels and fetal goiter, the dose of TRIAC was increased to 3.5 mg/day. To monitor the possible intrauterine hypothyroidism, another cordocentesis was performed at 33 weeks gestation, showing that TSH levels were reduced by 50% (from 287 to 144 mU/L). Furthermore, a simultaneous ultrasound examination revealed a clear reduction in fetal goiter. After this latter cordocentesis, acute complications occured, prompting delivery by cesarean section. The female neonate was critically ill, with multiple-organ failure and respiratory distress syndrome. In addition, a small goiter and biochemical features ofhypothyroidism were noted transiently and probably related to the prematurity of the infant. At present, the baby is clinically euthyroid, without goiter, and only exhibits biochemical features of RTH. In summary, although further fetal studies in cases of RTH are necessary to determine whether elevated TSH levels with a markedly reduced bioactivity are a common finding, our data suggest transient biochemical hypothyroidism in RTH during fetal development. Furthermore, we advocate prenatal diagnosis of RTH and adequate treatment of the disease in case of maternal hyperthyroidism, to avoid fetal thyrotrope hyperplasia, reduce fetal goiter, and maintain maternal euthyroidism during pregnancy.

Adult↗
PubMed1998

A role for helix 3 of the TRbeta ligand-binding domain in coactivator recruitment identified by characterization of a third cluster of mutations in resistance to thyroid hormone.

Resistance to thyroid hormone (RTH) has hitherto been associated with thyroid hormone beta receptor (TRbeta) mutations which cluster in two regions (alphaalpha 310-353 and alphaalpha 429-461) of the hormone-binding domain and closely approximate the ligand-binding cavity. Here, we describe a third cluster of RTH mutations extending from alphaalpha 234-282 which constitute a third boundary of the ligand pocket. One mutant, T277A, exhibits impaired transactivation which is disproportionate to its mildly reduced ligand affinity (Ka). T3-dependent recruitment of coactivators (SRC-1, ACTR) by mutant receptor-RXR heterodimers was reduced in comparison with wild-type. Cotransfection of SRC-1 restored transactivation by T277A. In the TRbeta crystal structure this helix 3 residue is surface-exposed and is in close proximity to residues L454 and E457 in helix 12 which are known to be critical for coactivator interaction, suggesting that they all constitute part of a receptor-coactivator interface. The transcriptional function of other mutants (A234T, R243W/Q, A268D, Delta276I, A279V, R282S) in this cluster correlated with their reduced Ka and they inhibited wild-type TRbeta action in a dominant negative manner. DNA binding, heterodimerization and corepressor recruitment were preserved in all mutants, signifying the importance of these attributes for dominant negative activity and correlating with the absence of natural mutations in regions bordering the third cluster which mediate these functions.

Amino Acid Sequence↗
PubMed1998

Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia.

Congenital hypothyroidism occurs in one of every three to four thousand newborns, owing to complete or partial failure of thyroid gland development. Although thyroid hypoplasia has recently been associated with mutations in the thyrotropin (TSH) receptor, the cause of thyroid agenesis is unknown. Proteins including thyroid transcription factors 1 (TTF-1; refs 4,5) and 2 (TTF-2; refs 6,7) and Pax8 (refs 8,9) are abundant in the developing mouse thyroid and are known to regulate genes expressed during its differentiation (for example, thyroid peroxidase and thyroglobulin genes). TTF-2 is a member of the forkhead/winged-helix domain transcription factor family, many of which are key regulators of embryogenesis. Here we report that the transcription factor FKHL15 (ref. 11) is the human homologue of mouse TTF-2 (encoded by the Titf2 gene) and that two siblings with thyroid agenesis, cleft palate and choanal atresia are homozygous for a missense mutation (Ala65Val) within its forkhead domain. The mutant protein exhibits impaired DNA binding and loss of transcriptional function. Our observations represent the first description of a genetic cause for thyroid agenesis.

Abnormalities, Multiple↗
PubMed1998

Reversible pituitary enlargement in the syndrome of resistance to thyroid hormone.

