Thyroid Receptors

7252019 Thyroid Receptors

httpslidepdfcomreaderfullthyroid-receptors 110

TRa receptor mutations extend the spectrumof syndromes of reduced sensitivity tothyroid hormone

Virginie

Vlaeminck-Guillem 12 Steacutephanie

Espiard 3

Freacutedeacuteric

Flamant 4

Jean-Louis

Weacutemeau 3

1 Hospices civils de Lyon centre hospitalier Lyon Sud service de biochimiebiologie moleacuteculaire Sud chemin du Grand-Revoyet 69495 Pierre-Beacutenite France

2 Universiteacute Lyon 1 faculteacute de meacutedecine Lyon Est centre Leacuteon-Beacuterard centre derecherche en canceacuterologie de Lyon Inserm 1052 CNRS 5286 69373 Lyon cedex08 France

3 CHRU de Lille hocircpital Huriez service dendocrinologie et meacutetabolisme 59000Lille France

4 Universiteacute de Lyon CNRS Inra universiteacute Claude-Bernard Lyon 1 Eacutecole normalesupeacuterieure de Lyon Institut de geacutenomique fonctionnelle de Lyon 69007 LyonFrance

CorrespondenceVirginie Vlaeminck-Guillem Hospices civils de Lyon centre hospitalier Lyon Sudservice de biochimie biologie moleacuteculaire Sud chemin du Grand-Revoyet69495 Pierre-Beacutenite Francevirginievlaeminck-guillemuniv-lyon1fr

Available online 12 November 2015

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

clinicalphenotype (resistance to thyroid hormone type a) associating symptoms of untreated mild con-genital

hypothyroidism

and

a

near-normal

range of

free

and

total

thyroid

hormones

and

TSH

(the

T4T3 ratio is nevertheless usually low) The phenotype can diversely include short stature (due togrowth retardation) dysmorphic syndrome (face and limb extremities) psychoneuromotor disor-ders

constipation

and

bradycardia

The

identified

genetic

abnormalities

are

located

within

theligand-binding domain and result in defective T3 binding an abnormally strong interaction withcorepressors

and

a

dominant

negative

activity

against

still

functional

receptors

The

identification

ofpatients

with

consistent

phenotypes

and

the

underlying

mutations

are

warranted

to

better

delineatethe

spectrum

of

the

syndromes

of

reduced

sensitivity

to

thyroid

hormone

Reacutesumeacute

Les

mutations

du

reacutecepteur

TRalpha

eacutetendent

le

spectre

des

syndromes

de

sensibiliteacute

reacuteduite

aux

hormones

thyroiumldiennes

Depuis

2012

huit

anomalies

diffeacuterentes

du

gegravene

THRA qui

code

le

reacutecepteur

TR a1 des

hormones

thyroiumldiennes

ont

eacuteteacute

rapporteacutees

chez

14

patients

reacutepartis

dans

9

familles

Elles

induisent

un

pheacutenotype (forme a de la reacutesistance aux hormones thyroiumldiennes) associant des signes eacutevoquant

tome 44 gt n811 gt novembre2015

httpdxdoiorg101016jlpm201507022copy 2015 Elsevier Masson SAS All rights reserved

1 1 0 3

L i t e r a t u r e r e v i e w

Presse Med 2015 44 1103ndash1112

en

ligne

sur

on

line

onwwwem-consultecomrevuelpmwwwsciencedirectcom

ENDOCRINOLOGIE



IntroductionThe 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 thyroidhormone receptor (TRb) with the first clinical description occur-

ring

in

1967

[2]

and

the

first

demonstration

of

the

underlyingmolecular mechanism in 1989 [3] The secondary description oftypical

sporadic

and

familial

cases

though

without

identifiedabnormality of the

THRB (thyroid hormone receptor beta) gene

(currently

estimated

at

about

15

of

cases)

quickly

suggestedthe possibility of other molecular causes for the lack of tissuesensitivity to the action of TH [4ndash6] It was not until the mid-2000s

that

abnormalities

in

transmembrane

transport

and

THmetabolism were described as the cause of this reduced sensi-tivity

of

target

tissues

to

TH

action

affecting

respectively

theMCT8 gene (monocarboxylate transporter 8) and the SBP2 gene(selenocysteine

insertion

sequence-binding

protein

2)

[7ndash10]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

Whileviable murine models (review in [11]) of inactivation [12] ormutation

[13]

in

the

THRA

gene

have

rapidly

been

publishedmutations in humans were considered by the simple reason oftheir absence to be extremely rare lethal or subclinicallyexpressed The phenotype of patients in whom

THRA gene

mutations

were

finally

described

is

retrospectively

suggestiveof

that

described

over

10

years

previously

in

murine

models

It

isremarkable however to notice that the first case of RTH due toTRa

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

targetingbut

during

whole

genome

sequencing

[14]

Likewise

the

twoother

cases

described

in

the

same

year

were

discovered

througha

candidate

gene

approach

after

ruling

out

an

abnormalityaffecting a TH transporter or deiodinase [15] Patients indeedpresent

with

quite

normal

thyroid

laboratory

testing

a

confus-ing situation that usually lead patients to present themselves innon-endocrinological clinical departmentsThe

molecular

decoding

of

RTHa has

only

just

begun

and

thedescription of at least several tens of cases will be able to

precisely delineate its clinical spectrum At present only14

patients

with

RTHa

have

been

found

in

the

literatureamongst 9 distinct families [14ndash21] And although their commonclinical aspects are emerging the analysis also clearly showsdiversity

in

the

phenotype

The

purpose

of

this

review

is

topresent published cases of RTHa and to provide details on theirunderlying

molecular mechanisms particularly in the light ofavailable

murine

models

The

objective

is

to

thus

promote

thediagnostic

identification

of

patients

in

order

to

better

define

theextent of the clinical manifestations related to congenital anom-alies of TH action

Clinical presentation and biologyAlthough

14

patients

with

identified

genetic

abnormalities

havebeen reported in the literature clinical data for only 13 of themare

available

The

genetic

identification

for

the

fourteenth

wasdone as part of whole genome sequencing in subjects withfamilial forms of autism [19] Abnormality of the

THRA gene was

not specifically investigated and no description of the case wasavailable

other

than

the

fact

that

the

female

patient

who

wasautistic had a brother who was also an autistic non-carrier of theTHRA

mutation [19]The patients included 9 women and 5 menbut

it

is

too

early

to

define

a

sex

ratio

(it

is

11

in

RTHb [1])

Thecases were sporadic (de novo mutation) or familial (mutationtransmitted by a parent who was a carrier) In the reportedcases

the

age

at

the

molecular

diagnosis

varied

(seven

childrenor adolescents and seven adults) which contributes to certainvariations in the clinical descriptions and even in the adultsuncertainty as to the description of the phenotype in childhoodThe

clinical

presentation

of

RTHa

always

includes

although

to

varying

degrees

the

combination

of

a

dysmorphic

syndromeand psychomotor development disorders (table

I ) Of note is theabsence

of

goiter

which

is

usually

among

the

typical

manifes-tations of RTHb Generally there are signs of mild to moderateuntreated

congenital

hypothyroidism

The

near-normal

valuesof the laboratory thyroid function tests (cf below) must thensignal

the

possibility

of

RTHa

and

prompt

a

genetic

analysis

ofthe patient The manifestations related to hypothyroidism thusreported are mild to moderate intellectual deficit decreasedstature

alterations

in

ossification

macroglossia

and

chronic

une

hypothyroiumldie

congeacutenitale

modeacutereacutee

non

traiteacutee

et

une

(quasi-)

normaliteacute

des

formes

libres

et

totales

des

hormones

thyroiumldiennes

et

de

la

TSH

(le

ratio

T4T3

est

toutefois

habituellement

diminueacute) Le pheacutenotype peut inclure agrave des degreacutes divers une courte taille (par retard de

croissance)

un

syndrome

dysmorphique

(face

et

extreacutemiteacutes

des

membres)

des

troubles

neuro-psychomoteurs

une

constipation

et

une

bradycardie

Les

anomalies

geacuteneacutetiques

ont

eacuteteacute

identi 1047297 eacutees dans le domaine de liaison du ligand et aboutissent agrave un deacutefaut de liaison de la T3 uneinteraction

anormalement

forte

avec

les

coreacutepresseurs

et

une

activiteacute

dominante

neacutegative

sur

les

reacutecepteurs

resteacutes

fonctionnels

La

reconnaissance

des

cas

et

lidenti 1047297 cation

des

mutations

sous-

jacentes

sont

indispensables

pour

mieux

deacute1047297 nir le

spectre

des

syndromes

de

sensibiliteacute

reacuteduite

aux hormones thyroiumldiennes

V Vlaeminck-Guillem S Espiard F Flamant J-LWeacutemeau

tome 44 gt n811

gt novembre 2015 1 1 0 4




constipation

The

dysmorphic

syndrome

combines

small

staturedecreased

limb

length

with

a

trunk

that

is

of

rather

normal

size(even elongated in the thoracic portion) and multiple facialanomalies

that

may

include

macrocephaly

(the

need

for

acaesarean section was reported several times) rather coarsefeatures hypertelorism of the eyeballs a short and wide nosemicrognathism

delayed

tooth

eruption

a

short

neck

or

evenmacroglossia The decreased stature is related to growth retar-dation

(sometimes

detected

in

utero)

and

can

even

border

ondwarfism [21] The feet and hands may be enlarged

Malformations

have

also

been

reported

such

as

congenitalhip

dislocation

or

coxa

valga

One

described

case

included

aunique malformation syndrome (sufficiently significant to pro-voke

a

separate

publication

more

than

10

years

before

thediscovery of the molecular substratum [22]) with bilateralagenesis of the clavicles unilateral humero-radial synostosiselbow

dislocation

syndactyly

of

the

4th

and

5th

toes

absence

ofthe 12th rib scoliosis and hip dysplasia [21] (presentationsuggestive

of

cleidocranial

dysostosis

[2324]) With

regard

topsychomotor status there have been reports of abnormalities in

TABLE IClinical

phenotype

of

the

14

published

cases

of

resistance

to

thyroid

hormone

due

to

a

defective

TRa

receptor

Gender Females n = 9Males n = 5

Age at the molecular diagnosis Childrenteenagers 6 to 18 years (n = 7)Adults 25 to 60 years (n = 7)

Origin European Caucasian n = 13North-American n = 1

Dysmorphic syndrome

Figure

Growth retardation n = 10Height Small in 9 patients Normal in 3 patients

Weight Thinness n = 1Ideal weight n = 3

Overweight n = 1Obesity n = 3

Long thorax n = 6Short limbs n = 7 No in 3 other patients

Face dysmorphism

Macrocephaly n = 11Coarse facial features n = 6 (no in a

7th patient)

Eye hypertelorism n = 7Flat nasal bridge upturned nose n = 8Short neck n = 4 (no in a 5th patient)

Micrognathia n = 2Macroglossia n = 5 (no in a 6th patient)

Delayed tooth eruption n = 2Malformations n = 5Ends of the limbs n = 3 (congenital dislocation coxa valga)Hip n = 1Cleidocranial dysplasia n = 5

Cognition disorders

Psychomotor disorders Yes n = 7

No n = 7Cognitive defect No defect n = 2

Mild defect n = 7Moderate 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 Microcytic n = 10Macrocytic n = 3

TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE

tome 44 gt n811 gt novembre2015 1 1 0 5




coordination learning to walk and reading Mild to severeintellectual

deficit

has

often

been

reported

but

is

not

systematic[2021] Constipation is nearly constant with an early appear-ance

in

childhood

one

case

of

diarrhoea

occurring

late

inadulthood was described [21] Bradycardia another sign sug-

gestive of hypothyroidism is sometimes reported [141617]Overweight is also possible particularly in adults [15ndash18] Bodytemperature

appears

normal

[1518] whereas

the

baselinemetabolism

is

decreased

[14161721] Finally

cases

of

carpaltunnel syndrome have been reported [17] as is sometimesdescribed

in

association

with

myxoedema

of

hypothyroidismThe routine laboratory tests are normal except for anaemiawhich

is

consistently

present

in

all

clinical

descriptions

but

israther moderate It is usually normocytic though sometimesmacrocytic

[1721]) Hypercholesterolemia

may

also

occur[15ndash1820] Insulin-like

growth

factor

1

may

be

low

in

childrenand adolescents patients [14ndash1618]

