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Endocrinology Vol. 140, No. 12 5901-5906
Copyright © 1999 by The Endocrine Society

ARTICLES

Three Novel Mutations at Serine 314 in the Thyroid Hormone ß Receptor Differentially Impair Ligand Binding in the Syndrome of Resistance to Thyroid Hormone1

M. Gurnell2,3, O. Rajanayagam2, M. Agostini2,4, R. J. D. Clifton-Bligh5, T. Wang, P. M. J. Zelissen, F. van der Horst, A. van de Wiel, E. Macchia, A. Pinchera, J. W. R. Schwabe and V. K. K. Chatterjee

Department of Medicine, University of Cambridge, Addenbrooke’s Hospital (M.G., O.R., M.A., R.J.D.C.-B., V.K.K.C.), Cambridge, United Kingdom CB2 2QQ; the Dipartimento di Endocrinologia e Metabolismo, Università di Pisa (M.A., E.M., A.P.), 56124 Pisa, Italy; the Department of Clinical Biochemistry, Leicester Royal Infirmary (T.W.), Leicester, United Kingdom LE1 5WW; the Department of Endocrinology, University Hospital (P.M.J.Z.), Utrecht, The Netherlands; the Department of Clinical Chemistry, Eemland Hospital (F.v.d.H.), 3800 BM Amersfoort, The Netherlands; and the Medical Research Council Laboratory of Molecular Biology (J.W.R.S.), Cambridge, United Kingdom CB2 2QH; Department of Endocrinology (Ar.d.W), Eemland Hospital, 3800 BM Amersfoort, The Netherlands

Address all correspondence and requests for reprints to: Dr. V. K. K. Chatterjee, Department of Medicine, University of Cambridge, Level 5, Addenbrooke’s Hospital, Hills Road, Cambridge, United Kingdom CB2 2QQ. E-mail:kkc1{at}mole.bio.cam.ac.uk


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The syndrome of resistance to thyroid hormone is associated with diverse mutations in the ligand-binding domain of the thyroid hormone ß receptor, localizing to three clusters around the hormone binding cavity. Here, we report three novel resistance to thyroid hormone mutations (S314C, S314F, and S314Y), due to different nucleotide substitutions in the same codon, occurring in six separate families. Functional characterization of these mutant receptors showed marked differences in their properties. S314F and S314Y receptor mutants exhibited significant transcriptional impairment in keeping with negligible ligand binding and were potent dominant negative inhibitors of wild-type receptor action. In contrast, the S314C mutant bound ligand with reduced affinity, such that its functional impairment and dominant negative activity manifest at low concentrations of thyroid hormone, but are more reversible at higher T3 concentrations. The degree of functional impairment of mutant receptors in vitro may correlate with the magnitude of thyroid dysfunction in vivo. Modelling these mutations using the crystal structure of thyroid hormone receptor ß shows why ligand binding is perturbed and why the phenylalanine/tyrosine mutations are more deleterious than cysteine.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
RECOGNITION that the syndrome of resistance to thyroid hormone (RTH) is linked to the thyroid hormone ß receptor (TRß) gene locus (1) has led to the identification of an increasing number of natural mutations whose functional characterization has provided important insights into structure-function relationships in this receptor. RTH is characterized by elevated serum free thyroid hormones (FT4 and FT3) in the presence of unsuppressed TSH levels, reflecting resistance to the normal negative feedback mechanisms within the hypothalamus and pituitary (2). The degree of resistance within peripheral tissues determines whether thyrotoxic clinical features are associated with the condition (3). An autosomal dominant mode of inheritance, in conjunction with the recognition that receptor mutants are functionally impaired, has led to the proposal that these abnormal proteins are able to inhibit the function of their wild-type (WT) counterparts in a dominant negative manner (4, 5). Such dominant negative inhibition requires the preservation of DNA-binding and heterodimerzation functions in mutant receptors (6, 7, 8), consonant with the observation that no RTH mutants have hitherto been reported in the DNA-binding or dimerization domains of TRß. In fact the majority of natural mutations cluster around the ligand binding pocket (9) and impair hormone binding.

