Presse Med.

2015; 44: 11031112

TRa receptor mutations extend the spectrum

of syndromes of reduced sensitivity to
thyroid hormone

Literature review

ENDOCRINOLOGIE

en ligne sur / on line on

www.em-consulte.com/revue/lpm
www.sciencedirect.com

Virginie Vlaeminck-Guillem 1,2, Stphanie Espiard 3, Frdric Flamant 4, Jean-Louis Wmeau 3

Available online: 12 November 2015

1. Hospices civils de Lyon, centre hospitalier Lyon Sud, service de biochimie

biologie molculaire Sud, chemin du Grand-Revoyet, 69495 Pierre-Bnite, France
2. Universit Lyon 1, facult de mdecine Lyon Est, centre Lon-Brard, centre de
recherche en cancrologie de Lyon, Inserm 1052 CNRS 5286, 69373 Lyon cedex
08, France
3. CHRU de Lille, hpital Huriez, service d'endocrinologie et mtabolisme, 59000
Lille, France
4. Universit de Lyon, CNRS, Inra, universit Claude-Bernard Lyon 1, cole normale
suprieure de Lyon, Institut de gnomique fonctionnelle de Lyon, 69007 Lyon,
France

Correspondence:
Virginie Vlaeminck-Guillem, Hospices civils de Lyon, centre hospitalier Lyon Sud,
service de biochimie biologie molculaire Sud, chemin du Grand-Revoyet,
69495 Pierre-Bnite, France.
virginie.vlaeminck-guillem@univ-lyon1.fr

Summary
Since 2012, eight different abnormalities have been described in the THRA gene (encoding the TRa1
thyroid hormone receptor) of 14 patients from 9 families. These mutations induce a clinical
phenotype (resistance to thyroid hormone type a) associating symptoms of untreated mild congenital hypothyroidism and a near-normal range of free and total thyroid hormones and TSH (the T4/
T3 ratio is nevertheless usually low). The phenotype can diversely include short stature (due to
growth retardation), dysmorphic syndrome (face and limb extremities), psychoneuromotor disorders, constipation and bradycardia. The identified genetic abnormalities are located within the
ligand-binding domain and result in defective T3 binding, an abnormally strong interaction with
corepressors and a dominant negative activity against still functional receptors. The identification of
patients with consistent phenotypes and the underlying mutations are warranted to better delineate
the spectrum of the syndromes of reduced sensitivity to thyroid hormone.

Rsum
Les mutations du rcepteur TRalpha tendent le spectre des syndromes de sensibilit
rduite aux hormones thyrodiennes

tome 44 > n811 > novembre 2015

http://dx.doi.org/10.1016/j.lpm.2015.07.022
2015 Elsevier Masson SAS. All rights reserved.

1103

Depuis 2012, huit anomalies diffrentes du gne THRA, qui code le rcepteur TRa1 des hormones
thyrodiennes, ont t rapportes chez 14 patients rpartis dans 9 familles. Elles induisent un
phnotype (forme a de la rsistance aux hormones thyrodiennes) associant des signes voquant

Literature review

V. Vlaeminck-Guillem, S. Espiard, F. Flamant, J-L Wmeau

une hypothyrodie congnitale modre non traite et une (quasi-) normalit des formes libres et
totales des hormones thyrodiennes et de la TSH (le ratio T4/T3 est toutefois habituellement
diminu). Le phnotype peut inclure des degrs divers une courte taille (par retard de
croissance), un syndrome dysmorphique (face et extrmits des membres), des troubles
neuro-psychomoteurs, une constipation et une bradycardie. Les anomalies gntiques ont t
identies dans le domaine de liaison du ligand et aboutissent un dfaut de liaison de la T3, une
interaction anormalement forte avec les corpresseurs et une activit dominante ngative sur les
rcepteurs rests fonctionnels. La reconnaissance des cas et l'identication des mutations sousjacentes sont indispensables pour mieux dnir le spectre des syndromes de sensibilit rduite
aux hormones thyrodiennes.