Radiological

exams

are

done

to

investigate

potential

malforma-tion syndromes [2021] Skull X-rays in children confirm macro-cephaly and show delay of ossification in the fontanels and thepersistence of wormian bones (which reflect ossification abnor-malities)

[14]

Ossification

delay

is

also

evidenced

by

epiphysealdysgenesis

(femoral

heads)

[141518]

and

by

delayed

boneage An ovoid appearance of the vertebrae is possible [20] Inadults

X-rays

again

show

macrocephaly

with

thickening

of

theskull vault (occipital in particular) and enlargement of the frontalbone [1617] Cortical bone thickening has also been describedon

the

long

bones

of

the

limbs

[16] Osteodensitometric

meas-urements

in

adults

are

usually

normal

[16ndash1821]The signs of hypothyroidism that are typically found lead logi-cally to an investigation of thyroid function tests Though pro-viding

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

normallaboratory values and the more or less pronounced signs ofhypothyroidism

(including

the

dysmorphic

syndrome)

thatshould suggest the diagnosis of RTHa It is the opposite condi-

tion of RTHb where the symptoms of hyperthyroidism are ratherminimal in association with laboratory indications of hyperthy-roidism

(table

II )

In

this

respect

it

can

be

seen

that

thedissociation

between

the

clinical

and

laboratory

observationsis a key element of RTH both in the alpha and the beta formsThe

thyroid

hormone

values

both

in

their

free

and

total

formsare more or less normal There is a tendency however for T4 tobe

slightly

low

and

T3

slightly

high

As

a

result

there

is

adecreased T4T3 ratio which was the only consistent factorin

all

the

published

cases

The

TSH

is

normal

(though

low

insome

cases)

It

should

be

noted

that

neonatal

screening

forhypothyroidism which is based on TSH cannot identify RTHa

Several

patients

received

treatment

with

levothyroxine

some-times even before the clinical or specific molecular diagnosisThe clinical effects are inconclusive particularly because cogni-tive disorders and dysmorphic syndrome are often alreadyestablished

and

definitive

[14] Benefits

can

be

seen

for

brady-cardia

energy

levels

bowel

function

and

carpal

tunnel

syn-drome [1617] There is usually an increase in the concentrationsof

thyroid

hormones

and

a

quick

and

predictable

suppression

ofTSH which reflects the successful adaptation of the hypotha-lamic-pituitary axis Improvement of the other abnormal labo-ratory

values

(blood

cholesterol

anaemia)

is

not

constant

Molecular bases of RTHa

The functional thyroid receptors are the isoforms TRb1 TRb2andTRa1 They are present in the nucleus of the target cells as

TABLE IIClinical

and

biological

phenotypes

of

the

a

and

b

syndromes

of

resistance

to

thyroid

hormones

RTHa RTHb

Involved gene THRA THRB

Involved receptors TRa11 TRb1TRb2

Clinical phenotype Mild hypothyroidism(short height dysmorphic syndrom)

Mild hyperthyroidism (tachycardia nervousness)

Goiter No Yes

fT3 High-normal High

fT4 Low normal High

T4T3 ratio Low Low

TSH Normal or low High

1Some mutations of the THRA gene also involve non-functional isoforms such as the TRa2 protein


tome 44 gt n811





dimers They are capable of binding on theDNA specific targetsequences (thyroid

hormone response elements

or

TREs)which are located in the regulatory sequences (promotersenhancers) of

the target

genes Like the other

nuclear

recep-tors they in fact behave like ligand-inducible transcription

factors In the absence of hormones and through interactionwith cofactors that repress their transcriptional activity (core-pressors) the

TR reduces

the expression

of

the target

genesLigandbindingenables the TR to releasecorepressors to

recruitactivating partners of transcription (coactivators) and to theninduce

the transcription

of

the target

genes

To

fulfil all

thesefunctions (DNA-binding hormone binding transactivationactivity) the TRs are

organized

into

modules an

N -terminustransactivation domain a DNA-binding domain (DBD) a hingedomain

and a

ligand-binding domain

(LBD) Organized

as

asuccession

of

12

helices this last domain

has on

its C -terminusthe transactivation domain the activity of which is exerted in

the presence

of

the ligand

Indeedmodifications

of

the recep-tor structure occur during hormone binding and involve moreparticularly the 12th helix (H12) which includes the last C -terminus amino acidsIn

the

b

form

of

RTH

the

abnormality

is

carried

by

the

THRB

gene

The

mutations

are

essentially

distributed

over

the

LBD

andthe hinge domain (they do not affect the DNA-binding domainor

the

N -terminus

transactivation

domain)

(1047297 gure

1)

Threeregions rich in cytosine and guanine clusters (CpG islands)are particularly subject to genetic abnormalities (hot spots)[1]

even

though

some

mutations

have

been

reported

outsideof

these

hot

spots

[25] The

two functional

isoforms

producedfrom the THRB gene differing at their N -terminus (TRb1 andTRb2) are both concerned by these

C -terminus abnormalitiesDNA

binding

is

preserved

and

classically

the

mutated

receptorshave a reduced or absence of affinity for T3 They can also havenormal affinity for T3 but a constitutional inability to interactwith

coactivators

[1]

The

phenotype

is

expressed

while

a

singlecopy of the gene is usually involved (heterozygous mutation)The explanation lies in a dominant negative activity exerted bythe mutant receptors on the still functional isoforms By dime-rizing

with

them

they

prevent

the

release

of

the

corepressorsthe recruitment of the coactivators and finally transcriptionalactivity In 90 of cases the identified mutations are missensepoint

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

(whichstops protein translation) it may involve the deletion or inser-tion

of

a

nucleotide

base

which

then

leads

to

a

modification

ofthe reading frame and translation of the genetic message intoan erroneous protein message In the case of nonsense muta-tions

or

modifications

of

the

reading

frame

the

affected

recep-tors are truncated on a more or less long part of their

C -terminusCurrently

close

to

500

families

have

thus

been

identified

ascarriers of a THRB gene abnormality and close to 200 different

mutations have been identified (the same mutation may becarried by several different families) [1]As

of

now

there

are

8

known

different

mutations

affecting

theTHRA gene in patients with RTHa (table III ) As with THRB theyare located in the ligand-binding domain (1047297 gure

2) They alsoinvolve

point

mutations

(missense

or

nonsense)

or

abnormali-ties (insertion or deletion of a nucleotide) that result in modifi-cation of the reading frame thus causing a truncated receptorAs with RTHb point mutations seem to be predominant (6 out of8

times)

These

were

de

novo

mutations

in

6

patients

In4 patients the abnormality occurred through autosomal domi-nant transmission by an affected parent (father or mother)Contrary

to

isoforms

TRb1 and

TRb2

which

differ

on

their

N -

terminus

the

main

isoforms

produced

from

the

THRA

geneTRa1

and

TRa2

differ

on

their

C -terminus

They

share

a

commonprotein sequence up until the 360th amino acid the sequencesthen

diverge

resulting

in

a

functional

LBD

for

TRa1

and

an

LBDthat is incapable of binding T3 for TRa2 Six of the eight abnor-malities detected are located in the part of the gene concerningonly

TRa1 [14ndash161920] the

two

others

concern

the

commonsequence between TRa1 and TRa2 [1721] Several of themutations

identified

in

the

THRA

gene

in

cases

of

RTHa

werealso identified in the THRB gene in cases of RTHb A263V (THRA)

Figure

1

The

main

isoforms

produced

by

the

THRB

gene

and

themutations

described

in

the

b

form

of

resistance

to

thyroid

hormonesThe 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 thehinge

domain (D) which separates it from the DNA-binding domain (C) and theN -terminus

transactivation domain (AB) Theyare present in the common sequenceof isoforms

TRb1

and TRb2 Three areas are particularly sensitive to mutations (hot spots) and

are foundbetween aminoacids234and 282 ( 1) 309 and 353 ( 2) and 426 and

460 ( 3 numbering in 461 amino acids of the TRb1

receptor)

TRa

receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE





and

A317V

(THRB) [17] R384C

and

R438C

[1926] C392X

andC446X

mutations

[2027] Modification

of

the

reading

framefrom amino acid 382 in TRa1 (due to the insertion of a nucleo-tide base in the

THRA gene) [15] has also been reported in the

equivalent

residue

of

TRb1TRb2 (insertions

of

several

bases

inthe THRB gene) [28] although the erroneous consecutivesequence is not the same For the other

THRA gene mutations

with

no

strict

equivalent

in

the

THRB

gene

similar

mutationshave been described either resulting in another substitution oroccurring in a neighbouring residue One notable exceptionhowever is the N359Y mutation [21] which has no strictequivalent

and

in

which

the

corresponding

amino

acid

in

theTRb1TRb2 sequence is not in one of the three known hotspots (a partial explanation for this may lie in the distinctivefeatures

of

the

phenotype

associated

with

this

mutation

see

below)

In

any

case

comparison

of

the a

and b

forms

of

RTH

foridentical

or

equivalent

mutations

enables

the

respective

rolesof the different receptors to be specified In general then the b

receptors

seem

to

be

clearly

involved

in

the

hypothalamic-pituitary feedback loop while the a receptors are more involvedin the peripheral effects of THSeveral

TRa1 mutants

have

been

examined

in

functional

stud-ies Their common points include their incapability to induce theexpression

of

target

genes

and

their

dominant

negative

repres-sor activity over the normal TRa1 receptor [14ndash172129] When

it

was

evaluated

the

affinity

for

T3

was

reduced

[161721]Moreover

the

dominant

negative

activity

seems

to

be

exertedon the TRb1 receptor [152129] The still small number ofreported cases does not enable the formulation of genotypendashphenotype

correlations

For

example

only

two

mutations

affectboth TRa1 and TRa2 While the A263V mutation does not resultin a phenotype different from that observed for mutations thatonly

affect

TRa1 [17]the

phenotype

associated

with

the

N359Ymutation is particular due to the incidence (coincidental) of amarked malformation syndrome and hypercalcemia from para-thyroid hyperplasia and even to the absence of constipation andintellectual

deficit

(though

this

absence

has

also

been

observedin other cases) [21] Whether other isoforms produced from theTHRA

gene (TRa3 p43 P30 TRD1 and TRD2) are implicated inthe

phenotype

also

deserves

to

be

explored

[21] Although

this

needs

to

be

substantiated

with

subsequent

clinical

cases

thereis

a

tendency

for

more

serious

forms

to

exist

with

the

mutationoccurring early in the sequence and resulting in truncation Themost

significant

intellectual

deficit

(IQ

of

22)

was

described

forthe mutation involving the 18 amino acid deletion of TRa1 [20]Conversely patients with normal IQs are carriers of missensepoint

mutations

that

only

substitute

one

amino

acid

for

another[2021] In RTHb the severe forms are also often related toTRb1TRb2

truncations

[28] It

is

likely

that

truncations

(result-ing in the lack of C -terminal helix 12) induce more severe

TABLE IIIDescription

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

involvedfamilies

Number of

involvedpatients

THRA gene mutations2 Type of protein

mutation

Consequences for protein

functions

Involved

isoforms

References

A263V 1 3 Single base substitution (CxxxxT) Missense Single aminoacid substitution TRa1TRa2

[17]

N359Y 1 1 Single base substitution (C1075G) Missense Single aminoacid substitution TRa1TRa2

[21]

A382fs388X 1 1 Single base deletion(1144delG)

Frameshift Wrong sequence from A382then premature truncation at

position 388

TRa1 [16]

R384C 1 1 Single base substitution (C1150 T) Missense Single aminoacid substitution TRa1 [19]

C392X 1 1 Single base substitution (C1176A) No-sense Premature truncation atposition C392

TRa1 [20]

F397fs406X 1 2 Single base insertion(1144insT) Frameshift

Wrong sequence from F397then premature truncation atposition 406

TRa1 [1518]

P398R 1 1 Single base substitution (C1150 T) Missense Single aminoacid substitution TRa1 [20]

E403X 3 4 Single base substitution (C1176A) No-sense Premature truncation atposition E403

TRa1 [1420]