Here we describe three novel single nucleotide substitutions in TRß associated with RTH that result in different missense mutations at residue 314 (S314C, S314F, and S314Y). Examination of the crystal structure of TRß suggests that Ser314 plays a structural role in ligand binding. Functional characterization of the natural mutants allowed us to study how the different amino acid substitutions at this position affected receptor function. Although all the mutations affected ligand binding, there were significant differences in the extent of the alteration with corresponding variation in their transcriptional and dominant negative properties.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Clinical and genetic analyses
Serum FT4 and FT3 levels were measured with a Delfia fluoroimmunometric assay (Wallac, Inc., Milton Keynes, UK). TSH levels were determined with a sensitive second generation assay (Delfia, Wallac, Inc.). The coefficient of variation was less than 10% in all instances.

Genomic DNA was extracted from peripheral blood leukocytes using standard techniques. Exons 7–10 of TRß1 from each index case were amplified by PCR using intronic primers and sequenced as previously described (10). Each mutation was verified in three independent reactions, and other family members were screened for the presence of the identified mutation.

Plasmid constructs
Receptor mutations were generated by site-directed mutagenesis of WT human TRß1 complementary DNA and confirmed by direct sequencing as reported previously (6). Both wild-type and mutant receptors were subcloned into pGEM7z and the eukaryotic expression vector RSV (containing the Rous sarcoma virus enhancer and promoter) for in vitro and in vivo studies, respectively. For functional assays, a reporter gene containing a direct repeat thyroid response element (TRE) spaced by four nucleotides (DR+4) from the malic enzyme gene upstream of the thymidine kinase promoter and luciferase (MAL-TKLUC) was cotransfected with receptor expression vectors and a ß-galactosidase reference plasmid (Bos-ßgal) as described previously (6).

Hormone and DNA binding assays
Receptor proteins were synthesized by coupled transcription and translation (Promega Corp., Southampton, UK). T3 binding affinities were determined using a modification of a filter assay, and binding affinity constants (Ka) were calculated using Scatchard analyses from three separate experiments on independently generated protein samples (11).

Receptor binding to DNA was assessed by electrophoretic mobility shift assays using in vitro translated receptors quantitated by SDS-PAGE analysis and a 32P-labeled oligonucleotide duplex corresponding to an everted repeat (F2) TRE from the chick lysozyme gene. TR exhibits both homodimeric and heterodimeric [with the retinoid X receptor (RXR)] binding to this TRE, with dissociation of the homodimer on addition of ligand. Details of the oligonucleotide duplex sequences and reaction conditions have been described previously (6).

Cell culture and transient transfection assays
JEG-3 (human choriocarcinoma) cells were grown in Optimem containing 2% (vol/vol) FCS and 1% (vol/vol) penicillin, streptomycin, and fungizone (Life Technologies, Inc., Paisley, Scotland). Eighteen hours before transfection the medium was changed to Optimem with 2% charcoal-stripped FCS. Twenty-four-well plates of cells were transfected by a 5-h exposure to calcium phosphate containing the reporter plasmid MAL-TKLUC (500 ng), TRß1 expression vectors (50 ng), and the internal control plasmid Bos-ßgal (200 ng). After an additional 36 h, cells were lysed, and extracts were assayed for luciferase and ß-galactosidase activity using standard methods (11).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Clinical and genetic analyses
The clinical features and biochemistry in six families with RTH are shown in Table 1Go. All patients exhibited thyroid function tests characteristic of RTH: namely, elevated serum free T4 and free T3 with an inappropriately normal TSH. Although index cases presented with goiter or thyrotoxic symptoms, most affected family members were asymptomatic and were detected by screening. One patient (no. IV) first presented with Graves’ disease, but subsequent thyroid function tests in remission were consistent with RTH. Direct sequencing of exons 7–10 of TRß1 of index cases showed that each individual was heterozygous for a single nucleotide substitution at codon 314 in exon 9. A single nucleotide change in the WT sequence TCC (serine), corresponding to a missense mutation, was noted in each family: cases I, II, and III, TTC (phenylalanine)-S314F; cases IV and V, TAC (tyrosine)-S314Y; and case VI, TGC (cysteine)-S314C. There was complete concordance between the presence of a receptor defect and the abnormal biochemistry associated with RTH, suggesting that these receptor abnormalities were highly likely to be causative.


