Domestic Animal Endocrinology 65 (2018) 1–8

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Domestic Animal Endocrinology

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domestic-animal-endocrinology

Congenital dyshormonogenic hypothyroidism with goiter

caused by a sodium/iodide symporter (SLC5A5) mutation
in a family of Shih-Tzu dogs
E.A. Soler Arias a, *, V.A. Castillo a, J.D. Garcia a, J.C. Fyfe b
a
Universidad de Buenos Aires, Facultad de Ciencias Veterinarias, Hospital Escuela de Medicina Veterinaria, Unidad de
Endocrinología, Buenos Aires, Argentina
b
Laboratory of Comparative Medical Genetics and Department of Microbiology and Molecular Genetics, College of Veterinary
Medicine, Michigan State University, East Lansing, MI, USA

a r t i c l e i n f o a b s t r a c t

Article history: An iodide transport defect (ITD) in the thyroid gland was determined to cause congenital
Received 5 January 2018 dyshormonogenic hypothyroidism with goiter (CDHG) in 2 members of a family of Shih-
Received in revised form 20 March 2018 Tzu dogs. Strikingly, both dogs were also diagnosed with dilated cardiomyopathy at 24
Accepted 17 April 2018
and 1.5 mo of age. The only sign of hypothyroidism was a moderate growth delay in the
adult dog. The ITD was recognized by the absence of uptake of technetium-99m in the
Keywords:
salivary glands (sg) and goiter observed by scintigraphy. In the same scan, radiopharma-
Dilated cardiomyopathy
ceutical uptake was found in the anterior mediastinum of both dogs and in the right
Iodide transport defect
NIS axillary lymph node in the oldest dog. A follicular thyroid carcinoma was diagnosed by
RNA splicing histopathology after thyroidectomy of the older dog. An adenomatous goiter with ectopic
Thyroid scintigraphy thyroid tissue, and degenerative changes in myocardium were the findings after necropsy
in the youngest dog. A homozygous mutation of the intron 9 splice acceptor site of SLC5A5
gene, encoding the sodium/iodine symporter (NIS), was found in the DNA of one of the
affected dogs. The mutation was a single base transition of guanine > adenine (G > A) at
position 45,024,672 of dog chromosome 20 (CFA20). Five of eight healthy dogs, including
both parents of one of the dogs exhibiting CDHG, were heterozygous A/G, and the other 3
were homozygous for the wild-type allele G/G. No sequence variant was found in thyroid
peroxidase of the affected dog. Congenital dyshormonogenic hypothyroidism with goiter
in this family is an autosomal recessive trait. Our findings are the first evidence of an
SLC5A5 mutation in dogs and establish a new genetic cause of CDHG.
Ó 2018 Elsevier Inc. All rights reserved.

1. Introduction hypoplasia, and ectopia) or in exceptional cases by inheri-

Acquired primary hypothyroidism is a common disease
in adult dogs that is usually caused by lymphocytic
destruction or idiopathic atrophy of the thyroid gland [1].
By contrast, congenital primary hypothyroidism (CH) is a
rare and underdiagnosed endocrine disorder in dogs,
attributed to dysgenesis of thyroid gland (eg, agenesis,
* Corresponding author. Tel.: þ54 11 38231967; fax: þ54 11 47745104.
E-mail address: mveterinario@yahoo.es (E.A. Soler Arias).
ted defects of thyroid hormone synthesis, also called dys-
hormonogenesis (eg, thyroid peroxidase gene [TPO]
mutation) [2–7]. The first step in the synthesis of thyroid
hormones is the transport of iodide from plasma through
the basolateral membrane of thyroid epithelial cells, and
this is mediated by the sodium/iodine symporter (NIS).
Expression of NIS (encoded by SLC5A5) is regulated by the
action of thyroid-stimulating hormone (TSH) via its re-
ceptor. Inactivating mutations in SLC5A5 produce an iodide
transport defect (ITD) that leads to congenital dyshormo-
nogenic hypothyroidism (CDH) in humans, sometimes