Introduction

1104

The syndromes of reduced sensitivity to thyroid hormone (TH)

[1] were long limited only to resistance to thyroid hormone
(RTH) due to an abnormality of the beta form of the thyroid
hormone receptor (TRb), with the first clinical description occurring in 1967 [2] and the first demonstration of the underlying
molecular mechanism in 1989 [3]. The secondary description of
typical sporadic and familial cases, though without identified
abnormality of the THRB (thyroid hormone receptor, beta) gene
(currently estimated at about 15% of cases), quickly suggested
the possibility of other molecular causes for the lack of tissue
sensitivity to the action of TH [46]. It was not until the mid2000s that abnormalities in transmembrane transport and TH
metabolism were described as the cause of this reduced sensitivity of target tissues to TH action, affecting, respectively, the
MCT8 gene (monocarboxylate transporter 8) and the SBP2 gene
(selenocysteine insertion sequence-binding protein 2) [710].
The responsibility of the THRA (thyroid hormone receptor, alpha)
gene, which encodes the other functional TH receptor (TRa1),
had been suggested but could not be demonstrated. While
viable murine models (review in [11]) of inactivation [12] or
mutation [13] in the THRA gene have rapidly been published,
mutations in humans were considered, by the simple reason of
their absence, to be extremely rare, lethal or subclinically
expressed. The phenotype of patients in whom THRA gene
mutations were finally described is retrospectively suggestive
of that described over 10 years previously in murine models. It is
remarkable however to notice that the first case of RTH due to
TRa abnormality (named RTHa in contrast with RTHb [10]),
recognized as a state of hypothyroidism with normal thyroid
function test, was not identified in 2012 through direct targeting
but during whole genome sequencing [14]. Likewise, the two
other cases described in the same year were discovered through
a candidate gene approach, after ruling out an abnormality
affecting a TH transporter or deiodinase [15]. Patients indeed
present with quite normal thyroid laboratory testing, a confusing situation that usually lead patients to present themselves in
non-endocrinological clinical departments.
The molecular decoding of RTHa has only just begun, and the
description of at least several tens of cases will be able to

precisely delineate its clinical spectrum. At present, only

14 patients with RTHa have been found in the literature
amongst 9 distinct families [1421]. And although their common
clinical aspects are emerging, the analysis also clearly shows
diversity in the phenotype. The purpose of this review is to
present published cases of RTHa, and to provide details on their
underlying molecular mechanisms, particularly in the light of
available murine models. The objective is to thus promote the
diagnostic identification of patients in order to better define the
extent of the clinical manifestations related to congenital anomalies of TH action.

Clinical presentation and biology

Although 14 patients with identified genetic abnormalities have
been reported in the literature, clinical data for only 13 of them
are available. The genetic identification for the fourteenth was
done as part of whole genome sequencing in subjects with
familial forms of autism [19]. Abnormality of the THRA gene was
not specifically investigated, and no description of the case was
available other than the fact that the female patient, who was
autistic, had a brother who was also an autistic non-carrier of the
THRA mutation [19]. The patients included 9 women and 5 men,
but it is too early to define a sex ratio (it is 1:1 in RTHb [1]). The
cases were sporadic (de novo mutation) or familial (mutation
transmitted by a parent who was a carrier). In the reported
cases, the age at the molecular diagnosis varied (seven children
or adolescents, and seven adults), which contributes to certain
variations in the clinical descriptions, and even, in the adults,
uncertainty as to the description of the phenotype in childhood.
The clinical presentation of RTHa always includes, although to
varying degrees, the combination of a dysmorphic syndrome
and psychomotor development disorders (table I). Of note is the
absence of goiter, which is usually among the typical manifestations of RTHb. Generally there are signs of mild to moderate
untreated congenital hypothyroidism. The near-normal values
of the laboratory thyroid function tests (cf. below) must then
signal the possibility of RTHa and prompt a genetic analysis of
the patient. The manifestations related to hypothyroidism thus
reported are mild to moderate intellectual deficit, decreased
stature, alterations in ossification, macroglossia and chronic

