Original Article
Brief Report
Resistance to Thyrotropin Caused by Mutations in the Thyrotropin-Receptor Gene
N Engl J Med 1995; 332:155-160January 19, 1995
- Article
Hormone-resistance syndromes can be broadly defined as conditions resulting from reduced or absent end-organ responsiveness to biologically active hormones. They are caused by defects in hormone receptors or post-receptor defects.1-3 Mutations in the thyroid hormone–receptor β gene cause resistance to thyroid hormone, which is characterized by elevated serum thyroid hormone concentrations with few or no clinical and biochemical manifestations of thyroid hormone excess and, most notably, normal or slightly increased thyrotropin secretion.1 Mutations that inactivate the thyrotropin receptor or the G (guanine nucleotide–binding) protein that couples the receptor to adenylate cyclase should cause thyrotropin resistance, resulting in either hypothyroidism or euthyroidism with increased thyrotropin secretion, depending on the completeness of the defect. There have been several reports of patients with congenital hypothyroidism,4-6 including some with familial hypothyroidism,7 and an apparent resistance to the action of thyrotropin. However, sequencing of the thyrotropin and thyrotropin-receptor genes in these patients revealed no abnormalities.8
We describe three siblings who were euthyroid and had normal serum concentrations of thyroid hormone but high concentrations of thyrotropin. They had mutations in both alleles of the thyrotropin-receptor gene, one inherited from each parent. The mutant thyrotropin receptor inherited from the father had almost no biologic activity, and that inherited from the mother had reduced activity.
Case Reports
The propositus, the second of three daughters born to unrelated parents, had a blood thyrotropin concentration of 103 mU per liter (normal, <20) on neonatal screening. Her thyroid gland was normal on radioiodide scanning. At 16 days of age, she had a serum thyrotropin concentration of 47 mU per liter and a serum thyroxine (T4) concentration of 9.2 μg per deciliter (119 nmol per liter); the 24-hour uptake of radioiodide by the thyroid was 23 percent (normal, 8 to 30 percent). Because of the high serum thyrotropin values, she was treated with T4.
These results prompted the testing of her older sister (Daughter 1), then four years of age, whose physical and mental development was normal. Her serum thyrotropin concentration was 80 mU per liter (normal, 0.5 to 6.2), and her serum T4 concentration was 9.8 μg per deciliter (126 nmol per liter; normal, 6.0 to 13.0 μg per deciliter [77 to 167 nmol per liter]). She had a normal thyroidal radioiodide scan, with a three-hour uptake of 9 percent. One year later she was treated with T4 at a daily dose of 50 μg, which reduced her serum thyrotropin concentration to 38 mU per liter. Four years later, the youngest daughter (Daughter 3) was also found to have a high blood thyrotropin concentration (96 mU per liter) at birth, with a normal T4 concentration (13.0 μg per deciliter [168 nmol per liter]). After the high thyrotropin value was confirmed by its measurement in serum (53 mU per liter), she was treated with T4.
All family members had thyroid glands of normal size, and none had symptoms or signs of hypothyroidism at any time. The three girls continued to develop normally without adjustment of their T4 doses, which at the time of our study were lower than the usual replacement dose (Table 1Table 1
Tests of Thyroid Function in Members of a Family with Resistance to Thyrotropin.). The results of thyroid-function tests in the three girls before and 3, 6, and 12 months after the discontinuation of T4 therapy as well as in their parents are shown in Table 1. Additional studies in the eldest girl conducted two months after T4 was discontinued revealed a serum glycoprotein hormone α-subunit concentration of 0.6 μg per liter (normal, <1.0) and no serum antithyrotropin antibodies, as determined by the binding of radiolabeled thyrotropin to serum immunoglobulins. Her serum thyrotropin concentration increased from 66 mU per liter to a peak of 338 mU per liter 15 minutes after the intravenous administration of 400 μg of thyrotropin-releasing hormone. Serum calcium, parathyroid hormone, luteinizing hormone, and follicle-stimulating hormone concentrations were all normal. The child's bone age was 14 years at a chronologic age of 12.3 years. The parents consented to these studies.Methods
Tests of Thyroid Function
Serum T4 and triiodothyronine (T3) concentrations were measured by radioimmunoassay (Diagnostic Products, Los Angeles), and thyrotropin by chemiluminescence assay (Nichols Institute, San Juan Capistrano, Calif.). The serum free T4 index was calculated as the product of the serum T4 and T4-resin uptake values.9 Serum free T4 and free T3 concentrations were measured by equilibrium dialysis (Nichols Institute).
Clinical Studies
The responsiveness of the pituitary and peripheral tissues to thyroid hormone was evaluated in the eldest daughter (Daughter 1).1 She was given a dose of 25 μg of T3 every 12 hours for three days, followed by a 50-μg dose every 12 hours for three days. Blood samples were obtained before and 12 hours after the last 25-μg and 50-μg dose for the measurement of serum T4, T3, free T4 index, thyrotropin, sex hormone–binding globulin, alkaline phosphatase, cholesterol, and creatine kinase.
Preparation of Genomic DNA, RNA, and Complementary DNA and DNA Sequencing
Genomic DNA was isolated from peripheral-blood leukocytes. Total RNA was extracted from the same source by the acid guanidinium thiocyanate technique.10 The coding regions (exons 2 and 3) of the thyrotropin β gene and exon 10 of the thyrotropin-receptor gene were sequenced, with genomic DNA used as the template. Sequences of exon 1 through the 5' end of exon 10 of the thyrotropin-receptor gene were obtained from complementary DNA (cDNA) synthesized by reverse transcription of very small amounts of thyrotropin-receptor messenger RNA from blood mononuclear cells (illegitimate transcription). DNA was amplified by the polymerase chain reaction (PCR) with specific oligonucleotide primers, subcloned into M13 bacteriophages or pBluescript plasmids, and then sequenced (Sequenase, U.S. Biochemical, Cleveland). The sequences of the oligonucleotide primers used are available elsewhere.