We report pituitary enlargement after radioiodine ablation in a patient with elevated thyroid hormones and features of hyperthyroidism. Serum thyrotropin (TSH) levels were elevated despite normal circulating thyroid hormones, suggesting inappropriate TSH secretion associated either with a TSH secreting pituitary adenoma or resistance to thyroid hormone (RTH). Normal serum glycoprotein alpha-subunit levels and a preserved TSH response to thyrotropin-releasing hormone (TRH) favored RTH and this diagnosis was confirmed by showing the patient to be heterozygous for a missense mutation (R438H) in the thyroid hormone beta receptor (TRbeta) gene. Thyroxine replacement in supraphysiological doses were required to normalize TSH levels and resulted in regression of the pituitary enlargement, suggesting hyperplasia rather than coincident tumor. This case illustrates the need to avoid thyroid ablation in RTH patients and the importance of supraphysiological thyroxine replacement to prevent pituitary hyperplasia.

Female↗
PubMed1998

A novel TR beta mutation (R383H) in resistance to thyroid hormone syndrome predominantly impairs corepressor release and negative transcriptional regulation.

Resistance to thyroid hormone (RTH) is characterized by elevated serum thyroid hormones, failure to suppress pituitary TSH secretion, and variable T3 responsiveness in peripheral tissues. The disorder is associated with diverse mutations that cluster within three areas of the thyroid hormone beta(TR beta) receptor. Here, we report a novel RTH mutation (R383H), which is located in a region not known to harbor naturally occurring mutations. Although the R383H mutant receptor activated positively regulated genes to an extent comparable to wild-type (WT), negative transcriptional regulation of human TSH alpha and TRH promoters was impaired in either TR beta 1 or TR beta 2 contexts, and WT receptor function was dominantly inhibited. T3-dependent changes in basal transcription with R383H were also impaired: on the TRH promoter, basal activation by unliganded R383H was not reversed by T3 to the same extent as WT; similarly transcriptional silencing by an unliganded Gal4-R383H fusion was not relieved at a T3 concentration that derepressed WT. In keeping with this, ligand-dependent corepressor release by R383H, either in a protein-protein interaction assay or as a DNA-bound heterodimer with retinoid X receptor on either positive or negative thyroid hormone response elements, was disproportionately impaired relative to its ligand-binding affinity, whereas its T3-dependent recruitment of coactivator was unimpaired. These properties were shared by another previously described RTH mutant (R429Q), and in the crystal structure of TR alpha the homologous residues interact in a polar invagination. Our data indicate a role for these residues in mediating negative transcriptional regulation and facilitating corepressor release and suggest that predominant impairment of these functions may be the minimal requirements for causation of RTH.

Arginine↗
PubMed1997

Activators of peroxisome proliferator-activated receptor gamma have depot-specific effects on human preadipocyte differentiation.

Activation of peroxisome proliferator-activated receptor (PPAR) gamma, a nuclear receptor highly expressed in adipocytes, induces the differentiation of murine preadipocyte cell lines. Recently, thiazolidinediones (TZDs), a novel class of insulin-sensitizing compounds effective in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) have been shown to bind to PPARgamma with high affinity. We have examined the effects of these compounds on the differentiation of human preadipocytes derived from subcutaneous (SC) and omental (Om) fat. Assessed by lipid accumulation, glycerol 3-phosphate dehydrogenase activity, and mRNA levels, subcultured preadipocytes isolated from either SC or Om depots did not differentiate in defined serum-free medium. Addition of TZDs (BRL49653 or troglitazone) or 15-deoxyDelta12,14prostaglandin J2 (a natural PPARgamma ligand) enhanced markedly the differentiation of preadipocytes from SC sites, assessed by all three criteria. The rank order of potency of these agents in inducing differentiation matched their ability to activate transcription via human PPARgamma. In contrast, preadipocytes from Om sites in the same individuals were refractory to TZDs, although PPARgamma was expressed at similar levels in both depots. The mechanism of this depot-specific TZD response is unknown. However, given the association between Om adiposity and NIDDM, the site-specific responsiveness of human preadipocytes to TZDs may be involved in the beneficial effects of these compounds on in vivo insulin sensitivity.