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ENDOCRINOLOGIE

Literature review

TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity to

thyroid hormone

TABLE I
Clinical phenotype of the 14 published cases of resistance to thyroid hormone due to a defective TRa receptor
Gender

Origin

Children/teenagers: 6 to 18 years (n = 7)
Adults: 25 to 60 years (n = 7)
European Caucasian: n = 13
North-American: n = 1

Dysmorphic syndrome
Figure
Growth retardation
Height

n = 10
Small in 9 patients

Normal in 3 patients

Thinness: n = 1
Ideal weight: n = 3

Overweight: n = 1
Obesity: n = 3

n=6
n=7

No in 3 other patients

n = 11
n=6

(no in a 7th patient)

Eye hypertelorism
Flat nasal bridge, upturned nose
Short neck

n=7
n=8
n=4

(no in a 5th patient)

Micrognathia
Macroglossia

n=2
n=5

(no in a 6th patient)

Weight
Long thorax
Short limbs
Face dysmorphism
Macrocephaly
Coarse facial features

Delayed tooth eruption

Malformations
Ends of the limbs
Hip
Cleidocranial dysplasia
Cognition disorders
Psychomotor disorders
Cognitive defect

n=2
n=5
n = 3 (congenital dislocation; coxa valga)
n=1
n=5
Yes: n = 7
No: n = 7
No defect: n = 2
Mild defect: n = 7
Moderate to severe defect: n = 4

Bradycardia

n=5

(no in 3 other patients)

Constipation

n = 11

(no in a 12th patient)

Hypercholesterolemia

n = 11

(no in a 12th patient)

Anemia

constipation. The dysmorphic syndrome combines small stature,

decreased limb length with a trunk that is of rather normal size
(even elongated in the thoracic portion), and multiple facial
anomalies that may include macrocephaly (the need for a
caesarean section was reported several times), rather coarse
features, hypertelorism of the eyeballs, a short and wide nose,
micrognathism, delayed tooth eruption, a short neck or even
macroglossia. The decreased stature is related to growth retardation (sometimes detected in utero) and can even border on
dwarfism [21]. The feet and hands may be enlarged.

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Microcytic: n = 10
Macrocytic: n = 3

Malformations have also been reported, such as congenital

hip dislocation or coxa valga. One described case included a
unique malformation syndrome (sufficiently significant to provoke a separate publication, more than 10 years before the
discovery of the molecular substratum [22]), with bilateral
agenesis of the clavicles, unilateral humero-radial synostosis,
elbow dislocation, syndactyly of the 4th and 5th toes, absence of
the 12th rib, scoliosis and hip dysplasia [21] (presentation
suggestive of cleidocranial dysostosis [23,24]). With regard to
psychomotor status, there have been reports of abnormalities in

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Age at the molecular diagnosis

Females: n = 9
Males: n = 5

Literature review

V. Vlaeminck-Guillem, S. Espiard, F. Flamant, J-L Wmeau

coordination, learning to walk and reading. Mild to severe

intellectual deficit has often been reported but is not systematic
[20,21]. Constipation is nearly constant, with an early appearance in childhood; one case of diarrhoea, occurring late in
adulthood, was described [21]. Bradycardia, another sign suggestive of hypothyroidism, is sometimes reported [14,16,17].
Overweight is also possible, particularly in adults [1518]. Body
temperature appears normal [15,18], whereas the baseline
metabolism is decreased [14,16,17,21]. Finally, cases of carpal
tunnel syndrome have been reported [17], as is sometimes
described in association with myxoedema of hypothyroidism.
The routine laboratory tests are normal except for anaemia,
which is consistently present in all clinical descriptions but is
rather moderate. It is usually normocytic though sometimes
macrocytic [17,21]). Hypercholesterolemia may also occur
[1518,20]. Insulin-like growth factor 1 may be low in children
and adolescents patients [1416,18].
Radiological exams are done to investigate potential malformation syndromes [20,21]. Skull X-rays in children confirm macrocephaly, and show delay of ossification in the fontanels and the
persistence of wormian bones (which reflect ossification abnormalities) [14]. Ossification delay is also evidenced by epiphyseal
dysgenesis (femoral heads) [14,15,18] and by delayed bone
age. An ovoid appearance of the vertebrae is possible [20]. In
adults, X-rays again show macrocephaly with thickening of the
skull vault (occipital in particular) and enlargement of the frontal
bone [16,17]. Cortical bone thickening has also been described
on the long bones of the limbs [16]. Osteodensitometric measurements in adults are usually normal [1618,21].
The signs of hypothyroidism that are typically found lead logically to an investigation of thyroid function tests. Though providing reassurance when values are normal or low normal, they