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  		Table 1. Biochemical and genetic data from six RTH families

 
Hormone and DNA binding
All natural mutations in TRß cluster in the ligand binding domain, and consequently, the majority exhibit reduced hormone binding. Accordingly, each mutation was introduced into the WT TRß1 complementary DNA, and in vitro synthesized proteins were assayed for binding of [125I]T3. As expected from their location within the ligand binding domain, mutant receptors demonstrated impaired binding compared with wild-type receptor. Scatchard analyses indicated that their ligand affinities were reduced with a marked difference in the magnitude of the abnormality between mutations. Thus, in comparison with a wild-type Ka (±SEM) of 0.68 x 1010 M-1 (0.11), the S314C mutant bound ligand with a slightly reduced affinity [Ka, 0.48 x 1010 (0.07) M-1]. In contrast, with the S314F and S314Y mutant receptor proteins no specific radiolabeled T3 binding was detected, suggesting a marked ligand binding defect.

Previous studies have shown that TR is able to bind DNA as both a homodimer and a heterodimer with RXR and that homodimeric complexes dissociate after binding of ligand (12). We tested homo- and heterodimeric binding of WT and mutant receptors using an everted repeat TRE configuration and hypothesized that mutant receptor homodimer dissociation would be variably altered depending on the degree of impairment in hormone binding. In the absence of ligand, WT receptor formed homo- and heterodimer complexes and after the addition of 100 nM T3, the homodimer complex dissociated readily (Fig. 1Go). In comparison, the addition of 100 nM T3 resulted in a differential displacement of homodimer between mutants, with a rank order of WT > S314C > S314F> S314Y.



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  		Figure 1. Differential dissociation of TRß homodimers in response to T3 on the F2 everted repeat TRE. Using an electrophoretic mobility supershift assay, in vitro translated TRß (WT or mutants: S314C, S314F, and S314Y) and RXR were coincubated with the chick lysozyme F2 TRE in the absence or presence of T3 (100 nM). Complexes were resolved by PAGE. The locations of homodimer (TR-TR) and heterodimer (RXR-TR) complexes are indicated.

 
Functional activity and dominant negative inhibition
To evaluate their transcriptional properties, expression vectors encoding WT or mutant receptors were cotransfected with a reporter gene (MAL-TKLUC) containing a direct repeat TRE configuration. In comparison with WT receptor, S314Y was transcriptionally inactive even at the highest concentration of T3 (1000 nM), whereas S314F produced detectable activity (10–15% of the maximal WT response) only at 100 and 1000 nM T3. In marked contrast, although impaired relative to WT at the lower concentrations of ligand (0.1 and 1.0 nM), the S314C mutant exhibited a right-shifted activation profile, attaining a maximal transcriptional response comparable to that of WT at 100 nM T3 (Fig. 2Go).



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  		Figure 2. T3-dependent transcriptional activation of the malic enzyme (MAL-TKLUC) reporter gene by WT and mutant (S314C, S314F, S314Y) TRs. JEG-3 cells were cotransfected with WT or mutant TRß expression plasmids together with the reporter construct MAL-TKLUC and an internal control plasmid (Bos-ßgal). Hormone-dependent activation in response to increasing amounts of T3 was normalized against the internal control and expressed as a percentage of the maximum WT receptor response. The data shown represent the mean ± SEM of at least three experiments, each performed in triplicate.

 
Consonant with its dominant mode of inheritance, it has been suggested that the mutant receptors in RTH inhibit the action of their WT counterparts in a dominant negative manner (4, 5). We therefore examined the dominant negative potency of each RTH mutant in transient transfection analyses using the same TRE. Either WT receptor alone or equal amounts of WT and mutant receptor were cotransfected with MAL-TKLUC, and transcriptional activity was assayed at either low (1 nM) or high (1000 nM) T3 concentrations. At 1 nM T3, coexpressed S314F or S314Y mutants reduced trans-activation by WT receptor comparably (WT alone 100%; WT plus S314F or WT plus S314Y, 45%), whereas cotransfected S314C mutant was less inhibitory (WT, 100%; WT plus S314C, 68%). Similarly, at the higher T3 concentration, dominant negative inhibition by the S314C mutant was less marked with 80% trans-activation of WT alone, whereas S314F and S314Y continued to exert significant inhibitory effects (trans-activation, 60% of WT alone; Fig. 3Go).