1The numbering is based on the TRa1 protein sequence (common to the TRa2 sequence until the amicoacid 360)2All mutations are located in exon 9 of the THRA gene (last exon of TRa1 and the secondlast for TRa2)


tome 44 gt n811





Figure 2

The

main

isoforms

produced

by

the

THRA

gene

and

the

mutations

described

in

the

a

form

of

resistance

to

thyroid

hormonesIsoform TRa1 isa functional receptor capable of binding DNA and T3 and influencingunder thecontrolof thelatter theexpression of target genes Isoform TRa2

is incapable of

binding thehormoneand behaves like a weak dominant negative inhibitor of the T3 functionalreceptorsFor now themutations found in RTHa rein the T3 binding domain (E)

while

thehinge domain(D) theDNA-binding domain (C)and theN -terminus transactivation domain (AB) arespared Themutationsconcern the commonsequence of thetwo

isoforms TRa1andTRa2 oronlyaffectthe C -terminussequence of TRa1 (numbering in410 amino acids ofthe TRa1 receptor) Thepoint mutations arerepresentedby a star and

the

frameshift mutations by a star at the level of the first mutated amino acid fol lowed 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






phenotype by profoundly affecting TR function through totalinability

to

interact

with

coactivatorsThe genotypendashphenotype correlations may in fact need to beinvestigatedin

animal

modelsMicewith

complete

inactivationof the THRA andor

THRB genes have been reported [11] but

may not represent the most relevant models as the absence ofa receptor does nothave the same consequences as the expres-sion

of

an

abnormal receptor

The comparison

is

more

logical inanimal

models

with

an

artificially

introduced

mutation For theTHRA

gene thereare fourdifferentmodels available that are allbased

on

a

mutation

of

the hormone-binding domain in

onlythe TRa1 receptor (1047297 gure 2 no model with mutation affectingTRa1

and TRa2)

One model

introduced

in

TRa1 the PV

muta-tion [13] which was identified in a patientwith RTHb (insertionof

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

providephenotypic data that are complementary to those reported inhuman cases The growth retardation with impairment in ossi-fication is consistent in all animals [132931ndash34] The role ofTRa1

in

the development

of

chondrocytes

is probably a

deter-mining factor

as

the

elective introduction

of

the

L400R

muta-tion in the chondrocytes is sufficient to induce the phenotype[35]

The severity

of

the bone phenotype however

is

variabledepending on the models The bone phenotype of the R384Cmutation for instance was observed in young mice and dis-appeared in

the adultmice

[29]

In humans this

mutationwasreported in

a

girl though

it

is

only

known that

she

was

a

carrierof a familial form of autism without other information on herphenotype It is interesting to observe that the R384C mice hadsignificant psychomotor

disorders

with

anxiety memoryimpairment and depression (which are possible even fre-quent manifestations of autism) [3637] Cerebellar ataxiawas

also

observed

in

another

model

[31]

which

is

somewhatsimilar to the clumsiness and awkwardness described in thegait or the handling of objects in several patients with RTHa[141617] In animals these psychoneuromotor disorders arerelated

to impairment

of

neurogenesis

in

the hippocampus(lack of certain GABAergic interneurons) [38] and diminishpartially with levothyroxine [3638] This reduction on treat-ment

is not

observed

for the

bone

phenotype [39] as

was

also

reported in

humans Another

common

point of

the animalmodels

with

TRa1 mutations

is the

near-normality

of

TH

serumlevels On the other hand TSH has been found to be high inseveral

models

[1332]

as

opposed to its usual observed nor-mality in patients with RTHa (high-normal values in one case[16]) The T4T3 ratio and the reverse T3 (rT3) found to be lowin

patients with

RTHa

are

considered

an

indication of

theperipheral metabolism of TH Interestingly high levels of type1

deiodinase

(responsible for the conversion

of

T4

into

T3 andfor 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 [293132]which

was

rather

mild

but

accompanied

by

inadaptation

tostress [40] Bradycardia was reported in patients with RTHa

[141617] but the rare functional heart explorations that weredone did not demonstrate serious abnormalities [16] Bradycar-dia

is

probably

the

result

of

the

direct

effect

of

TH

on

themyocardium

(known

target

tissue

of

TH

expressing

ratherTRa1) abnormalities of calcium flux and contractility wereobserved

in

one

model

[41] However

there

is

probably

anothermechanism involved namely deregulation of the autonomicnervous

system

due

to

abnormal

brain

development

[4042]The same mechanism (lack of cerebral control on the autonomicnervous

system)

has

been

suggested

as

an

explanation

forthermogenesis

abnormalities

These

abnormalities

have

notbeen actually reported (not explored) in patients with RTHa

A

reduction

in

body

temperature

andor

a

cold

intolerance

wasdescribed in two murine models [3132] Dysfunction of thebrown fat is suspected related to deregulation of the autonomicnervous system caused by abnormal brain development [38]Increased

vasodilatation

again

related

to

the

autonomic

ner-vous

system

was

supposedly

also

observed

in

one

of

the

mo-dels with abnormal thermogenesis [43]One

patient

with

RTHa

had

weight

loss

(occurring

in

childhoodand continuing in adulthood) [21] while the other patients hadnormal or increased weight [15ndash18] One murine model exhib-ited

overweight

(without

increased

food

intake)

hepatic

stea-tosis

and

insulin

resistance

[32] but

a

controversy

exists

aboutthe real responsibility of THRA mutation Two others models hadhyperphagia without weight gain resistance to tube-feedingmild

adiposity

due

to

impairment

of

adipogenesis

and

low

liverconcentrations of lipids [44ndash46] The same mechanism aninteraction with PPARg has been suggested in both of thesecontrary

situations

[4547]

ConclusionsTowards the end of the 1980s the first descriptions of abnor-malities of the

THRB gene in patients with RTHb generated a

very

large

number

of

questions

about

the

possibility

of

muta-tions

in

the

THRA

gene

Answers

have

arrived

more

than

20

yearslater with the description of clinical phenotypes that are quite

particular

abnormalities

suggestive

of

mild

untreated

congeni-tal hypothyroidism in conjunction with thyroid function teststhat are more or less normal and therefore discordant For themoment

suggestive

symptoms

are

short

stature

hypothyroid-ism-like

facial

shape

and

low

T4T3

ratio

It

is

worthy

to

notethat

the

whole

exome

database

(httpexacbroadinstituteorg) contains 68

THRA missense or frameshift mutations with

most

of

them

predicted

to

alter

TRa1 function

It

is

thereforelikely that several patients in the general population haveundiagnosed RTHa with milder phenotype As in RTHb it is


tome 44 gt n811





the discordance between the clinical and the laboratory datathat

should

stand

out

for

the

clinician

The

identification

ofpatients with authenticated abnormalities of the

THRA gene

is

essential

for

improving

the

definition

of

the

clinical

spectrumof RTHa and more generally of all RTH and syndromes of

reduced sensitivity to thyroid hormones This improved pheno-typic definition will enable genotypendashphenotype correlations tobe

formulated

and

perhaps

the

development

of

therapeuticguidelines

The

reported

cases

show

that

the

administrationof TH in patients with RTHa does not improve all the symptomsprobably

because

the

therapeutic

management

occurs

too

latefor certain abnormalities that have already become definitivelyestablished

andor

because

the

tissue

resistance

is

too

severeThe extreme dependence for TH during the brain development isa

clear

example

of

the

need

for

early

treatment

The

significance

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

abnormality

The

different

murine

models

with

diversegenetic abnormalities may thus be valuable tools for testing thetherapeutic

approaches

Assuming

that

the

resistance

is

toosevere to be managed by hormonal treatment identification

of the major role in animals of the interaction of mutated TRa1with corepressors such as NCoR [48] was crucial Indeed it ledto

the

demonstration

of

the

partial

reversal

of

the

abnormalTHRA

gene

phenotype

through

the

coexpression

of

a

mutantNCoR unable to interact with the TRs [49] and through theadministration

of

an

inhibitor

of

the

corepressors-associatedhistone deacetylase activity [50]

Disclosure of interest the authors declare that they have no conflicts ofinterest concerning this article

References[1] Dumitrescu AM Refetoff S The syndromes

of reduced sensitivity to thyroid hormoneBiochim Biophys Acta 201318303987ndash 4003

[2] Refetoff S DeWind LT

DeGroot LJ Familialsyndrome combining deaf-mutism stuppledepiphyses goiter and abnormally high PBIpossible target organ refractoriness to thyroidhormone J Clin Endocrinol Metab196727279ndash 94

[3] Sakurai A TakedaK Ain K Ceccarelli P NakaiA Seino S et al Generalized resistance tothyroid hormone associated with a mutationin the ligand-binding domain of the humanthyroid hormone receptor beta Proc Nat l

Acad Sci U S A 1989868977ndash 81

[4] Vlaeminck-Guillem V Margotat A Torresani J DHerbomez M Decoulx M Wemeau JLResistance to thyroid hormone in a familywith no TRbeta gene anomaly pathogenichypotheses Ann Endocrinol (Paris)200061149ndash 94

[5] Weiss RE

Hayashi Y

Nagaya T

Petty KJMurata Y Tunca H et al Dominant inheri-tance of resistance to thyroid hormone notlinked to defects in the thyroid hormonereceptor alpha or beta genes may be dueto a defective cofactor J Clin EndocrinolMetab1996814196ndash 203

[6] Pohlenz J Weiss RE

Macchia PE Pannain SLau IT Ho H et al Five new families with

resistance to thyroid hormone not caused bymutations in the thyroid hormone receptorbeta gene J Clin Endocrinol Metab1999843919ndash 28

[7] DumitrescuAM Liao XH Abdullah MS Lado-Abeal J Majed FA Moeller LC et al Muta-tions in SECISBP2 result in abnormal thyroidhormone metabolism Nat Genet2005371247ndash 52

[8] Dumitrescu AM Liao XH Best TB Brock-mann K Refetoff S A novel syndromecombining thyroid and neurological

abnormalities is associated with mutationsin a monocarboxylate transporter gene Am J Hum Genet 200474168ndash 75

[9] Friesema EC Grueters A

Biebermann HKrude H von Moers A Reeser M et alAssociation between mutations in a thyroidhormone transporter and

severe X-linked psy-chomotor retardation Lancet 20043641435ndash 7

[10] Refetoff S Bassett JH

Beck-Peccoz P Bernal JBrent G Chatterjee K et al Classificationandproposednomenclaturefor inheriteddefects ofthyroid hormone action cell transport andmetabolism Eur Thyroid J 201437ndash 9

[11] Vlaeminck-Guillem V Wemeau JL

Physiolo-gie et physiopathologie des reacutecepteurs thyr-oiumldiens lapport des modegraveles murins AnnEndocrinol (Paris) 200061440ndash 51

[12] Wikstrom L Johansson C Salto C Barlow CCampos Barros A Baas F et al Abnormalheart rate and body temperature in micelacking thyroid hormone receptor alpha 1EMBO J 199817455ndash 61

[13] Kaneshige M Suzuki H Kaneshige K Cheng J Wimbrow H Barlow C et al A targeteddominant negative mutation of the thyroidhormone alpha 1 receptor causes increasedmortality infertility and dwarfism in miceProc Natl Acad Sci U S A 20019815095ndash 100

[14] Bochukova E Schoenmakers N Agostini M

Schoenmakers E RajanayagamO Keogh JMet al A mutation in the thyroid hormonereceptor alpha gene N Engl J Med2012366243ndash 9

[15] van Mullem A van Heerebeek R Chrysis DVisser E Medici M Andrikoula M et alClinical phenotype and mutant TRalpha1 NEngl J Med 20123661451ndash 3

[16] Moran C

Schoenmakers N Agostini MSchoenmakers E Offiah A

Kydd

A et alAn adult female with resistance to thyroidhormone mediated by defective thyroid

hormone receptor alpha J Cl in EndocrinolMetab 2013984254ndash 61

[17] Moran C Agostini M Visser WE Schoen-makers E SchoenmakersN Offiah AC etalResistance to thyroid hormone caused by amutation in thyroid hormone receptor (TR)alpha1 and

TRalpha2 clinical biochemicaland genetic analyses

of three

related patientsLancet Diabet Endocrinol 20142619ndash 26

[18] van Mullem AA Chrysis D Eythimiadou AChroni E Tsatsoulis A de Rijke YB et alClinical phenotype of a new type of thyroidhormone resistance caused by a mutation ofthe TRalpha1 receptor consequences of LT4

treatment J Clin Endocrinol Metab2013983029ndash 38

[19] Yuen RK Thiruvahindrapuram B Merico DWalker S Tammimies K Hoang N et alWhole-genome sequencing of quartetfamilies with autism spectrum disorder NatMed 201521185ndash 91