Adipocytes↗
PubMed1997

Thyroid hormone-mediated enhancement of heterodimer formation between thyroid hormone receptor beta and retinoid X receptor.

A subset of nuclear receptors, including those for thyroid hormone (TR), retinoic acid, vitamin D3, and eicosanoids, can form heterodimers with the retinoid X receptor (RXR) on DNA regulatory elements in the absence of their cognate ligands. In a mammalian two-hybrid assay, we have found that recruitment of a VP16-RXR chimera by a Gal4-TRbeta ligand-binding domain fusion is enhanced up to 50-fold by thyroid hormone (T3). This was also observed with a mutant fusion, Gal4-TR(L454A), lacking ligand-inducible activation function (AF-2) and unable to interact with putative coactivators, suggesting that the AF-2 activity of TR or intermediary cofactors is not involved in this effect. The wild-type and mutant Gal4-TR fusions also exhibited hormone-dependent recruitment of RXR in yeast. Hormone-dependent recruitment of RXR was also evident with another Gal4-TR mutant, AHTm, which does not interact with the nuclear receptor corepressor N-CoR, suggesting that ligand-enhanced dimerization is not a result of T3-induced corepressor release. Finally, we have shown that the interaction between RXR and TR is augmented by T3 in vitro, arguing against altered expression of either partner in vivo mediating this effect. We propose that ligand-dependent heterodimerization of TR and RXR in solution may provide a further level of control in nuclear receptor signaling.

Cell Nucleus↗
PubMed1997

Transcriptional activation by peroxisome proliferator-activated receptor gamma is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site.

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) regulates transcription in response to prostanoid and thiazolidinedione ligands and promotes adipocyte differentiation. The amino-terminal A/B domain of this receptor contains a consensus mitogen-activated protein kinase site in a region common to PPARgamma1 and -gamma2 isoforms. The A/B domain of human PPARgamma1 was phosphorylated in vivo, and this was abolished either by mutation of serine 84 to alanine (S84A) or coexpression of a phosphoprotein phosphatase. In vitro, this domain was phosphorylated by ERK2 and JNK, and this was markedly reduced in the S84A mutant. A wild type Gal4-PPARgamma(A/B) chimera exhibited weak constitutive transcriptional activity. Remarkably, this was significantly enhanced in the S84A mutant fusion. Ligand-dependent activation by full-length mouse PPARgamma2 was also augmented by mutation of the homologous serine in the A/B domain to alanine. The nonphosphorylatable form of PPARgamma was also more adipogenic. Thus, phosphorylation of a mitogen-activated protein kinase site in the A/B region of PPARgamma inhibits both ligand-independent and ligand-dependent transactivation functions. This observation provides a potential mechanism whereby transcriptional activation by PPARgamma may be modulated by growth factor or cytokine-stimulated signal transduction pathways involved in adipogenesis.

Animals↗
PubMed1997

A natural transactivation mutation in the thyroid hormone beta receptor: impaired interaction with putative transcriptional mediators.

The syndrome of resistance to thyroid hormone is characterized by elevated serum free thyroid hormones, failure to suppress pituitary thyrotropin secretion, and variable peripheral refractoriness to hormone action. Here we describe a novel leucine to valine mutation in codon 454 (L454V) of the thyroid hormone beta receptor (TR beta) in this disorder, resulting in a mutant receptor with unusual functional properties. Although the mutant protein binds ligand comparably to wild-type receptor and forms homo- and heterodimers on direct repeat, everted repeat, or palindromic thyroid response elements, its ability to activate transcription via these elements is markedly impaired. The hydrophobic leucine residue lies within an amphipathic alpha-helix at the carboxyl terminus of TR beta and the position of the homologous residue in the crystal structure of TR alpha indicates that its side chain is solvent-exposed and might interact with other proteins. We find that two putative transcriptional mediators (RIP140 and SRC-1) exhibit hormone-dependent association with wild-type TR. In comparison, the interaction of this natural mutant (L454V) and artificial mutants (L454A, E457A) with RIP140 and SRC-1 is markedly reduced. Furthermore, coexpression of SRC-1 is able to restore the transcriptional activity of the L454V mutant receptor, indicating that the interaction of this residue with accessory proteins is critical for transcriptional activation. Finally, the occurrence of the L454V mutation in resistance to thyroid hormone, together with impaired negative regulation of the thyroid-stimulating hormone alpha promoter by this mutant, suggests that the amphipathic alpha-helix also mediates hormone-dependent transcriptional inhibition, perhaps via interaction with these or other accessory factors.