must attract attention when there is a discrepancy with the

clinical presentation. It is this dissociation between normal
laboratory values and the more or less pronounced signs of
hypothyroidism (including the dysmorphic syndrome) that
should suggest the diagnosis of RTHa. It is the opposite condition of RTHb where the symptoms of hyperthyroidism are rather
minimal, in association with laboratory indications of hyperthyroidism (table II). In this respect, it can be seen that the
dissociation between the clinical and laboratory observations
is a key element of RTH, both in the alpha and the beta forms.
The thyroid hormone values, both in their free and total forms,
are more or less normal. There is a tendency however for T4 to
be slightly low and T3 slightly high. As a result, there is a
decreased T4/T3 ratio, which was the only consistent factor
in all the published cases. The TSH is normal (though low in
some cases). It should be noted that neonatal screening for
hypothyroidism, which is based on TSH, cannot identify RTHa.
Several patients received treatment with levothyroxine, sometimes even before the clinical or specific molecular diagnosis.
The clinical effects are inconclusive, particularly because cognitive disorders and dysmorphic syndrome are often already
established and definitive [14]. Benefits can be seen for bradycardia, energy levels, bowel function and carpal tunnel syndrome [16,17]. There is usually an increase in the concentrations
of thyroid hormones and a quick and predictable suppression of
TSH, which reflects the successful adaptation of the hypothalamic-pituitary axis. Improvement of the other abnormal laboratory values (blood cholesterol, anaemia) is not constant.

Molecular bases of RTHa

The functional thyroid receptors are the isoforms TRb1, TRb2 and
TRa1. They are present in the nucleus of the target cells as

TABLE II
Clinical and biological phenotypes of the a and b syndromes of resistance to thyroid hormones

Involved gene

RTHb

THRA

THRB

TRb1
TRb2

Involved receptors

TRa1

Clinical phenotype

Mild hypothyroidism
(short height, dysmorphic syndrom)

Mild hyperthyroidism (tachycardia, nervousness)

No

Yes

fT3

High-normal

High

fT4

Low normal

High

Low

Low

Normal or low

High

Goiter

T4/T3 ratio
TSH
1

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RTHa

Some mutations of the THRA gene also involve non-functional isoforms such as the TRa2 protein.

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tome 44 > n811 > novembre 2015

Figure 1
The main isoforms produced by the THRB gene and the
mutations described in the b form of resistance to thyroid
hormones
The isoforms TRb1 and TRb2 are functional receptors capable of binding DNA and T3
and influencing, under the control of the latter, the expression of target genes. The
mutations found in RTHb are concentrated in the T3 binding domain (E) and the hinge
domain (D), which separates it from the DNA-binding domain (C) and the N-terminus
transactivation domain (A/B). They are present in the common sequence of isoforms
TRb1 and TRb2. Three areas are particularly sensitive to mutations ("hot spots'') and
are found between amino acids 234 and 282 ( 1), 309 and 353 ( 2), and 426 and
460 ( 3; numbering in 461 amino acids of the TRb1 receptor).