[20] Tylki-Szymanska A Acuna-Hidalgo R Kra- jewska-Walasek M Lecka-Ambroziak ASteehouwer M Gi lissen C et al Thyroidhormone resistance syndrome due to muta-tions in the thyroid hormone receptor alphagene (THRA) J Med Genet 201552312ndash 6

[21] Espiard S Savagner F

Flamant F

Vlaeminck-Guillem V Guyot R Munier M

et al A novelmutation in THRA gene associated with an

atypical phenotype of resistance to thyroidhormone J Clin Endocrinol Metab 2015 jc20151120

[22] Faivre L Cormier-Daire V GenevieveD PintoG Goulet O

Munnich A

et al A novelsyndrome with dwarfism poorly muscledbuild absent clavicles humeroradial fusionslender bones oligodactyly and micro-gnathia Clin Dysmorphol 200110181ndash 4

[23] Mundlos S Cleidocranial dysplasia clinicaland molecular genetics J Med Genet199936177ndash 82






[24] Mundlos S Otto F

Mundlos C Mulliken JBAylsworth AS Albright S et a l Mutat ionsinvolving the transcription factor CBFA1

causecleidocranial dysplasia Cell 199789773ndash 9

[25] Margotat A

Sarkissian G Malezet-Desmou-lins C Peyrol N Vlaeminck Guillem V

Wemeau JL

et al Ident if ication of eightnew mutations in the c-erbAB gene ofpatients with resistance to thyroid hormoneAnn Endocrinol 200162220ndash 5

[26] Adams M Matthews C Coll ingwood TNToneY

Beck-Peccoz P ChatterjeeKK Geneticanalysis of 29 kindreds with generalized andpituitary resistance to thyroid hormone Iden-tification of thirteen novel mutations in thethyroid hormone receptor beta gene J ClinInvest 199494506ndash 15

[27] Groenhout EG Dorin RI Generalized thyroidhormone resistance due to a deletion of thecarboxy terminus of the c-erbA beta receptorMol Cell Endocrinol 19949981ndash 8

[28] Wu SY CohenRN SimsekE Senses DA Yar

NE Grasberger H et al A novel thyroidhormone receptor-beta mutation that failsto bind nuclear receptor corepressor in apatient as an apparent cause of severe pre-dominantly pituitary resistance to thyroid hor-mone J Clin Endocrinol Metab 2006911887ndash 95

[29] Tinnikov A Nordstrom K Thoren P Kindblom JM Malin S Rozell B et al Retardation ofpost-natal development caused by a nega-tively acting thyroid hormone receptoralpha1 EMBO J 2002215079ndash 87

[30] Parrilla R

Mixson AJ McPherson JA

McClas-key JH Weintraub BD Characterization ofseven novel mutations of the c-erbA betagene in unrelated kindreds with generalizedthyroidhormone resistance Evidence for twohot spot regions of the l igand bindingdomain J Clin Invest 1991882123ndash 30

[31] Quignodon L VincentS Winter H Samarut JFlamant F A point mutation in the

activationfunction2 domainof thyroidhormonereceptoralpha1 expressed after CRE-mediated recom-bination partially recapitulates hypothyroid-ism Mol Endocrinol 2007212350ndash 60

[32] Liu YY

Schultz JJ

Brent GA A thyroidhormone receptor alpha gene mutation

(P398H) is associated with visceral adiposityand impaired catecholamine-stimulated lipo-lysis in mice J Biol Chem 200327838913ndash 20

[33] OShea PJ Bassett JH ChengSY Williams GRCharacterization of skeletal phenotypes ofTRalpha1 and TRbeta mutant mice implica-

tions for tissue thyroid status and T3 targetgene expression Nucl Recept Signal 20064e011

[34] OShea PJ Bassett JH Sriskantharajah S YingH Cheng SY Williams GR Contrasting ske-leta l phenotypes in mice with an identicalmutation targeted to thyroid hormone recep-tor alpha1 or beta Mol Endocrinol2005193045ndash 59

[35] Desjardin C

Charles C

Benoist-Lasselin CRiviere J Gilles M Chassande O et alChondrocytes play a major role in the stimu-lation of bone growth by thyroid hormoneEndocrinology 20141553123ndash 35

[36] Venero C Guadano-Ferraz A Herrero AINordstrom K Manzano J de Escobar GM

et al Anxiety memory impairmentand loco-motor dysfunction caused by a mutant thyr-oid hormone receptor alpha1 can beameliorated by T3 treatment Genes Dev2005192152ndash 63

[37] Pilhatsch M

Winter C

Nordstrom K Venn-strom B Bauer M

Juckel G Increaseddepressive behaviour in mice harboring themutant thyroid hormone receptor alpha 1Behav Brain Res 2010214187ndash 92

[38] Kapoor R

van Hogerlinden M

Wallis KGhosh H Nordstrom K Vennstrom Bet al Unliganded thyroid hormone receptoralpha1 impairs adult hippocampal neurogen-esis FASEB J 2010244793ndash 805

[39] Bassett JH Boyde A Zikmund T Evans HCroucher PI

Zhu X

et al

Thyroid hormonereceptor alpha mutation causes a severe

andthyroxine-resistant skeletaldysplasiain femalemice Endocrinology 20141553699ndash 712

[40] Mittag J Davis B Vujovic M Arner AVennstromB Adaptations of theautonomousnervous system controlling heart rate areimpairedby amutant thyroid hormone recep-tor-alpha1 Endocrinology 20101512388ndash 95

[41] Tavi P Sjogren M Lunde PK Zhang SJAbbate F

Vennstrom B et al Impaired

Ca2+ handling and contraction in cardiomyo-cytes from mice with a dominant negativethyroid hormone receptor alpha1 J Mol CellCardiol 200538655ndash 63

[42] Mittag J Lyons DJ Sall strom J Vujovic MDudazy-Gralla S Warner A

et al Thyroid

hormone is required for hypothalamic neu-rons regulating cardiovascular functions J ClinInvest 2013123509ndash 16

[43] Warner A RahmanA Solsjo P Gottschling KDavis B Vennstrom B et al Inappropriateheatdissipation ignitesbrown fat thermogen-esis in mice with a mutant thyroid hormonereceptor alpha1 Proc Natl Acad Sci U S A201311016241ndash 46

[44] SjogrenM AlkemadeA

MittagJ

NordstromK KatzA Rozell B etal Hypermetabolisminmice caused by the central action of an unli-ganded thyroid hormone receptor alpha1EMBO J 2007264535ndash 45

[45] Ying H Araki O Furuya F Kato Y Cheng SYImpaired adipogenesis caused by a mutated

thyroid hormone alpha1 receptor Mol CellBiol 2007272359ndash 71

[46] Araki O

Ying H Zhu XG Willingham MCChengSY Distinct dysregulationof lipid meta-bolismbyunligandedthyroid hormone recep-tor isoforms Mol Endocrinol 200923308ndash 15

[47] Liu YY

Heymann RS Moatamed F

Schultz JJSobel D Brent GA A mutant thyroid hor-mone receptor alphaantagonizesperoxisomeproliferator-activated receptor alpha signalingin vivo and impairs fatty acid oxidation Endo-crinology 20071481206ndash 17

[48] Fozzatt i L Lu C

Kim DW Cheng SY Differ-ential recruitment of nuclear coregulatorsdirects the isoform-dependent action ofmutant thyroid hormonereceptorsMol Endo-crinol 201125908

ndash 21

[49] Fozzatti

L Kim

DW

ParkJW Willingham

MCHollenberg AN Cheng SY Nuclear receptorcorepresso r (NCOR1) regulates in vivoactions ofa mutated

thyroid

hormone recep-tor alpha Proc Natl

Acad

Sci U S A20131107850ndash 5

[50] Kim DW ParkJW

Willingham MC Cheng SYA histone deacetylase inhibitor improveshypothyroidism caused by a TRalpha1mutant Hum Mol Genet 2014232651ndash 64


tome 44 gt n811





IntroductionThe 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 thyroidhormone receptor (TRb) with the first clinical description occur-

ring

in

1967

[2]

and

the

first

demonstration

of

the

underlyingmolecular mechanism in 1989 [3] The secondary description oftypical

sporadic

and

familial

cases

though

without

identifiedabnormality of the

THRB (thyroid hormone receptor beta) gene

(currently

estimated

at

about

15

of

cases)

quickly

suggestedthe possibility of other molecular causes for the lack of tissuesensitivity to the action of TH [4ndash6] It was not until the mid-2000s

that

abnormalities

in

transmembrane

transport

and

THmetabolism were described as the cause of this reduced sensi-tivity

of

target

tissues

to

TH

action

affecting

respectively

theMCT8 gene (monocarboxylate transporter 8) and the SBP2 gene(selenocysteine

insertion

sequence-binding

protein

2)

[7ndash10]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

Whileviable murine models (review in [11]) of inactivation [12] ormutation

[13]

in

the

THRA

gene

have

rapidly

been

publishedmutations in humans were considered by the simple reason oftheir absence to be extremely rare lethal or subclinicallyexpressed The phenotype of patients in whom

THRA gene

mutations

were

finally

described

is

retrospectively

suggestiveof

that

described

over

10

years

previously

in

murine

models

It

isremarkable however to notice that the first case of RTH due toTRa

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

targetingbut

during

whole

genome

sequencing

[14]

Likewise

the

twoother

cases

described

in

the

same

year

were

discovered

througha

candidate

gene

approach

after

ruling

out

an

abnormalityaffecting a TH transporter or deiodinase [15] Patients indeedpresent

with

quite

normal

thyroid

laboratory

testing

a

confus-ing situation that usually lead patients to present themselves innon-endocrinological clinical departmentsThe

molecular

decoding

of

RTHa has

only

just

begun

and

thedescription of at least several tens of cases will be able to

precisely delineate its clinical spectrum At present only14

patients

with

RTHa

have

been

found

in

the

literatureamongst 9 distinct families [14ndash21] And although their commonclinical aspects are emerging the analysis also clearly showsdiversity

in

the

phenotype

The

purpose

of

this

review

is

topresent published cases of RTHa and to provide details on theirunderlying

molecular mechanisms particularly in the light ofavailable

murine

models

The

objective

is

to

thus

promote

thediagnostic

identification

of

patients

in

order

to

better

define

theextent of the clinical manifestations related to congenital anom-alies of TH action

Clinical presentation and biologyAlthough

14

patients

with

identified

genetic

abnormalities

havebeen reported in the literature clinical data for only 13 of themare

available

The

genetic

identification

for

the

fourteenth

wasdone as part of whole genome sequencing in subjects withfamilial forms of autism [19] Abnormality of the

THRA gene was

not specifically investigated and no description of the case wasavailable

other

than

the

fact

that

the

female

patient

who

wasautistic had a brother who was also an autistic non-carrier of theTHRA

mutation [19]The patients included 9 women and 5 menbut

it

is

too

early

to

define

a

sex

ratio

(it

is

11

in

RTHb [1])

