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Thyroid Unit Department of Medicine Beth Israel Hospital and Harvard Medical School Boston, Massachusetts 02215
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS and METHODSREFERENCES |
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337T, P453H) mutations in both TR-ß isoforms. The ability of
mutant TRs to act as dominant negative inhibitors of wild type TR-ß
function on positive and negative thyroid hormone response elements
(pTREs and nTREs, respectively) was evaluated in transient transfection
assays. PRTH mutants had no significant dominant negative activity as
TR-ß1 isoforms on pTREs found in peripheral tissues or on nTREs found
on genes regulating TSH synthesis. PRTH mutants, in contrast, had
strong dominant negative activity on these same nTREs as TR-ß2
isoforms. Cotransfected retinoid X receptor-
was required for
negative T3 regulation via the TR-ß1 isoform
but was not necessary for negative regulation via the TR-ß2 isoform
in CV-1 cells. The differing need for retinoid X receptor
cotransfection demonstrates two distinct negative
T3-regulatory pathways, one mediated by the
TR-ß1 and the other mediated by TR-ß2. The selective effect of
PRTH mutations on the TR-ß2 isoform found in the hypothalamus and
pituitary vs. the TR-ß1 isoform found in peripheral
tissues suggests a molecular mechanism for the PRTH disorder. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS and METHODSREFERENCES |
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Clinically, thyroid hormone resistance can be divided into two entities: generalized resistance to thyroid hormone (GRTH) and central or pituitary resistance to thyroid hormone (PRTH) (4). In both syn-dromes there is thyroid hormone resistance at the level of the pituitary and hypothalamus causing inappropriate TSH secretion and, in turn, elevated thyroid hormone levels. In GRTH there is also peripheral resistance, often resulting in a hypothyroid- or euthyroid-appearing patient. In PRTH, however, peripheral sensitivity to thyroid hormone is preserved and the individual suffers thyrotoxic symptomatology from the elevated levels of circulating T3 (4a). A molecular mechanism to explain these two clinical phenotypes has proved elusive, and many authors have concluded that they are part of a spectrum of the same disorder (9, 10, 11).
Both GRTH and PRTH mutations congregate in two major hot spots in the
ligand-binding domain of TR-ß (Fig. 1
) (12, 13). GRTH
mutations have also been reported in the hinge region, suggesting a
third hot spot for mutations at the TR-ß locus (11, 14, 15).
Alternative promoter utilization at the TR-ß locus yields two
isoforms of the TR-ß: TR-ß1, which is ubiquitously expressed, and
TR-ß2, which is expressed almost exclusively in the anterior
pituitary, hypothalamus, and elsewhere in the brain (16, 17, 18, 19, 20). While the
TR-ß isoforms are identical in their DNA- and ligand-binding domains,
they differ significantly in their N-terminal A/B domains. A functional
difference between the two TR-ß isoforms in thyroid hormone
regulation would provide a molecular mechanism for tissue-specific
regulation of gene expression (21). In this study, therefore, the role
of the TR-ß2 isoform in mediating the PRTH syndrome was
evaluated.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS and METHODSREFERENCES |
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, seven TR-ß mutations were evaluated in this
study. Two of the mutations (337T and P453H) significantly reduce
T3 binding and cause GRTH (3, 22). One of the mutations
(R338W) preserves T3 binding and is reported to cause both
GRTH and PRTH, although reports of this mutation causing PRTH
predominate (11, 23, 24). The latter studies have included specific
measurements of thyroid hormone action in the periphery. The remaining
four mutations (R338L, V349M, R429Q, and I431T) are reported to cause
PRTH (11, 25). Patients with R338L (25a) and R429Q (25) mutations have
had detailed measurements of thyroid hormone action in the periphery,
indicating they indeed have PRTH. Measurements of peripheral thyroid
hormone action in patients with V349M and I431T mutations have not been
described, making the diagnosis of PRTH less certain in these patients.