mutations have been identified (the same mutation may be

carried by several different families) [1].
As of now there are 8 known different mutations affecting the
THRA gene in patients with RTHa (table III). As with THRB, they
are located in the ligand-binding domain (gure 2). They also
involve point mutations (missense or nonsense) or abnormalities (insertion or deletion of a nucleotide) that result in modification of the reading frame, thus causing a truncated receptor.
As with RTHb, point mutations seem to be predominant (6 out of
8 times). These were de novo mutations in 6 patients. In
4 patients, the abnormality occurred through autosomal dominant transmission by an affected parent (father or mother).
Contrary to isoforms TRb1 and TRb2, which differ on their Nterminus, the main isoforms produced from the THRA gene,
TRa1 and TRa2, differ on their C-terminus. They share a common
protein sequence up until the 360th amino acid; the sequences
then diverge, resulting in a functional LBD for TRa1, and an LBD
that is incapable of binding T3 for TRa2. Six of the eight abnormalities detected are located in the part of the gene concerning
only TRa1 [1416,19,20]; the two others concern the common
sequence between TRa1 and TRa2 [17,21]. Several of the
mutations identified in the THRA gene in cases of RTHa were
also identified in the THRB gene in cases of RTHb: A263V (THRA)

1107

dimers. They are capable of binding, on the DNA, specific target

sequences (thyroid hormone response elements or TREs),
which are located in the regulatory sequences (promoters,
enhancers) of the target genes. Like the other nuclear receptors, they in fact behave like ligand-inducible transcription
factors. In the absence of hormones and through interaction
with cofactors that repress their transcriptional activity (corepressors), the TR reduces the expression of the target genes.
Ligand binding enables the TR to release corepressors, to recruit
activating partners of transcription (coactivators) and to then
induce the transcription of the target genes. To fulfil all these
functions (DNA-binding, hormone binding, transactivation
activity), the TRs are organized into modules: an N-terminus
transactivation domain, a DNA-binding domain (DBD), a hinge
domain, and a ligand-binding domain (LBD). Organized as a
succession of 12 helices, this last domain has on its C-terminus
the transactivation domain, the activity of which is exerted in
the presence of the ligand. Indeed, modifications of the receptor structure occur during hormone binding and involve more
particularly the 12th helix (H12), which includes the last Cterminus amino acids.
In the b form of RTH, the abnormality is carried by the THRB
gene. The mutations are essentially distributed over the LBD and
the hinge domain (they do not affect the DNA-binding domain
or the N-terminus transactivation domain) (gure 1). Three
regions, rich in cytosine and guanine clusters (CpG islands),
are particularly subject to genetic abnormalities (hot spots)
[1], even though some mutations have been reported outside
of these hot spots [25]. The two functional isoforms produced
from the THRB gene, differing at their N-terminus (TRb1 and
TRb2), are both concerned by these C-terminus abnormalities.
DNA binding is preserved, and classically, the mutated receptors
have a reduced or absence of affinity for T3. They can also have
normal affinity for T3 but a constitutional inability to interact
with coactivators [1]. The phenotype is expressed while a single
copy of the gene is usually involved (heterozygous mutation).
The explanation lies in a dominant negative activity exerted by
the mutant receptors on the still functional isoforms. By dimerizing with them, they prevent the release of the corepressors,
the recruitment of the coactivators, and finally, transcriptional
activity. In 90% of cases, the identified mutations are missense
point mutations (a nucleotide base is changed into another,
resulting in an amino acid substitution on the protein [1]).
Sometimes the point mutation is a nonsense mutation (which
stops protein translation); it may involve the deletion or insertion of a nucleotide base, which then leads to a modification of
the reading frame, and translation of the genetic message into
an erroneous protein message. In the case of nonsense mutations or modifications of the reading frame, the affected receptors are truncated on a more or less long part of their C-terminus.
Currently, close to 500 families have thus been identified as
carriers of a THRB gene abnormality, and close to 200 different

ENDOCRINOLOGIE

Literature review

TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity to

thyroid hormone

Literature review

V. Vlaeminck-Guillem, S. Espiard, F. Flamant, J-L Wmeau

TABLE III
Description of the known mutations in THRA gene (encoding the thyroid hormone receptor TRa1) in patients with the a syndrome of
resistance to thyroid hormone
Protein
mutation1