Thecases were sporadic (de novo mutation) or familial (mutationtransmitted by a parent who was a carrier) In the reportedcases

the

age

at

the

molecular

diagnosis

varied

(seven

childrenor adolescents and seven adults) which contributes to certainvariations in the clinical descriptions and even in the adultsuncertainty as to the description of the phenotype in childhoodThe

clinical

presentation

of

RTHa

always

includes

although

to

varying

degrees

the

combination

of

a

dysmorphic

syndromeand psychomotor development disorders (table

I ) Of note is theabsence

of

goiter

which

is

usually

among

the

typical

manifes-tations of RTHb Generally there are signs of mild to moderateuntreated

congenital

hypothyroidism

The

near-normal

valuesof the laboratory thyroid function tests (cf below) must thensignal

the

possibility

of

RTHa

and

prompt

a

genetic

analysis

ofthe patient The manifestations related to hypothyroidism thusreported are mild to moderate intellectual deficit decreasedstature

alterations

in

ossification

macroglossia

and

chronic

une

hypothyroiumldie

congeacutenitale

modeacutereacutee

non

traiteacutee

et

une

(quasi-)

normaliteacute

des

formes

libres

et

totales

des

hormones

thyroiumldiennes

et

de

la

TSH

(le

ratio

T4T3

est

toutefois

habituellement

diminueacute) Le pheacutenotype peut inclure agrave des degreacutes divers une courte taille (par retard de

croissance)

un

syndrome

dysmorphique

(face

et

extreacutemiteacutes

des

membres)

des

troubles

neuro-psychomoteurs

une

constipation

et

une

bradycardie

Les

anomalies

geacuteneacutetiques

ont

eacuteteacute

identi 1047297 eacutees dans le domaine de liaison du ligand et aboutissent agrave un deacutefaut de liaison de la T3 uneinteraction

anormalement

forte

avec

les

coreacutepresseurs

et

une

activiteacute

dominante

neacutegative

sur

les

reacutecepteurs

resteacutes

fonctionnels

La

reconnaissance

des

cas

et

lidenti 1047297 cation

des

mutations

sous-

jacentes

sont

indispensables

pour

mieux

deacute1047297 nir le

spectre

des

syndromes

de

sensibiliteacute

reacuteduite

aux hormones thyroiumldiennes


tome 44 gt n811





constipation

The

dysmorphic

syndrome

combines

small

staturedecreased

limb

length

with

a

trunk

that

is

of

rather

normal


that

may

include

macrocephaly

(the

need

for


delayed

tooth

eruption

a

short

neck

or


(sometimes

detected

in

utero)

and

can

even

border


Malformations

have

also

been

reported

such

as

congenitalhip

dislocation

or

coxa

valga

One

described

case

included


a

separate

publication

more

than

10

years

before


dislocation

syndactyly

of

the

4th

and

5th

toes

absence


of

cleidocranial

dysostosis

[2324]) With

regard


TABLE IClinical

phenotype

of

the

14

published

cases

of

resistance

to

thyroid

hormone

due

to

a

defective

TRa

receptor




Dysmorphic syndrome

Figure





Face dysmorphism


7th patient)




Cognition disorders














deficit

has

often

been

reported

but

is

not


in

childhood

one

case

of

diarrhoea

occurring

late



appears

normal

[1518] whereas

the

baselinemetabolism

is

decreased

[14161721] Finally

cases

of


in

association

with

myxoedema

of


is

consistently

present

in

all

clinical

descriptions

but



may

also


growth

factor

1

may

be

low

in


Radiological

exams

are

done

to

investigate

potential


[14]

Ossification

delay

is

also

evidenced

by


(femoral

heads)

[141518]

and

by

delayed


X-rays

again

show

macrocephaly

with

thickening

of


the

long

bones

of

the

limbs


meas-urements

in

adults

are

usually

normal


reassurance

when

values

are

normal

or

low

normal

they


clinical

presentation

It

is

this

dissociation

between


(including

the

dysmorphic

syndrome)



(table

II )

In

this

respect

it

can

be

seen

that

thedissociation

between

the

clinical

and

laboratory


thyroid

hormone

values

both

in

their

free

and

total


slightly

low

and

T3

slightly

high

As

a

result

there

is


all

the

published

cases

The

TSH

is

normal

(though

low

insome

cases)

It

should

be

noted

that

neonatal

screening


Several

patients

received

treatment

with

levothyroxine


and

definitive

[14] Benefits

can

be

seen

for

brady-cardia

energy

levels

bowel

function

and

carpal

tunnel


thyroid

hormones

and

a

quick

and

predictable

suppression


values

(blood

cholesterol

anaemia)

is

not

constant



TABLE IIClinical

and

biological

phenotypes

of

the

a

and

b

syndromes

of

resistance

to

thyroid

hormones

RTHa RTHb





Goiter No Yes


fT4 Low normal High

T4T3 ratio Low Low




tome 44 gt n811







or


the target


nuclear



TR reduces

the expression

of

the target



the transcription

of

the target

genes

To

fulfil all


organized

into

modules an


and a


(LBD) Organized

as

asuccession

of

12


has on


the presence

of

the ligand

Indeedmodifications

of


the

b

form

of

RTH

the

abnormality

is

carried

by

the

THRB

gene

The

mutations

are

essentially

distributed

over

the

LBD


the

N -terminus

transactivation

domain)

(1047297 gure

1)


even

though

some

mutations

have

been

reported

outsideof

these

hot

spots

[25] The

two functional

isoforms



binding

is

preserved

and

classically

the

mutated


coactivators

[1]

The

phenotype

is

expressed

while

a


with

them

they

prevent

the

release

of

the


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


of

a

nucleotide

base

which

then

leads

to

a

modification


or

modifications

of

the

reading

frame

the

affected



close

to

500

families

have

thus

been

identified



of

now

there

are

8

known

different

mutations

affecting


2) They alsoinvolve

point

mutations

(missense

or

nonsense)

or


times)

These

were

de

novo

mutations

in

6

patients


to

isoforms

TRb1 and

TRb2

which

differ

on

their

N -

terminus

the

main

isoforms

produced

from

the

THRA

geneTRa1

and

TRa2

differ

on

their

C -terminus

They

share

a


diverge

resulting

in

a

functional

LBD

for

TRa1

and

an



two

others

concern

the


identified

in

the

THRA

gene

in

cases

of

RTHa


Figure

1

The

main

isoforms

produced

by

the

THRB

gene

and

themutations

described

in

the

b

form

of

resistance

to

thyroid


and





TRb1




receptor)

TRa






and

A317V

(THRB) [17] R384C

and

R438C

[1926] C392X

andC446X

mutations

[2027] Modification

of

the

reading



equivalent

residue

of


of

several

bases


THRA gene mutations

with

no

strict

equivalent

in

the

THRB

gene

similar


and

in

which

the

corresponding

amino

acid

in


of

the

phenotype

associated

with

this

mutation

see

below)

In

any

case

comparison

of

the a

and b

forms

of

RTH

foridentical

or

equivalent

mutations

enables

the

respective


receptors

seem

to

be

clearly

involved

in

the


TRa1 mutants

have

been

examined

in

functional


of

target

genes

and

their

dominant

negative


it

was

evaluated

the

affinity

for

T3

was

reduced

[161721]Moreover

the

dominant

negative

activity

seems

to

be


correlations

For

example

only

two

mutations


affect

TRa1 [17]the

phenotype

associated

with

the


deficit

(though

this

absence

has

also

been



phenotype

also

deserves

to

be

explored

[21] Although

this

needs

to

be

substantiated

with

subsequent

clinical

cases

thereis

a

tendency

for

more

serious

forms

to

exist

with

the


significant

intellectual

deficit

(IQ

of

22)

was

described


mutations

that

only

substitute

one

amino

acid

for


truncations

[28] It

is

likely

that

truncations



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

involvedfamilies

Number of

involvedpatients


mutation


functions

Involved

isoforms

References


[17]


[21]



position 388

TRa1 [16]



TRa1 [20]



TRa1 [1518]



TRa1 [1420]



tome 44 gt n811





Figure 2

The

main

isoforms

produced

by

the

THRA

gene

and

the

mutations

described

in

the

a

form

of

resistance

to

thyroid


is incapable of


while



the











to

interact

with


animal

modelsMicewith

complete




of

an

abnormal receptor

The comparison

is

more

logical inanimal

models

with

an

artificially

introduced



on

a

mutation

of



and TRa2)

One model

introduced

in

TRa1 the PV


several

nucleotides

with

modification of

the reading

frame)[30]

while

the others

introduce

point

mutations

R384C



RTHa

[19])

L400R

[31]

and P398H

[32] These models


in

the development

of

chondrocytes

is probably a

deter-mining factor

as

the


of

the

L400R


The severity

of


is


the adultmice

[29]

In humans this


a

girl though

it

is

only

known that

she

was

a


disorders

with


also

observed

in

another

model

[31]

which

is


to impairment

of

neurogenesis

in


is not

observed

for the

bone

phenotype [39] as

was

also

reported in

humans Another

common

point of

the animalmodels

with

TRa1 mutations

is the

near-normality

of

TH


models

[1332]

as


patients with

RTHa

are

considered

an

indication of


deiodinase


of

T4

into



detected

in


was

rather

mild

but

accompanied

by

inadaptation



is

probably

the

result

of

the

direct

effect

of

TH

on

themyocardium

(known

target

tissue

of

TH

expressing


in

one

model

[41] However

there

is

probably


system

due

to

abnormal

brain

development


system)

has

been

suggested

as

an

explanation

forthermogenesis

abnormalities

These

abnormalities

have


A

reduction

in

body

temperature

andor

a

cold

intolerance


vasodilatation

again

related

to

the

autonomic

ner-vous

system

was

supposedly

also

observed

in

one

of

the


patient

with

RTHa

had

weight

loss

(occurring

in


overweight

(without

increased

food

intake)

hepatic

stea-tosis

and

insulin

resistance

[32] but

a

controversy

exists


adiposity

due

to

impairment

of

adipogenesis

and

low


situations

[4547]



very

large

number

of

questions

about

the

possibility

of

muta-tions

in

the

THRA

gene

Answers

have

arrived

more

than

20


particular

abnormalities

suggestive

of

mild

untreated


suggestive

symptoms

are

short

stature


facial

shape

and

low

T4T3

ratio

It

is

worthy

to

notethat

the

whole

exome

database



most

of

them

predicted

to

alter

TRa1 function

It

is



tome 44 gt n811






should

stand

out

for

the

clinician

The

identification


THRA gene

is

essential

for

improving

the

definition

of

the

clinical



formulated

and

perhaps

the

development

of


The

reported

cases

show

that

the


because

the

therapeutic

management

occurs

too


andor

because

the

tissue

resistance

is

too


clear

example

of

the

need

for

early

treatment

The

significance


abnormality

The

different

murine

models

with


approaches

Assuming

that

the

resistance

is



the

demonstration

of

the

partial

reversal

of

the

abnormalTHRA

gene

phenotype

through

the

coexpression

of

a


of

an

inhibitor

of

the










[5] Weiss RE

Hayashi Y

Nagaya T




















[16] Moran C


Kydd





of three







Flamant F





Munnich A











[25] Margotat A


Wemeau JL








[30] Parrilla R





[32] Liu YY

Schultz JJ






[35] Desjardin C

Charles C




[37] Pilhatsch M

Winter C



[38] Kapoor R

van Hogerlinden M



Zhu X

et al








et al Thyroid




MittagJ




[46] Araki O


[47] Liu YY





ndash 21

[49] Fozzatti

L Kim

DW

ParkJW Willingham


thyroid


Acad


[50] Kim DW ParkJW



tome 44 gt n811





constipation

The

dysmorphic

syndrome

combines

small

staturedecreased

limb

length

with

a

trunk

that

is

of

rather

normal


that

may

include

macrocephaly

(the

need

for


delayed

tooth

eruption

a

short

neck

or


(sometimes

detected

in

utero)

and

can

even

border


Malformations

have

also

been

reported

such

as

congenitalhip

dislocation

or

coxa

valga

One

described

case

included


a

separate

publication

more

than

10

years

before


dislocation

syndactyly

of

the

4th

and

5th

toes

absence


of

cleidocranial

dysostosis

[2324]) With

regard


TABLE IClinical

phenotype

of

the

14

published

cases

of

resistance

to

thyroid

hormone

due

to

a

defective

TRa

receptor




Dysmorphic syndrome

Figure





Face dysmorphism


7th patient)




Cognition disorders














deficit

has

often

been

reported

but

is

not


in

childhood

one

case

of

diarrhoea

occurring

late



appears

normal

[1518] whereas

the

baselinemetabolism

is

decreased

[14161721] Finally

cases

of


in

association

with

myxoedema

of


is

consistently

present

in

all

clinical

descriptions

but



may

also


growth

factor

1

may

be

low

in


Radiological

exams

are

done

to

investigate

potential


[14]

Ossification

delay

is

also

evidenced

by


(femoral

heads)

[141518]

and

by

delayed


X-rays

again

show

macrocephaly

with

thickening

of


the

long

bones

of

the

limbs


meas-urements

in

adults

are

usually

normal


reassurance

when

values

are

normal

or

low

normal

they


clinical

presentation

It

is

this

dissociation

between


(including

the

dysmorphic

syndrome)



(table

II )

In

this

respect

it

can

be

seen

that

thedissociation

between

the

clinical

and

laboratory


thyroid

hormone

values

both

in

their

free

and

total


slightly

low

and

T3

slightly

high

As

a

result

there

is


all

the

published

cases

The

TSH

is

normal

(though

low

insome

cases)