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  		Figure 3. Dominant negative inhibition of wild-type (WT) receptor activity by mutant receptors. JEG-3 cells were cotransfected with 500 ng of the reporter plasmid MAL-TKLUC, 200 ng of the internal control Bos-ßgal and either 100 ng WT expression vector alone or 50 ng each of wild-type and mutant receptor vectors. Corrected luciferase activity was measured after incubation with low (1 nM) or high (1000 nM) T3 concentrations, and values are expressed as a percentage of the maximal WT receptor response. The data shown represent the mean ± SEM of at least three experiments, each performed in triplicate.

 
In view of the marked differences in ligand binding affinity, trans-activation, and dominant negative activity of the S314 mutants in vitro, we sought to determine whether this might be reflected in the degree of resistance to thyroid hormone action in vivo. A previous study has suggested that the magnitude of elevation of circulating free T4 (reflecting the degree of resistance within the pituitary-thyroid axis) may correlate with the degree of impairment in hormone binding affinities of mutant receptor proteins in vitro (13). We therefore compared circulating free T4 levels in individuals harboring the three different codon 314 mutations (Fig. 4Go). Interestingly, those with the S314Y or F mutation, on the average, exhibited higher FT4 levels than patients with the S314C mutation, with a trend that, although not significant, suggests a correlation between the degree of resistance and the extent of mutant receptor dysfunction.



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  		Figure 4. Circulating FT4 levels in individuals harboring each of the three codon 314 mutations. FT4 levels, expressed as the fold increment relative to the upper limit of the normal reference range (denoted 1.0), were calculated for all individuals shown in Table 1Go, except the index case in pedigree V, in whom the pituitary-thyroid axis had been altered by previous thyroid surgery. For each mutation, values shown represent the mean ± SEM.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We have identified six kindreds with RTH harboring three different amino acid substitutions (S314C, S314F, and S314Y) at the same codon in the TRß gene. All affected individuals exhibited pathognomonic biochemical features with elevated circulating free thyroid hormones and nonsuppressed TSH, in keeping with the idea that this disorder is characterized by resistance within the hypothalamic-pituitary-thyroid axis. Two of the mutations (S314F and S314Y) were identified in separate families with no apparent shared ancestry, suggesting that they had arisen independently in a mutation-prone GC-rich region as has been documented previously in RTH (14). Most affected individuals were asymptomatic or noted to have a goiter, but in four cases thyrotoxic features were present. There was no clear correlation between clinical features and the underlying genetic defect, underscoring the variable clinical phenotype in this disorder (3).

RTH also exhibits molecular heterogeneity, being associated with diverse mutations that all localize to the ligand binding domain of the TRß gene. On the basis of their transcriptional and hormone binding properties, it has been suggested that RTH mutants can be subdivided into three categories (15): type I mutants exhibit reduced trans-activation consistent with the degree of impairment in their ability to bind ligand, type II mutants show a disproportionate loss of trans-activation relative to their altered ligand binding affinity, and type III mutants exhibit negligible ligand binding and comparably impaired trans-activation. In this study, the mutations we have identified in codon 314 of TRß exhibited divergent functional properties. The S314C substitution resulted in a moderate impairment in hormone binding. Consonant with this, it exhibited a type I trans-activation profile, with functional impairment at lower T3 levels but full trans-activation at higher T3 concentrations. In contrast, the S314F and S314Y substitutions resulted in severely attenuated ligand binding. These mutants showed type III transcriptional responses, with S314Y being unable to activate transcription, and S314F achieving only 15% of the maximal WT response at 1000 nM T3.