With the exception of I431T, TRs containing these mutations bind well
to T3. These mutations were introduced into either a
TR-ß1 or TR-ß2 cDNA, using site-directed mutagenesis, and inserted
into a viral expression vector (pSG5) for use in transient transfection
studies. All transfections in this study were performed in a
TR-deficient cell line (CV-1 cells), in the absence of a suitable
pituitary cell line, which is also TR deficient.
Certain PRTH Mutants Have Weak Dominant Negative Activity on
Positive Thyroid Hormone Response Elements
We first sought to determine the function of each of these
mutations on thyroid hormone-regulated genes expressed in peripheral
tissues. In peripheral tissues such as the kidney, heart, and liver,
TR-ß1 and TR-1 mRNAs are readily detected by Northern blot
analysis and together represent 82–90% of total T3
binding activity (25b). In contrast, TR-ß2 mRNA is not detected by
Northern analysis, and TR-ß2 protein represents a small fraction of
T3-binding capacity in these same tissues (10–18%).
Because TR-ß1 is the major TR-ß isoform expressed in peripheral
tissues, each mutation was only tested in the context of the TR-ß1
isoform. As a model for thyroid hormone action in peripheral tissues,
two copies of positive thyroid hormone response elements (pTREs) were
fused upstream of a heterologous promoter luciferase construct
(pTK109-Luc) for use in transient transfection assays. Shown in Fig. 2A are the dominant negative activities of each mutant
on a well characterized pTRE found in a number of thyroid
hormone-regulated genes (Direct repeat with a 4-bp gap [Dr+4]).
Dominant negative activity is plotted with 100% meaning complete
interference with WT TR-ß1 T3-mediated stimulation. The
I431T, V349M, P453H, and 337T mutations all had significant dominant
negative activity on this element at 2.5 nM T3.
Essentially equivalent results were obtained at 10 nM
T3 (data not shown). In contrast, the PRTH mutants, R338L,
R338W, and R429Q, were unable to block wild type (WT) TR-ß1 function
on this element at 2.5 nM (Fig. 2A) or 10 nM
T3 (data not shown). Similar results were obtained with
another naturally occurring pTRE [inverted palindrome (F2)] except
that the putative PRTH mutant I431T was without effect, and the GRTH
mutant P453H had less dominant negative activity (Fig. 2B). Others have
also reported the lack of dominant negative activity of PRTH mutants as
TR-ß1 isoforms on pTREs (27, 28).
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) or 10 nM T3 (Fig. 2D).
The I431T and V349M mutants had between 50% and 70% dominant negative
activity on the WT TR at either 2.5 or 10 nM
T3. Finally, R429Q, R338W, and R338L had weak dominant
negative activity on this element (<40%) at 2.5 nM
T3 (Fig. 2C) and even less activity (<30%) at 10
nM T3 (Fig. 2D). Taken together, the I431T and
V349M putative PRTH mutations function like GRTH mutants on pTREs found
in the periphery. In contrast, three PRTH mutations (R429Q, R338W, and
R338L) have weak or no dominant negative activity on these same
elements.
The Dominant Negative Activity of PRTH Mutants on Negative Thyroid
Hormone Response Elements Depends on the TR-ß Isoform
Dominant negative activity on genes negatively regulated by
thyroid hormone was next evaluated. In contrast to peripheral tissues,
TR-ß2 is a major isoform in the anterior pituitary and hypothalamus.
We therefore tested the function of both TR-ß isoforms on genes
expressed in the anterior pituitary and hypothalamus that are
responsible for control of thyroid hormone synthesis. The human TRH and
common -subunit gene promoters were inserted into a luciferase
reporter construct and used in transient transfection assays of CV-1
cells. The TSH-ß promoter was not used in this study because of its
very low expression in this cell line. On the TRH promoter, the 337T
mutation had complete dominant negative activity in the context of the
TR-ß1 isoform (Fig. 3). Dominant negative activity is
plotted with 100% meaning complete interference with WT TR-ß1
T3-mediated inhibition. The P453H, V349M, and I431T
mutations had approximately 50% dominant negative activity as TR-ß1
isoforms. In contrast the PRTH mutants, R429Q, R338W, and R338L had
little or no activity on the same reporter as TR-ß1 isoforms even at
10-fold excess of mutant vs. WT TR-ß1 expression
vector.