It

should

be

noted

that

neonatal

screening


Several

patients

received

treatment

with

levothyroxine


and

definitive

[14] Benefits

can

be

seen

for

brady-cardia

energy

levels

bowel

function

and

carpal

tunnel


thyroid

hormones

and

a

quick

and

predictable

suppression


values

(blood

cholesterol

anaemia)

is

not

constant



TABLE IIClinical

and

biological

phenotypes

of

the

a

and

b

syndromes

of

resistance

to

thyroid

hormones

RTHa RTHb





Goiter No Yes


fT4 Low normal High

T4T3 ratio Low Low




tome 44 gt n811







or


the target


nuclear



TR reduces

the expression

of

the target



the transcription

of

the target

genes

To

fulfil all


organized

into

modules an


and a


(LBD) Organized

as

asuccession

of

12


has on


the presence

of

the ligand

Indeedmodifications

of


the

b

form

of

RTH

the

abnormality

is

carried

by

the

THRB

gene

The

mutations

are

essentially

distributed

over

the

LBD


the

N -terminus

transactivation

domain)

(1047297 gure

1)


even

though

some

mutations

have

been

reported

outsideof

these

hot

spots

[25] The

two functional

isoforms



binding

is

preserved

and

classically

the

mutated


coactivators

[1]

The

phenotype

is

expressed

while

a


with

them

they

prevent

the

release

of

the


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


of

a

nucleotide

base

which

then

leads

to

a

modification


or

modifications

of

the

reading

frame

the

affected



close

to

500

families

have

thus

been

identified



of

now

there

are

8

known

different

mutations

affecting


2) They alsoinvolve

point

mutations

(missense

or

nonsense)

or


times)

These

were

de

novo

mutations

in

6

patients


to

isoforms

TRb1 and

TRb2

which

differ

on

their

N -

terminus

the

main

isoforms

produced

from

the

THRA

geneTRa1

and

TRa2

differ

on

their

C -terminus

They

share

a


diverge

resulting

in

a

functional

LBD

for

TRa1

and

an



two

others

concern

the


identified

in

the

THRA

gene

in

cases

of

RTHa


Figure

1

The

main

isoforms

produced

by

the

THRB

gene

and

themutations

described

in

the

b

form

of

resistance

to

thyroid


and





TRb1




receptor)

TRa






and

A317V

(THRB) [17] R384C

and

R438C

[1926] C392X

andC446X

mutations

[2027] Modification

of

the

reading



equivalent

residue

of


of

several

bases


THRA gene mutations

with

no

strict

equivalent

in

the

THRB

gene

similar


and

in

which

the

corresponding

amino

acid

in


of

the

phenotype

associated

with

this

mutation

see

below)

In

any

case

comparison

of

the a

and b

forms

of

RTH

foridentical

or

equivalent

mutations

enables

the

respective


receptors

seem

to

be

clearly

involved

in

the


TRa1 mutants

have

been

examined

in

functional


of

target

genes

and

their

dominant

negative


it

was

evaluated

the

affinity

for

T3

was

reduced

[161721]Moreover

the

dominant

negative

activity

seems

to

be


correlations

For

example

only

two

mutations


affect

TRa1 [17]the

phenotype

associated

with

the


deficit

(though

this

absence

has

also

been



phenotype

also

deserves

to

be

explored

[21] Although

this

needs

to

be

substantiated

with

subsequent

clinical

cases

thereis

a

tendency

for

more

serious

forms

to

exist

with

the


significant

intellectual

deficit

(IQ

of

22)

was

described


mutations

that

only

substitute

one

amino

acid

for


truncations

[28] It

is

likely

that

truncations



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

involvedfamilies

Number of

involvedpatients


mutation


functions

Involved

isoforms

References


[17]


[21]



position 388

TRa1 [16]



TRa1 [20]



TRa1 [1518]



TRa1 [1420]



tome 44 gt n811





Figure 2

The

main

isoforms

produced

by

the

THRA

gene

and

the

mutations

described

in

the

a

form

of

resistance

to

thyroid


is incapable of


while



the











to

interact

with


animal

modelsMicewith

complete




of

an

abnormal receptor

The comparison

is

more

logical inanimal

models

with

an

artificially

introduced



on

a

mutation

of



and TRa2)

One model

introduced

in

TRa1 the PV


several

nucleotides

with

modification of

the reading

frame)[30]

while

the others

introduce

point

mutations

R384C



RTHa

[19])

L400R

[31]

and P398H

[32] These models


in

the development

of

chondrocytes

is probably a

deter-mining factor

as

the


of

the

L400R


The severity

of


is


the adultmice

[29]

In humans this


a

girl though

it

is

only

known that

she

was

a


disorders

with


also

observed

in

another

model

[31]

which

is


to impairment

of

neurogenesis

in


is not

observed

for the

bone

phenotype [39] as

was

also

reported in

humans Another

common

point of

the animalmodels

with

TRa1 mutations

is the

near-normality

of

TH


models

[1332]

as


patients with

RTHa

are

considered

an

indication of


deiodinase


of

T4

into



detected

in


was

rather

mild

but

accompanied

by

inadaptation



is

probably

the

result

of

the

direct

effect

of

TH

on

themyocardium

(known

target

tissue

of

TH

expressing


in

one

model

[41] However

there

is

probably


system

due

to

abnormal

brain

development


system)

has

been

suggested

as

an

explanation

forthermogenesis

abnormalities

These

abnormalities

have


A

reduction

in

body

temperature

andor

a

cold

intolerance


vasodilatation

again

related

to

the

autonomic

ner-vous

system

was

supposedly

also

observed

in

one

of

the


patient

with

RTHa

had

weight

loss

(occurring

in


overweight

(without

increased

food

intake)

hepatic

stea-tosis

and

insulin

resistance

[32] but

a

controversy

exists


adiposity

due

to

impairment

of

adipogenesis

and

low


situations

[4547]



very

large

number

of

questions

about

the

possibility

of

muta-tions

in

the

THRA

gene

Answers

have

arrived

more

than

20


particular

abnormalities

suggestive

of

mild

untreated


suggestive

symptoms

are

short

stature


facial

shape

and

low

T4T3

ratio

It

is

worthy

to

notethat

the

whole

exome

database



most

of

them

predicted

to

alter

TRa1 function

It

is



tome 44 gt n811






should

stand

out

for

the

clinician

The

identification


THRA gene

is

essential

for

improving

the

definition

of

the

clinical



formulated

and

perhaps

the

development

of


The

reported

cases

show

that

the


because

the

therapeutic

management

occurs

too


andor

because

the

tissue

resistance

is

too


clear

example

of

the

need

for

early

treatment

The

significance


abnormality

The

different

murine

models

with


approaches

Assuming

that

the

resistance

is



the

demonstration

of

the

partial

reversal

of

the

abnormalTHRA

gene

phenotype

through

the

coexpression

of

a


of

an

inhibitor

of

the










[5] Weiss RE

Hayashi Y

Nagaya T




















[16] Moran C


Kydd





of three







Flamant F





Munnich A











[25] Margotat A


Wemeau JL








[30] Parrilla R





[32] Liu YY

Schultz JJ






[35] Desjardin C

Charles C




[37] Pilhatsch M

Winter C



[38] Kapoor R

van Hogerlinden M



Zhu X

et al








et al Thyroid




MittagJ




[46] Araki O


[47] Liu YY





ndash 21

[49] Fozzatti

L Kim

DW

ParkJW Willingham


thyroid


Acad


[50] Kim DW ParkJW



tome 44 gt n811






deficit

has

often

been

reported

but

is

not


in

childhood

one

case

of

diarrhoea

occurring

late



appears

normal

[1518] whereas

the

baselinemetabolism

is

decreased

[14161721] Finally

cases

of


in

association

with

myxoedema

of


is

consistently

present

in

all

clinical

descriptions

but



may

also


growth

factor

1

may

be

low

in


Radiological

exams

are

done

to

investigate

potential


[14]

Ossification

delay

is

also

evidenced

by


(femoral

heads)

[141518]

and

by

delayed


X-rays

again

show

macrocephaly

with

thickening

of


the

long

bones

of

the

limbs


meas-urements

in

adults

are

usually

normal


reassurance

when

values

are

normal

or

low

normal

they


clinical

presentation

It

is

this

dissociation

between


(including

the

dysmorphic

syndrome)



(table

II )

In

this

respect

it

can

be

seen

that

thedissociation

between

the

clinical

and

laboratory


thyroid

hormone

values

both

in

their

free

and

total


slightly

low

and

T3

slightly

high

As

a

result

there

is


all

the

published

cases

The

TSH

is

normal

(though

low

insome

cases)

It

should

be

noted

that

neonatal

screening


Several

patients

received

treatment

with

levothyroxine


and

definitive

[14] Benefits

can

be

seen

for

brady-cardia

energy

levels

bowel

function

and

carpal

tunnel


thyroid

hormones

and

a

quick

and

predictable

suppression


values

(blood

cholesterol

anaemia)

is

not

constant



TABLE IIClinical

and

biological

phenotypes

of

the

a

and

b

syndromes

of

resistance

to

thyroid

hormones

RTHa RTHb





Goiter No Yes


fT4 Low normal High

T4T3 ratio Low Low




tome 44 gt n811







or


the target


nuclear



TR reduces

the expression

of

the target



the transcription

of

the target

genes

To

fulfil all


organized

into

modules an


and a


(LBD) Organized

as

asuccession

of

12


has on


the presence

of

the ligand

Indeedmodifications

of


the

b

form

of

RTH

the

abnormality

is

carried

by

the

THRB

gene

The

mutations

are

essentially

distributed

over

the

LBD


the

N -terminus

transactivation

domain)

(1047297 gure

1)


even

though

some

mutations

have

been

reported

outsideof

these

hot

spots

[25] The

two functional

isoforms



binding

is

preserved

and

classically

the

mutated


coactivators

[1]

The

phenotype

is

expressed

while

a


with

them

they

prevent

the

release

of

the


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


of

a

nucleotide

base

which

then

leads

to

a

modification


or

modifications

of

the

reading

frame

the

affected



close

to

500

families

have

thus

been

identified



of

now

there

are

8

known

different

mutations

affecting


2) They alsoinvolve

point

mutations

(missense

or

nonsense)

or


times)

These

were

de

novo

mutations

in

6

patients


to

isoforms

TRb1 and

TRb2

which

differ

on

their

N -

terminus

the

main

isoforms

produced

from

the

THRA

geneTRa1

and

TRa2

differ

on

their

C -terminus

They

share

a


diverge

resulting

in

a

functional

LBD

for

TRa1

and

an



two

others

concern

the


identified

in

the

THRA

gene

in

cases

of

RTHa


Figure

1

The

main

isoforms

produced

by

the

THRB

gene

and

themutations

described

in

the

b

form

of

resistance

to

thyroid


and





TRb1




receptor)

TRa






and

A317V

(THRB) [17] R384C

and

R438C

[1926] C392X

andC446X

mutations

[2027] Modification

of

the

reading



equivalent

residue

of


of

several

bases


THRA gene mutations

with

no

strict

equivalent

in

the

THRB

gene

similar


and

in

which

the

corresponding

amino

acid

in


of

the

phenotype

associated

with

this

mutation

see

below)

In

any

case

comparison

of

the a

and b

forms

of

RTH

foridentical

or

equivalent

mutations

enables

the

respective


receptors

seem

to

be

clearly

involved

in

the


TRa1 mutants

have

been

examined

in

functional


of

target

genes

and

their

dominant

negative


it

was

evaluated

the

affinity

for

T3

was

reduced

[161721]Moreover

the

dominant

negative

activity

seems

to

be


correlations

For

example

only

two

mutations


affect

TRa1 [17]the

phenotype

associated

with

the


deficit

(though

this

absence

has

also

been



phenotype

also

deserves

to

be

explored

[21] Although

this

needs

to

be

substantiated

with

subsequent

clinical

cases

thereis

a

tendency

for

more

serious

forms

to

exist

with

the


significant

intellectual

deficit

(IQ

of

22)

was

described


mutations

that

only

substitute

one

amino

acid

for


truncations

[28] It

is

likely

that

truncations



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

involvedfamilies

Number of

involvedpatients


mutation


functions

Involved

isoforms

References


[17]


[21]



position 388

TRa1 [16]



TRa1 [20]



TRa1 [1518]



