help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ando, S.
Right arrow Articles by Yen, P. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ando, S.
Right arrow Articles by Yen, P. M.
The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 11 5572-5576
Copyright © 2001 by The Endocrine Society

Other Original Articles

Somatic Mutation of TRß Can Cause a Defect in Negative Regulation of TSH in a TSH-Secreting Pituitary Tumor

Shinichiro Ando, Nicholas J. Sarlis, Edward H. Oldfield and Paul M. Yen

Molecular Regulation and Neuroendocrinology Section, Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.A., N.J.S., P.M.Y.), and Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (E.H.O.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Paul M. Yen, M.D., Molecular Regulation and Neuroendocrinology Section, Clinical Endocrinology Branch, National Institutes of Health, Building 10, Room 8D12, Bethesda, Maryland 20892. E-mail: pauly{at}intra.niddk.nih.gov

Abstract

In patients with TSH-secreting tumors (TSHomas), serum TSH is poorly suppressed by thyroid hormone. The mechanism for this defect in negative regulation of TSH secretion is not known. To investigate the possibility of a somatic mutation of TR causing this defect, we performed mutational analysis of TRß by RT-PCR using RNA obtained from five surgically resected TSHomas. In one TSHoma, we identified a somatic mutation in the ligand-binding domain of TRß that caused a His to Tyr substitution at codon 435 of TRß1 corresponding to codon 450 of TRß2. Interestingly, this mutation occurred in the same codon as two mutations (TRßH435L and H435Q) previously identified in patients with the syndrome of resistance to thyroid hormone. This mutant TRß had impaired T3 binding and T3-mediated negative regulation. It also blocked the negative regulation by wild-type TRß2 on glycoprotein hormone {alpha}-subunit and TSHß reporter genes in cotransfection studies. Our results demonstrate that somatic mutation of TRß occurred in a TSHoma and was probably responsible for the defect in negative regulation of TSH by thyroid hormone in the tumor.

TSH-SECRETING TUMORS (TSHomas) are rare pituitary tumors that constitutively secrete TSH and cause hyperthyroidism. TSHomas exhibit a defect in the negative regulation of TSH by thyroid hormone. The cause of this defect is not known, but could involve somatic mutations of TRs in the tumor that, in turn, could interfere with normal regulation of the glycoprotein hormone {alpha}-subunit and TSHß genes, which encode the subunits of TSH.

TRs are members of the nuclear hormone receptor superfamily and are encoded on two distinct TR genes, TR{alpha} and TRß. The TRß gene generates two isoforms, TRß1 and TRß2 (1). TRß1 and TRß2 proteins have identical DNA- and ligand-binding domains, but different amino-termini due to alternative promoter choice (2). Although TRß1 is widely expressed, TRß2 is mainly expressed in the anterior pituitary gland. Recent studies with TRß2-selective knockout mice showed the physiological importance of this isoform in negative regulation of TSH by thyroid hormone (3).

Mutations in the TRß gene have been found in patients with the syndrome of resistance to thyroid hormone (RTH) (4), an autosomal dominant inherited disorder in which patients have elevated thyroid hormone levels and elevated or inappropriately normal TSH levels. RTH is clinically divided into two forms based on phenotype pattern: generalized resistance, which has both pituitary and peripheral resistance to T3 (GRTH), and pituitary resistance to T3 (PRTH). Patients with the latter form, have predominantly hyperthyroid symptoms. However, there is no distinction between these two forms at the genetic level, as germline mutations in one of the TRß alleles are found in both forms (5, 6). The resultant mutant TRßs have mutations in the ligand-binding domain and typically bind thyroid hormone poorly. They also have decreased transcriptional activity and interfere with the transcriptional regulation by wild-type TRs (dominant negative activity) in cotransfection studies. Indeed, mutant TRs have been shown to block the transcriptional regulation of glycoprotein hormone {alpha}-subunit and TSHß reporter genes by wild-type TRs (7, 8).

Given the precedent of TRß mutations in patients with RTH, we hypothesized that mutations of TR may be a mechanism for the defective negative regulation of TSH subunits in TSHomas and performed mutational analysis of TRß isolated from several surgically resected TSHoma samples.

