Triiodothyronine binding to lymphocyte nuclei and plasma cyclic AMP response to intravenous glucagon in patients with peripheral resistance to thyroid hormones

1981 ◽  
Vol 97 (1) ◽  
pp. 54-59 ◽  
Author(s):  
A. Elewaut ◽  
M. De Baets ◽  
A. Vermeulen
Keyword(s):  
Thyroid Hormone ◽  
Cyclic Amp ◽  
Binding Capacity ◽  
Peripheral Resistance ◽  
Resistance To Thyroid Hormone ◽  
Binding Characteristics ◽  
Nuclear Binding ◽  
Resistance To Thyroid Hormones ◽  
The Family

Abstract. In vitro studies of nuclear binding of triiodothyronine (T3) in lymphocytes were performed in three members of a family with hereditary peripheral resistance to thyroid hormone action. Ficoll-Hypaque® purified lymphocytes were used; the binding characteristics were analyzed by Scatchard's methods. In 5 euthyroid subjects the apparent mean equilibrium association constant (Ka) was 6.1 × 109 1/mol and the mean maximal binding capacity (Cap) 14.4 × 10−15 mol/ 100 μg DNA. In the 3 members of the family one single set of saturable T3 nuclear binding sites with affinity constants similar to those in the controls (mean Ka = 3.2 × 109 1/mol; mean Cap = 17.4 × 10−15 mol/100 μg DNA) were found. The glucagon stimulated increase in plasma cyclic AMP was studied in 6 healthy subjects and the four members of the family. The plasma cyclic AMP levels of the patients with hormone resistance were generally within the normal range. These observations demonstrate that in these patients with peripheral resistance to thyroid hormone binding of T3 to the receptor in the nucleus of lymphocytes is normal; in relation to the high circulating thyroid hormone levels, the thyroid hormone mediated cyclic AMP response is disturbed, suggesting that the defect is at the post-receptor effector level.

TRIIODOTHYRONINE BINDING TO LYMPHOCYTES FROM EUTHYROID SUBJECTS AND A PATIENT WITH PERIPHERAL RESISTANCE TO THYROID HORMONE

1976 ◽  
Vol 83 (1) ◽  
pp. 64-70 ◽  
Author(s):  
Kristian Liewendahl
Keyword(s):  
Thyroid Hormone ◽  
Binding Sites ◽  
Binding Capacity ◽  
Human Lymphocytes ◽  
Peripheral Resistance ◽  
Subsequent Treatment ◽  
Affinity Constant ◽  
Prolonged Incubation ◽  
Resistance To Thyroid Hormone ◽  
The Mean

ABSTRACT Triiodothyronine (T3) binding to Ficoll-Isopaque purified human lymphocytes was studied. During incubation of lymphocytes with [125I]T3 in a calcium-free medium at 37°C, maximal uptake of T3 in nuclei occurred after 2 h and declined after prolonged incubation. Incubation of lymphocytes with T3 concentrations ranging from 1 × 10−11 to 1 × 10−9 mol/l and subsequent treatment with Triton X-100 to strip off [125I]T3 bound with low affinity was used for the estimation of affinity and capacity of nuclear T3 binding sites. The mean equilibrium affinity constant (Ka) estimated with the Scatchard method in 11 euthyroid healthy subjects was 4.5 × 109 1/mol, and the mean maximal binding capacity 25 × 10−15 mol/100 μg DNA. In a female patient with peripheral resistance to thyroid hormone action, the estimated Ka was 3.5 × 109 1/mol and the number of T3 binding sites 37 × 10−15 mol/100 μg DNA. Although not statistically different from the mean value in euthyroid subjects, this Ka value was outside the range of control values observed and was considered presumptive evidence that the nuclear T3 receptors in this patient have abnormally low affinity for its ligand. The nuclear T3 binding capacity in this patient was significantly increased.