Number of Number of
involved
involved
families
patients

THRA gene mutations2

Type of protein
mutation

Consequences for protein

functions

A263V

Single base substitution (CxxxxT)

Missense

Single aminoacid substitution

TRa1
TRa2

[17]

N359Y

Single base substitution (C1075G)

Missense

Single aminoacid substitution

TRa1
TRa2

[21]

A382fs388X

Single base deletion

(1144delG)

Frameshift

Wrong sequence from A382

then premature truncation at
position 388

TRa1

[16]

R384C

Single base substitution (C1150 T)

Missense

Single aminoacid substitution

TRa1

[19]

C392X

Single base substitution (C1176A)

No-sense

Premature truncation at
position C392

TRa1

[20]

F397fs406X

Single base insertion

(1144insT)

Frameshift

Wrong sequence from F397

then premature truncation at
position 406

TRa1

[15,18]

P398R

Single base substitution (C1150 T)

Missense

Single aminoacid substitution

TRa1

[20]

E403X

Single base substitution (C1176A)

No-sense

Premature truncation at
position E403

TRa1

[14,20]

1
2

The numbering is based on the TRa1 protein sequence (common to the TRa2 sequence until the amicoacid 360).
All mutations are located in exon 9 of the THRA gene (last exon of TRa1 and the second last for TRa2).

and A317V (THRB) [17], R384C and R438C [19,26], C392X and
C446X mutations [20,27]. Modification of the reading frame
from amino acid 382 in TRa1 (due to the insertion of a nucleotide base in the THRA gene) [15] has also been reported in the
equivalent residue of TRb1/TRb2 (insertions of several bases in
the THRB gene) [28], although the erroneous consecutive
sequence is not the same. For the other THRA gene mutations,
with no strict equivalent in the THRB gene, similar mutations
have been described, either resulting in another substitution or
occurring in a neighbouring residue. One notable exception,
however, is the N359Y mutation [21], which has no strict
equivalent, and in which the corresponding amino acid in the
TRb1/TRb2 sequence is not in one of the three known hot
spots (a partial explanation for this may lie in the distinctive
features of the phenotype associated with this mutation, see
below). In any case, comparison of the a and b forms of RTH, for
identical or equivalent mutations, enables the respective roles
of the different receptors to be specified. In general, then the b
receptors seem to be clearly involved in the hypothalamicpituitary feedback loop, while the a receptors are more involved
in the peripheral effects of TH.
Several TRa1 mutants have been examined in functional studies. Their common points include their incapability to induce the
expression of target genes and their dominant negative repressor activity over the normal TRa1 receptor [1417,21,29]. When

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Involved References
isoforms

it was evaluated, the affinity for T3 was reduced [16,17,21].

Moreover, the dominant negative activity seems to be exerted
on the TRb1 receptor [15,21,29]. The still small number of
reported cases does not enable the formulation of genotype
phenotype correlations. For example, only two mutations affect
both TRa1 and TRa2. While the A263V mutation does not result
in a phenotype different from that observed for mutations that
only affect TRa1 [17], the phenotype associated with the N359Y
mutation is particular due to the incidence (coincidental?) of a
marked malformation syndrome and hypercalcemia from parathyroid hyperplasia, and even to the absence of constipation and
intellectual deficit (though this absence has also been observed
in other cases) [21]. Whether other isoforms produced from the
THRA gene (TRa3, p43, P30, TRD1 and TRD2) are implicated in
the phenotype also deserves to be explored [21]. Although this
needs to be substantiated with subsequent clinical cases, there
is a tendency for more serious forms to exist with the mutation
occurring early in the sequence and resulting in truncation. The
most significant intellectual deficit (IQ of 22) was described for
the mutation involving the 18 amino acid deletion of TRa1 [20].
Conversely, patients with normal IQs are carriers of missense
point mutations that only substitute one amino acid for another
[20,21]. In RTHb, the severe forms are also often related to
TRb1/TRb2 truncations [28]. It is likely that truncations (resulting in the lack of C-terminal helix 12) induce more severe