Subjects and Methods

Patients

Five TSHoma samples were obtained from patients who underwent transsphenoidal surgery at NIH. Clinical data from the five patients are shown in Table 1Go. Patient 1 had a delayed TSH response to TRH stimulation, whereas the other patients had no response to TRH, which is typical of patients with TSHomas (4, 9) (Fig. 1Go). The clinical data of the patient who was found to have a somatic mutation (patient 1) are the following. A 52-yr-old female had been treated in the past with subtotal thyroidectomy and radioactive ablation for a presumed diagnosis of Graves’ disease. Thyroid function tests revealed a TSH level of 121.6 µU/ml (normal, 0.43–4.60), free T4 of 1.7 ng/dl (normal, 0.9–1.6), and glycoprotein hormone {alpha}-subunit of 5.3 µg/liter (normal, <5.0). Serum GH and PRL levels were normal. A magnetic resonance imaging scan demonstrated a 17-mm pituitary adenoma with extension into the right cavernous sinus. The patient underwent transsphenoidal resection of the pituitary tumor. Immunohistochemical analysis of the tumor showed positive staining for TSH and glycoprotein hormone {alpha}-subunit. Thyroid function tests performed postoperatively revealed a TSH level of 7.4 µU/ml and a free T4 level of 1.0 ng/dl. The patient has subsequently received pituitary radiotherapy and octreotide therapy.


View this table:
[in this window]
[in a new window]
  		Table 1. Clinical and laboratory data from patients with TSHoma at the initial presentation

 


View larger version (23K):
[in this window]
[in a new window]
  		Figure 1. TSH response to TRH. The percent increase in TSH was calculated as the TSH level after 500 µg TRH stimulation divided by the baseline TSH level .

 
RT-PCR and sequences of TRß1 and TRß2

Total RNA was extracted from five TSHoma tissues using TRIzol (Life Technologies, Inc., Gaithersburg, MD). RNA was reverse transcribed into cDNA using Moloney murine leukemia virus reverse transcriptase (Stratagene, La Jolla, CA). Primers used for PCR amplification of TRß1 and TRß2 were 5'-ggatccagaatgattactaacctatgactc-3'(TR ß1 sense), 5'-accagggaaacaaaatgaactactgtatgc-3'(TRß2 sense), and 5'-ggaattataggaaggaatccagtcagtcta-3' (TRß1 and TRß2 common antisense).

PCR amplification of genomic DNA

Genomic DNA was isolated from patient 1’s TSHoma and peripheral leukocytes. Primers used for PCR amplification of exon 10 of TRß1 (corresponding to exon 7 of TRß2) were 5'-tccatctctgaatcaatgtccatc-3' (sense) and 5'-gagctaggcaatggaatgaaatgac-3' (antisense). PCR products were subcloned using a TA cloning kit (Invitrogen, Carlsbad, CA) and sequenced.

Construction of TR cDNA expression vectors

The full-length wild-type TRß2 cDNA was cloned into pcDNA. The mutation identified in patient 1’s TSHoma was introduced into TRß2 pcDNA, using a PCR-based site-directed mutagenesis and restriction fragment replacement strategy.

Cell culture, transfection, and functional assays

TSA 201 cells were grown in Opti-MEM (Life Technologies, Inc.) supplemented with 4% FCS pretreated with AG1-X8 resin (Bio-Rad Laboratories, Inc., Richmond, CA) to remove endogenous thyroid hormones. The cells were plated in six-well dishes and transfected 24 h later by the calcium phosphate precipitation method with 250 ng TR expression vector and 500 ng human glycoprotein hormone {alpha}-subunit promoter (-846 to +44) linked to pA3 luciferase reporter gene (10). Additionally, TSA201 cells were transfected with 400 ng TR expression vector and 200 ng human TSHß promoter (-1192 to +37) gene (11) linked to pA3 luciferase reporter gene and 200 ng human thyrotroph embryonic factor expression vector (12) with Lipofectamine Plus (Life Technologies, Inc.). Eight hours after transfection, the cells were incubated for 40 h with Opti-MEM medium containing 1% resin-treated FCS with and without 50 nM T3. The cells were lysed and assayed for luciferase activity. Luciferase activity was normalized according to protein concentration.