0739-7240/$ – see front matter Ó 2018 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.domaniend.2018.04.005
2 E.A. Soler Arias et al. / Domestic Animal Endocrinology 65 (2018) 1–8

associated with the presence of goiter [8]. In humans, NIS
dysfunction can be recognized by failure of technetium-
99m (99mTc) or radioactive iodide uptake in thyroid and
salivary glands (sg) during scintigraphy [9,10]. To date, 16
different mutations of SLC5A5 causing autosomal recessive
loss of NIS function have been reported in humans [8].
There is marked clinical heterogeneity among patients with
SLC5A5 mutations, ranging from euthyroidism to severe
hypothyroidism [8]. Anatomical malformations of the
heart, but not myocardial contractility dysfunction, are
associated with CDH in humans [11]; cardiac disease has
not been reported in young dogs with CDH to date.
On the other hand, the emergence of a carcinoma or
thyroid adenoma in human patients with CDH has been
documented in isolated cases [9–14], but only in 2 of these
was an SLC5A5 mutation present [9,10]. We report here the
first mutation of SLC5A5 causing congenital dyshormono-
genic hypothyroidism with goiter (CDHG) in a family of
Shih-Tzu dogs and its association with cardiomyopathy and
follicular thyroid carcinoma.
2. Case reports
Shih-Tzu dogs produced in 6 related litters were clini-
cally evaluated on suspicion of CH (Fig. 1). All dogs received
a good quality commercial diet. One female and 2 males of
eleven dogs physically examined had large, firm, bilateral
goiter (Fig. 2), noticed by the owner since 3 wk of life. The
affected female in litter III died at 4 mo of age, before thy-
roid function was evaluated. Of the other 2 dogs with goiter,
case 1 in litter II was first examined at 2 yr of age, and case 2
in litter IV was examined at 6 wk of age. Both dogs had a
low-intensity heart murmur, cough, and exercise intoler-
ance. Both had normal hearing, neurological functions, and
proportionate body growth, but case 1 was smaller than its
littermates (Fig. 3). Both were diagnosed with CH based on
the increased plasma TSH (case 1: 0.95; case 2: 0.72,
reference value [RV]: <0.35 ng/mL) associated with
decreased total thyroxine (TT4) concentrations (case 1: 0.9;
case 2: 0.97, RV: 1–3 mg/dL) and free thyroxine (FT4)
(case 1: 0.3; case 2: 0.42, RV: 0.6–3 ng/mL). At the same
time, dyshormonogenesis was suspected due to the finding
of goiter.
Ultrasonographic examination of the thyroid gland using
a linear transducer (10–5 MHz) and a portable ultrasound
machine (Mindray M5, Sinebi) revealed in both cases
enlarged thyroid glands with abundant central and pe-
ripheral vascularization. In case 1, the thyroid borders were
irregular with multinodular, heterogeneous parenchyma,
whereas in case 2, the parenchyma was homogeneous with
regular borders. The total thyroid volume (TTV) was
elevated in both cases (case 1: 10.7 cm3, and case 2:
2.58 cm3, normal TTV <0.22 cm3 according to Brömel [15]).
Dilated cardiomyopathy (DCM) was diagnosed in both
dogs by echocardiography, using the mean RVs in M-mode
according to prediction intervals for BW (4 Kg) reported by
Cornell [16] (Table 1).
Both dogs received hormone replacement therapy
immediately after diagnosis of CH, starting with 20 mg/kg
PO q24h of sodium levothyroxine (LT4). In addition, treat-
ment for heart disease was with enalapril (0.25 mg/kg PO
q12h) in case 1, and benazepril and spironolactone (0.5 and
2 mg/kg, PO q24h, respectively) in case 2 were initiated.
At the first recheck of case 1 three months after diag-
nosis, plasma TT4 and FT4 concentrations were within the
normal range, but not so for plasma TSH and the cardiac
function (Table 1). There was a slight increase in TTV (5%).
Sodium levothyroxine treatment was discontinued for 1 wk
in preparation for thyroid scintigraphy. Recheck of case 2
six months after diagnosis revealed plasma TT4 and FT4
concentrations still below the normal range, normalization
of TSH, and steady TTV, but with worsening of cardiac
function (Table 1). Pimobendan (0.5 mg/kg PO q24h) was
added to the treatment regime with increased dose and
frequency of LT4 administration. As in case 1, thyroid
scintigraphy was indicated, and LT4 therapy was inter-
rupted for 1 wk.
Diagnosis of ITD was based on absent and poor uptake of
99
mTcO 4 (technetium 99, metastable sodium pertechne-
tate) in the salivary and thyroid glands for both dogs with