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). The PRTH mutants, R429Q, R338W,
and R338L, as TR-ß2 isoforms were converted into strong dominant
negative inhibitors on the TRH gene; and the dominant negative activity
of the I431T and V349M mutants was greater as TR-ß2 vs.
TR-ß1 isoforms. This was not true, however, of the GRTH mutants that
had essentially similar dominant negative activity on the TRH promoter
as either TR-ß1 or TR-ß2 isoforms, suggesting that the isoform
differences on the TRH promoter were due to specific TR-ß
mutations.
Identical experiments were performed using the common -subunit
gene promoter as the reporter construct and a 10-fold excess of mutant
vs. WT TR-ß1 or TR-ß2 expression vector (Fig. 4). Note that the PRTH mutants, R429Q, R338W, and R338L,
had no significant dominant negative activity on this promoter in the
context of the TR-ß1 isoform and near 100% activity as TR-ß2
isoforms. The putative PRTH mutants, I431T and V349M, competed as
effectively as either TR-ß1 or TR-ß2 isoforms, similar to data
obtained with the TRH promoter (Fig. 3). Likewise, the GRTH mutants
were effective competitors in either isoform. These results indicate
that the R429Q, R338W, and R338L mutations display consistent and
dramatic TR-ß isoform differences on two negatively regulated genes
involved in the central control of thyroid hormone synthesis.
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, both GRTH and PRTH mutants had significant
dominant negative activity as TR-ß2 isoforms at all concentrations of
T3 tested (Fig. 5). Interestingly, however,
the dominant negative activity for all of the PRTH mutations (except
for I431T and V349M) and one of the GRTH mutants (P453H) was reduced at
higher T3 concentration from approximately 80% to 100% at
1 nM T3 to 40% to 60% at 10 nM
T3. Other investigators have noted that supraphysiological
T3 concentrations can reduce dominant negative activity of
RTH mutations presumably by increasing T3 binding to less
avid receptors (26). Parallel experiments were also performed using the
TR-ß1 isoform and varying the T3 concentration from 1–10
nM. At 10 nM T3, none of the
mutations in this study had dominant negative activity on the TRH
promoter except for 337T, which retained 100% activity (data not
shown). Thus, PRTH mutations in the TR-ß2 isoform display significant
dominant negative activity on the TRH promoter over a wide range of
T3 concentrations.
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-Subunit Genes-subunit
genes had been performed at a 10-fold excess of the mutant
vs. WT TR-ß, experiments were repeated at a 1:1 ratio of
WT to mutant TRß expression vector. Data obtained from the TRH
promoter are shown in Fig. 6A. PRTH mutants in the
TR-ß1 isoform were weak dominant negative inhibitors of WT TR-ß1 at
a 1:1 ratio as noted previously at a 10-fold excess of mutant receptor.
In contrast, the GRTH mutant (337T) in the TR-ß1 isoform had
strong activity on the TRH promoter. When these mutants were expressed
in the TR-ß2 isoform, stronger dominant negative activity on the TRH
promoter was observed with the PRTH mutants, and weaker dominant
negative activity was found with the GRTH mutant. Since the anterior
pituitary contains both TR-ß1 and TR-ß2, we also wanted to
determined whether PRTH mutants in the TR-ß2 isoform could compete
against WT TR-ß1 function. Note that each of the PRTH mutants in the
TR-ß2 isoform (stippled bars) had significant dominant
negative activity against WT TR-ß1, although they were better
competitors against WT TR-ß2 function (black bars).