T3 binding assay

The T3 binding affinities of wild-type TRß2 and TRßH450Y protein were measured in transfected CV-1 cells as described previously (13).

Results

Mutational analysis of TRß1 and TRß2

Total RNA from five TSHomas was prepared and subjected to RT-PCR amplification of full-length TRß1 and TRß2. Sequence analysis of the PCR fragments from patient 1’s cDNA revealed a single C to T transition in all 31 TRß1 clones and 18 of 21 TRß2 clones (86%) at cDNA nucleotide 1588 (GenBank accession no. X04707) and converted the codon for histidine (CAT) to tyrosine (TAT; Fig. 2Go). This resulted in a point mutation in the ligand-binding domains of TRß1 at codon 435 and TRß2 at codon 450. We did not find any mutation in TRß1 or TRß2 in the other four TSHomas. Genomic DNA from the TSHoma and peripheral leukocytes of patient 1 was extracted, and TRß1 exon 10 (TRß2 exon 7) was amplified by PCR. The sequence of the genomic DNA of TSHoma showed both mutations in 7 of 12 clones (58%) and normal sequence in 5 of 12 clones (42%) at nucleotide 1588. In contrast, genomic DNA of peripheral leukocytes only showed the normal TRß gene sequence. These findings demonstrate that patient 1’s TSHoma contained a somatic mutation in 1 of the TRß alleles. Interestingly, mutations at the same position were found in patients with GRTH (TRß1H435L) and PRTH (TRß1H435Q; Fig. 2Go) (14).



View larger version (25K):
[in this window]
[in a new window]
  		Figure 2. Identification of a somatic mutation of the TRß gene in a TSHoma of patient 1. A, Sequencing of the TRß gene in a TSHoma of patient 1 revealed a C to T transition at the 1588 TRß gene resulting in a His to Tyr substitution. B, The structures of TRß1 and TRß2 and the locations of TRß1H435Y and corresponding mutant TRß2H450Y are indicated. The mutations at the same amino acid for GRTH and PRTH are shown.

 
Functional characterization of the mutant TRß

We introduced the mutation found in patient 1 into a TRß2 expression vector by PCR-based site-directed mutagenesis. The encoded protein, TRß2H450Y, did not show any detectable T3 binding (data not shown), as expected since TRßH435L and H435Q previously were not reported to have significant T3 binding (15). To investigate the transcriptional activity of TRß2H450Y on glycoprotein hormone {alpha}-subunit and TSHß gene regulation, expression vectors of wild-type TRß2 and TRß2H450Y were transiently transfected into TSA201 cells. Wild-type TRß2 showed T3-dependent negative regulation of glycoprotein hormone {alpha}-subunit and TSHß genes, whereas TRß2H450Y was unable to do so (Fig. 3Go). Cotransfection of TRß2H450Y with the wild-type TRß2 blocked T3-dependent negative regulation of both glycoprotein hormone {alpha}-subunit and TSHß genes by wild-type TRß2 (Fig. 4Go). These results demonstrate that TRß2H450Y exerted dominant negative activity on wild-type receptor regulation of these target genes.



View larger version (23K):
[in this window]
[in a new window]
  		Figure 3. Transcriptional activity of TRß2 and TRß2H450Y on genes encoding TSH subunits. Equal amounts pcDNA expression vectors for TRß2 and TRß2H450Y were cotransfected with glycoprotein {alpha}-subunit or TSHß luciferase reporter vectors into TSA 201 cells as described in Subjects and Methods. The cells were incubated with 50 nM T3 for 40 h and harvested, and luciferase activity was measured. Data are the mean ± SD from nine individual samples. The asterisk indicates a significant difference between TRß2H450Y-dependent and TRß2-dependent luciferase activity in the presence of T3 (P < 0.01) determined by unpaired t tests. A, Glycoprotein hormone {alpha}-subunit luciferase activity; B, TSHß luciferase activity.

