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PubMedDate not supplied

A case of Resistance to Thyroid Hormone without mutation in the thyroid hormone receptor beta.

BACKGROUND: Resistance to Thyroid Hormone (RTH) is a condition caused by tissue hyposensitivity to the effects of circulating thyroid hormone, and may be misdiagnosed as hyperthyroidism. AIMS: We report the first case of RTH in an Irish patient highlighting the clinical features and the pathophysiological mechanism underlying the characteristic laboratory abnormalities found in the condition. METHODS: We describe an isolated case of RTH initially misdiagnosed as hyperthyroidism, and detail the investigations which ultimately led to the correct diagnosis. Genetic screening of the thyroid hormone receptor beta gene was performed. RESULTS: Thyroid function tests including T3 suppression test and TRH-stimulation test suggested a diagnosis of RTH. Genetic testing failed to demonstrate a mutation in the thyroid hormone receptor. CONCLUSION: RTH is a rare inherited condition that may be misdiagnosed as hyperthyroidism. The case we describe most likely results from a de novo mutation in an as yet undiscovered gene. RTH should be considered in patients with elevated thyroid hormone levels and normal TSH so that unnecessary and potentially harmful treatment can be avoided.

Adult↗
PubMed1990

[The effect of three kinds of thyroid hormone preparations on serum thyroid hormone and TSH in primary hypothyroidism].

Thirty-eight cases of primary hypothyroidism were treated prospectively with three kinds of thyroid hormone preparations, including Levothyroxine, L-triiodothyronine and dry thyroid preparation. A protocol of different dosages with same biologic effects was followed: 100 micrograms Levothyroxine approximately 40-60 mg dry thyroid preparation approximately 30-40 micrograms L-triiodothyronine. During drug replacement treatment, the change serum T3 and TSH is more sensitive than that of serum T4 and reverse T3. Both of serum T3 and T4 can directly inhibit the secretion of pituitary TSH, but serum T4 is more closely related to TSH than is T3. In judging the overdose, the level of serum T4 is a superior indicator to the level of T3. The best time to take thyroid hormone preparations is at bedtime.

Humans↗
PubMed1989

Identification of nuclear factors that enhance binding of the thyroid hormone receptor to a thyroid hormone response element.

Using a gel shift assay, we analyzed the binding of in vitro translated alpha- and beta-thyroid hormone (T3) receptors to a T3-response element (TRE) derived from the rat GH gene. No receptor-TRE complexes were observed when translated receptor alone was incubated with the TRE. However, addition of a nuclear extract from liver to the translational products resulted in the formation of two receptor-DNA complexes for both the alpha- and beta-receptors. These complexes were shown to contain translated receptor by comigration of 32P-labeled TRE and 35S-labeled receptor in the gel shift assay. A competition experiment demonstrated that formation of the complexes was sequence specific. Preincubation of the liver nuclear extract at 60 C abolished formation of both complexes indicating that receptor-TRE binding required a heat-labile nuclear factor. Phosphocellulose chromatography of the nuclear extract resulted in separation of the activities required for formation of the two complexes. Analysis of nuclear extracts from different tissues revealed that one complex formed in the presence of all extracts, whereas the second complex appeared predominantly with a nuclear extract from liver. Addition of T3 to the binding reaction had no effect on receptor-TRE complex formation. We suggest that nuclear factors interact with the T3 receptor to enhance hormone-independent binding to a TRE.

Binding, Competitive↗
PubMed1992

Transcriptional stimulation by thyroid hormone of a cytosolic thyroid hormone binding protein which is homologous to a subunit of pyruvate kinase M1.