Confirmation of the Mutations and Haplotyping
To confirm the presence of each mutation and polymorphism (cytosine or adenine at position 253),11 degenerate oligonucleotide primers complementary to sequences near but not overlapping the variant nucleotide were synthesized. The primers were designed so that the product of amplification would create a unique restriction site only in the presence of the variant nucleotide (endonuclease-digestion allele-specific–primer method).11,12
After the subjects' genomic DNA was amplified by PCR, the DNA fragments were digested with the appropriate enzymes and then subjected to electrophoresis in a 3 percent NuSieve–1 percent agarose gel. Partial cleavage of the PCR products indicated that the mutant nucleotide was present in one of the two alleles.
Construction of Wild-Type and Mutant Thyrotropin-Receptor cDNA Expression Vectors
The full-length wild-type thyrotropin-receptor cDNA was cloned into pSVL.13 Appropriate DNA fragments carrying each mutation and polymorphism identified in the subjects were replaced to generate vectors expressing alanine at position 162 (Ala162), threonine at position 52 and alanine at position 162 (Thr52-Ala162), and asparagine at position 167 (Asn167). The final constructs were verified by sequencing.
The reporter-gene construct, -846 α-Luc, responsive to cyclic AMP,14 contained 846 base pairs (bp) of the 5'-flanking sequence and 44 bp of exon 1 of the human glycoprotein α-subunit gene linked to the luciferase gene in the plasmid pA3 Luc.
Functional Studies of the Thyrotropin Receptors in a Transient Transfection System
Cos-7 cells were propagated in Dulbecco's modified Eagle's medium (GIBCO BRL, Gaithersburg, Md.) containing 10 percent fetal-calf serum at 37°C and 5 percent carbon dioxide. The cells were plated in 12-well dishes in concentrations of 2×105 cells per well and transfected 24 hours later by the calcium phosphate precipitation method15 with 1 μg of the reporter vector, -846 α-Luc, and 1 μg of each of the thyrotropin-receptor expression vectors described above. Eight to 12 hours after transfection, the cells were washed and incubated for 48 hours with the complete medium in the absence or presence of various amounts of recombinant human thyrotropin (Genzyme, Cambridge, Mass.). The cells were lysed and assayed for luciferase activity (Promega, Madison, Wis.). The individual data points we report are the means (± range) for duplicate incubation mixtures, expressed as multiples of the base-line level of luciferase activity in the absence of thyrotropin.
Results
The results of thyroid-function tests of all family members are shown in Table 1. The distinctive features of the syndrome in the three daughters were high serum thyrotropin concentrations and normal serum free T4 index, free T4, and free T3 values. Both parents had slightly increased serum thyrotropin concentrations and normal serum T4 and T3 concentrations. Discontinuation of T4 treatment in the three girls resulted in an increase in serum thyrotropin concentrations, though the magnitude of the increase varied. Three and six months after the discontinuation of T4 treatment, serum T4 and free T4 index values were lower than those measured during therapy and, in two of the three girls, serum T3 concentrations were higher. At one year, the serum T4, T3, and free T4 index values equaled those measured during T4 treatment. The girls' growth continued to be normal.
The results of administering two doses of T3 to the eldest daughter are shown in Table 2Table 2
Responses to the Administration of T3 in the Eldest Daughter (Daughter 1) in a Family with Resistance to Thyrotropin and in Nine Normal Subjects.. The fractional decrease in the serum thyrotropin concentration and the changes in serum sex hormone–binding globulin, alkaline phosphatase, cholesterol, and creatine kinase concentrations were normal, indicating normal sensitivity of the pituitary thyrotrophs and peripheral tissues to thyroid hormone. Furthermore, the decrease in serum thyrotropin was accompanied by a corresponding decline in serum T4 and free T4 values, indicating that the secretion of thyroid hormone was dependent on thyrotropin.The coding region from 10 clones of the thyrotropin β gene isolated from the eldest daughter had normal sequences. This result indicated that the defect did not involve the β subunit of thyrotropin, which confers the biologic activity of the hormone, and therefore that the abnormality was most likely in a step mediating the action of thyrotropin.
The thyrotropin-receptor gene of the eldest daughter was then sequenced in its entirety. Different nucleotide substitutions were detected in each of the two alleles (Figure 1Figure 1
Sequencing Gel Showing the Mutations in Exon 6 of the Thyrotropin Receptor in the Eldest Daughter of a Family with Resistance to Thyrotropin.), indicating the presence of compound heterozygosity. Both mutations were located in exon 6, which encodes the midportion of the extracellular domain of the thyrotropin receptor. In one allele the normal thymine at position 599 was replaced by an adenine, resulting in the replacement of isoleucine by asparagine at position 167. In the other allele, the normal cytosine at position 583 was replaced by a guanine, resulting in the replacement of proline by alanine at position 162. The latter allele also contained a previously described polymorphic variant in exon 1 (threonine [ACC] instead of proline [CCC] at position 52).11 We confirmed the presence of the same nucleotide substitutions in all three girls. Furthermore, we traced each of the two mutant alleles to the corresponding parent (Figure 2Figure 2
Confirmation of the Mutations in the Thyrotropin-Receptor Gene in Members of the Study Family.). The paternal allele contained adenine at position 599, and the maternal allele guanine at position 583. The heterozygous state of each parent was confirmed by the presence of one normal allele (Figure 2).The functional activities of the mutant thyrotropin receptors and the wild-type receptor are shown in Figure 3AFigure 3
Biologic Function of the Mutant Thyrotropin Receptors and the Wild-Type Thyrotropin Receptor. and Figure 3B. In cells transfected with the wild-type thyrotropin receptor, the maximal luciferase activity induced by thyrotropin was 20 times the basal level. Approximately 10 times more thyrotropin was required for an equal effect in cells transfected with maternal mutant thyrotropin receptor (Thr52-Ala162). The thyrotropin responses of cells containing the thyrotropin receptor with Ala162 and the usual proline at position 52 (Pro52-Ala162) were similar to those of the maternal mutant thyrotropin receptor (Thr52-Ala162). Cells containing the paternal mutant thyrotropin receptor (Asn167) had almost no thyrotropin-inducible activity (Figure 3A). Cotransfection of the wild-type thyrotropin receptor with each of the mutant thyrotropin receptors, to simulate the heterozygous state of the parents, resulted in responses to low thyrotropin concentrations indistinguishable from those of cells expressing the wild-type thyrotropin receptor alone and a slightly reduced response at high thyrotropin concentrations. In contrast, in cells transfected with equal amounts of mutant maternal and paternal thyrotropin receptors, to simulate the compound heterozygous state of the three daughters, almost 20 times more thyrotropin was required to produce the same effect as in cells transfected with the wild-type thyrotropin receptor alone (Figure 3B).Discussion