Adaptor Proteins, Signal Transducing↗
PubMed1997

The expression of thyroid hormone receptors in human bone.

The mechanism of action of thyroid hormones on bone is poorly understood. Thyroid hormones may act on bone cells either indirectly by increasing secretion of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), or directly by influencing target genes via specific nuclear receptors. The presence of thyroid hormone receptors (TRs) has been demonstrated in human and rodent osteoblast-like cells and cell lines and recently in osteoclasts derived from an osteoclastoma in vitro. However, their presence in human bone in situ has not been reported. We have used specific polyclonal antibodies to TR-alpha 1, -alpha 2, and -beta 1 to investigate the expression of these receptors in sections of human osteophytes and heterotopic bone. Osteoblasts and osteoclasts were identified by alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP), respectively, whereas chondrocytes were identified morphologically. At sites of endochondral and intramembranous bone formation, TR-beta 1 and the splice variant -alpha 2 were widely expressed by proliferating, mature, and hypertrophic chondrocytes and also in cells within the fibrous tissue and at the bone forming surfaces, respectively. They were also detected in osteoblasts, osteoclasts, and a few osteocytes at sites of bone remodeling. In contrast, TR-alpha 1 was the least expressed and was present mainly in osteoblasts at remodeling sites and in a few mature and undifferentiated chondrocytes. Our results show, for the first time, the presence and distribution of TRs in human bone in situ and suggest that the skeletal actions of thyroid hormones may be mediated via these receptors. Further studies are required to define the role of the individual receptor isoforms in bone metabolism.

Acid Phosphatase↗
PubMed1997

Serum levels of carboxyterminal cross-linked telopeptide of type I collagen (ICTP) in the differential diagnosis of the syndromes of inappropriate secretion of TSH.