We have recently shown that the monomer of rat pituitary pyruvate kinase subtype M1 (p58-M1) is a cytosolic binding protein for 3,3',5-triiodo-L-thyronine (T3). To understand the role p58-M1 plays in thyroid hormone action, we examined the regulation of p58-M1 by T3 in GH3 cells. Expression of p58-M1 was evaluated by metabolically labeling GH3 cells cultured in regular medium, thyroid hormone depleted medium (Td medium), or Td medium supplemented with T3 (Td + T3 medium) followed by immunoprecipitation. T3 stimulates the expression of p58-M1 by 2-fold. Analysis by pulse-chase experiments indicates that the increased expression is not due to the increase of stability of p58-M1. Northern analysis of mRNA prepared from cells cultured in regular, Td, or Td + T3 medium demonstrates that T3 increases the accumulation of cytoplasmic mRNA by 2-fold. Nuclei from cells cultured in the three conditions were prepared, and the rates of synthesis of nascent nuclear RNA were compared by an in vitro transcription assay. Addition of T3 stimulates the rate of transcription by 2-fold. The parallel and identical magnitude in the increase of transcription rate and the accumulation of mRNA indicates that T3 stimulates the synthesis of p58-M1 by increasing the transcriptional activity of its gene.

Animals↗
PubMed1992

The regulation of thyroid hormone receptor beta genes by thyroid hormone in Xenopus laevis.

The mRNA level of the two Xenopus laevis thyroid hormone receptor beta (TR beta) genes is up-regulated in tadpoles and cultured cells by the addition of thyroid hormone (TH). Up-regulation of transcripts of the 5' most exon is detectable 2-3 h before that of full-length TR beta mRNA, strongly suggesting that up-regulation is under transcriptional control. The TH-induced up-regulation in cultured cells is inhibited by cycloheximide when measured either by a transcription initiation assay that measures transcripts of the 5' most exon or by synthesis of full-length TR beta mRNA. From this we conclude that in cultured cells protein synthesis is required for up-regulation of TR beta mRNA. The up-regulation of TR beta mRNA by TH in tadpoles is only partially inhibited by protein synthesis inhibitors. A survey of "thyroid response" genes in the literature reveals that the reported change in gene expression is, in most cases, sensitive to protein synthesis inhibition. This is true of genes with demonstrable thyroid hormone response elements. If an unknown protein must be synthesized to effect up-regulation of a thyroid hormone response gene, it calls into question assays that only take into account the binary reaction between thyroid hormone receptor and a putative thyroid hormone response element.

Animals↗
PubMed1994

Physiology of the steroid-thyroid hormone nuclear receptor superfamily.

Glucocorticoids, other steroid hormones, thyroid hormones and vitamin-derived hormones (including retinoids) all exert their effects by the regulation of hormone-responsive target genes within the cell nucleus. These hormones bind to a series of specific nuclear receptor proteins that function as hormone-inducible transcription factors. The receptors are structurally homologous, are related to the avian erythroblastosis oncogene v-erbA, and exhibit remarkable evolutionary conservation. Together they form the steroid-thyroid hormone nuclear receptor superfamily. This chapter describes the structure and functions of the various family members and highlights the differences and similarities that occur between individual receptor proteins. Type I receptors, which include glucocorticoid receptor and other steroid receptor proteins, interact as homodimers with target sequences of DNA containing two receptor binding sites arranged as a palindrome. Type II receptors, which include receptors for retinoids, thyroid hormone and vitamin D3, bind as heterodimers (or homodimers) to DNA sequences in which two or more receptor-binding sites are arranged as a direct repeat or as other more complex configurations. The complexity of both receptor-DNA and receptor-receptor interactions predicts the potential for considerable cross-talk between various hormone-activated pathways. Thus, the specificity of hormone action and its regulation is discussed in relation to the structural and functional characteristics of the receptors and their molecular mechanisms of action. Finally, potential sites of regulation of hormone action, from circulating hormone levels in the periphery to their delivery to the cell and final site of action in the nucleus, are highlighted to provide a perspective for the following chapters in this volume and to indicate their clinical significance.

Animals↗
PubMed1988

[Thyroid hormone metabolism in nonthyroidal illness. I. Changes in thyroid hormone metabolism in dogs with experimental myocardial infarction and effect of thyroid hormone administration on their hemodynamics].