 


View larger version (42K):
[in this window]
[in a new window]
  		Figure 4. Dominant negative activity of TRß2H450Y on TRß2 regulation of genes encoding TSH subunits. TSA 201 cells were transfected with equal amounts of TRß2 and TRß2spl with glycoprotein hormone {alpha}-subunit or TSHß luciferase vector. The cells were incubated with 50 nM T3 and harvested, and luciferase activity was measured. The fold T3 inhibition is calculated as luciferase activity in the absence of T3 divided by luciferase activity in the presence of T3. Data are the mean ± SD from nine individual samples. The asterisk indicates the difference in fold T3 inhibition of TRß2 together with TRß2H450Y compared with fold T3 inhibition of TRß2 alone (P < 0.01) determined by ANOVA. A, Glycoprotein hormone {alpha}-subunit luciferase activity; B, TSHß luciferase activity.

 
Discussion

We have identified and characterized a novel TRß mutant in a TSHoma caused by somatic mutation. Although TRß mutations have been described in patients with RTH, a somatic mutation of TRß has not been previously identified in TSHomas. The TRß mutant had undetectable T3 binding and impaired negative regulation of glycoprotein hormone {alpha}-subunit and TSHß genes. It also exerted dominant negative activity against wild-type TRß2. These characteristics are almost identical with those described for TRß mutations at the same codon in RTH patients (TRßH435R, H435Q). These results strongly suggest that the defect in the negative regulation of TSH in the TSHoma of patient 1 was due to somatic mutation of the TRß gene. Similar to our identification of a somatic TR mutation in a TSHoma, a somatic mutation of the GR was reported in a pituitary adenoma of a patient with Nelson’s syndrome (16).

A high mutant to normal TRß mRNA ratio in the TSHoma may be an additional mechanism for the dysregulation of TSH secretion, as Mixson et al. (17) reported the differential expression of mutant and normal TRß alleles in fibroblasts from patients with RTH. One possible mechanism for differential expression could be suppression of the normal TRß gene allele in the TSHoma due to DNA methylation of the promoter, as hypermethylation of tumor-suppressor gene promoters has been shown to be a mechanism for tumor-suppressor inactivation in tumors (18). In this connection, it is interesting to note that we detected only mutant TRß1 and mostly mutant TRß2 cDNA clones from our RT-PCR reactions of the TSHoma RNA.

Recently, we found a variant form of TRß2 due to aberrant alternative splicing (TRß2spl) from a TSHoma (19). Gittoes et al. (20) reported low expression levels of TRß and TR{alpha} mRNA in two TSHomas; thus, reduced expression of TR in TSHomas may be another mechanism for the defect of negative regulation of TSH. Additionally, mutations or altered expression of coactivators or corepressors also could contribute to the pituitary resistance to thyroid hormone exhibited by TSHomas (21). Thus, multiple steps along the TR signaling pathway could contribute to the defective negative regulation of TSH in TSHomas.

Some features of patient 1’s clinical data, such as her delayed TSH response to TRH stimulation and normal glycoprotein hormone {alpha}-subunit/TSH ratio (22), are more similar to those of patients with RTH rather than those with TSHomas. Patients with TSHomas typically have minimal or no TSH response to TRH stimulation and have elevated glycoprotein hormone {alpha}-subunit/TSH ratios. In this connection, the patient with the splice variant form of TRß in the TSHoma (19) had a partial response to TRH stimulation as TSH rose from a baseline of 10.3 to 16.7 µU/ml 30 min after TRH stimulation. In contrast to patient 1, this patient’s glycoprotein hormone {alpha}-subunit/TSH ratio was high. The four other TSHomas studied did not have any mutations in TRß1 and TRß2. These patients had no response to TRH and high glycoprotein hormone {alpha}-subunit/TSH ratios, which are characteristic of patients with TSHomas. Although we studied only a small number of patients, it appears that the two patients with TSHomas who had abnormal TRßs had TRH stimulation tests similar to those of RTH patients, whereas those patients who did not have detectable TRß mutations had no TSH response to TRH. These findings suggest that the TRH stimulation test may potentially distinguish between two subsets of TSHomas with different mechanisms for pituitary resistance to thyroid hormone: those that involve TRs and those that may involve other pathways. It is possible that TRH signaling be involved in the second pathway; however, it should be noted that a previous study did not detect TRH receptor or Gs{alpha} mutations in TSHomas, so the defect may occur downstream of these initial signaling steps (23).