Conversely, the GRTH mutant in the TR-ß2 isoform (stippled
bar) had significant dominant negative activity against either WT
TR-ß1 or TR-ß2, although it was a better competitor as a TR-ß1
isoform against WT TR-ß1 function (white bar). In data not
shown, these PRTH mutants in the TR-ß1 isoform had no significant
activity against WT TR-ß2 function on the TRH promoter. Similar
results were obtained at a 1:1 ratio of WT vs. mutant TR-ß
on the common -subunit gene promoter as shown in Fig. 6B. Thus, PRTH
mutants in the TR-ß2, but not TR-ß1, isoform were effective
competitors against both WT TR isoforms in the pituitary. The GRTH
mutant (337T), in contrast, competed against WT TR-ß function in
both the TR-ß1 and TR-ß2 isoform but was distinctly superior as a
competitor in the TR-ß1 isoform.
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on T3
inhibition of the TRH and common -subunit genes and a negative
control promoter from the thymidine kinase gene (TK199). As noted in
Fig. 7, TR-ß1 at 100 ng transfected was able to
negatively regulate the TRH and common -subunit genes only in the
presence of cotransfected RXR-. We have previously demonstrated on
the TRH promoter that TR-ß1 could negatively regulate the TRH
promoter in CV-1 cells but only at higher amounts of TR-ß1
cotransfected (500 ng)(31). Negative T3 regulation under
these conditions was also increased (from 2- to 4.5-fold) by
cotransfected RXR-, consistent with an RXR dependence for
T3 regulation by the TR-ß1 isoform. In contrast, TR-ß2
was able to regulate both promoters in the absence or presence of
cotransfected RXR. As expected, TK199 was not negatively regulated in
this cell line. These data could not be explained by TR-ß isoform
differences in binding to a TRH response element, as TR-ß1 and
TR-ß2 bound equally well as monomers, homodimers, or heterodimers
with RXR- to this response element (data not shown). Regardless of
the mechanism, these results are consistent with previous reports
demonstrating that both of these promoters are strongly negatively
regulated by TR-ß1 in JEG-3 cells, which have abundant RXR- (32),
and suggest that pathways for negative regulation by TR-ß1 and
TR-ß2 vary in their response to cellular RXR. The relative
contribution of TR-ß isoforms in T3 inhibition may,
therefore, depend on either the type or quantity of RXR expressed in
cells.
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- subunit genes in CV-1 cells in the absence of cotransfected RXR,
comparisons between the two TR-ß isoforms was performed in the
presence of cotransfected RXR in all studies described above. We wanted
to determine, therefore, whether the dominant negative activity of the
PRTH mutants was altered in the absence of cotransfected RXR. Results
obtained with three PRTH mutants (R429Q, R338W, R338L) and one GRTH
mutant (337T) in the TR-ß2 isoform in the absence of cotransfected
RXR are shown in Fig. 8. Importantly, dominant negative
activity by the PRTH mutants in the TR-ß2 isoform was 100%,
indicating that PRTH mutants were effective competitors in the TR-ß2
isoform in either the presence or absence of cotransfected RXR.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS and METHODSREFERENCES |
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In order for PRTH to represent a distinct clinical and biochemical
entity, PRTH mutants should have the following two in vitro
characteristics: 1) lack of dominant negative activity on genes
expressed in peripheral tissues; and 2) significant dominant negative
activity on genes involved in regulating TSH secretion. Three of the
PRTH mutants have these characteristics: R338L, R338W, and R429Q. Each
has weak dominant negative activity on positive TREs found in
peripheral tissues via the TR-ß1 isoform expressed in those tissues.
This is in part due to the fact that these mutations do not interfere
with T3 binding. Two PRTH mutations (V349M and I431T), in
contrast, behaved biochemically like GRTH mutations on these elements.
In addition, R338L, R338W, and R429Q are all strong dominant inhibitors
on the TRH and common -subunit genes in the TR-ß2, but not the
TR-ß1, isoform. These PRTH mutants should, however, lack dominant
negative activity on other genes negatively regulated by T3
in the periphery (e.g. myosin heavy chain ß), since
TR-ß2 is not expressed in peripheral tissues. Thus, TR-ß isoforms
mediate negative T3 regulation via different mechanisms.