Fig. 1. Pedigree of a family of Shih-Tzu dogs with congenital dyshormonogenic hypothyroidism and goiter (CDHG). Roman numerals are litter numbers. Squares
indicate males and circles indicate females. Filled symbols indicate dogs affected with CDHG and heart disease, and the half-filled symbols indicate CDHG carriers
(G/A) determined by SLC5A5 mutation genotyping. Genotypically normal dogs (G/G) are marked with the letter “n” inside the symbol. Dogs dead at the time of
the molecular investigation and from which DNA was not available are marked with an oblique bar on the symbol. Cases 1 and 2 of this report are marked with
the respective numeral. A presumptively affected dog in litter III that was not genotyped for the SLC5A5 mutation is indicated by a shaded symbol.
 E.A. Soler Arias et al. / Domestic Animal Endocrinology 65 (2018) 1–8 3

Fig. 2. External appearance of goiter (arrow) in both affected Shih-Tzu dogs with congenital dyshormonogenic hypothyroidism with goiter. Case 1 at 2 yr of age
(A), left thyroid lobe (LTL): 8  5.5  3 cm and right thyroid lobe (RTL): 5.5  4.5  3 cm. Case 2 at 6 wk of age (B), LTL: 4.45  2  1.7 cm, and RTL: 4.8  3.1 
2.2 cm.

CDHG during scintigraphy. In addition, radiopharmaceu-
tical uptake in the right axillary region of case 1 and in
anterior mediastinum of both cases was observed, findings
compatible with a metastatic thyroid process and/or
ectopic thyroid tissue (Fig. 4).
Lymphadenectomy and total thyroidectomy were per-
formed in case 1. During the procedure multiple adhesions
of the thyroid gland capsule and invasion of thyroid tissue
into adjacent tissues of the neck were observed (Fig. 5).
Cardiac and thyroid function worsened after surgery,
requiring supplementation with vitamin D2 (2400 UI PO
q96h) and calcium citrate (950 mg PO q12h [200 mg
elemental calcium]) due to the removal of the 4 parathyroid
glands that were buried in the goiter. Progressive increases
in the LT4 dose and frequency were also necessary, until
finally reaching normal concentrations of serum FT4 at 9
mo and TSH at 12 mo after thyroidectomy (Table 1). How-
ever, an improvement in myocardial contractility was only

Fig. 3. Panel A shows the dog of case 1 (left) at 2 yr of age with evident growth retardation caused by the congenital dyshormonogenic hypothyroidism with
goiter (CDHG) and her normal littermate sister (right). Panels B and C show the 2 dogs with CDHG exhibiting normal and proportional appearance during
hormone replacement therapy at 6 yr in case 1 (B) and 6 mo in case 2 (C).
4 E.A. Soler Arias et al. / Domestic Animal Endocrinology 65 (2018) 1–8

Table 1
Diagnosis, follow-up, and treatment of dogs with congenital dyshormonogenic hypothyroidism with goiter and dilated cardiomyopathy.