TRa1 [1420]



tome 44 gt n811





Figure 2

The

main

isoforms

produced

by

the

THRA

gene

and

the

mutations

described

in

the

a

form

of

resistance

to

thyroid


is incapable of


while



the











to

interact

with


animal

modelsMicewith

complete




of

an

abnormal receptor

The comparison

is

more

logical inanimal

models

with

an

artificially

introduced



on

a

mutation

of



and TRa2)

One model

introduced

in

TRa1 the PV


several

nucleotides

with

modification of

the reading

frame)[30]

while

the others

introduce

point

mutations

R384C



RTHa

[19])

L400R

[31]

and P398H

[32] These models


in

the development

of

chondrocytes

is probably a

deter-mining factor

as

the


of

the

L400R


The severity

of


is


the adultmice

[29]

In humans this


a

girl though

it

is

only

known that

she

was

a


disorders

with


also

observed

in

another

model

[31]

which

is


to impairment

of

neurogenesis

in


is not

observed

for the

bone

phenotype [39] as

was

also

reported in

humans Another

common

point of

the animalmodels

with

TRa1 mutations

is the

near-normality

of

TH


models

[1332]

as


patients with

RTHa

are

considered

an

indication of


deiodinase


of

T4

into



detected

in


was

rather

mild

but

accompanied

by

inadaptation



is

probably

the

result

of

the

direct

effect

of

TH

on

themyocardium

(known

target

tissue

of

TH

expressing


in

one

model

[41] However

there

is

probably


system

due

to

abnormal

brain

development


system)

has

been

suggested

as

an

explanation

forthermogenesis

abnormalities

These

abnormalities

have


A

reduction

in

body

temperature

andor

a

cold

intolerance


vasodilatation

again

related

to

the

autonomic

ner-vous

system

was

supposedly

also

observed

in

one

of

the


patient

with

RTHa

had

weight

loss

(occurring

in


overweight

(without

increased

food

intake)

hepatic

stea-tosis

and

insulin

resistance

[32] but

a

controversy

exists


adiposity

due

to

impairment

of

adipogenesis

and

low


situations

[4547]



very

large

number

of

questions

about

the

possibility

of

muta-tions

in

the

THRA

gene

Answers

have

arrived

more

than

20


particular

abnormalities

suggestive

of

mild

untreated


suggestive

symptoms

are

short

stature


facial

shape

and

low

T4T3

ratio

It

is

worthy

to

notethat

the

whole

exome

database



most

of

them

predicted

to

alter

TRa1 function

It

is



tome 44 gt n811






should

stand

out

for

the

clinician

The

identification


THRA gene

is

essential

for

improving

the

definition

of

the

clinical



formulated

and

perhaps

the

development

of


The

reported

cases

show

that

the


because

the

therapeutic

management

occurs

too


andor

because

the

tissue

resistance

is

too


clear

example

of

the

need

for

early

treatment

The

significance


abnormality

The

different

murine

models

with


approaches

Assuming

that

the

resistance

is



the

demonstration

of

the

partial

reversal

of

the

abnormalTHRA

gene

phenotype

through

the

coexpression

of

a


of

an

inhibitor

of

the










[5] Weiss RE

Hayashi Y

Nagaya T




















[16] Moran C


Kydd





of three







Flamant F





Munnich A











[25] Margotat A


Wemeau JL








[30] Parrilla R





[32] Liu YY

Schultz JJ






[35] Desjardin C

Charles C




[37] Pilhatsch M

Winter C



[38] Kapoor R

van Hogerlinden M



Zhu X

et al








et al Thyroid




MittagJ




[46] Araki O


[47] Liu YY





ndash 21

[49] Fozzatti

L Kim

DW

ParkJW Willingham


thyroid


Acad


[50] Kim DW ParkJW



tome 44 gt n811







or


the target


nuclear



TR reduces

the expression

of

the target



the transcription

of

the target

genes

To

fulfil all


organized

into

modules an


and a


(LBD) Organized

as

asuccession

of

12


has on


the presence

of

the ligand

Indeedmodifications

of


the

b

form

of

RTH

the

abnormality

is

carried

by

the

THRB

gene

The

mutations

are

essentially

distributed

over

the

LBD


the

N -terminus

transactivation

domain)

(1047297 gure

1)


even

though

some

mutations

have

been

reported

outsideof

these

hot

spots

[25] The

two functional

isoforms



binding

is

preserved

and

classically

the

mutated


coactivators

[1]

The

phenotype

is

expressed

while

a


with

them

they

prevent

the

release

of

the


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


of

a

nucleotide

base

which

then

leads

to

a

modification


or

modifications

of

the

reading

frame

the

affected



close

to

500

families

have

thus

been

identified



of

now

there

are

8

known

different

mutations

affecting


2) They alsoinvolve

point

mutations

(missense

or

nonsense)

or


times)

These

were

de

novo

mutations

in

6

patients


to

isoforms

TRb1 and

TRb2

which

differ

on

their

N -

terminus

the

main

isoforms

produced

from

the

THRA

geneTRa1

and

TRa2

differ

on

their

C -terminus

They

share

a


diverge

resulting

in

a

functional

LBD

for

TRa1

and

an



two

others

concern

the


identified

in

the

THRA

gene

in

cases

of

RTHa


Figure

1

The

main

isoforms

produced

by

the

THRB

gene

and

themutations

described

in

the

b

form

of

resistance

to

thyroid


and





TRb1




receptor)

TRa






and

A317V

(THRB) [17] R384C

and

R438C

[1926] C392X

andC446X

mutations

[2027] Modification

of

the

reading



equivalent

residue

of


of

several

bases


THRA gene mutations

with

no

strict

equivalent

in

the

THRB

gene

similar


and

in

which

the

corresponding

amino

acid

in


of

the

phenotype

associated

with

this

mutation

see

below)

In

any

case

comparison

of

the a

and b

forms

of

RTH

foridentical

or

equivalent

mutations

enables

the

respective


receptors

seem

to

be

clearly

involved

in

the


TRa1 mutants

have

been

examined

in

functional


of

target

genes

and

their

dominant

negative


it

was

evaluated

the

affinity

for

T3

was

reduced

[161721]Moreover

the

dominant

negative

activity

seems

to

be


correlations

For

example

only

two

mutations


affect

TRa1 [17]the

phenotype

associated

with

the


deficit

(though

this

absence

has

also

been



phenotype

also

deserves

to

be

explored

[21] Although

this

needs

to

be

substantiated

with

subsequent

clinical

cases

thereis

a

tendency

for

more

serious

forms

to

exist

with

the


significant

intellectual

deficit

(IQ

of

22)

was

described


mutations

that

only

substitute

one

amino

acid

for


truncations

[28] It

is

likely

that

truncations



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

involvedfamilies

Number of

involvedpatients


mutation


functions

Involved

isoforms

References


[17]


[21]



position 388

TRa1 [16]



TRa1 [20]



TRa1 [1518]



TRa1 [1420]



tome 44 gt n811





Figure 2

The

main

isoforms

produced

by

the

THRA

gene

and

the

mutations

described

in

the

a

form

of

resistance

to

thyroid


is incapable of


while



the











to

interact

with


animal

modelsMicewith

complete




of

an

abnormal receptor

The comparison

is

more

logical inanimal

models

with

an

artificially

introduced



on

a

mutation

of



and TRa2)

One model

introduced

in

TRa1 the PV


several

nucleotides

with

modification of

the reading

frame)[30]

while

the others

introduce

point

mutations

R384C



RTHa

[19])

L400R

[31]

and P398H

[32] These models


in

the development

of

chondrocytes

is probably a

deter-mining factor

as

the


of

the

L400R


The severity

of


is


the adultmice

[29]

In humans this


a

girl though

it

is

only

known that

she

was

a


disorders

with


also

observed

in

another

model

[31]

which

is


to impairment

of

neurogenesis

in


is not

observed

for the

bone

phenotype [39] as

was

also

reported in

humans Another

common

point of

the animalmodels

with

TRa1 mutations

is the

near-normality

of

TH


models

[1332]

as


patients with

RTHa

are

considered

an

indication of


deiodinase


of

T4

into



detected

in


was

rather

mild

but

accompanied

by

inadaptation



is

probably

the

result

of

the

direct

effect

of

TH

on

themyocardium

(known

target

tissue

of

TH

expressing


in

one

model

[41] However

there

is

probably


system

due

to

abnormal

brain

development


system)

has

been

suggested

as

an

explanation

forthermogenesis

abnormalities

These

abnormalities

have


A

reduction

in

body

temperature

andor

a

cold

intolerance


vasodilatation

again

related

to

the

autonomic

ner-vous

system

was

supposedly

also

observed

in

one

of

the


patient

with

RTHa

had

weight

loss

(occurring

in


overweight

(without

increased

food

intake)

hepatic

stea-tosis

and

insulin

resistance

[32] but

a

controversy

exists


adiposity

due

to

impairment

of

adipogenesis

and

low


situations

[4547]



very

large

number

of

questions

about

the

possibility

of

muta-tions

in

the

THRA

gene

Answers

have

arrived

more

than

20


particular

abnormalities

suggestive

of

mild

untreated


suggestive

symptoms

are

short

stature


facial

shape

and

low

T4T3

ratio

It

is

worthy

to

notethat

the

whole

exome

database



most

of

them

predicted

to

alter

TRa1 function

It

is



tome 44 gt n811






should

stand

out

for

the

clinician

The

identification


THRA gene

is

essential

for

improving

the

definition

of

the

clinical



formulated

and

perhaps

the

development

of


The

reported

cases

show

that

the


because

the

therapeutic

management

occurs

too


andor

because

the

tissue

resistance

is

too


clear

example

of

the

need

for

early

treatment

The

significance


abnormality

The

different

murine

models

with


approaches

Assuming

that

the

resistance

is



the

demonstration

of

the

partial

reversal

of

the

abnormalTHRA

gene

phenotype

through

the

coexpression

of

a


of

an

inhibitor

of

the










[5] Weiss RE

Hayashi Y

Nagaya T




















[16] Moran C


Kydd





of three







Flamant F





Munnich A











[25] Margotat A


Wemeau JL








[30] Parrilla R





[32] Liu YY

Schultz JJ






[35] Desjardin C

Charles C




[37] Pilhatsch M

Winter C



[38] Kapoor R

van Hogerlinden M



Zhu X

et al








et al Thyroid




MittagJ




[46] Araki O


[47] Liu YY





ndash 21

[49] Fozzatti

L Kim

DW

ParkJW Willingham


thyroid


Acad


[50] Kim DW ParkJW



tome 44 gt n811





and

A317V

(THRB) [17] R384C

and

R438C

[1926] C392X

andC446X

mutations

[2027] Modification

of

the

reading



equivalent

residue

of


of

several

bases


THRA gene mutations

with

no

strict

equivalent

in

the

THRB

gene

similar


and

in

which

the

corresponding

amino

acid

in


of

the

phenotype

associated

with

this

mutation

see

below)

In

any

case

comparison

of

the a

and b

forms

of

RTH

foridentical

or

equivalent

mutations

enables

the

respective


receptors

seem

to

be

clearly

involved

in

the


TRa1 mutants

have

been

examined

in

functional


of

target

genes

and

their

dominant

negative


it

was

evaluated

the

affinity

for

T3

was

reduced

[161721]Moreover

the

dominant

negative

activity

seems

to

be


correlations

For

example

only

two

mutations


affect

TRa1 [17]the

phenotype

associated

with

the


deficit

(though

this

absence

has

also

been



phenotype

also

deserves

to

be

explored

[21] Although

this

needs

to

be

substantiated

with

subsequent

clinical

cases

thereis

a

tendency

for

more

serious

forms

to

exist

with

the


significant

intellectual

deficit

(IQ

of

22)

was

described


mutations

that

only

substitute

one

amino

acid

for


truncations

[28] It

is

likely

that

truncations



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

involvedfamilies

Number of

involvedpatients


mutation


functions

Involved

isoforms

References


[17]


[21]



position 388

TRa1 [16]



TRa1 [20]



TRa1 [1518]



TRa1 [1420]



tome 44 gt n811





Figure 2

The

main

isoforms

produced

by

the

THRA

gene

and

the

mutations

described

in

the

a

form

of

resistance

to

thyroid


is incapable of


while



the











to

interact

with


animal

modelsMicewith

complete




of

an

abnormal receptor

The comparison

is

more

logical inanimal

models

with

an

artificially

introduced



on

a

mutation

of



and TRa2)