tome 44 > n811 > novembre 2015

ENDOCRINOLOGIE

Literature review

TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity to

thyroid hormone

Figure 2
The main isoforms produced by the THRA gene and the mutations described in the a form of resistance to thyroid hormones

tome 44 > n811 > novembre 2015

1109

Isoform TRa1 is a functional receptor capable of binding DNA and T3 and influencing, under the control of the latter, the expression of target genes. Isoform TRa2 is incapable of
binding the hormone and behaves like a weak, dominant negative inhibitor of the T3 functional receptors. For now, the mutations found in RTHa re in the T3 binding domain (E),
while the hinge domain (D), the DNA-binding domain (C) and the N-terminus transactivation domain (A/B) are spared. The mutations concern the common sequence of the two
isoforms TRa1 and TRa2 or only affect the C-terminus sequence of TRa1 (numbering in 410 amino acids of the TRa1 receptor). The point mutations are represented by a star and
the frameshift mutations by a star at the level of the first mutated amino acid followed by a blue box representing the modified sequence.
The four mutations introduced in the THRA gene to try to generate murine models of the a form of resistance to thyroid hormones are also indicated in italic font (R384C,
P394fs406X, P398H and L400R). The numbering for the murine isoform TRa1 is the same as for the human isoform.

1110

Literature review

V. Vlaeminck-Guillem, S. Espiard, F. Flamant, J-L Wmeau

phenotype by profoundly affecting TR function through total

inability to interact with coactivators.
The genotypephenotype correlations may in fact need to be
investigated in animal models. Mice with complete inactivation
of the THRA and/or THRB genes have been reported [11] but
may not represent the most relevant models, as the absence of
a receptor does not have the same consequences as the expression of an abnormal receptor. The comparison is more logical in
animal models with an artificially introduced mutation. For the
THRA gene, there are four different models available that are all
based on a mutation of the hormone-binding domain in only
the TRa1 receptor (gure 2; no model with mutation affecting
TRa1 and TRa2). One model introduced in TRa1 the PV mutation [13], which was identified in a patient with RTHb (insertion
of several nucleotides with modification of the reading frame)
[30], while the others introduce point mutations: R384C [29]
(corresponding exactly to a THRA mutation in a patient with
RTHa [19]), L400R [31] and P398H [32]. These models provide
phenotypic data that are complementary to those reported in
human cases. The growth retardation with impairment in ossification is consistent in all animals [13,29,3134]. The role of
TRa1 in the development of chondrocytes is probably a determining factor, as the elective introduction of the L400R mutation in the chondrocytes is sufficient to induce the phenotype
[35]. The severity of the bone phenotype, however, is variable
depending on the models. The bone phenotype of the R384C
mutation, for instance, was observed in young mice and disappeared in the adult mice [29]. In humans, this mutation was
reported in a girl, though it is only known that she was a carrier
of a familial form of autism, without other information on her
phenotype. It is interesting to observe that the R384C mice had
significant psychomotor disorders with anxiety, memory
impairment and depression (which are possible, even frequent, manifestations of autism) [36,37]. Cerebellar ataxia
was also observed in another model [31], which is somewhat
similar to the clumsiness and awkwardness described in the
gait or the handling of objects in several patients with RTHa
[14,16,17]. In animals, these psychoneuromotor disorders are
related to impairment of neurogenesis in the hippocampus
(lack of certain GABAergic interneurons) [38] and diminish
partially with levothyroxine [36,38]. This reduction on treatment is not observed for the bone phenotype [39], as was also
reported in humans. Another common point of the animal
models with TRa1 mutations is the near-normality of TH serum
levels. On the other hand, TSH has been found to be high in
several models [13,32] as opposed to its usual observed normality in patients with RTHa (high-normal values in one case
[16]). The T4/T3 ratio and the reverse T3 (rT3), found to be low
in patients with RTHa, are considered an indication of the
peripheral metabolism of TH. Interestingly, high levels of type
1 deiodinase (responsible for the conversion of T4 into T3 and
for the clearance of rT3) have been measured in the liver of one