BACKGROUND AND OBJECTIVE: Serum TSH assay is a very sensitive and specific index of thyroid hormone (TH) action. Nevertheless, in particular clinical situations, such as those of inappropriate TSH secretion, the measurement of additional parameters evaluating peripheral TH action may be required in order to achieve a correct diagnosis and to assess the impact that thyroid hormone have on a given tissue. The availability of a specific RIA for serum carboxy-terminal cross-linked telopeptide of type I collagen (ICTP) prompted us to study the usefulness of this specific marker of bone resorption in the differential diagnosis of thyroid disorders. DESIGN: Serum ICTP levels were measured in: (a) 10 patients with TSH-secreting pituitary adenoma (TSH-oma), (b) 40 with thyroid hormone resistance (RTH), as well as in (c) 28 patients with Graves' disease or toxic nodular goitre, (d) 31 with autoimmune primary hypothyroidism (PH) and in 8 of them during L-T4 replacement therapy, (e) 23 with central hypothyroidism (CH) during L-T4 therapy and 2 months after its withdrawal, and (f) 26 during TSH-suppressive treatment for goitre or non-metastatic differentiated thyroid cancer. Results were compared with those obtained in 2 groups of normal controls (Group A, n = 61, age range: 23-68 years; Group B, n = 32, age range: 6-15 years). METHODS: Serum TSH, free T4 (FT4) and free T3 (FT3) were measured by immunofluorometric assays. Serum ICTP was measured by a specific RIA with a sensitivity of 0.5 +/- 0.1 microgram/l, and intra- and interassay coefficients of variation lower than 6%. RESULTS: Mean values of serum ICTP levels in adult controls were 3.8 +/- 1.6 (+/-SD) microgram/l, while in pre- or peri-pubertal controls it was higher than in adults (14.4 +/- 3.1 micrograms/l). Patients with TSH-oma showed significantly increased ICTP levels (8.7 +/- 5.0 micrograms/l, P < 0.001 vs controls), in contrast to those with RTH (3.0 +/- 1.0 micrograms/l, P < 0.02 vs controls). In the differential diagnosis of inappropriate secretion of TSH, ICTP values above 5 micrograms/l strongly indicated the presence of a TSH-oma. Circulating ICTP concentrations were definitely high in thyrotoxic patients (9.4 +/- 4.7 micrograms/l, P < 0.001) and values overlapping the normal range were observed in 8 cases, thus giving to this test a sensitivity and specificity of 71% and 93%, respectively. In contrast, serum ICTP levels in both PH and CH untreated patients were in the normal range, although significantly lower than in controls (2.6 +/- 1.0 and 1.8 +/- 0.7 micrograms/l, P < 0.001). During replacement therapy, ICTP levels rose significantly in both hypothyroid groups (5.1 +/- 2.5 and 2.7 +/- 1.3 micrograms/l). In 2 CH patients, borderline high ICTP levels (7.0 and 7.1 micrograms/l), associated with FT3 concentrations in the upper limit of the normal range, suggested the presence of L-T4 overtreatment; L-T4 dose reduction was followed by the decrease of both indices in a more physiological range (ICTP: 4.2 and 4.7 micrograms/l; FT3: 8.5 and 6.0 pmol/l). In patients treated with TSH-suppressive therapy at the minimal effective dose, ICTP levels did not significantly differ from those observed in adult controls (4.3 +/- 2.0 micrograms/l). The overall correlations between serum ICTP and FT4 or FT3 levels were highly significant (P < 0.001). CONCLUSIONS: The present data indicate that serum type I collagen (ICTP) concentrations are modulated by circulating thyroid hormone concentrations. ICTP measurement is particularly useful in the differential diagnosis of the syndromes of inappropriate TSH secretion, in estimating thyroid hormone impact on bone in primary hyperthyroid states, and its longitudinal evaluation may reveal L-T4 overtreatment in patients on substitutive or TSH-suppressive therapy.

Adenoma↗
PubMed1997

Clinical and hormonal outcome after two years of triiodothyroacetic acid treatment in a child with thyroid hormone resistance.

We report here a new family with thyroid hormone resistance (RTH), with phenotypic variability among subjects. Particular emphasis is given to the clinical and hormonal outcome after 2 years of triiodothyroacetic acid (TRIAC) treatment in an affected child with peripheral thyrotoxic features (pituitary RTH [PRTH]). The genetic defect was a substitution in position 1642 (C to A) within the exon 10 of thyroid hormone receptor beta1 (TRbeta1) gene, resulting in the codon change P453T. The mutant receptor had a significantly reduced triiodothyronine (T3) binding affinity. Within this family, the child and the mother suffered from hyperthyroidism and were clinically classified as PRTH, while the maternal grandmother was clinically euthyroid, indicating a generalized form of the disease (GRTH). Rapid normalization of heart rate was initially obtained by the association of the cardioselective beta-blocker atenolol with TRIAC. Nevertheless, long-term TRIAC therapy, through its lowering action of serum thyrotropin (TSH) and thyroid hormone levels, maintained a normal heart rate after atenolol discontinuation and normalized the neurological disturbances and the clinical signs in the child, without any apparent side effect. In fact, growth velocity remained unchanged and no alteration of several parameters of thyroid hormone action at the tissue level was observed, whereas soluble interleukin-2 receptor levels improved significantly, confirming the safety and efficacy of long-term TRIAC therapy for PRTH also during childhood. We thus recommend testing the efficacy of TRIAC therapy in all RTH patients presenting with clinical features of hyperthyroidism.