Thyrotropin exerts its biologic action by binding to the extracellular domain of the thyrotropin receptor located on the plasma membrane of thyroid follicular cells. This interaction is believed to cause a structural change in the intracellular domain of the receptor. The main effect of the latter is activation of the αs subunit of the G protein, which stimulates the activity of adenylate cyclase and leads to the generation of cyclic AMP, which mediates virtually all the biologic effects of thyrotropin.16,17 The thyrotropin receptor is encoded by a single gene located on chromosome 14.16 Recently, somatic18,19 and germ-line20 mutations have been reported in the thyrotropin-receptor gene (Figure 4Figure 4
Structure of the Thyrotropin Receptor and Location of Known Mutations.) as well as in the G-protein gene2,21 that conferred constitutive activation of adenylate cyclase, resulting in autonomous hyperthyroidism.In the family we studied, all three siblings had high serum thyrotropin concentrations and normal T4 concentrations. The abnormality was demonstrated at birth in two of the three siblings. The persistence of the high serum thyrotropin concentrations was not compatible with transient infantile hyperthyrotropinemia.22 The normal growth and development of the eldest girl (Daughter 1), who did not receive thyroid hormone until the age of five years, suggested that her increased thyrotropin secretion was not due to primary hypothyroidism. The persistent hyperthyrotropinemia in the three siblings suggested that the disorder was inherited. The borderline elevation of serum thyrotropin concentrations in the parents indicated that the inheritance was recessive. Nevertheless, there was no history of consanguinity, a contention supported by the different ethnic origins of the parents (a German father and an Italian–Bohemian mother).
Among the possible defects, that involving the G protein, as has been described in pseudohypoparathyroidism,2 was least likely, since the abnormality was confined to the thyroid. Short-term administration of T3 demonstrated intact regulation of thyrotropin secretion and normal responses of peripheral tissues, ruling out abnormalities of the thyroid hormone receptor. Furthermore, thyroid secretion was thyrotropin-dependent. Thus, a variant thyrotropin molecule with reduced biologic activity or a defective thyrotropin receptor was the most likely cause of the abnormality in this family. An abnormality in the α subunit of thyrotropin was unlikely because of its normal concentration in serum as well as because of the normal serum luteinizing hormone and follicle-stimulating hormone concentrations. Gene sequencing revealed a normal thyrotropin β coding sequence.
Complete sequencing of the thyrotropin-receptor gene revealed a different point mutation in each of the two alleles in the three girls, one allele derived from each parent. This finding established the compound heterozygous inheritance of the defect and the recessive manifestation of the phenotype. The likelihood that both mutant alleles would be transmitted to each of the three daughters is (1/4)3, or 1.6 percent. The two mutations are five amino acids apart in exon 6, which encodes the midportion of the extracellular domain of the thyrotropin receptor (Figure 4).
Important areas of thyrotropin binding and signal transduction of the thyrotropin receptor have been mapped in the extracellular, transmembrane, and intracellular domains of the molecule.17,23-26 Although the functional importance of the region encoded by exon 6 of the thyrotropin receptor has not been studied in detail, the substitution of leucine for the normal proline at position 162 slightly decreased the responsiveness to thyrotropin.27 In this family, functional assays demonstrated that the paternal mutant thyrotropin receptor had almost no thyrotropin-inducible activity and that the maternal mutant thyrotropin receptor had 1/10 the normal activity. Replacement of the polymorphic variant threonine at position 52 in the maternal mutant thyrotropin receptor with the more common proline did not alter the defect. Cells transfected with equal amounts of wild-type and mutant paternal or maternal thyrotropin receptors, to simulate the condition of the heterozygous parents, had normal responses to low thyrotropin concentrations and slightly reduced responses to high concentrations. These findings are compatible with the presence of slightly elevated serum thyrotropin concentrations in the parents. Cells cotransfected with the mutant maternal and paternal thyrotropin receptors, as inherited in the three daughters, required almost 20 times more thyrotropin to produce the level of activity observed in cells transfected with wild-type thyrotropin receptor alone.
These observations explain the 20-fold elevation in serum thyrotropin concentrations in the three daughters that was necessary to maintain normal thyroid hormone secretion. However, the precise mechanisms responsible for the impaired signal transduction and maintenance of a high serum thyrotropin concentration remain unknown. Since the mutations are located in the extracellular domain of the thyrotropin receptor, they may reduce the binding affinity for thyrotropin, a hypothesis we were unable to verify because of a low level of thyrotropin-receptor expression in the transient expression system. It is also possible that the substituted amino acids could alter signal transduction without affecting thyrotropin binding.24 The mechanism enabling these subjects to maintain high serum thyrotropin concentrations despite their normal serum thyroid hormone concentrations is a matter of speculation, but possibilities include mild, subclinical hypothyroidism, increased frequency of pulses of thyrotropin secretion, and a resetting of the threshold for thyroid hormone–induced suppression of thyrotropin secretion.28
Presented in part at the 76th annual meeting of the Endocrine Society, Anaheim, Calif., June 15–18, 1994.
Supported in part by grants from the National Institutes of Health (DK-15070) and the Public Health Service (RR-00055).
We are indebted to Professor Gilbert Vassart for providing the wild-type thyrotropin-receptor cDNA expression vector and to Dr. J. Larry Jameson for providing the -846 α-Luc reporter vector.
Source Information
From the Departments of Medicine (T.S., Y.H., S.R.) and Pediatrics (S.R.) and the J.P. Kennedy, Jr., Mental Retardation Research Center (S.R.), University of Chicago, and the Department of Pediatrics, Loyola University (M.E.G.) — all in Chicago.