To asses the changes in thyroid hormone metabolism after the onset of acute myocardial infarction (AMI), serum T4 and T3 levels were serially measured for 24 hours after the coronary artery ligation in dogs. The effect of thyroid hormone administration on hemodynamics in these dogs were also studied to clarify the possible usefulness of thyroid hormone therapy in nonthyroidal illness (NTI). Dogs were anesthetized with ketamine using "Micro-Mini" drip administration. Coronary artery ligation was performed in 8 dogs (MI group) Open chest operation was performed in 8 dogs, but their coronary arteries were not ligated and were used as control (cont. group). Blood samples were drawn before and 1, 3, 6, 12, 18 and 24 hours after coronary artery ligation, and serum levels of T4 and T3 were measured using the TDX T4 system and a commercial RIA kit, respectively. Various hemodynamic parameters (heat rate, mean blood pressure, max dp/dt, left ventricular end-diastolic pressure, cardiac output) were measured at the same time mentioned above. All the hemodynamic parameters remained within normal range for 24 hours in the control group. Serum T4 and T3 levels, however, showed slight, but significant decreases due to general anesthesia and open chest operation in the control group. On the other hand, hemodynamic parameters were maintained in the normal ranges only for 12 hours, and gradually deteriorated in the MI group. Moreover, it was remarkable that both T4 and T3 levels were decreased immediately after the ligation in this group, T4 being less than 0.1 micrograms/dl and T3 less than 10 ng/dl. They continued to show the low values thereafter. When T4 (30 micrograms/24 hours), and T3(7, 14 or 21 micrograms/24 hours) were continuously infused intravenously for 24 hours after the coronary artery ligation in 10 dogs, serum T4 levels were maintained in the normal range of the dog (1.5-3.6 micrograms/dl) and the serum T3 levels were increased to the low normal range. However, there were no significant differences in hemodynamic indices between the thyroid hormone treated groups and the non-treated group. These data show that T4 and T3 concentrations decrease prior to the deterioration of cardiac function. Moreover, the present findings also suggest that administration of thyroid hormone has no benefit in patients with NTI associated with low T4 and T3 levels.

Animals↗
PubMed1975

Thyroid metabolism in the recessive sex-linked dwarf female chicken. 1. Age related changes in thyroid hormone synthesis and circulating thyroid hormone levels.

Age related changes in the levels of circulating thyroid hormones as well as the type of hormones synthesized in the thyroid glands from normal and sex-linked recessive dwarf, female chickens were studied. The impact of the presence of the dwarf gene on the parameters measured was minimal but significant alterations in the types of hormones produced in the thyroid gland with increasing age were observed. As the birds approached sexual maturity, the synthesis of triiodothyronine increased sharply such that the ratio of triiodothyronine (T3): tetraiodothyronine (T4) was approximately 15:1. This was in contrast to the T3:T4 ratio of younger birds which was approximately 0.7:1.0. This shift in hormone synthesis was reflected in relatively more circulating T3 in laying hens when compared with younger birds. It was also noted that four week old dwarf birds had higher circulating T3 values than those found for the normals.

Age Factors↗
PubMed1994

Spectrum of transcriptional, dimerization, and dominant negative properties of twenty different mutant thyroid hormone beta-receptors in thyroid hormone resistance syndrome.

Resistance to thyroid hormone (RTH) is usually dominantly inherited and characterized by elevated thyroid hormone levels, impaired feedback inhibition of pituitary TSH production, and variable hormonal responsiveness in peripheral tissues. We have identified 20 different mutations in the thyroid hormone beta-receptor (TR beta) gene in RTH and assayed mutant receptor properties using the TSH alpha subunit gene promoter or promoters containing three different types of positive thyroid response element (TRE). Dominant negative inhibition of wild type TR beta action by mutant receptors was also tested. The mutant receptors exhibited differing transcriptional inhibitory properties and dominant negative potential with the TSH alpha promoter that correlated with their impaired hormone binding, whereas transactivation and dominant negative effects with promoters containing positive TREs varied depending on their configuration. Heterodimeric mutant receptor-retinoid X receptor (RXR) interactions, either in cultured cells or as TRE-bound complexes in gel retardation assays, were uniformly preserved, whereas homodimeric receptor interactions could not be detected in vivo, and in vitro homodimer formation on TREs was variably reduced or absent for some mutant proteins. We correlate these findings with the distribution of receptor mutations that cluster in two areas within the hormone binding domain outside putative dimerization regions and show that artificial mutations that impaired heterodimerization abrogated dominant negative activity. Therefore, we suggest that the dominant negative effect of mutant receptors in the pituitary-thyroid axis generates the characteristic biochemical abnormality of RTH and that variable resistance in other tissues may be due to response element-dependent differences in their dominant negative potential.