The differential diagnosis between TSHoma and PRTH can be difficult based on clinical grounds alone (24, 25). Pituitary magnetic resonance imaging and measurement of glycoprotein {alpha}-subunit (which are often elevated in TSHomas) are important in establishing the correct diagnosis (9). If there still remains an issue, particularly in cases where there may be residual tumor tissue, genomic analysis of TRß in peripheral leukocytes may be helpful. In this connection, there is a report of Cushing’s disease in a patient who had generalized glucocorticoid resistance due to a germline mutation of the GR (26). There also is a case report of a patient with a TSH-secreting microadenoma and PRTH, even though both are rare conditions (27). Unfortunately, no genetic analysis was performed, and the patient was presumed to have PRTH, as she maintained central hyperthyroidism even after removal of the microadenoma. These cases notwithstanding, it should be pointed out that among the more than 600 patients with RTH who have demonstrated mutations in the TRß gene, none of them has developed TSHomas (28, 29, 30). This would argue that mutations in the genes other than the TRß gene may contribute to the development and growth of TSHomas.

In conclusion, we have identified the first somatic mutation of the TRß gene from a TSHoma. This mutation was located in the same codon as mutant TRßs from patients with RTH. It exhibited impaired transcriptional activity and strong dominant negative activity on the transcriptional regulation of glycoprotein hormone {alpha}-subunit and TSHß reporter genes by wild-type TR. Thus, it is likely that the TRß mutation is one mechanism for the defective negative regulation of TSH by T3 observed in TSHomas.

Acknowledgments

We thank Dr. Frederic Wondisford (Beth Israel Hospital, Boston, MA) for human TRß2 expression and TSHß reporter vectors, as well as Dr. Laird Madison, Dr. Larry Jameson, and Mr. Kevin Long (Northwestern University, Chicago, IL) for glycoprotein hormone {alpha}-subunit reporter vector and TSA 201 cells. We also thank Dr. Merrill Marsh (NINDS, Bethesda, MD) for storing and maintaining the TSHoma samples.

Footnotes

Abbreviations: GRTH, Generalized resistance to thyroid hormone; PRTH, pituitary resistance to thyroid hormone; RTH, resistance to thyroid hormone; TSHoma, TSH-secreting tumor.

Received March 28, 2001.

Accepted July 23, 2001.