FAMILIAL PARTIAL PERIPHERAL RESISTANCE TO THYROID HORMONES

1978 ◽  
Vol 87 (2) ◽  
pp. 303-312 ◽  
Author(s):  
B.-A. Lamberg ◽  
S. Rosengård ◽  
K. Liewendahl ◽  
P. Saarinen ◽  
D. C. Evered
Keyword(s):  
Thyroid Hormones ◽  
Binding Capacity ◽  
Elevated Serum ◽  
Peripheral Resistance ◽  
Serum Concentrations ◽  
Resistance To Thyroid Hormones ◽  
The Family ◽  
Tsh Secretion ◽  
Circulating Antibodies

ABSTRACT A male aged 21 was found to have elevated serum PBI on several occasions. Further studies revealed clinical euthyroidism with raised serum concentrations of T4, T3 and free T4 with normal hormone binding capacity of the thyroxine binding proteins and normal thyroid-pituitary relationships. The response to TRH was high normal or on one occasion exaggerated. The extrathyroidal thyroxine pool and the daily turnover of thyroxine were considerably above the upper limit of the normal. The subject had no goitre. These findings indicated partial peripheral resistance to thyroid hormones including the pituitary gland. There were no circulating antibodies to thyroglobulin, thyroid microsomes, T4 or T3. A study of the propositus' family revealed an autosomal dominant heredity of this abnormality. Similar findings were found in the brother, mother and the two uncles of the propositus. In these subjects the serum concentrations of T4, T3 and free T4 as well as that of rT3 were raised above the normal. The subjects studied were clinically euthyroid. Goitre was present only in the older members of the family. The response to TRH was usually high normal or at times exaggerated and the basal TSH level seemed to fluctuate during years of follow-up indicating a continuous adjustment of the thyroid function by means of TSH secretion. The mother and the older uncle had previously been treated because of hyperthyroidism. Only the mother had circulating thyroid antibodies and none of the family members had antibodies against T4 or T3. This hereditary condition seems to have a very mild clinical manifestation in this family.

scholarly journals SAT-434 Phenotype and Genotype Analysis of Patients with Resistance to Thyroid Hormone β: A Single-Center Experience

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Karn Wejaphikul ◽  
Prapai Dejkhamron ◽  
Stefan Groeneweg ◽  
W Edward Visser ◽  
Kevalee Unachak ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Mutation Analysis ◽  
Novel Mutation ◽  
Family Members ◽  
Antithyroid Drugs ◽  
Thyroid Function Tests ◽  
Resistance To Thyroid Hormone ◽  
The Mean ◽  
The Impact

Abstract Introduction Resistance to thyroid hormone β (RTHβ) is caused by mutations in THRB, the gene that encodes thyroid hormone receptor β. The clinical phenotype is variable and may include goiter, tachycardia, and learning disability with or without hyperactive behavior. The biochemical hallmark of RTHβ is elevated T4 and T3 with non-suppressed TSH concentrations. We here describe the phenotype and genotype of three Thai patients diagnosed with RTHβ in a pediatric referral center. Patients had previously been misdiagnosed and inappropriately treated with antithyroid drugs (ATDs). Methods Clinical features and thyroid function tests (TFTs) of three unrelated RTHβ patients were retrospectively reviewed. Genomic DNA of the RTHβ patients and affected family members was amplified for exon 7-10 of the THRB gene and sequenced to identify mutation by Sanger sequencing. The impact of the p.L341V novel mutation on the affinity for T3 and T3-induced transcriptional activity was previously determined in vitro. Results Three female patients were diagnosed with RTHβ. All of them had been misdiagnosed with hyperthyroidism and treated with ATDs prior to referral. The mean age at diagnosis was 8 years. The main presenting symptoms were diffuse goiter and tachycardia. The mean duration of ATD treatment was 3 years. During the treatment, patients had fluctuating thyroid hormone and increased TSH levels. An older sister and mother of one patient also had similar TFTs abnormalities, for which the mother had undergone a subtotal thyroidectomy. RTHβ was diagnosed based on the high FT3 and FT4 with normal (non-suppressed) TSH concentrations and confirmed by mutation analysis. Anti-thyroid peroxidase, anti-thyroglobulin, and TSH receptor antibody (TRAb) were negative, excluding autoimmune thyroid disease. Heterozygous missense mutations of the THRB gene were identified in all patients and affected family members. Two mutations had been previously reported (p.R243W and p.L456F), and one mutation was novel (p.L341V). In vitro studies confirmed an important role of Leu341 in T3 binding of the TRβ and functional impairment of the p.L341V novel mutation and were reported separately. According to available literature, only nine Thai RTHβ patients (in three families) carrying three different mutations (p.G251V, p.M313T, and p.A317T) had been previously reported. Goiter was the most common clinical finding, and almost all patients had a history of receiving unnecessary treatment with ATDs. Conclusion We report a series of RTHβ patients carrying THRB gene mutations, including one novel mutation (p.L341V). Clinicians should be alert that RTHβ can be found in patients with goiter and tachycardia. Elevated T4 and T3 with non-suppressed TSH concentration is the main diagnostic clue for this disease. Mutation analysis allows definitive diagnosis of RTHβ and may help to avoid potential misdiagnosis and improper treatment.