Amino Acid Sequence↗
PubMed1992

The thyroid hormone receptors: molecular basis of thyroid hormone resistance.

Major progress has been achieved in the mechanism of action of thyroid hormones thanks to the identification of the T3 receptor as the product of the proto-oncogene c-erbA. Recognition of subsets of receptors with and without T3-binding properties and of the interaction of different receptors with each other leads to new insights in cell regulation and development. In thyroid hormone resistance, distinct mutations in the T3-binding domain of thyroid hormone receptor (TR)beta have been identified in unrelated families. No correlation between the type of mutation and tissue resistance has been established. Mutant TRs bind to thyroid hormone response elements (TREs) on both negative or positive T3-controlled genes. Subjects with heterozygous TR beta gene deletion are not affected, supporting the hypothesis that mutant TRs act through a dominant negative effect. In generalized thyroid hormone resistance, mutated TR beta may interfere through competition for TREs and/or formation of inactive dimers. Finally, deficiency in T3 receptor auxiliary protein or other accessory proteins or competition between mutant and normal TRs for these factors is not excluded.

Binding Sites↗
PubMed1997

Resistance to thyroid hormone caused by two mutant thyroid hormone receptors beta, R243Q and R243W, with marked impairment of function that cannot be explained by altered in vitro 3,5,3'-triiodothyroinine binding affinity.

Resistance to thyroid hormone (RTH) is a syndrome of reduced responsiveness to thyroid hormone caused by mutations in the thyroid hormone receptor beta (TRbeta) gene. Mutant TRbetas exhibit variable degrees of impaired T3 binding resulting in reduced T3-mediated function. The dominant mode of inheritance is attributed to the ability of mutant TRbetas to interfere with the function of the wild-type (WT) TR, a phenomenon known as dominant negative effect (DNE). We recently identified two families with RTH having mutations in amino acid 243 (R243Q and R243W) in whom the mechanism of RTH appears to be distinct from that of other natural TRbeta mutations. These mutations, which are located in the hinge domain of the TRbeta, do not significantly alter the binding affinity for T3, measured in vitro. The present study was undertaken to characterize the properties of these mutant TRbetas to understand the molecular basis of the RTH phenotype. Two other mutant TRbeta producing RTH with mild (320H) and severe (345R) impairment of T3 binding were studied in parallel. The results demonstrate that TRbetas 243Q and 243W could be translocated into the nucleus where they exerted normal ligand-independent repression of positively regulated thyroid hormone response elements. Yet, the addition of 10 nmol/L T3 failed to normalize the transactivation (16-13% of WT) and revert the DNE exerted by the two TRbeta mutants. In contrast, at this T3 concentration, the transactivation function of 320H was significantly higher (50% of WT), and the DNE was completely abolished, in keeping with the mild clinical form of RTH. Formation of 243Q and 243W homodimers on thyroid hormone response elements could not be as readily prevented by T3 as those formed by the WT and 320H TRbetas. These results suggest that the substitution of R243 in TRbeta produces RTH by increasing the propensity for the formation of tightly bound homodimers or by reduction of the receptor affinity for T3 only after it binds to DNA.

Animals↗
PubMed2002

Resistance to thyroid hormone in a patient without thyroid hormone receptor mutations.

Resistance to thyroid hormone (RTH) is a clinical syndrome characterized by elevated serum thyroid hormone (TH) levels, unsuppressed thyrotropin (TSH) levels, and tissue hyposensitivity to TH. In almost all cases, the genetic basis of RTH lies in mutation of one of the two TH receptor beta (TRbeta) alleles. Recently, patients from several families with phenotypic manifestations of RTH in the absence of TR mutations have been described. We report a case of a 31-year-old woman who presented with goiter, tachycardia, elevated TH levels, unsuppressed TSH, and "inappropriately normal" levels of peripheral TH action markers. In two separate clinical evaluations, the patient exhibited typical clinical and biochemical evidence for peripheral and pituitary RTH. Surprisingly, reverse transcriptase-polymerase chain reaction (RT-PCR) of full-length TRalpha and TRbeta mRNAs, and genomic PCR using primers flanking exons encoding the carboxy-terminal region of TRbeta failed to demonstrate mutations in the TRalpha or TRbeta genes. It is likely that defects in the regulation of TR genes or mutations in transcriptional cofactors involved in TR signaling account for this patient's phenotype.