References

  1. Lazar MA 1993 Thyroid hormone receptors: multiple forms, multiple possibilities. Endocr Rev 14:348–399[CrossRef][Medline]
  2. Wood WM, Dowding JM, Haugen BR, Bright TM, Gordon DF, Ridgway EC 1994 Structural and functional characterization of the genomic locus encoding the murine ß2 thyroid hormone receptor. Mol Endocrinol 8:1605–1617[Abstract]
  3. Abel ED, Boers ME, Pazos-Moura C, et al. 1999 Divergent roles for thyroid hormone receptor ß isoforms in the endocrine axis and auditory system. J Clin Invest 104:291–300[Medline]
  4. Refetoff S, Weiss RA, Usala SJ 1993 The syndromes of resistance to thyroid hormone. Endocr Rev 14:348–399
  5. Sasaki S, Nakamura H, Tagami T, et al. 1993 Pituitary resistance to thyroid hormone associated with a base mutation in the hormone-binding domain of the human 3,5,3'-triiodothyronine receptor-ß. J Clin Endocrinol Metab 76:1254–1258[Abstract]
  6. Mixson AJ, Renault JC, Ransom S, Bodenner DL, Weintraub BD 1993 Identification of a novel mutation in the gene encoding the ß-triiodothyronine receptor in a patient with apparent selective pituitary resistance to thyroid hormone. Clin Endocrinol (Oxf) 38:227–234[Medline]
  7. Tagami T, Jameson JL 1998 Nuclear corepressors enhance the dominant negative activity of mutant receptors that cause resistance to thyroid hormone. Endocrinology 139:640–650[Abstract/Free Full Text]
  8. Langlois MF, Zanger K, Monden T, Safer JD, Hollenberg AN, Wondisford FE 1997 A unique role of the ß-2 thyroid hormone receptor isoform in negative regulation by thyroid hormone. Mapping of a novel amino-terminal domain important for ligand-independent activation. J Biol Chem 272:24927–24933[Abstract/Free Full Text]
  9. Brucker-Davis F, Oldfield EH, Skarulis MC, Doppman JL, Weintraub BD 1999 Thyrotropin-secreting pituitary tumors: diagnostic criteria, thyroid hormone sensitivity, and treatment outcome in 25 patients followed at the National Institutes of Health. J Clin Endocrinol Metab 84:476–486[Abstract/Free Full Text]
  10. Tagami T, Madison LD, Nagaya T, Jameson JL 1997 Nuclear receptor corepressors activate rather than suppress basal transcription of genes that are negatively regulated by thyroid hormone. Mol Cell Biol 17:2642–2648[Abstract]
  11. Bodenner DL, Mroczynski MA, Weintraub BD, Radovick S, Wondisford FE 1991 A detailed functional and structural analysis of a major thyroid hormone inhibitory element in the human thyrotropin ß-subunit gene. J Biol Chem 266:21666–21673[Abstract/Free Full Text]
  12. Drolet DW, Scully KM, Simmons DM, et al. 1991 TEF, a transcription factor expressed specifically in the anterior pituitary during embryogenesis, defines a new class of leucine zipper proteins. Genes Dev 5:1739–1753[Abstract/Free Full Text]
  13. Ando S, Nakamura H, Sasaki S, et al. 1996 Introducing a point mutation identified in a patient with pituitary resistance to thyroid hormone (Arg338 to Trp) into other mutant thyroid hormone receptors weakens their dominant negative activities. J Endocrinol 151:293–300[Abstract]
  14. Tsukaguchi H, Yoshimasa Y, Fujimoto K, et al. 1995 Three novel mutations of thyroid hormone receptor ß gene in unrelated patients with resistance to thyroid hormone: two mutations of the same codon (H435L and H435Q) produce separate subtypes of resistance. J Clin Endocrinol Metab 80:3613–3616[Abstract]
  15. Nomura Y, Nagaya T, Tsukaguchi H, Takamatsu J, Seo H 1996 Amino acid substitutions of thyroid hormone receptor-ß at codon 435 with resistance to thyroid hormone selectively alter homodimer formation. Endocrinology 137:4082–4086[Abstract]
  16. Karl M, Von Wichert G, Kempter E, et al. 1996 Nelson’s syndrome associated with a somatic frame shift mutation in the glucocorticoid receptor gene. J Clin Endocrinol Metab 81:124–129[Abstract]
  17. Mixson AJ, Hauser P, Tennyson G, Renault JC, Bodenner DL, Weintraub BD 1993 Differential expression of mutant and normal ßT3 receptor alleles in kindreds with generalized resistance to thyroid hormone. J Clin Invest 91:2296–2300
  18. Jones PA, Laird PW 1999 Cancer epigenetics comes of age. Nat Genet 21:163–167[CrossRef][Medline]
  19. Ando S, Sarlis NJ, Krishnan J, Feng X, Refetoff S, Zhang MQ, Oldfield EH, Yen PM 2001 Aberrant alternative splicing of thyroid hormone receptor in a TSH-secreting pituitary tumor is a mechanism for hormone resistance. Mol Endocrinol 15:1529–1538.[Abstract/Free Full Text]
  20. Gittoes NJ, McCabe CJ, Verhaeg J, Sheppard MC, Franklyn JA 1998 An abnormality of thyroid hormone receptor expression may explain abnormal thyrotropin production in thyrotropin-secreting pituitary tumors. Thyroid 8:9–14[Medline]
  21. Weiss RE, Xu J, Ning G, Pohlenz J, O’Malley BW, Refetoff S 1999 Mice deficient in the steroid receptor co-activator 1 (SRC-1) are resistant to thyroid hormone. EMBO J 18:1900–1904[CrossRef][Medline]
  22. Beck-Peccoz P, Persani L, Faglia G 1992 Glycoprotein hormone alpha-subunit in pituitary adenomas. Trends Endocrinol Metab 3:41–45
  23. Dong Q, Brucker-Davis F, Weintraub BD, et al. 1996 Screening of candidate oncogenes in human thyrotroph tumors: absence of activating mutations of the G{alpha}q, G{alpha}11, G{alpha}s, or thyrotropin-releasing hormone receptor genes. J Clin Endocrinol Metab 81:1134–1140[Abstract]
  24. Akiyoshi F, Okamura K, Fujikawa M, et al. 1996 Difficulty in differentiating thyrotropin secreting pituitary microadenoma from pituitary-selective thyroid hormone resistance accompanied by pituitary incidentaloma. Thyroid 6:619–625[Medline]
  25. Safer JD, Colan SD, Fraser LM, Wondisford FE 2001 A pituitary tumor in a patient with thyroid hormone resistance: a diagnostic dilemma. Thyroid 11:281–291[CrossRef][Medline]
  26. Karl M, Lamberts SW, Koper JW, et al. 1996 Cushing’s disease preceded by generalized glucocorticoid resistance: clinical consequences of a novel, dominant-negative glucocorticoid receptor mutation. Proc Assoc Am Physicians 108:296–307[Medline]
  27. Watanabe K, Kameya T, Yamauchi A, et al. 1993 Thyrotropin-producing microadenoma associated with pituitary resistance to thyroid hormone. J Clin Endocrinol Metab 76:1025–1030[Abstract]
  28. Weiss RE, Refetoff S 2000 Resistance to thyroid hormone. Rev Endocr Metab Disord 1:97–108[CrossRef][Medline]
  29. Adams M, Matthews C, Collingwood TN, Tone Y, Beck-Peccoz P, Chatterjee KK 1994 Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone. Identification of thirteen novel mutations in the thyroid hormone receptor ß gene. J Clin Invest 94:506–515
  30. Brucker-Davis F, Skarulis MC, Grace MB, et al. 1995 Genetic and clinical features of 42 kindreds with resistance to thyroid hormone. The National Institutes of Health Prospective Study. Ann Intern Med.123:572–583