scholarly journals 418 PERIPHERAL RESISTANCE TO THYROID HORMONE IN AN INFANT

1981 ◽  
Vol 15 ◽  
pp. 509-509
Author(s):  
Paul B Kaplowitz ◽  
A Joseph D'Ercole ◽  
Robert D Utiger ◽  
Louis Underwood
Keyword(s):  
Thyroid Hormone ◽  
Peripheral Resistance ◽  
Resistance To Thyroid Hormone

Partial peripheral resistance to thyroid hormone

1981 ◽  
Vol 70 (5) ◽  
pp. 1115-1121 ◽  
Author(s):  
Michael M. Kaplan ◽  
Stephen L. Swartz ◽  
P.Reed Larsen
Keyword(s):  
Thyroid Hormone ◽  
Peripheral Resistance ◽  
Resistance To Thyroid Hormone

scholarly journals Factors affecting the binding of [3H]adenosine 3′:5′-cyclic monophosphate to protein kinase from bovine adrenal cortex

1977 ◽  
Vol 161 (3) ◽  
pp. 653-665 ◽  
Author(s):  
S O Døskeland ◽  
P M Ueland ◽  
H J Haga
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Adrenal Cortex ◽  
Binding Sites ◽  
Binding Capacity ◽  
Binding Assays ◽  
Factors Affecting ◽  
Binding Characteristics ◽  
Standard Curve ◽  
Low Concentrations

Inorganic salts, several proteins and traces of protein precipitants were tested to find out by what mechanisms they modulate the binding of cyclic [3H]AMP to protein kinase (ATP-protein phosphotransferase; EC 2.7.1.37). The separation of free and bound cyclic AMP by (NH4)2SO4 precipitation was unaffected by the above agents and was more reliable than the Millipore filtration technique. Several binding sites for cyclic AMP were revealed in adrenal-cortex extract. When this extract was used as binding reagent in an assay for cyclic AMP, the standard curve was distorted in the presence of KCl because the salt affected the different binding sites to a varying extent. At high ionic strenth the protein kinase isoenzyme I dissociated and showed an extraordinarily high affinity for cyclic AMP. Trichloroacetate and perchlorate at very low concentrations were able to dissociate the protein kinase and modulate its binding characteristics as well. A progressive decrease in the cyclic AMP-binding capacity occurred on prolonged incubations. The binding protein was protected against inactivation by 2-mercaptoethanol, EDTA and several proteins. It was more resistant to denaturation when complexed to cyclic AMP. The enhancement of cyclic AMP binding by bovine serum albumin was investigated in some detail and appeared to be a pure stabilizing effect. It is proposed that the competitive-binding assays for cyclic AMP based on protein kinase be conducted at high ionic strength and in the presence of stabilizers (protein, EDTA, 2-mercaptoethanol). The interference from agents that may dissociate the protein kinase or influence its stability will thus be decreased.