Address reprint requests to Dr. Refetoff at the University of Chicago, MC 3090, 5841 S. Maryland Ave., Chicago, IL 60637.
- References
References
1
Refetoff S ,Weiss RE ,Usala SJ . The syndromes of resistance to thyroid hormone. Endocr Rev 1993;14:348-399
Web of Science | Medline2
Weinstein LS ,Shenker A . G protein mutations in human disease. Clin Biochem 1993;26:333-338
CrossRef | Web of Science | Medline3
Rosenfeld RG ,Rosenbloom AL ,Guevara-Aguirre J . Growth hormone (GH) insensitivity due to primary GH receptor deficiency. Endocr Rev 1994;15:369-390
Web of Science | Medline4
Stanbury JB ,Rocmans P ,Buhler UK ,Ochi Y . Congenital hypothyroidism with impaired thyroid response to thyrotropin. N Engl J Med 1968;279:1132-1136
Full Text | Web of Science | Medline5
Medeiros-Neto GA ,Knobel M ,Bronstein MD ,Simonetti J ,Filho FF ,Mattar E . Impaired cyclic-AMP response to thyrotropin in congenital hypothyroidism with thyroglobulin deficiency. Acta Endocrinol (Copenh) 1979;92:62-72
Medline6
Codaccioni JL ,Carayon P ,Michel-Bechet M ,Foucault F ,Lefort G ,Pierron H . Congenital hypothyroidism associated with thyrotropin unresponsiveness and thyroid cell membrane alterations. J Clin Endocrinol Metab 1980;50:932-937
CrossRef | Web of Science | Medline7
Takamatsu J ,Nishikawa M ,Horimoto M ,Ohsawa N . Familial unresponsiveness to thyrotropin by autosomal recessive inheritance. J Clin Endocrinol Metab 1993;77:1569-1573
CrossRef | Web of Science | Medline8
Takeshita A ,Nagayama Y ,Yokoyama N , et al. Analysis of thyrotropin receptor gene mutation in congenital primary hypothyroidism associated with thyrotropin unresponsiveness. Thyroid 1993;3:T-91 abstract.9
Refetoff S ,Hagen SR ,Selenkow HA . Estimation of the T 4 binding capacity of serum TBG and TBPA by a single T 4 load ion exchange resin method. J Nucl Med 1972;13:2-12
Web of Science | Medline10
Chomczynski P ,Sacchi N . Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987;162:156-159
CrossRef | Web of Science | Medline11
Sunthornthepvarakul T ,Hayashi Y ,Refetoff S . Polymorphism of a variant human thyrotropin receptor (hTSHR) gene. Thyroid 1994;4:147-149
CrossRef | Web of Science | Medline12
Weiss RE ,Weinberg M ,Refetoff S . Identical mutations in unrelated families with generalized resistance to thyroid hormone occur in cytosine-guanine-rich areas of the thyroid hormone receptor beta gene: analysis of 15 families. J Clin Invest 1993;91:2408-2415
CrossRef | Web of Science | Medline13
Libert F ,Lefort A ,Gerard C , et al. Cloning, sequencing and expression of the human thyrotropin (TSH) receptor: evidence for binding of autoantibodies. Biochem Biophys Res Commun 1989;165:1250-1255
CrossRef | Web of Science | Medline14
Jameson JL ,Powers AC ,Gallagher GD ,Habener JF . Enhancer and promoter element interactions dictate cyclic adenosine monophosphate mediated and cell-specific expression of the glycoprotein hormone α-gene. Mol Endocrinol 1989;3:763-772
CrossRef | Web of Science | Medline15
Graham FL ,van der Eb AJ . A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology 1973;52:456-467
CrossRef | Web of Science | Medline16
Vassart G ,Dumont JE . The thyrotropin receptor and the regulation of thyrocyte function and growth. Endocr Rev 1992;13:596-611
Web of Science | Medline17
Nagayama Y ,Rapoport B . The thyrotropin receptor 25 years after its discovery: new insight after its molecular cloning. Mol Endocrinol 1992;6:145-156
CrossRef | Web of Science | Medline18
Parma J ,Duprez L ,Van Sande J , et al. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 1993;365:649-651
CrossRef | Web of Science | Medline19
Porcellini A ,Ciullo I ,Laviola L ,Amabile G ,Fenzi G ,Avvedimento VE . Novel mutations of thyrotropin receptor gene in thyroid hyperfunctioning adenomas: rapid identification by fine needle aspiration biopsy. J Clin Endocrinol Metab 1994;79:657-661
CrossRef | Web of Science | Medline20
Duprez L ,Parma K ,van Sande J , et al. Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism. Nat Genet 1994;7:396-401
CrossRef | Web of Science | Medline21
O'Sullivan C ,Barton CM ,Staddon SL ,Brown CL ,Lemoine NR . Activating point mutations of the gsp oncogene in human thyroid adenomas. Mol Carcinog 1991;4:345-349
CrossRef | Web of Science | Medline22
Miyai K, Harada T, Nose O, et al. Transient infantile hyperthyrotropinemia. In: Stockigt JR, Nagataki S, eds. Thyroid research VII: proceedings of the Eighth International Thyroid Congress, Sydney, Australia, 3–8 February, 1980. Oxford, England: Pergamon Press, 1980:33-6.