This article has been cited by other articles:


Home page
 J. Clin. Endocrinol. Metab.Home page
S. Mamanasiri, S. Yesil, A. M. Dumitrescu, X.-H. Liao, T. Demir, R. E. Weiss, and S. Refetoff
Mosaicism of a Thyroid Hormone Receptor-{beta} Gene Mutation in Resistance to Thyroid Hormone
J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3471 - 3477.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
H. Furumoto, H. Ying, G. V. R. Chandramouli, L. Zhao, R. L. Walker, P. S. Meltzer, M. C. Willingham, and S.-Y. Cheng
An Unliganded Thyroid Hormone {beta} Receptor Activates the Cyclin D1/Cyclin-Dependent Kinase/Retinoblastoma/E2F Pathway and Induces Pituitary Tumorigenesis
Mol. Cell. Biol., January 1, 2005; 25(1): 124 - 135.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
Y. Kato, H. Ying, M. C. Willingham, and S.-Y. Cheng
A Tumor Suppressor Role for Thyroid Hormone {beta} Receptor in a Mouse Model of Thyroid Carcinogenesis
Endocrinology, October 1, 2004; 145(10): 4430 - 4438.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Biol. CellHome page
P. Maruvada, N. I. Dmitrieva, J. East-Palmer, and P. M. Yen
Cell Cycle-dependent Expression of Thyroid Hormone Receptor-{beta} Is a Mechanism for Variable Hormone Sensitivity
Mol. Biol. Cell, April 1, 2004; 15(4): 1895 - 1903.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
A. Lania, G. Mantovani, and A. Spada
Genetics of Pituitary Tumors: Focus on G-Protein Mutations
Experimental Biology and Medicine, October 1, 2003; 228(9): 1004 - 1017.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ando, S.
Right arrow Articles by Yen, P. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ando, S.
Right arrow Articles by Yen, P. M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals