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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 2 649-653
Copyright © 1999 by The Endocrine Society

Original Studies

Thyroid Receptor {alpha}1 and {alpha}2 Mutations in Nonfunctioning Pituitary Tumors1

Chris J. McCabe, Neil J. Gittoes, Michael C. Sheppard and Jayne A. Franklyn

Department of Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH, United Kingdom

Address all correspondence and requests for reprints to: J.A. Franklyn, Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH, United Kingdom. E-mail: franklja{at}bham.ac.uk


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We previously reported that nonfunctioning tumors of the anterior pituitary exhibit reduced expression of thyroid receptor (TR) {alpha} and ß isoforms, an observation that may account for abnormalities of T3-mediated negative regulation of the glycoprotein hormone common {alpha}-subunit. Reduced TR protein was associated with a parallel reduction in TRß messenger RNA (mRNA), although TR{alpha}1 and {alpha}2 mRNA levels were similar in nonfunctioning tumors and normal pituitaries. Because TR{alpha} shows aberrant posttranscriptional processing, and TRß is under ligand-dependent autoregulation, we hypothesized that aberrant TR expression in nonfunctioning tumors may reflect mutation in receptor coding and regulatory sequences, and therefore screened TR{alpha} mRNA and TRß T3 response elements and ligand binding domains for sequence anomalies. Screening TR{alpha} mRNA in 23 tumors and subsequently sequencing candidate fragments identified one silent change from published sequences and three novel missense mutations, two in the common TR{alpha} region (ser45ile and lys370asn) and one that was {alpha}2 specific (ser377leu). TRß response elements failed to show any differences from published sequences in 14 nonfunctioning tumors. Sequencing of TRß ligand binding domains were also identical to wild type in 23 nonfunctioning tumors. The functional significance of the novel TR{alpha} mutations is unknown; definition of mutant TR action may provide insight into the role of TRs in the growth control of pituitary cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
CLINICALLY nonfunctioning tumors account for approximately 25% of all anterior pituitary neoplasms. Although termed nonfunctioning, such tumors are often characterized by elevated expression of the glycoprotein hormone {alpha}-subunit. Immunocytochemical staining demonstrates the presence of intact gonadotropins and/or subunits of these glycoprotein hormones in up to 79% of nonfunctioning tumors (1, 2, 3, 4, 5, 6, 7), whereas {alpha}-subunit expression is reported in between 40 and 70% (7, 8). In approximately 25% of cases, elevated circulating levels of {alpha}-subunit protein have been demonstrated (5, 7, 8, 9), and similarly, an increase in tumor messenger RNA (mRNA) expression has been described (1). Such increased {alpha}-subunit expression is observed despite normal or even elevated circulating concentrations of thyroid hormone (T3) and gonadal steroids (10), which normally act via a negative feedback mechanism to inhibit {alpha}-subunit production, suggesting abnormal thyroid receptor (TR) and/or steroid receptor function in these tumors. We have reported recently that nonfunctioning tumors demonstrate reduced expression of TR{alpha} and ß isoforms when compared with normal pituitaries (11). Despite a reduction in TR{alpha}1 and {alpha}2 protein as determined by tumor immunocytochemistry, we found that TR{alpha} mRNAs were present at normal levels, suggesting abnormality in posttranscriptional processing of these mRNAs. In contrast, we reported a reduction in both TRß protein and mRNAs in nonfunctioning tumors, findings consistent with a change in TRß gene transcription. In the present studies we examined the hypothesis that abnormalities of TR{alpha} and ß expression in nonfunctioning pituitary tumors reflect sequence abnormalities of the TR genes. To investigate a possible mechanism leading to aberrant TR{alpha} mRNA processing, we examined the frequency of mutations of TR{alpha} coding sequences in a series of nonfunctioning tumors. In view of our findings for TRß gene expression, and because TRß gene transcription may be autoregulated in a ligand- dependent manner (12), we also examined both promoter and ligand binding domains of the TRß gene for sequence abnormalities.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tissues

Clinically nonfunctioning pituitary macroadenomas were excised trans-sphenoidally from 23 patients (11 male, 12 female; age at the time of presentation 57 ± 2.2 yr (mean ± SE). Twelve normal human pituitary glands were obtained from postmortem proceedings (carried out within 12 to 24 h after death). All samples were stored at -80 C. Whole blood was also obtained from three subjects treated surgically for pituitary macroadenomas and found to have receptor mutations (see below).

RNA and DNA extraction

Total RNA was isolated from pituitary tissue using a single-step acid guanidinium phenol-chloroform extraction technique (13). Briefly, pituitary tissue was homogenized in the presence of RNAzol B (Biotech Laboratories, Houston, TX). Total RNA was extracted after centrifugation with 0.1 vol chloroform. The aqueous phase was mixed with an equal volume of isopropanol, and RNA was allowed to precipitate at -20 C overnight, before centrifugation and washing. DNA was extracted from pituitary tissue and blood leukocytes, using the DNace Clini Pure kit (Bioline, London, UK). Pituitary tissue was minced into approximately 10- to 20-mg pieces before following the manufacturer’s instructions and storing the resulting DNA at 4 C.

Reverse transcriptase PCR

RT was performed using avian myeloblastosis virus (AMV) reverse transcriptase (Promega Corp., Madison, WI) in a total reaction volume of 50 µL, with 2 µg pituitary total RNA, 60 pmol oligo(dT)15, 10 µL 5x AMV reverse transcriptase buffer (Promega Corp.), 5 µL deoxynucleotide triphosphate mix (200 µM each) (Boehringer Mannheim, Germany), 50 units of ribonuclease inhibitor (RNasin, Promega Corp.) and 15 units of AMV reverse trancriptase (Promega Corp.). Hot start PCR was carried out in 50 µL volumes using 1 µL of the resulting RT product, 30 pmol of each primer, 1 µL of deoxynucleotide triphosphate mix (200 µM each) (Boehringer Mannheim, Germany), 5 µL 10x PCR reaction buffer and 2 U Taq DNA polymerase (Boehringer Mannheim). Amplification of the GC-rich region encompassing the TRß1 promoter direct repeat (DR4) was carried out as above, but PCR reactions were supplemented with 5% dimethylsulfoxide and 5% glycerol. Amplification of the TRß1 ligand binding domain was achieved by nested PCR, with outer primers 4570 and 4571 and inner primers 607 and 608 (see Table 1Go for primer sequences). Oligonucleotide design was carried out using DNAStar software (Madison, WI).


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  		Table 1. Oligonucleotide sequences used for screening and sequencing TR{alpha} and ß cDNA

 
Screening

TR{alpha}1 and {alpha}2 mRNA from 23 nonfunctioning tumors and 12 normal pituitaries was screened for mutation using the RNase Mismatch Technique of Ambion, Inc. (Austin, Texas) (14). Specific primers were designed to enable the amplification of discrete TR{alpha}1 and {alpha}2 products of approximately 1 kilobase. Essentially, screening was accomplished following the methodology of the Ambion, Inc. RNase mismatch kit with minor modifications of the heterozygote short-cut protocol. Briefly, TR{alpha}1 and {alpha}2 complementary DNA (cDNA) was amplified with primers tagged with T7 promoter sequences, allowing subsequent PCR products to be transcribed in vitro. Reannealing of resulting single-stranded RNA from mutant and wild- type alleles resulted in inappropriate hybridization at any points of anomaly, which could then be recognized by RNase enzyme cutting at sites of mismatch. This allowed PCR fragments differing from wild-type sequences to be identified by agarose gel electrophoresis. TRß1 promoter and ligand binding domains were not subject to mismatch screening, but were instead sequenced directly.

Sequencing

TR{alpha}1 and {alpha}2 PCR fragments identified by RNase Mismatch screening as potentially different from wild type were analyzed on an ABI 377 automated sequencer, together with directly amplified TRß1 products. PCR products were purified for sequencing after excision from TAE agarose gels and elution using QIAQuick gel purification kits (Quiagen, Hilden, Germany). Fragment concentration was gauged in relation to a DNA mass ladder (Pharmacia, Uppsala, Sweden). Fifty to 100 ng of the resulting pure fragment was subsequently used per sequencing reaction, with 4 µL AmpliTaq (Perkin Elmer, Foster City, CA) and 3.2 pmol forward or reverse primer. Overlapping PCR fragments were sequenced in both directions using internal primers to yield products of 3–400 bp. Electropherograms were analyzed using DNASTAR software. PCR fragments from tumors containing potential mutations were further analyzed using restriction enzymes whose recognition sequences were either abolished or created by the nucleotide change in question.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
TR{alpha} sequences

Initial RNase Mismatch screens (Fig. 1Go) of overlapping fragments of TR{alpha}1 and {alpha}2 cDNA identified three fragments with potential TR{alpha}1 mRNA mutations and seven for {alpha}2. The three TR{alpha}1 candidate fragments were all identified as candidates for {alpha}2 mutations, suggesting common region TR{alpha} gene mutations. Subsequent sequencing of TR{alpha}1 and {alpha}2 coding region cDNA in the seven tumors identified by the screen process indicated that five of the potential mutations represented false positives from the screening technique (all of which were {alpha}2 specific), and one represented a silent common region difference from the published sequence (A to G at nucleotide position 168). Sequencing of the three remaining fragments revealed three heterozygous mutations (Fig. 1Go), two lying in the common TR{alpha} gene region, and one lying in the {alpha}2-specific region. The first mutation was a G to T missense exchange at nucleotide 190, resulting in a ser to ile substitution in amino acid 45, which lies in the shared A/B domain of the common TR{alpha} region, and which would therefore result in transcription of aberrant TR{alpha}1 and {alpha}2 mRNAs (Fig. 2Go). A second heterozygous missense mutation was confirmed at nucleotide position 1168, a G to C change resulting in a lys370asn amino acid substitution in the common {alpha} region. Third, a C to T substitution was noted at nucleotide position 1187, resulting in a ser to leu change in the {alpha}2-specific amino acid 377.



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  		Figure 1. RNase Mismatch (A), automated sequencing (B), and restriction digest (C) analysis of TR{alpha}1 and {alpha}2 cDNA sequences in nonfunctioning tumors. A, Five TR{alpha}1 PCR fragments of approximately 1 kilobase were screened (see Materials and Methods). The additional band in lane 1 determined that this fragment was treated as a candidate mutation and subsequently sequenced. B, Three heterozygous substitutions denoted by arrows, identified by forward and reverse sequencing. C, A restriction digest of mutation C1187T with TaqI. The additional band in lane 2 is indicative of the heterozygous loss of a TaqI cut site resulting from a C to T base change.

 


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  		Figure 2. Domain locations of ser45ile, lys370asn, and ser377leu mutations in TR{alpha}1 and {alpha}2 coding sequences.

 
The presence of all three mutations was investigated in leukocyte DNA from the respective patients and were found to be absent, indicating that the coding changes described represent bona fide mutations and not polymorphic deviations from published sequences. The C-terminal mutations lys370asn and ser377leu were associated with relatively aggressive tumors in vivo, with both patients diagnosed approximately 20 yr earlier than the mean age at diagnosis for the whole group of 23 subjects, and both tumors subsequently recurring after initial surgery (5 subjects from the group in total displayed tumor recurrence; mean age of patients showing two recurrences was 47.8 ± 5.7 yr (mean ± SE, n = 5)). The N-terminal substitution ser45ile, in contrast, was associated with a later than mean age at tumor diagnosis and no recurrence. Immunohistochemical investigation of TR{alpha}1, {alpha}2, and ß1 expression in the above patients revealed no detectable TR protein. Indeed, as we previously reported (11), only 3 of the 23 nonfunctioning tumors assessed revealed detectable TR protein of either isoform.

Three previously published TR{alpha} mutations described in hepatocellular carcinoma cell lines (15) were also investigated and found to be absent in all 23 nonfunctioning tumors studied. No coding changes were apparent either in the cDNA of any of the 12 normal pituitaries screened in this investigation.

TR ß1 sequences

Two thyroid response elements (TREs) [a palindromic (PAL) TRE at -890 to -866 and a direct repeat (DR4) at -186 to -170] in the upstream regulatory region of TRß1, implicated in autoregulation of the ß1 isoform, were also investigation for the presence of mutations in 14 nonfunctioning tumors and 2 normal pituitaries. No changes from published sequences were noted in either TRE in the tumors studied. To assess whether ligand binding domain mutations might affect the ligand-dependent autoregulation of TRß1 transcription, and hence explain the reduction in TRß mRNAs present in nonfunctioning tumors, the region encompassing nucleotides 1150 to 1698 of the TRß1 gene was also sequenced in 23 tumors and 2 normal pituitary glands. All tumors demonstrated wild-type ligand binding domains.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Although the pathogenesis of nonfunctioning tumors remains unclear, the majority of pituitary tumors are believed to derive from a monoclonal expansion of cells originating from a somatic genome alteration in the parent cell (16). Mutations in genes such as the gsp oncogene have previously been implicated in the pathogenesis of GH-secreting adenomas (17, 18, 19, 20, 21), and loss of heterozygosity on chromosome 11 has been demonstrated in 20% of nonfunctioning pituitary tumors (22). What is largely unexplored is the role of endocrine control of pituitary cells in contributing to pituitary tumor growth. Although mutations such as those described above may be directly involved in the pathogenesis of nonfunctioning tumors, a change in hormonal regulation of pituitary gene expression may well contribute to uncontrolled tumor cell proliferation.

Nonfunctioning tumors are a subset of pituitary tumors that may demonstrate aberrant negative regulation of the common {alpha}-subunit. We have previously shown that such tumors have reduced TR{alpha} and ß isoform expression (11). The low level of TR{alpha} protein in nonfunctioning tumors occurs in association with unaltered levels of TR{alpha} mRNA, whereas levels of TRß mRNA are reduced compared with those found in normal pituitaries. We therefore examined the hypothesis that this aberrant expression of TR{alpha} and ß in nonfunctioning tumors reflects a mutation in receptor coding and regulatory sequences.

In the present study, we identified three changes from wild-type coding sequences in TR{alpha} mRNA in a series of 23 nonfunctioning tumors investigated. The prevalence of these abnormalities indicates that TR{alpha} gene mutations do not provide a general explanation for the demonstrated reduction in TR{alpha} gene expression in human nonfunctioning tumors, but the described mutations may nonetheless provide insight into abnormal thyroid hormone-dependent regulation in specific tumors.

The functional significance of the described ser45ile mutation that occurs in the relatively poorly characterized common A/B domain is unclear. The A/B domain is believed to have transactivating properties, and recently, a 10-amino acid region of TR{alpha}1 was characterized that interacts with transcription factor IIB in chicken (23) and rat (24) models. A similar region exists in the A/B domain of human TR{alpha}1, with the described ser45ile mutation lying 12 amino acids downstream of this putative region. Any functional significance of this mutation is likely to stem from its ability to influence transactivation at this site. Mutations in the common region of TR{alpha} will affect both TR{alpha}1 and {alpha}2 variants, and may therefore have a significant impact on normal receptor function in the pituitary, especially if such TRs act in a dominant negative manner to interfere with normal receptor function through altered interactions with corepressors at the TRE, in a similar manner to heterozygous TRß1 mutations in syndromes of resistance to thyroid hormone (25). This is particularly relevant to the C-terminal lys370asn mutation, which substitutes an amino acid in the TR{alpha} ligand binding domain. For T3-mediated inhibition of transcription, unliganded TRs bind coactivators at the negative TRE, which dissociate in the presence of thyroid hormone, allowing corepressor association. An altered ability to bind thyroid hormone is likely therefore to affect the efficiency with which coactivators can dissociate from TR{alpha}1 in the presence of T3, in turn disrupting transcriptional inhibition of negatively regulated genes such as the glycoprotein hormone {alpha}-subunit. Indeed, three previously reported TR{alpha}1 mutations present in hepatocarcinoma cell lines (glu350lys, val390ala and pro398ser), which are in proximity to the lys370asn mutation reported here, abolish T3 binding affinity (15). The C-terminal TR{alpha}2-specific mutation ser377leu is unlikely to affect any T3-dependent functions of {alpha}2 receptors, given that this isoform is unable to bind ligand, but may alter its ability to interact with other nuclear receptors and transcription factors, and as such, interfere with wild-type receptor function. Because the three coding changes reported here were not found in leukocyte DNA from the respective patients, it is unlikely that they are merely polymorphic changes in sequence. In terms of the clinical associations, the C-terminal mutations lys370asn and ser377leu were associated with relatively early onset (age 36 and 38 yr, respectively) and tumor recurrence. The N-terminal substitution ser45ile was not, however, associated with either early onset or further recurrence, leading us to speculate that the C terminus of TR{alpha} isoforms may have functional roles in the control of tumor cell growth.

Direct sequencing of the two TREs upstream of the ß1 transcriptional start site failed to reveal any changes from published sequences (12, 26), indicating that the abnormally low levels of TRß mRNA observed in nonfunctioning tumors does not reflect sequence abnormalities in these regions of the TRß promoter. The defective negative feedback regulation apparent in nonfunctioning tumors is unlikely to be associated with an altered ability of TRß receptors to bind ligand, because none of the TRß ligand binding domains sequenced demonstrated any deviation from wild-type sequences. Therefore it would appear that TRß is down-regulated at the level of transcription in nonfunctioning tumors by trans-acting factor or factors unknown, and not by T3-dependent autoregulatory changes in TRß expression.

In summary, the novel TR mutations described here may be of functional significance in terms of TR action, and further definition of their functional properties may provide insight into the role of TRs in growth control in pituitary cells.


   Acknowledgments
 
We are grateful to R. Mitchell, R. Walsh, and A. Johnson for providing us with tumor samples at the time of surgery.


   Footnotes
 
1 This work was supported by the award of a Project Grant from the Medical Research Council United Kingdom. Back

Received February 18, 1998.

Revised September 11, 1998.

Accepted October 21, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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