The TR-ß1 isoform acts by an RXR-dependent pathway in which the PRTH
mutants have little effect in antagonizing normal T3
inhibition by TR-ß1. On the other hand, the TR-ß2 isoform acts
through a distinct pathway, which is not dependent on cotransfected
RXR, such that PRTH mutants, as TR-ß2 isoforms, exert significant
dominant negative activity against normal T3 inhibition by
either isoform.
GRTH mutants, by contrast, interfere with WT TR function as either
TR-ß1 or TR-ß2 isoforms. Both 337T and P453H have significant
dominant negative activity against pTREs as TR-ß1 isoforms and
negative TREs via either isoform. On certain TREs (F2, and TRH),
337T was a stronger dominant inhibitor than P453H, consistent with
previous reports. In addition, 337T was a superior competitor on
negative TREs (TRH and common -subunit, Fig. 6) as a TR-ß1
vs. TR-ß2 isoform, in contradistinction to PRTH mutants.
These data suggest that GRTH mutants can act either through the TR-ß1
or TR-ß2 pathway to cause central resistance to thyroid hormone.
Attempts have been made to correlate phenotype with location of mutation and/or T3-binding capacity of the mutant receptor (5, 7, 36). Previous authors have been unable to use these receptor characteristics to distinguish RTH syndromes. Our data confirm and extend these observations. Mutations found in either major hot spot caused clinical PRTH and have similar biochemical characteristics (R338L and R338W vs. R429Q) in our study. In addition, each of these PRTH mutations preserved near-normal T3 binding as did the V349M mutation, which biochemically resembles a GRTH mutation. Our data suggest that tissue-specific expression of TR-ß isoforms, coupled with a distinct effect of PRTH mutants on T3 inhibition via the TR-ß2 isoform, explains PRTH syndrome.
How PRTH mutants selectively alter the function of the TR-ß2 isoform
is unclear. Electrophoretic mobility shift assay studies reveal that
R338L, R338W, and R429Q are all homodimer deficient but heterodimerize
with RXR normally on both TRH and DR+4 elements as either isoform,
while V349M and I431T both homo- and heterodimerize on these elements
(data not shown and Ref.25). Perhaps the TR homodimer is critical for
T3 inhibition and mutations that disrupt homodimerization
cause PRTH. This is unlikely because TR homodimers are not thought to
be important for negative T3 regulation of the common
-subunit gene. In addition, it would not explain why PRTH mutants,
only as TR-ß2 isoforms, act as dominant negative inhibitors on the
TRH and common -subunit genes. Alternatively, the homodimer defect
may be a marker for a conformation change in the receptor that causes
PRTH via the TR-ß2 isoform. Finally, the homodimer defect may be
unrelated to the pathogenesis of the PRTH syndrome.
In summary, certain TR-ß mutations cause PRTH by converting the
centrally expressed TRß2 isoform into a dominant inhibitor of genes
that regulate TSH secretion. Importantly, these mutations do not
significantly alter T3 binding or the function of the
TR-ß1 isoform on thyroid hormone-responsive genes, thus limiting
resistance to only those tissues that express the TR-ß2. We,
therefore, propose the following model (Fig. 9) to
explain our findings and to provide a molecular framework for future
study of GRTH and PRTH syndromes. Two discrete pathways mediate
negative regulation of gene expression by thyroid hormone in the
anterior pituitary and hypothalamus. PRTH mutants interfere with the
TR-ß2 pathway to cause selective resistance in these tissues,
inappropriate TSH secretion, and elevated thyroid hormone levels. GRTH
mutants interfere with both pathways, causing both central and
peripheral resistance to thyroid hormone on negative TREs.