of the murine models [13]. Normal levels were however

detected in another [31].
Investigations of murine models found bradycardia [29,31,32],
which was rather mild but accompanied by inadaptation to
stress [40]. Bradycardia was reported in patients with RTHa
[14,16,17], but the rare functional heart explorations that were
done did not demonstrate serious abnormalities [16]. Bradycardia is probably the result of the direct effect of TH on the
myocardium (known target tissue of TH, expressing rather
TRa1); abnormalities of calcium flux and contractility were
observed in one model [41]. However, there is probably another
mechanism involved, namely deregulation of the autonomic
nervous system due to abnormal brain development [40,42].
The same mechanism (lack of cerebral control on the autonomic
nervous system) has been suggested as an explanation for
thermogenesis abnormalities. These abnormalities have not
been actually reported (not explored?) in patients with RTHa.
A reduction in body temperature and/or a cold intolerance was
described in two murine models [31,32]. Dysfunction of the
brown fat is suspected, related to deregulation of the autonomic
nervous system caused by abnormal brain development [38].
Increased vasodilatation, again related to the autonomic nervous system, was supposedly also observed in one of the models with abnormal thermogenesis [43].
One patient with RTHa had weight loss (occurring in childhood
and continuing in adulthood) [21], while the other patients had
normal or increased weight [1518]. One murine model exhibited overweight (without increased food intake), hepatic steatosis and insulin resistance [32], but a controversy exists about
the real responsibility of THRA mutation. Two others models had
hyperphagia without weight gain, resistance to tube-feeding,
mild adiposity due to impairment of adipogenesis, and low liver
concentrations of lipids [4446]. The same mechanism, an
interaction with PPARg, has been suggested in both of these
contrary situations [45,47].

Conclusions
Towards the end of the 1980s, the first descriptions of abnormalities of the THRB gene in patients with RTHb generated a
very large number of questions about the possibility of mutations in the THRA gene. Answers have arrived more than 20 years
later with the description of clinical phenotypes that are quite
particular: abnormalities suggestive of mild, untreated congenital hypothyroidism in conjunction with thyroid function tests
that are more or less normal and therefore discordant. For the
moment, suggestive symptoms are short stature, hypothyroidism-like facial shape and low T4/T3 ratio. It is worthy to note
that the whole exome database (http://exac.broadinstitute.
org) contains 68 THRA missense or frameshift mutations, with
most of them predicted to alter TRa1 function. It is therefore
likely that several patients in the general population have
undiagnosed RTHa with milder phenotype. As in RTHb, it is

tome 44 > n811 > novembre 2015

TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity to

thyroid hormone

of this seems to depend partially on the nature of the underlying

genetic abnormality. The different murine models, with diverse
genetic abnormalities, may thus be valuable tools for testing the
therapeutic approaches. Assuming that the resistance is too
severe to be managed by hormonal treatment, identification
of the major role in animals of the interaction of mutated TRa1
with corepressors, such as NCoR [48] was crucial. Indeed, it led
to the demonstration of the partial reversal of the abnormal
THRA gene phenotype through the coexpression of a mutant
NCoR unable to interact with the TRs [49], and through the
administration of an inhibitor of the corepressors-associated
histone deacetylase activity [50].

Literature review

the discordance between the clinical and the laboratory data

that should stand out for the clinician. The identification of
patients with authenticated abnormalities of the THRA gene
is essential for improving the definition of the clinical spectrum
of RTHa, and more generally of all RTH and syndromes of
reduced sensitivity to thyroid hormones. This improved phenotypic definition will enable genotypephenotype correlations to
be formulated and perhaps the development of therapeutic
guidelines. The reported cases show that the administration
of TH in patients with RTHa does not improve all the symptoms,
probably because the therapeutic management occurs too late
for certain abnormalities that have already become definitively
established and/or because the tissue resistance is too severe.
The extreme dependence for TH during the brain development is
a clear example of the need for early treatment. The significance

ENDOCRINOLOGIE

Disclosure of interest: the authors declare that they have no conflicts of

interest concerning this article.

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