One model

introduced

in

TRa1 the PV


several

nucleotides

with

modification of

the reading

frame)[30]

while

the others

introduce

point

mutations

R384C



RTHa

[19])

L400R

[31]

and P398H

[32] These models


in

the development

of

chondrocytes

is probably a

deter-mining factor

as

the


of

the

L400R


The severity

of


is


the adultmice

[29]

In humans this


a

girl though

it

is

only

known that

she

was

a


disorders

with


also

observed

in

another

model

[31]

which

is


to impairment

of

neurogenesis

in


is not

observed

for the

bone

phenotype [39] as

was

also

reported in

humans Another

common

point of

the animalmodels

with

TRa1 mutations

is the

near-normality

of

TH


models

[1332]

as


patients with

RTHa

are

considered

an

indication of


deiodinase


of

T4

into



detected

in


was

rather

mild

but

accompanied

by

inadaptation



is

probably

the

result

of

the

direct

effect

of

TH

on

themyocardium

(known

target

tissue

of

TH

expressing


in

one

model

[41] However

there

is

probably


system

due

to

abnormal

brain

development


system)

has

been

suggested

as

an

explanation

forthermogenesis

abnormalities

These

abnormalities

have


A

reduction

in

body

temperature

andor

a

cold

intolerance


vasodilatation

again

related

to

the

autonomic

ner-vous

system

was

supposedly

also

observed

in

one

of

the


patient

with

RTHa

had

weight

loss

(occurring

in


overweight

(without

increased

food

intake)

hepatic

stea-tosis

and

insulin

resistance

[32] but

a

controversy

exists


adiposity

due

to

impairment

of

adipogenesis

and

low


situations

[4547]



very

large

number

of

questions

about

the

possibility

of

muta-tions

in

the

THRA

gene

Answers

have

arrived

more

than

20


particular

abnormalities

suggestive

of

mild

untreated


suggestive

symptoms

are

short

stature


facial

shape

and

low

T4T3

ratio

It

is

worthy

to

notethat

the

whole

exome

database



most

of

them

predicted

to

alter

TRa1 function

It

is



tome 44 gt n811






should

stand

out

for

the

clinician

The

identification


THRA gene

is

essential

for

improving

the

definition

of

the

clinical



formulated

and

perhaps

the

development

of


The

reported

cases

show

that

the


because

the

therapeutic

management

occurs

too


andor

because

the

tissue

resistance

is

too


clear

example

of

the

need

for

early

treatment

The

significance


abnormality

The

different

murine

models

with


approaches

Assuming

that

the

resistance

is



the

demonstration

of

the

partial

reversal

of

the

abnormalTHRA

gene

phenotype

through

the

coexpression

of

a


of

an

inhibitor

of

the










[5] Weiss RE

Hayashi Y

Nagaya T




















[16] Moran C


Kydd





of three







Flamant F





Munnich A











[25] Margotat A


Wemeau JL








[30] Parrilla R





[32] Liu YY

Schultz JJ






[35] Desjardin C

Charles C




[37] Pilhatsch M

Winter C



[38] Kapoor R

van Hogerlinden M



Zhu X

et al








et al Thyroid




MittagJ




[46] Araki O


[47] Liu YY





ndash 21

[49] Fozzatti

L Kim

DW

ParkJW Willingham


thyroid


Acad


[50] Kim DW ParkJW



tome 44 gt n811





Figure 2

The

main

isoforms

produced

by

the

THRA

gene

and

the

mutations

described

in

the

a

form

of

resistance

to

thyroid


is incapable of


while



the











to

interact

with


animal

modelsMicewith

complete




of

an

abnormal receptor

The comparison

is

more

logical inanimal

models

with

an

artificially

introduced



on

a

mutation

of



and TRa2)

One model

introduced

in

TRa1 the PV


several

nucleotides

with

modification of

the reading

frame)[30]

while

the others

introduce

point

mutations

R384C



RTHa

[19])

L400R

[31]

and P398H

[32] These models


in

the development

of

chondrocytes

is probably a

deter-mining factor

as

the


of

the

L400R


The severity

of


is


the adultmice

[29]

In humans this


a

girl though

it

is

only

known that

she

was

a


disorders

with


also

observed

in

another

model

[31]

which

is


to impairment

of

neurogenesis

in


is not

observed

for the

bone

phenotype [39] as

was

also

reported in

humans Another

common

point of

the animalmodels

with

TRa1 mutations

is the

near-normality

of

TH


models

[1332]

as


patients with

RTHa

are

considered

an

indication of


deiodinase


of

T4

into



detected

in


was

rather

mild

but

accompanied

by

inadaptation



is

probably

the

result

of

the

direct

effect

of

TH

on

themyocardium

(known

target

tissue

of

TH

expressing


in

one

model

[41] However

there

is

probably


system

due

to

abnormal

brain

development


system)

has

been

suggested

as

an

explanation

forthermogenesis

abnormalities

These

abnormalities

have


A

reduction

in

body

temperature

andor

a

cold

intolerance


vasodilatation

again

related

to

the

autonomic

ner-vous

system

was

supposedly

also

observed

in

one

of

the


patient

with

RTHa

had

weight

loss

(occurring

in


overweight

(without

increased

food

intake)

hepatic

stea-tosis

and

insulin

resistance

[32] but

a

controversy

exists


adiposity

due

to

impairment

of

adipogenesis

and

low


situations

[4547]



very

large

number

of

questions

about

the

possibility

of

muta-tions

in

the

THRA

gene

Answers

have

arrived

more

than

20


particular

abnormalities

suggestive

of

mild

untreated


suggestive

symptoms

are

short

stature


facial

shape

and

low

T4T3

ratio

It

is

worthy

to

notethat

the

whole

exome

database



most

of

them

predicted

to

alter

TRa1 function

It

is



tome 44 gt n811






should

stand

out

for

the

clinician

The

identification


THRA gene

is

essential

for

improving

the

definition

of

the

clinical



formulated

and

perhaps

the

development

of


The

reported

cases

show

that

the


because

the

therapeutic

management

occurs

too


andor

because

the

tissue

resistance

is

too


clear

example

of

the

need

for

early

treatment

The

significance


abnormality

The

different

murine

models

with


approaches

Assuming

that

the

resistance

is



the

demonstration

of

the

partial

reversal

of

the

abnormalTHRA

gene

phenotype

through

the

coexpression

of

a


of

an

inhibitor

of

the










[5] Weiss RE

Hayashi Y

Nagaya T




















[16] Moran C


Kydd





of three







Flamant F





Munnich A











[25] Margotat A


Wemeau JL








[30] Parrilla R





[32] Liu YY

Schultz JJ






[35] Desjardin C

Charles C




[37] Pilhatsch M

Winter C



[38] Kapoor R

van Hogerlinden M



Zhu X

et al








et al Thyroid




MittagJ




[46] Araki O


[47] Liu YY





ndash 21

[49] Fozzatti

L Kim

DW

ParkJW Willingham


thyroid


Acad


[50] Kim DW ParkJW



tome 44 gt n811






to

interact

with


animal

modelsMicewith

complete




of

an

abnormal receptor

The comparison

is

more

logical inanimal

models

with

an

artificially

introduced



on

a

mutation

of



and TRa2)

One model

introduced

in

TRa1 the PV


several

nucleotides

with

modification of

the reading

frame)[30]

while

the others

introduce

point

mutations

R384C



RTHa

[19])

L400R

[31]

and P398H

[32] These models


in

the development

of

chondrocytes

is probably a

deter-mining factor

as

the


of

the

L400R


The severity

of


is


the adultmice

[29]

In humans this


a

girl though

it

is

only

known that

she

was

a


disorders

with


also

observed

in

another

model

[31]

which

is


to impairment

of

neurogenesis

in


is not

observed

for the

bone

phenotype [39] as

was

also

reported in

humans Another

common

point of

the animalmodels

with

TRa1 mutations

is the

near-normality

of

TH


models

[1332]

as


patients with

RTHa

are

considered

an

indication of


deiodinase


of

T4

into



detected

in


was

rather

mild

but

accompanied

by

inadaptation



is

probably

the

result

of

the

direct

effect

of

TH

on

themyocardium

(known

target

tissue

of

TH

expressing


in

one

model

[41] However

there

is

probably


system

due

to

abnormal

brain

development


system)

has

been

suggested

as

an

explanation

forthermogenesis

abnormalities

These

abnormalities

have


A

reduction

in

body

temperature

andor

a

cold

intolerance


vasodilatation

again

related

to

the

autonomic

ner-vous

system

was

supposedly

also

observed

in

one

of

the


patient

with

RTHa

had

weight

loss

(occurring

in


overweight

(without

increased

food

intake)

hepatic

stea-tosis

and

insulin

resistance

[32] but

a

controversy

exists


adiposity

due

to

impairment

of

adipogenesis

and

low


situations

[4547]



very

large

number

of

questions

about

the

possibility

of

muta-tions

in

the

THRA

gene

Answers

have

arrived

more

than

20


particular

abnormalities

suggestive

of

mild

untreated


suggestive

symptoms

are

short

stature


facial

shape

and

low

T4T3

ratio

It

is

worthy

to

notethat

the

whole

exome

database



most

of

them

predicted

to

alter

TRa1 function

It

is



tome 44 gt n811






should

stand

out

for

the

clinician

The

identification


THRA gene

is

essential

for

improving

the

definition

of

the

clinical



formulated

and

perhaps

the

development

of


The

reported

cases

show

that

the


because

the

therapeutic

management

occurs

too


andor

because

the

tissue

resistance

is

too


clear

example

of

the

need

for

early

treatment

The

significance


abnormality

The

different

murine

models

with


approaches

Assuming

that

the

resistance

is



the

demonstration

of

the

partial

reversal

of

the

abnormalTHRA

gene

phenotype

through

the

coexpression

of

a


of

an

inhibitor

of

the










[5] Weiss RE

Hayashi Y

Nagaya T




















[16] Moran C


Kydd





of three







Flamant F





Munnich A











[25] Margotat A


Wemeau JL








[30] Parrilla R





[32] Liu YY

Schultz JJ






[35] Desjardin C

Charles C




[37] Pilhatsch M

Winter C



[38] Kapoor R

van Hogerlinden M



Zhu X

et al








et al Thyroid




MittagJ




[46] Araki O


[47] Liu YY





ndash 21

[49] Fozzatti

L Kim

DW

ParkJW Willingham


thyroid


Acad


[50] Kim DW ParkJW



tome 44 gt n811






should

stand

out

for

the

clinician

The

identification


THRA gene

is

essential

for

improving

the

definition

of

the

clinical



formulated

and

perhaps

the

development

of


The

reported

cases

show

that

the


because

the

therapeutic

management

occurs

too


andor

because

the

tissue

resistance

is

too


clear

example

of

the

need

for

early

treatment

The

significance


abnormality

The

different

murine

models

with


approaches

Assuming

that

the

resistance

is



the

demonstration

of

the

partial

reversal

of

the

abnormalTHRA

gene

phenotype

through

the

coexpression

of

a


of

an

inhibitor

of

the










[5] Weiss RE

Hayashi Y

Nagaya T




















[16] Moran C


Kydd





of three







Flamant F





Munnich A











[25] Margotat A


Wemeau JL








[30] Parrilla R





[32] Liu YY

Schultz JJ






[35] Desjardin C

Charles C




[37] Pilhatsch M

Winter C



[38] Kapoor R

van Hogerlinden M



Zhu X

et al








et al Thyroid




MittagJ




[46] Araki O


[47] Liu YY





ndash 21

[49] Fozzatti

L Kim

DW

ParkJW Willingham


thyroid


Acad


[50] Kim DW ParkJW



tome 44 gt n811








[25] Margotat A


Wemeau JL








[30] Parrilla R





[32] Liu YY

Schultz JJ






[35] Desjardin C

Charles C




[37] Pilhatsch M

Winter C



[38] Kapoor R

van Hogerlinden M



Zhu X

et al








et al Thyroid




MittagJ




[46] Araki O


[47] Liu YY





ndash 21

[49] Fozzatti

L Kim

DW

ParkJW Willingham


thyroid


Acad


[50] Kim DW ParkJW



tome 44 gt n811



Thyroid Receptors

Documents

Transcript of Thyroid Receptors