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MATERIALS and METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS and METHODSREFERENCES |
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337T and P453H (3, 22), the PRTH mutation R429Q (25),
and the putative PRTH mutations R338L, R338W, V349M, and I431T (11)
(Fig. 1). Mutations chosen included two that bind T3 poorly
(337T, I431T) and five that bind T3 in the same order of
magnitude as WT (R338L, R338W, V349M, R429Q, P453H) to remove poor
binding as an explanation for observed phenomena.
Site-directed mutagenesis (CLONTECH, Palo Alto, CA) was used to create
the mutations in the context of the human TR-ß1 isoform (37). All
mutations were confirmed by DNA sequencing of the TR-ß1 C terminus.
The common region of TR-ß was transferred into either the TR-ß1 or
TR-ß2 expression vector as a PstI/BamHI
fragment forming the mutant receptor isoforms. The expression vector
used in this study was pSG5, containing either WT or mutant
TR-ß cDNAs as EcoRI fragments. The human TR-ß1 cDNA was
used as the WT TR-ß1. The WT TR-ß2 was fashioned by inserting the
amino terminus of the rat TR-ß2 as an
EcoRI/SacI fragment into the TR-ß1 cDNA in
place of the amino terminus of the TR-ß1. The human RXR- as an
EcoRI fragment was inserted into the same expression vector
(38). Expression vector plasmid preparations used in this study were
carefully quantitated by agarose gel electrophoresis. To confirm the
integrity and quality of each expression vector, plasmid DNA
preparation, in vitro translation with
[35S]methionine, was performed using T7 polymerase, and
the products were analyzed by SDS-PAGE.
Reporter constructs included two copies of idealized pTREs: palindrome
(Pal, Ref.11), inverted palindrome (chicken lysozyme F2, Ref.39), and
direct repeat with a 4-bp interval (DR+4, Ref.11). The negative
response elements included the 5'-flanking sequences for the TRH and
the common glycoprotein -subunit gene (5, 31). In the case of the
positive reporters, constructs contained the pTRE element fused
upstream of a -109 thymidine kinase promoter and the luciferase gene
to measure activity. The negative reporter constructs included their
own promoters and were also fused upstream of the luciferase gene. The
luciferase reporter gene was derived from pSV0 and contains two
transcriptional stop sequences upstream of the promoter to prevent
read-through transcription. The reporter was documented to have neither
positive nor negative thyroid hormone responses in the absence of
response elements.
Transfections were performed in CV-1 cells, which are relatively RXR
deficient (29, 30), and thereby provided an opportunity to examine the
importance of limiting concentrations of RXR. Each transfection
included a WT TR-ß expression vector (100 ng), a mutant or WT TR-ß
expression vector (100 ng or 1 µg), an RXR- expression vector
except where indicated (100 ng), and a response element reporter
construct (10 µg). Cell cultures were transfected using a
calcium-phosphate precipitation method, and precipitate was applied for
16 h in DMEM containing 10% FBS, glutamine, and appropriate
antimicrobials. The next day, medium was removed and DMEM containing
both anion exchange and charcoal-stripped FBS (10%) was added ±
T3. Most of the experiments used 2.5 nM
T3, although other concentrations were used as noted. Data
were pooled from at least three independent experiments and displayed
as mean ± SE.
Gel-shift studies were performed with proteins derived from a coupled
in vitro transcription/translation reaction in reticulocyte
lysate. Three to four microliters of either TR-ß1, TR-ß2, or
RXR- lysate were used in binding studies on either a radiolabeled
Dr+4 or TRH element according to published methods (31).
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ACKNOWLEDGMENTS |
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-glycoprotein subunit gene
promoter, Dr. Mitchell Lazar for the rat TR-ß2 cDNA, and Dr. Ronald
Evans for the RXR- cDNA. |
FOOTNOTES |
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This work was supported by NIH Grants DK-02423 (to J.D.S), DK-02354 (to A.N.H.), and DK-43653 and DK-49126 (to F.E.W.) and the McLaughlin Foundation (to M.F.L.).
Received for publication August 2, 1996. Revision received October 9, 1996. Accepted for publication October 10, 1996.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS and METHODSREFERENCES |
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