23
Nagayama Y ,Nagataki S . The thyrotropin receptor: its gene expression and structure-function relationships. Thyroid Today 1994;17:1-924
Nagayama Y ,Rapoport B . Role of the carboxyl-terminal half of the extracellular domain of the human thyrotropin receptor in signal transduction. Endocrinology 1992;131:548-552
CrossRef | Web of Science | Medline25
Kosugi S ,Okajima F ,Ban T ,Hidaka A ,Shenker A ,Kohn LD . Substitutions of different regions of the third cytoplasmic loop of the thyrotropin (TSH) receptor have selective effects on constitutive, TSH-, and TSH receptor autoantibody-stimulated phosphoinositide and 3',5'-cyclic adenosine monophosphate signal generation. Mol Endocrinol 1993;7:1009-1020
CrossRef | Web of Science | Medline26
Mori T ,Sugawa H ,Piraphatdist T ,Inoue D ,Enomoto T ,Imura H . A synthetic oligopeptide derived from human thyrotropin receptor sequence binds to Graves' immunoglobulin and inhibits thyroid stimulating antibody activity but lacks interactions with TSH. Biochem Biophys Res Commun 1991;178:165-172
CrossRef | Web of Science | Medline27
Nagayama Y ,Rapoport B . Thyroid stimulating autoantibodies in different patients with autoimmune thyroid disease do not all recognize the same components of the human thyrotropin receptor: selective role of receptor amino acids Ser25-Glu30 . J Clin Endocrinol Metab 1992;75:1425-1430
CrossRef | Web of Science | Medline28
Lewis GF ,Alessi CA ,Imperial JG ,Refetoff S . Low serum free thyroxine index in ambulating elderly is due to a resetting of the threshold of thyrotropin feedback suppression. J Clin Endocrinol Metab 1991;73:843-849
CrossRef | Web of Science | Medline
- Citing Articles (80)
Citing Articles
1
Li Shao, Hua Jiang, Jun Liang, Xianping Niu, Lili Teng, Hua Zhang. (2011) Study on the Relationship Between TSHR Gene and Thyroid Diseases. Cell Biochemistry and Biophysics 61:2, 377-382
CrossRef2
L. Persani, G. Gelmini, F. Marelli, P. Beck-Peccoz, M. Bonomi. (2011) Syndromes of resistance to TSH. Annales d'Endocrinologie 72:2, 60-63
CrossRef3
Joaquin Lado-Abeal, Isabel Castro-Piedras, Fernando Palos-Paz, Jose Ignacio Labarta-Aizpún, Ramon Albero-Gamboa. (2011) A Family with Congenital Hypothyroidism Caused by a Combination of Loss-of-Function Mutations in the Thyrotropin Receptor and Adenylate Cyclase-Stimulating G Alpha-Protein Subunit Genes. Thyroid 21:2, 103-109
CrossRef4
Anthony Ciarallo, William Makis, Javier-A. Novales-Diaz. (2011) Incidental Papillary Thyroid Carcinoma in a Patient Presenting With Gravesʼ Hyperthyroidism and Concomitant Obstructive Sequestered Intrathoracic Multinodular Goiter. Clinical Nuclear Medicine 36:2, 145-147
CrossRef5
Ruben Diaz, Ghada El-Hajj Fuleihan, Edward M. Brown. 2011. Parathyroid Hormone and Polyhormones: Production and Export. .
CrossRef6
V. Nebes, J. Wall. 2011. Membrane Receptor-Linked Disease States. .
CrossRef7
Virginia D. Sarapura, David F. Gordon, Mary H. Samuels. 2011. Thyroid-stimulating Hormone. , 167-203.
CrossRef8
Erik A. C. Alves, Cleber M. Cruz, Clebson P. Pimentel, Rita C. M. Ribeiro, Andrea K. C. R. Santos, Milena C. F. Caldato, Luiz C. Santana-da-Silva. (2010) High Frequency of D727E Polymorphisms in Exon 10 of the TSHR Gene in Brazilian Patients with Congenital Hypothyroidism. Journal of Pediatric Endocrinology and Metabolism 23:12, 1321-1328
CrossRef9
Hakan Cangul, Neil V. Morgan, Julia R. Forman, Halil Saglam, Zehra Aycan, Tahsin Yakut, Tuna Gulten, Omer Tarim, Ece Bober, Yasar Cesur, Gail A. Kirby, Shanaz Pasha, Mutlu Karkucak, Erdal Eren, Semra Cetinkaya, Veysel Bas, Korcan Demir, Sevil A. Yuca, Esther Meyer, Michaela Kendall, Wolfgang Hogler, Timothy G. Barrett, Eamonn R. Maher. (2010) Novel TSHR mutations in consanguineous families with congenital nongoitrous hypothyroidism. Clinical Endocrinology 73:5, 671-677
CrossRef10
Kenneth J. Valenzano, Elfrida R. Benjamin, Patricia René, Michel Bouvier. 2010. Pharmacological Chaperones: Potential for the Treatment of Hereditary Diseases Caused by Mutations in G Protein-Coupled Receptors. , 460-510.
CrossRef11
Joachim Pohlenz, Guy Van Vliet. 2010. Developmental Abnormalities of the Thyroid. , 97-104.
CrossRef12
(2009) Glycoprotein hormone. British Journal of Pharmacology 158, S56-S56
CrossRef13
(2009) 7TM RECEPTORS. British Journal of Pharmacology 158, S5-S101
CrossRef14
Brenda Kohn, Helmut Grasberger, Leslie L. Lam, Alfonso Massimiliano Ferrara, Samuel Refetoff. (2009) A Somatic Gain-of-Function Mutation in the Thyrotropin Receptor Gene Producing a Toxic Adenoma in an Infant. Thyroid 19:2, 187-191
CrossRef15
Giuseppina De Marco, Patrizia Agretti, Marta Camilot, Francesca Teofoli, Luciano Tatò, Paolo Vitti, Aldo Pinchera, Massimo Tonacchera. (2009) Functional studies of new TSH receptor (TSHr) mutations identified in patients affected by hypothyroidism or isolated hyperthyrotrophinaemia. Clinical Endocrinology 70:2, 335-338
CrossRef16
ALAN M. RICE, SCOTT A. RIVKEES. 2008. Receptor Transduction of Hormone Action. , 26-73.