We have shown that all three codon 314 mutants are able to inhibit the transcriptional activity of WT TR when they are coexpressed. This dominant negative effect has been observed previously with a large number of other RTH mutants and is in keeping with the dominant mode of inheritance of this disorder (6, 11, 16). Gel mobility shift assays indicate that all three codon 314 mutants retain the ability to bind to DNA and heterodimerize with RXR. This observation supports previous hypotheses that DNA binding and heterodimerization are functional properties that are critical for RTH mutants to exert dominant negative activity (6, 7, 8). In addition to differences in transcriptional function, our studies suggest that the three S314 mutants differ in dominant negative potency, as at both low (1 nM) and high (1000 nM) concentrations of T3, the S314F and S314Y mutants inhibited WT receptor function more strongly than S314C. It has been suggested that the ability of some RTH mutants to form TR homodimers that constitutively repress basal transcription may contribute to their dominant negative inhibitory potency (17, 18, 19). In keeping with this hypothesis, we note that the weaker dominant negative mutant S314C formed TR homodimers that dissociated more readily with T3, whereas the more potent S314F and S314Y mutants formed homodimer complexes that were less T3 reversible. Interestingly, the extent of thyroid dysfunction in vivo appeared consistent with the magnitude of receptor dysfunction in vitro.

To investigate the potential reasons for the marked divergence in their functional properties, we modelled the effect of the different amino acid changes in Ser314 in human TRß (20). Figure 5aGo shows that the side-chain of Ser314 plays a structural role in the periphery of the hydrophobic ligand binding cavity, consistent with our functional data indicating its importance in hormone binding. When viewed in greater detail (Fig. 5bGo), it is evident that this serine is tightly packed in van der Waal’s contact with the side-chains of Ile353, Ile431, and Leu428, with the hydroxyl group of Ser314 within hydrogen bonding distance of the carbonyls of Met310 and Glu311. Mutation of Ser314 to a cysteine would probably weaken these hydrogen bonds. However, as the side-chain volumes of serine and cysteine are so similar, few structural perturbations might be anticipated, explaining the relatively modest effect on ligand binding. In contrast, when Ser314 is replaced by a phenylalanine, the bulky aromatic side-chain of the latter clashes sterically with Ile431, Met310, and ligand (Fig. 5cGo). Rotation of the side-chain of Met310 to accommodate this results in a clash with His435 and Phe459. We suggest that such steric effects may be more deleterious, and indeed, it is known that different substitutions of His435 in TRß markedly impair ligand binding (21).



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  		Figure 5. a, The crystal structure of human TRß is shown, with Ser314 located in the periphery of the ligand binding cavity. b, Enlarged view showing the residues in contact with Ser314. c, The mutation of Ser314 to Phe was modelled by replacing the side-chain and then selecting the most favorable rotamer conformation. The orientation for the phenylalanine shown here is the only one that did not clash badly with the peptide backbone. However, this orientation clashed with the side-chains of Met310 and Ile431. The orientation of Met310 could be adjusted to avoid the clash with the phenylalanine, but this caused it to clash with both Phe459 and His435. In conclusion, the bulky aromatic side-chain cannot readily be accommodated without significant structural perturbations.

 
In conclusion, we have described three novel mutations in TRß in RTH due to distinct nucleotide substitutions at a single codon (314) that differentially impair receptor function. Our data suggest that the degree of functional impairment in vitro correlates with the extent to which interaction of Ser314 with T3 is disrupted and might also be related to the magnitude of thyroid dysfunction in vivo.


   Acknowledgments
 
We thank R. Wagner and R. Fletterick for providing the coordinates for the human TRß crystal structure.


   Footnotes
 
1 This work was supported by the Wellcome Trust. Back

2 M.G., O.R., and M.A. contributed equally to this work. Back

3 Wellcome Training Fellow. Back

4 Supported by a British Council-Centro Nazionale Richerche grant. Back

5 Commonwealth Foundation Research Scholar. Back

Received May 13, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Usala SJ, Bale AE, Gesundheit N, Weinberger C, Lash RW, Wondisford FE, McBride OW, Weintraub BD 1988 Tight linkage between the syndrome of generalized thyroid hormone resistance and the human c-erbA ß gene. Mol Endocrinol 2:1217–1220[Abstract]
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