Changes in cytosolic 3,5,3′-tri-iodo-l-thyronine (T3) binding activity during administration of l-thyroxine to thyroidectomized rats: cytosolic T3-binding protein and its activator act as intracellular regulators for nuclear T3 binding

1989 ◽  
Vol 123 (1) ◽  
pp. 99-104 ◽  
Author(s):  
Y. Nishii ◽  
K. Hashizume ◽  
K. Ichikawa ◽  
T. Miyamoto ◽  
S. Suzuki ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Nuclear Receptor ◽  
Binding Capacity ◽  
Binding Protein ◽  
Binding Activity ◽  
Affinity Constant ◽  
Maximal Binding

ABSTRACT Changes in the amount of cytosolic 3,5,3′-tri-iodo-l-thyronine (T3)-binding protein (CTBP) and its activator during administration of l-thyroxine (T4) to thyroidectomized rats were investigated. Thyroidectomy decreased the amount of CTBP in the kidney, whereas the activator was not significantly modified by thyroidectomy. The activator was increased by administration of T4 to thyroidectomized rats. The amount of CTBP was also increased by administration of T4. The activator increased the maximal binding capacity (MBC) without changes in the affinity constant for T3 binding in CTBP. A T4-induced increase in MBC in cytosol inhibited nuclear T3 binding in vitro by competition of T3 binding between CTBP and the nuclear receptor. These results suggest that thyroid hormone increases the capacity for cytosolic T3 binding through increasing the amount of CTBP and its activator, and that these increases play a role in regulating the amount of T3 that binds to its nuclear receptor. Journal of Endocrinology (1989) 123, 99–104

scholarly journals Persistent COUP-TFII Expression Underlies the Myopathy and Impaired Muscle Regeneration Observed in Resistance to Thyroid Hormone-Alpha

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A814-A814
Author(s):  
Paola Aguiari ◽  
Yan-Yun Liu ◽  
Astgik Petrosyan ◽  
Sheue-Yann Cheng ◽  
Gregory A Brent ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Thyroid Hormone ◽  
Muscle Regeneration ◽  
Myogenic Differentiation ◽  
Skeletal Muscle Regeneration ◽  
Hormone Signaling ◽  
Muscle Loss ◽  
Resistance To Thyroid Hormone ◽  
Skeletal Muscle Loss

Abstract Myopathic changes, including muscular dystrophy and weakness, are commonly described in hypothyroid and hyperthyroid patients. Thyroid hormone signaling, via activation of thyroid nuclear receptor alpha (THRA), plays an essential role in maintaining muscle mass, function, and regeneration. A mouse model of resistance to thyroid hormone carrying a frameshift mutation in the THRA gene (THRA-PV) is associated with accelerated skeletal muscle loss with aging and impaired regeneration after injury(1,2). We previously demonstrated that the expression of nuclear orphan receptor chicken ovalbumin upstream promoter-factor II (COUP-TFII, or Nr2f2) persists during myogenic differentiation in THRA-PV myoblasts and skeletal muscle of aged THRA- PV mice. COUP-TFII is known to regulate myogenesis negatively and has a role in Duchenne-like Muscular Dystrophies(3). COUP-TFII physically and functionally interacts with THRA in primary myoblasts isolated from WT and THRA-PV mice, as demonstrated via co-immunoprecipitation and chromatin-immunoprecipitation. We observed that satellite cells from THRA-PV mice display impaired myoblast proliferation and in vitro myogenic differentiation compared to WT cells. However, the silencing of COUP-TFII expression using siRNA probes restores in vitro myogenic potential of THRA-PV myoblasts and shifts the mRNA expression profile closer to WT myoblasts, with a higher proliferation of myoblasts and a higher number of fully differentiated myotubes after 5 days of myogenic induction. Moreover, RNAseq analysis on myoblasts from THRA-PV mice after COUP-TFII knockdown shows that COUP-TFII silencing reverses the transcriptomic profile of THRA-PV myoblasts and results in reactivation of pathways involved in muscle function and extracellular matrix remodeling/deposition. These findings indicate that the persistent COUP-TFII expression in THRA-PV mice is responsible for the abnormal muscle phenotype. In conclusion, COUP-TFII and THRA cooperate during murine post-natal myogenesis, and COUP-TFII is critical for the accelerated skeletal muscle loss with aging and impaired muscle regeneration after injury in THRA-PV mice. These studies can help increase our knowledge of the mechanisms involved in thyroid hormone signaling during skeletal muscle regeneration, ultimately increasing the possibility of designing more specific treatments for patients with thyroid hormone-induced myopathies. References: 1. Milanesi, A., et al., Endocrinology 2016; 2. Kaneshige, M. et al., Proc Natl Acad Sci U S 2001; 3. Lee HJ, et al, Sci Rep. 2017.

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