Age (mo) Thyroid function finding Echocardiographic findings [16] Oral treat.
a
TSH (ng/mL) TT4 (mg/dL)
a a
FT4 (ng/dL) LVIDs (mm) LVIDd (mm) SF (%) LT4 (mg/kg)

Case 1
24 0.95 0.9 0.3 20.5 28.5 28 20*
27 0.64 1.4 0.9 22.3 29 23 20*
Case 1-PT
30 1.17 1.1 0.6 22.4 28.5 21 25**
39 0.58 1.2 21.5 28 23 30**
42 0.20 1.6 21.8 28.5 23 35**
50 0.22 1.4 21.3 30 29b 35**
78 0.05 2.3 3 18.1 26.3 31b 35**
Case 2
1.5 0.72 0.97 0.42 27.2 36.2 25 20*
7.5 0.29 0.7 0.3 28.0 35 22 25**
14 1.46 1.82 1.33 24.6 40 39b 30**
Reference value <0.35 1–3 0.6–3 11–19 19–28 >25 20

Abbreviations: FT4, free thyroxine; LT4, sodium levothyroxine [q24h* or q12h**]; LVIDd, left ventricular internal diameter at end diastole; LVIDs, left
ventricular internal diameter at end systole; PT, post-thyroidectomy; SF, shortening fractional; treat, treatment, TSH, thyrotrophin; TT4, total thyroxine.
a
Chemiluminescence immunoassays.
b
Performed under treatment with 0.5 mg/kg PO q24h with pimobendan.

achieved 8 mo after the treatment with pimobendan, once
thyroid function had been normalized.
A recheck of case 2 was performed at 14 mo of age.
Plasma TT4 and FT4 concentrations were within reference
ranges with plasma TSH elevated, the goiter was the same
size, and cardiac function had improved (Table 1). The dose
of LT4 was increased, but the dog died suddenly and un-
expectedly 1 wk later. At necropsy, the thyroid lobes had
regular borders without adhesions, but had prominent
vasculature (Fig. 5). The heart was dilated with thin walls in
both ventricles, and in addition, a 1 cm nodule was
observed in the intrapericardial aortic fat (Fig. 5).
Lymph node, thyroid (surgery and necropsy), the
intrapericardial nodule, and left ventricular wall muscle
obtained at necropsy were fixed by immersion in 10%
formalin and embedded in paraffin. Five micron sections
were stained with hematoxylin and eosin. In case 1, a
follicular thyroid carcinoma was diagnosed based on the
infiltrating growth of the neoplasm in the thyroid capsule
(Fig. 6) and in the metastasis in the axillary lymph node. In
case 2, an adenomatous goiter and intrapericardial thyroid
ectopic tissue were demonstrated by positive staining with
a mouse monoclonal antithyroglobulin antibody
(SC365997, diluted 1: 200 in PBS, Santa Cruz Biotech-
nology) (Fig. 6).
3. Materials and methods
3.1. Dogs
Ten dogs, 2 with CDHG and ITD, and 8 clinically healthy
with an average age of 5.4 yr (range: 1–10 yr), all belonging
to the same Shih-Tzu family, were included in the study.
The diagnosis of CDHG and ITD was based on the combi-
nation of clinical signs and low plasma TT4 and FT4 con-
centrations and poor uptake of 99mTc in the salivary and
thyroid glands.

Fig. 4. Thyroid scintigraphic images in ventral position of a healthy dog (A) and 2 dogs with congenital dyshormonogenic hypothyroidism with goiter due to an
iodide transport defect, case 1 (B) and case 2 (C). The image capture was made 15 min after IV injection of 148 Mbq of the radioisotope 99mTcO 4 (technetium 99,
metastable sodium pertechnetate) in a gamma planar camera (Picker). Panel A shows salivary glands (sg) and both lobes of the thyroid (tg) of a normal dog
exhibiting abundant uptake of the radioisotope. In (B) and (C), there was poor and diffuse 99mTc uptake in the goiters (arrowheads), absence of uptake in sg
(circles) and focal uptake in anterior mediastinum (curved arrows). Case 1 (B) exhibited pathological 99mTc uptake in the right axillary lymph node (black arrow).
 E.A. Soler Arias et al. / Domestic Animal Endocrinology 65 (2018) 1–8 5