Adult↗
PubMed1994

Immunization against vasoactive intestinal peptide does not affect thyroid hormone secretion or thyroid blood flow.

Vasoactive intestinal peptide (VIP) is present in thyroid parasympathetic nerves. To assess the involvement of endogenous VIP in the regulation of thyroid function, blood levels of thyroid hormones and thyroid blood flows (TBF) were measured after systemic immunization against VIP or after transection of the superior laryngeal nerves in male rats, which reduced the thyroid content of VIP but did not affect blood levels of thyroid hormones or TBF. Anti-VIP monoclonal antibody or anti-VIP serum was used for immunization against VIP in normal rats. In addition, VIP antibody was given to rats fed an iodine-deficient diet for 5 days to examine the involvement of this peptide in iodine deficiency-induced increases in TBF. Effects were measured at different times (90 s, 30 min, 1 h, and 5 days) after immunoneutralization, but none of these treatments changed blood levels of thyroid hormones or TBF in normal or iodine-deficient rats. However, passive immunization against VIP was associated with a high binding capacity of rat plasma to VIP, and this treatment reduced blood levels of prolactin as well as blood flows to the duodenum, stomach, and lung. These findings suggest that the VIP present in thyroid nerves is not involved in maintaining basal thyroid hormone secretion or TBF and that this neuropeptide does not mediate thyroid vascular adjustments to dietary iodine deficiency.

Animals↗
PubMed1994

[Molecular mechanism of thyroid hormone synthesis].

Thyroid peroxidase catalyzes the two-electron oxidations of tyrosine and monoiodotyrosine, and one-electron oxidation of diiodotyrosine. This difference in the oxidation, with tyrosine and diiodotyrosine, is also observed in the reaction of thyroid peroxidase with 0.2 and 0.7% iodine thyroglobulins. The results support the hypothesis that the increase in the diiodotyrosine residue in thyroglobulin inhibits further iodination by switching the catalytic cycle to oxidative coupling, to form thyroid hormones. Thyroid hormone synthesis requires iodide, H2O2, thyroglobulin and thyroid peroxidase. The stimulation of iodide uptake and H2O2 generation in the thyroid, as well as, protein synthesis of thyroglobulin and thyroid peroxidase in response to TSH has been reported. The regulation of thyroid hormone synthesis in the thyroid peroxidase reaction and through the peroxidase system is summarized.

Animals↗
PubMed2003

A role for thyroid hormone transporters in transcriptional regulation by thyroid hormone receptors.

Thyroid hormones (THs) must be taken up by target cells to act at the genomic level through binding to nuclear thyroid hormone receptors (TRs). Extensive study has been made of mechanisms by which TH-bound TRs regulate transcription, yet little is known about the critical upstream step, i.e. how THs enter the cell. Growing evidence suggests that saturable transport mechanisms mediate the greater part of TH movement across the plasma membrane and have important roles in the regulation of TH bioavailability. For example, System L is a multifunctional transport system serving as a plasma membrane transporter of THs and amino acids in mammalian cells. We have used two complementary systems, the Xenopus oocyte (which has negligible basal System L activity) and the mammalian BeWo cell line (which has System L activity for TH transport), to investigate the role of this representative TH transporter in nuclear action of THs. We demonstrate that overexpression of System L in Xenopus oocytes increases both cytoplasmic and nuclear delivery of THs from external medium and also enhances transcriptional activation by TRs. Conversely, blocking endogenous System L activity in BeWo cells with specific inhibitors reduces both TH uptake and TR function. These results indicate that plasma membrane TH transporters such as System L may have important roles in gene regulation by TRs.

Amino Acid Sequence↗