Biomarkers↗
PubMed1997

Resistance to thyroid hormone.

Resistance to thyroid hormone (RTH) is usually dominantly inherited and is characterized by elevated free thyroid hormones in the serum and failure to suppress pituitary thyroid stimulating hormone (TSH) secretion with variable refractoriness to hormone action in peripheral tissues. Two major forms of the disorder are recognized: asymptomatic individuals with generalized resistance (GRTH) and patients with thyrotoxic features, suggesting predominant pituitary resistance (PRTH). Molecular genetic analyses indicate that both GRTH and PRTH are associated with diverse mutations in the thyroid hormone receptor beta gene, which localize to three regions in the hormone binding domain of the receptor. In addition to being functionally impaired, the mutant receptors are also able to inhibit their wild-type counterparts in a dominant negative manner. Recognized features of RTH include failure to thrive, growth retardation and attention-deficit hyperactivity disorder in childhood, and goitre and thyrotoxic cardiac symptoms in adults. The pathogenesis of variable tissue resistance is not fully understood but may be related to the differing tissue distributions of a and b thyroid hormone receptors and variable dominant negative activity of mutant receptors on different target genes.

Adult↗
PubMed1997

Two novel mutations in the thyrotropin (TSH) receptor gene in a child with resistance to TSH.

The TSH receptor is a G protein-coupled receptor that mediates the effects of TSH in thyroid development, growth, and synthetic function. We report here that a child with features of TSH resistance, including markedly increased serum TSH concentrations and low normal thyroid hormone levels, is a compound heterozygote for two novel mutations in the TSH receptor gene. One allele has a G to A transition corresponding to an arginine to glutamine change at codon 109 (R109Q) in the extracellular domain of the receptor. The other allele has a G to A transition corresponding to a premature termination codon at tryptophan 546 (W546X) in the fourth transmembrane segment. Each parent is heterozygous for one mutation, and both parents have normal thyroid function. Cells transiently transfected with the R109Q mutant exhibited reduced membrane binding of [125I]TSH and impaired signal transduction in response to TSH. In contrast, the W546X mutant was nonfunctional, with negligible membrane radioligand binding. Our findings indicate that a single normal TSH receptor allele is sufficient for normal thyroid function, but that the compound abnormality in the proband leads to TSH resistance.

Amino Acid Sequence↗
PubMed1997

Thyroid hormone resistance syndrome manifests as an aberrant interaction between mutant T3 receptors and transcriptional corepressors.

Nuclear hormone receptors are hormone-regulated transcription factors that play critical roles in chordate development and homeostasis. Aberrant nuclear hormone receptors have been implicated as causal agents in a number of endocrine and neoplastic diseases. The syndrome of Resistance to Thyroid Hormone (RTH) is a human genetic disease characterized by an impaired physiological response to thyroid hormone. RTH is associated with diverse mutations in the thyroid hormone receptor beta-gene. The resulting mutant receptors function as dominant negatives, interfering with the actions of normal thyroid hormone receptors coexpressed in the same cells. We report here that RTH receptors interact aberrantly with a newly recognized family of transcriptional corepressors variously denoted as nuclear receptor corepressor (N-CoR), retinoid X receptor interacting protein-13 (RIP-13), silencing mediator for retinoid and thyroid hormone receptors (SMRT), and thyroid hormone receptor-associating cofactor (TRAC). All RTH receptors tested exhibit an impaired ability to dissociate from corepressors in the presence of thyroid hormone. Two of the RTH mutations uncouple corepressor dissociation from hormone binding; two additional RTH mutants exhibit an unusually strong interaction with corepressor under all hormone conditions tested. Finally, artificial mutants that abolish corepressor binding abrogate the dominant negative activity of RTH mutants. We suggest that an altered corepressor interaction is likely to play a critical role in the dominant negative potency of RTH mutants and may contribute to the variable phenotype in this disorder.

Cell Line↗