CrossRef17
Zhe Feng YUAN, Hua Qing MAO, Yan Fei LUO, Yi Dong WU, Zheng SHEN, Zheng Yan ZHAO. (2008) Thyrotropin Receptor and Thyroid Transcription Factor-1 Genes Variant in Chinese Children with Congenital Hypothyroidism. Endocrine Journal 55:2, 415-423
CrossRef18
Marta Camilot, Francesca Teofoli, Monica Vincenzi, Francesca Federici, Silvia Perlini, Luciano Tatò. (2007) Implementation of a Congenital Hypothyroidism Newborn Screening Procedure with Mutation Detection on Genomic DNA Extracted from Blood Spots: The Experience of the Italian Northeastern Reference Center. Genetic Testing 11:4, 387-390
CrossRef19
Massimo Tonacchera, Caterina Di Cosmo, Giuseppina De Marco, Patrizia Agretti, Mariaelena Banco, Anna Perri, Elena Gianetti, Lucia Montanelli, Paolo Vitti, Aldo Pinchera. (2007) Identification of TSH receptor mutations in three families with resistance to TSH. Clinical Endocrinology 67:5, 712-718
CrossRef20
Patrizia Agretti, Giuseppina De Marco, Alessandra Capodanno, Eleonora Ferrarini, Antonio Dimida, Daniela Sansone, Paola Collecchi, Aldo Pinchera, Paolo Vitti, Massimo Tonacchera. (2007) A Fast Method to Detect Cell Surface Expression of Thyrotropin Receptor (TSHr): The Microchip Flow Cytometry Analysis. Thyroid 17:9, 861-868
CrossRef21
Anat Ben-Shlomo, Shlomo Melmed. (2007) Pituitary hormone receptors and tumorigenesis. Nature Reviews Cancer 7:9,
CrossRef22
A. Jeziorowska, B. Pniewska-Siark, E. Brzeziańska, D. Pastuszak-Lewandoska, A. Lewiński. (2006) A Novel Mutation in the Thyrotropin (Thyroid-Stimulating Hormone) Receptor Gene in a Case of Congenital Hypothyroidism. Thyroid 16:12, 1303-1309
CrossRef23
Carina M. Rivolta, Héctor M. Targovnik. (2006) Molecular advances in thyroglobulin disorders. Clinica Chimica Acta 374:1-2, 8-24
CrossRef24
Andrea G Lania, Giovanna Mantovani, Anna Spada. (2006) Mechanisms of Disease: mutations of G proteins and G-protein-coupled receptors in endocrine diseases. Nature Clinical Practice Endocrinology & Metabolism 2:12, 681-693
CrossRef25
Paolo Beck-Peccoz, Luca Persani, Davide Calebiro, Marco Bonomi, Deborah Mannavola, Irene Campi. (2006) Syndromes of hormone resistance in the hypothalamic–pituitary–thyroid axis. Best Practice & Research Clinical Endocrinology & Metabolism 20:4, 529-546
CrossRef26
Keisuke Kanda, Haruo Mizuno, Yukari Sugiyama, Hiroki Imamine, Hajime Togari, Kazumichi Onigata. (2006) Clinical significance of heterozygous carriers associated with compensated hypothyroidism in R450H, a common inactivating mutation of the thyrotropin receptor gene in Japanese. Endocrine 30:3, 383-388
CrossRef27
Ya-Xiong Tao. (2006) Inactivating mutations of G protein-coupled receptors and diseases: Structure-function insights and therapeutic implications. Pharmacology & Therapeutics 111:3, 949-973
CrossRef28
Katsuhiko Tsunekawa, Kazumichi Onigata, Tadashi Morimura, Takayuki Kasahara, Soroku Nishiyama, Tomohito Kamoda, Masatomo Mori, Akihiro Morikawa, Masami Murakami. (2006) Identification and Functional Analysis of Novel Inactivating Thyrotropin Receptor Mutations in Patients with Thyrotropin Resistance. Thyroid 16:5, 471-479
CrossRef29
S P H Alexander, A Mathie, J A Peters. (2006) Glycoprotein hormone. British Journal of PharmacologyS45-S45
CrossRef30
Marian Ludgate, Dagmar Fuhrer. 2006. Thyroid Dysfunction: Molecular Genetics. .
CrossRef31
Helmut Grasberger, Martine Vaxillaire, Silvana Pannain, John C. Beck, Aviva Mimouni-Bloch, Vincent Vatin, Gilbert Vassart, Philippe Froguel, Samuel Refetoff. (2005) Identification of a locus for nongoitrous congenital hypothyroidism on chromosome 15q25.3-26.1. Human Genetics 118:3-4, 348-355
CrossRef32
Ali-Asghar Mirsaeid Ghazi, Arash Ordookhani, Marina Pourafkari, Masoumeh Fallahian, Adeleh Bahar, Mehdi Hedayati, Ali Hafizi, Fereidoun Azizi. (2005) Intrauterine Diagnosis and Management of Fetal Goitrous Hypothyroidism: A Report of an Iranian Family with Three Consecutive Pregnancies Complicated by Fetal Goiter. Thyroid 15:12, 1341-1347
CrossRef33
Yvonne Böttcher, Markus Eszlinger, Anke Tönjes, Ralf Paschke. (2005) The genetics of euthyroid familial goiter. Trends in Endocrinology & Metabolism 16:7, 314-319
CrossRef34
Marta Camilot, Francesca Teofoli, Alberto Gandini, Roberto Franceschi, Anna Rapa, Andrea Corrias, Gianni Bona, Giorgio Radetti, Luciano Tato. (2005) Thyrotropin receptor gene mutations and TSH resistance: variable expressivity in the heterozygotes. Clinical Endocrinology 63:2, 146-151
CrossRef35
Rossella Gaudino, Catherine Garel, Paul Czernichow, Juliane Leger. (2005) Proportion of various types of thyroid disorders among newborns with congenital hypothyroidism and normally located gland: a regional cohort study. Clinical Endocrinology 62:4, 444-448
CrossRef36
Kirsten Börgel, Joachim Pohlenz, Hans G. Koch, Jurgen H. Bramswig. (2005) Long-Term Carbimazole Treatment of Neonatal Nonautoimmune Hyperthyroidism due to a New Activating TSH Receptor Gene Mutation (Ala428Val). Hormone Research 64:4, 203-208
CrossRef37
Torsten Schöneberg, Angela Schulz, Heike Biebermann, Thomas Hermsdorf, Holger Römpler, Katrin Sangkuhl. (2004) Mutant G-protein-coupled receptors as a cause of human diseases. Pharmacology & Therapeutics 104:3, 173-206
CrossRef38
Annette Richter-Unruh, Berthold P. Hauffa, Nicole Pfarr, Joachim Pohlenz. (2004) Congenital Primary Hypothyroidism in a Turkish Family Caused by a Homozygous Nonsense Mutation (R609X) in the Thyrotropin Receptor Gene. Thyroid 14:11, 971-974
CrossRef39
J.Larry Jameson. (2004) Molecular mechanisms of end-organ resistance. Growth Hormone & IGF Research 14, 45-50
CrossRef40
Akira Hishinuma, Narumi Ohmika, Takashi Namatame, Tamio Ieiri. (2004) TTF-2 stimulates expression of 17 genes, including one novel thyroid-specific gene which might be involved in thyroid development. Molecular and Cellular Endocrinology 221:1-2, 33-46
CrossRef41
S.-M. Park, R. J. Clifton-Bligh, P. Betts, V. K. K. Chatterjee. (2004) Congenital hypothyroidism and apparent athyreosis with compound heterozygosity or compensated hypothyroidism with probable hemizygosity for inactivating mutations of the TSH receptor. Clinical Endocrinology 60:2, 220-227
CrossRef42
Dagmar Führer, Peter Lachmund, Istvan-Tibor Nebel, Ralf Paschke. (2003) The Thyrotropin Receptor Mutation Database: Update 2003. Thyroid 13:12, 1123-1126
CrossRef43
José C Moreno, Jan J.M de Vijlder, Thomas Vulsma, Carrie Ris-Stalpers. (2003) Genetic basis of hypothyroidism: recent advances, gaps and strategies for future research. Trends in Endocrinology & Metabolism 14:7, 318-326
CrossRef44
Meyer Knobel, Geraldo Medeiros-Neto. (2003) An Outline of Inherited Disorders of the Thyroid Hormone Generating System. Thyroid 13:8, 771-801
CrossRef45
G Van Vliet. (2003) Development of the thyroid gland: lessons from congenitally hypothyroid mice and men. Clinical Genetics 63:6, 445-455
CrossRef46
O. E. Janssen, Beate Quadbeck, S. Refetoff. (2003) Resistenz gegen TSH/Resistance to Thyrotropin. LaboratoriumsMedizin 27:1-2, 60-66
CrossRef47
Roy E. Weiss, Peter M. Sadow. 2003. Thyroid Hormone Receptor, TSH and TSH Receptor Mutations. , 477-483.
CrossRef48
Francesca Calaciura, Giueppe Miscio, Angelo Coco, Daniela Leonardi, Carmela Cisternino, Concetto Regalbuto, Maura Bozzali, Raffaella Maiorana, Annalisa Ranieri, Anna Carta, Massimo Buscema, Vincenzo Trischitta, Lidia Sava, Vittorio Tassi. (2002) Genetics of Specific Phenotypes of Congenital Hypothyroidism: A Population-Based Approach. Thyroid 12:11, 945-951
CrossRef49
Carina M. Rivolta, Christian M. Moya, Fernando M. Mendive, Héctor M. Targovnik. (2002) Genotyping and Characterization of Two Polymorphic Microsatellite Markers Located Within Introns 29 and 30 of the Human Thyroglobulin Gene. Thyroid 12:9, 773-779
CrossRef50
P. Bretones, L. Duprez, J. Parma, M. David, G. Vassart, P. Rodien. (2001) A Familial Case of Congenital Hypothyroidism Caused by a Homozygous Mutation of the Thyrotropin Receptor Gene. Thyroid 11:10, 977-980
CrossRef51
Mary P. Gillam, Peter Kopp. (2001) Genetic defects in thyroid hormone synthesis. Current Opinion in Pediatrics 13:4, 364-372
CrossRef52
B. Corvilain, J. Van Sande, J. E. Dumont, G. Vassart. (2001) Somatic and germline mutations of the TSH receptor and thyroid diseases. Clinical Endocrinology 55:2, 143-158
CrossRef53
Héctor M. Targovnik, Carina M. Rivolta, Fernando M. Mendive, Christian M. Moya, Jussara Vono, Geraldo Medeiros-Neto. (2001) Congenital Goiter with Hypothyroidism Caused by a 5′ Splice Site Mutation in the Thyroglobulin Gene. Thyroid 11:7, 685-690
CrossRef54
Tomohisa Nagashima, Masami Murakami, Kazumichi Onigata, Tadashi Morimura, Kanji Nagashima, Masatomo Mori, Akihiro Morikawa. (2001) Novel Inactivating Missense Mutations in the Thyrotropin Receptor Gene in Japanese Children with Resistance to Thyrotropin. Thyroid 11:6, 551-559
CrossRef55
Dagmar Fuhrer, Ralf Paschke. (2000) Thyroid-stimulating hormone receptor mutations: update and clinical implications. Current Opinion in Endocrinology & Diabetes 7:5, 288-294
CrossRef56
Jörg Gromoll, Martina Bröcker, Michael Derwahl, Wolfgang Höppner. (2000) Detection of Mutations in Glycoprotein Hormone Receptors. Methods 21:1, 83-97
CrossRef57
Luca Chiovato, Paola Lapi, Mariastella Zannini, Roberto Di Lauro. (1999) Congenital hypothyroidism: searching for its genetic basis. Current Opinion in Endocrinology & Diabetes 6:4, 277
CrossRef58
SABINE COSTAGLIOLA, THONGKUN SUNTHORNTEPVARAKUL, ISABELLE MIGEOTTE, JACQUELINE VAN SANDE, ANDREY M. KAJAVA, SAMUEL REFETOFF, GILBERT VASSART. (1999) Structure-Function Relationships of Two Loss-of-Function Mutations of the Thyrotropin Receptor Gene. Thyroid 9:10, 995-1000
CrossRef59
DOV TIOSANO, SILVANA PANNAIN, GILBERT VASSART, JASMINE PARMA, RUTH GERSHONI-BARUCH, HANNA MANDEL, RACHEL LOTAN, YUNES ZAHARAN, MENUHA PERY, ROY E. WEISS, SAMUEL REFETOFF, ZE'EV HOCHBERG. (1999) The Hypothyroidism in an Inbred Kindred with Congenital Thyroid Hormone and Glucocorticoid Deficiency is Due to a Mutation Producing a Truncated Thyrotropin Receptor. Thyroid 9:9, 887-894
CrossRef60
Paolo E Macchia, Mario De Felice, Roberto Di Laurot. (1999) Molecular genetics of congenital hypothyroidism. Current Opinion in Genetics & Development 9:3, 289-294
CrossRef61
A Grüters, H Krude, H Biebermann, KP Liesenkötter, T Schöneberg, T Gudernamm. (1999) Alterations of neonatal thyroid function. Acta Paediatrica 88:s428, 17-22
CrossRef62
JAANA SIMANAINEN, AMELIE KINCH, KERSTIN WESTERMARK, BRITA WINSA, MATS BENGTSSON, FRANK SCHUPPERT, BENGT WESTERMARK, NILS-ERIK HELDIN. (1999) Analysis of Mutations in Exon 1 of the Human Thyrotropin Receptor Gene: High Frequency of the D36H and P52T Polymorphic Variants. Thyroid 9:1, 7-11
CrossRef63
Laurence Duprez, Jasmine Parma, Jacqueline Van Sande, Patrice Rodien, Jacques E. Dumont, Gilbert Vassart, Marc Abramowicz. (1998) TSH Receptor Mutations and Thyroid Disease. Trends in Endocrinology & Metabolism 9:4, 133-140
CrossRef64
AKIRA HISHINUMA, JUNTA TAKAMATSU, YUMIKO KANNO, SHIGERU YOSHIDA, TAMIO IEIRI. (1998) Analysis of the Promoter of the Thyrotropin Receptor Gene and the Entire Genomic Sequence of Thyroid Transcription Factor-1 in Familial Congenital Hypothyroidism due to Thyrotropin Unresponsiveness. Thyroid 8:4, 305-309
CrossRef65
Epstein, Franklin H., , Paschke, Ralf, Ludgate, Marian, . (1997) The Thyrotropin Receptor in Thyroid Diseases. New England Journal of Medicine 337:23, 1675-1681
Full Text66
de Roux, Nicolas, Young, Jacques, Misrahi, Micheline, Genet, Roger, Chanson, Philippe, Schaison, Gilbert, Milgrom, Edwin, . (1997) A Family with Hypogonadotropic Hypogonadism and Mutations in the Gonadotropin-Releasing Hormone Receptor. New England Journal of Medicine 337:22, 1597-1603
Full Text67
Biebermann, HeikiGrüters, Annette, , Schöneberg, Torsten, Gudermann, Thomas, . (1997) Congenital Hypothyroidism Caused by Mutations in the Thyrotropin-Receptor Gene. New England Journal of Medicine 336:19, 1390-1391
Full Text68
DELBERT A. FISHER. (1997) Fetal Thyroid Function: Diagnosis and Management of Fetal Thyroid Disorders. Clinical Obstetrics and Gynecology 40:1, 16-31
CrossRef69
Massimo Tonacchera, Filomena Cetani, Sabine Costagliola, Jacqueline Sande, Samuel Refetoff, Gilbert Vassart. (1996) Functional Characteristics of a Variant Thyrotropin Receptor. European Journal of Biochemistry 238:2, 490-494
CrossRef70
N. de Roux, M. Misrahi, N. Chatelain, B. Gross, E. Milgrom. (1996) Microsatellites and PCR primers for genetic studies and genomic sequencing of the human ISH receptor gene. Molecular and Cellular Endocrinology 117:2, 253-256
CrossRef71
Philip A. Masters, Richard J. Simons. (1996) Clinical use of sensitive assays for thyroid-stimulating hormone. Journal of General Internal Medicine 11:2, 115-127
CrossRef72
Brigitte Van Eyll, Burkhard Göke, Andreas Wilmen, Rüdiger Göke. (1996) Exchange of W39 by A within the N-terminal extracellular domain of the GLP-1 receptor results in a loss of receptor function. Peptides 17:4, 565-570
CrossRef73
Ralf Paschke, Jacqueline Van Sande, Jasmine Parma, Gilbert Vassart. (1996) The TSH receptor and thyroid diseases. Baillière's Clinical Endocrinology and Metabolism 10:1, 9-27
CrossRef74
Elzbieta Biesiada, Perrie M. Adams, Douglas R. Shanklin, George S. Bloom, Stuart A. Stein. (1996) Biology of the congenitally hypothyroid hyt/ hyt mouse. Advances in Neuroimmunology 6:4, 309-346
CrossRef75
Xuliang Jiang, Michel Dreano, David R Buckler, Shirley Cheng, Arnaud Ythier, Hao Wu, Wayne A Hendrickson, Nabil El Tayar. (1995) Structural predictions for the ligand-binding region of glycoprotein hormone receptors and the nature of hormone–receptor interactions. Structure 3:12, 1341-1353
CrossRef76
Andrey V Kajava, Gilbert Vassart, Shoshana J Wodak. (1995) Modeling of the three-dimensional structure of proteins with the typical leucine-rich repeats. Structure 3:9, 867-877
CrossRef77
ROBERT M. CUDDIHY, WILLIAM P. BRYANT, REBECCA S. BAHN. (1995) Normal Function in Vivo of a Homozygotic Polymorphism in the Human Thyrotropin Receptor. Thyroid 5:4, 255-257
CrossRef78
Andrew Shenker. (1995) G protein-coupled receptor structure and function: The impact of disease-causing mutations. Baillière's Clinical Endocrinology and Metabolism 9:3, 427-451
CrossRef79
Katie A. Woods, Angela Weber, Adrian J.L. Clark. (1995) The molecular pathology of pituitary hormone deficiency and resistance. Baillière's Clinical Endocrinology and Metabolism 9:3, 453-487
CrossRef80
Utiger, Robert D., . (1995) Thyrotropin-Receptor Mutations and Thyroid Dysfunction. New England Journal of Medicine 332:3, 183-185
Full Text
- Letters