Fig. 5. Panel A shows the intraoperative macroscopic appearance of neoplastic thyroid tissue with multiple adhesions of the capsule into adjacent tissues of the
neck in case 1. Panel B (case 2) the enlarged thyroid lobes with smooth borders and prominent vasculature (necropsy). Panel C shows the ectopic thyroid tissue
observed at the heart base of case 2 and cut in half (arrow). Bar ¼ 1 cm. Panels D–F compare the appearance and size of thyroid in case 1 (D), case 2 (E), and a
normal dog (F). Bar ¼ 1 cm.

Fig. 6. Panel A, case 1. Follicular thyroid carcinoma, infiltrative growth of follicular epithelial cells in thyroid capsule. Hematoxylin-eosin. Bar ¼ 50 mm. Panels B–D,
case 2. Panel B, nodule of ectopic thyroid tissue inserted into intrapericardial aortic fat with positivity for antithyroglobulin. Bar ¼ 500 mm. In (C), adenomatous
goiter tissue, exhibiting proliferation of irregular shaped and sized follicles with abundant colloid and broad sectors of cuboidal cell hyperplasia. Positive staining
with antithyroglobulin. Bar ¼ 100 mm.
6 E.A. Soler Arias et al. / Domestic Animal Endocrinology 65 (2018) 1–8

3.2. Molecular investigations
Blood from one of the CDHG-affected dogs (case 1) and
8 clinically normal dogs from the same family was collected
in sodium EDTA for isolation of DNA by routine methods.
All NIS exons with flanking splice sites of the SLC5A5 gene
were amplified by PCR using primers chosen from the
canine reference genome assembly (CanFam 3.1; sequences
available on request). Amplicons were sequenced on both
strands by dideoxynucleotide chain-termination methods
using the PCR primers as sequencing primers. Sequences
were aligned to the canine reference sequence (CanFam 3.1,
2011 assembly) using the SeqMan Pro program of the
DNAstar suite of sequence analysis software (Madison, WI).
In addition, all exons of the TPO gene of the affected dog
were amplified and sequenced as described previously [3].
(Fig. 7). The mutation was a single base transition of gua-
nine > adenine (G > A) at position 45,024,672 of dog
chromosome 20 (CFA20). A G nucleotide at this position is
crucial for proper splicing of SLC5A5 RNA. The splice site
mutation predicts loss of exon 10, at a minimum, and a shift
of the translation reading frame that predicts 54 amino
acids of altered protein sequence before a premature stop
codon (UAG) in exon 12. Such a foreshortened protein
would not be functional, but more likely is that nonsense-
mediated decay of the abnormal mRNA intervenes and
prevents protein translation of the abnormal message [17].
Five of 8 clinically healthy dogs in the Shih-Tzu family,
including both parents of the case 2 affected dog, were
heterozygous (A/G) and the other 3 were homozygous for
the wild-type allele (G/G).

3.3. Ethical approval
The study was approved by the Ethics Committee of the
Faculty of Veterinary Sciences of the University of Buenos
Aires, complying with current national laws and interna-
tional regulations on the use of animals in clinical studies.
All owners signed their consent to the study.
4. Results
4.1. Deoxyribonucleic acid sequence analysis
No sequence variant was found in TPO of the affected
dog. However, a homozygous mutation (A/A) of the splice
acceptor site was found in intron 9 of the SLC5A5 gene
5. Discussion
Congenital dyshormonogenic hypothyroidism with
goiter due to an ITD in the thyroid occurs as an autosomal
recessive trait in Shih-Tzu dogs due to a mutation in the
SLC5A5 gene that encodes the NIS. Increased plasma TSH
and decreased TT4 and FT4 concentrations with respect to
baseline values, presence of goiter from 3 wk of life, and no
history of antithyroid drugs in the mother or dietary iodide
deficiency or excess were sufficient for the diagnosis of
CDHG in both cases [1,7]. The absence of 99mTc uptake in sg
and poor uptake in the thyroid tissue with elevated plasma
TSH and goiter were relevant findings confirming thyroid
dyshormonogenesis mediated by an ITD. Because both
affected dogs exhibited normal hearing, pendrin (SLC26A4)
mutation seemed unlikely. The NIS is the protein involved

Fig. 7. Polymerase chain reaction amplicons flanking the intron 9/exon 10 boundary were sequenced. The electrophoretograms of a normal dog (top), an affected
dog (bottom), and the dam of an affected dog (middle) are shown. The crucial AG dinucleotide of the normal splice acceptor site is underlined in the normal
sequence. The homozygous A mutation of the affected dog is indicated by the triangle, whereas the dam exhibits A/G heterozygosity at the same position.
 E.A. Soler Arias et al. / Domestic Animal Endocrinology 65 (2018) 1–8
in the active transport of iodide in the basolateral plasma
membrane of thyroid follicular cells that is also expressed
in striated cells of the ducts of sg [18,19]. A defect in the
function of the NIS can be recognized by the absence of
radioactive iodine or 99mTc uptake in both sites of expres-
sion through scintigraphy, as in the cases reported here and
previously in human patients [9,10].
Contrary to what happened in puppies affected by TPO
enzyme defects and other forms of CH, dogs affected by
the SLC5A5 mutation did not exhibit typical signs of CH
(eg, mental dullness, disproportionate dwarfism, alopecia,
and dermatological problems) [1,3]. This finding is similar
to that reported in human patients with variable loss of
functionality of SLC5A5 due to mutation, which present
great clinical and biochemical heterogeneity ranging from
euthyroidism to severe hypothyroidism (in less <10%) [8].
Various explanations for this phenomenon in humans
have been attributed to preservation of some residual
activity of the mutated NIS, to its overexpression induced
by the sustained effect of high concentrations of TSH, or
to contribution of iodine provided in maternal milk and
subsequently maintained by diets rich in iodine [8,18]. In
our cases, it is possible that hyperplasic ectopic thyroid
tissue (heart base), with demonstrated uptake of 99mTc,
emerged as a compensatory mechanism induced by
excess TSH in an attempt to maintain euthyroidism,
slowing down the severity and appearance of clinical
signs [20].
The supplementation of LT4 from 6 wk of life in case 2
prevented the delay in growth observed in the first case,
but did not produce regression of goiter in either case.
This last finding is generally observed in dogs with dys-
hormonogenic goiter treated with LT4, unlike as in those
with transient juvenile hypothyroidism with goiter due to
nutritional iodine deficiency in which regression of the
goiter was obtained after treatment with potassium io-
dide (KI) [3,21,22]. In humans with goiter due a dietary
iodide deficit and in some patients with ITD and goiter
confirmed by absent radiopharmaceutical uptake in thy-
roid and sg, but without confirmed SLC5A5 mutation,
there is almost complete reduction of goiter after the
treatment with KI [23,24]. In our cases, we did not use KI
due to lack of experience with KI use in dogs, absolute
absence of 99mTc uptake in sg, reduction in TSH concen-
tration when starting treatment with LT4, and the
possible complication of heart disease if a state of thyro-
toxicosis occurred [23,25].
In human medicine, a patient with CH without a
goiter at the time of diagnosis with ITD developed a mild
goiter at 8 yr of age while receiving KI as a treatment and
at age 11 yr presented multiple masses that were diag-
nosed as follicular thyroid adenoma [9]. On the other
hand, the emergence of an adenomatous goiter and
subsequent follicular variant papillary carcinoma was
found in a 40-yr-old woman while receiving treatment
with LT4 for CH with ITD without goiter due to SLC5A5
gene mutation. The mechanisms involved in the devel-
opment of thyroid carcinoma in both patients were not
found, although somatic mutations of several oncogenes
(BRAF, RAS, H, K, N) were ruled out, giving greater
prominence to a germline SLC5A5 mutation in the latter
7
report [10]. In our cases, we hypothesized that the
findings in the histopathology were directly proportional
to the time of exposure of the thyroid tissue to the high
concentrations of TSH induced by the ITD for synthesis
of thyroid hormones [26]. A shorter time of exposure to
TSH in case 2 was consistent with hyperplastic tissue
and adenomatous goiter, whereas 2 yr of exposure could
generate a follicular thyroid carcinoma in case 1.
Epidemiologically, papillary thyroid carcinoma is more
frequent in humans than follicular type, except in
iodine-deficient areas of the world where the follicular
type is more frequent, thus highlighting the roll of
iodine deficiency in the pathogenesis of thyroid cancer
[26]. In recent years, the role of NIS in the pathogenesis
of thyroid cancer has been studied. Sodium/iodine
symporter overexpression is observed in most thyroid
cancer cases, but expression is within the cell and not on
the plasma membrane, leading to failure of transporter
functionality [27,28].
With the exception of the Portuguese water dog,
Manchester terrier, and the standard schnauzer, DCM is a
disease that occurs in adult dogs of large breeds [29–31]. In
this report, DCM was associated with hypothyroidism in
both cases, perhaps due to an effect on the expression and
activity of proteins involved in cardiac muscle contractility,
such as phospholamban (PLB) [32]. In rat’s heart, phos-
phorylation of PLB is regulated by thyroid hormones and
correlates with improvement of left ventricular contrac-
tility [32]. Contrary to expectation, therefore, supplemen-
tation with LT4, even at high doses, did not improve
myocardial contraction in either dog. This was similar to
findings reported in doberman pinchers with DCM and
hypothyroidism [33]. As suggested by findings in humans
with heart failure, the lack of response to LT4 supplemen-
tation may be caused by negative regulation of thyroid
hormone receptors a1 and b1 and higher conversion of T4
to reverse T3 by myocardial deiodinase type III [34]. These
mechanisms have not been studied in dogs, so it is
impossible to establish a direct effect of hypothyroidism on
DCM in the dogs reported here. Recent investigations
suggest that the enzymatic machinery of thyroid hormone
synthesis, including SLC5A5, is expressed in cardiac myo-
cytes and may be altered in heart failure, but it is not clear
how local production of thyroid hormone may affect the
myocardium [35].
In conclusion, the mutation found in SLC5A5 predicts
loss of NIS function. This is coincident with diagnosis of ITD
in dogs exhibiting CDHG, evident through the absent and
poor uptake of 99mTc in goiter and sg in affected dogs. Our
findings are currently the first evidence of a mutation in the
NIS gene (SLC5A5) in the dog and establish a new genetic
cause of permanent CDHG in this species, and a new mu-
tation not previously reported in human patients with ITD.
A direct effect or a correlation between CDHG and devel-
opment or progression of DCM in this family is not obvious,
with only 2 dogs affected by both disorders observed.
Finally, development of follicular thyroid carcinoma ap-
pears to be a consequence of the effect of TSH on follicular
thyroid cells induced by intracellular iodine deficiency.
However, a direct role of NIS in thyroid carcinogenesis
cannot be ruled out.
8 E.A. Soler Arias et al. / Domestic Animal Endocrinology 65 (2018) 1–8
Acknowledgments
The authors thank the veterinarians Guillermo Belere-
nian (cardiological evaluation), Pablo Hall (intrasurgical
images), and David Espinoza, Alberto Vartabedian (histo-
pathology revision). The authors also thank Sra. Irma Silva
Ruiz and Sr. Horacio Albino, who contributed all the dogs
for the study, collected the data for the pedigree, and
allowed the necropsy. The authors declare they have no
conflicts of interest.
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