Identification of a novel de novo GATA3 mutation in a patient with HDR syndrome
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Identification of a novel de novo GATA3 mutation in a patient with HDR syndrome
Liu Chen 1
Bing Chen 1
Wuilin Leng 1
Xiaotian Lui 1
Qinan Wu 1
Xinshou Ouyang 0
Ziwen Liang 1
0 Section of Digestive Disease, Department of Internal Medicine, Yale University School of Medicine , New Haven, CT , USA
1 Department of Endocrinology, First Affiliated Hospital of Third Military Medical University , Chongqing , China
We describe the case of a 21-year-old male with hypocalcaemia, hyperphosphataemia, recurrent limb twitch, deafness, proteinuria, increased serum creatinine and urea nitrogen levels, and shrinkage of both kidneys. Brain computed tomography showed intracranial calcifications. The patient was diagnosed with hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR) syndrome. DNA sequence analysis of the GATA3 gene showed a novel de novo mutation, c. 529dupC (p. Arg177profs*126), in exon 2, resulting in a frameshift mutation with a premature stop codon after a new 126 amino acid sequence. We provide further evidence that HDR syndrome is caused by haploinsufficiency of GATA3.
eol>HDR syndrome; GATA3; phenotypic spectrum; mutation analysis
deafness and renal dysplasia (HDR) syndrome
is a rare autosomal-dominant genetic
disease that was first reported in 1977.1–3 Due
to phenotypic heterogeneity, patients may
exhibit two or three symptoms of the triad,
and can have concomitant clinical
manifestations such as craniofacial abnormalities,
neuropathy or ankylodactyly. Deafness is
the characteristic manifestation of HDR
Genetic mutations resulting in
haploinsufficiency of the GATA3 (GATA binding
protein 3) gene can lead to HDR syndrome.6
In humans, GATA3 is expressed in the
parathyroid, kidney, inner ear, thymus and
central nervous system.7 The GATA3
protein forms three major functional regions
via space folding, including a specific DNA
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binding and recognition region,
transcriptional activation region and nuclear
localization region. The transcriptional
activation region includes two activation
domains (TA1 and TA2) and two zinc
finger DNA-binding domains (ZnF1 and
ZnF2). Functional studies have found that
ZnF2 is essential for DNA binding, while
ZnF1 stabilizes binding and mediates
interactions with GATA zinc-finger binding
Several GATA3 mutation types are
associated with HDR syndrome, including
deletion, base substitution, frameshift, insertion
and splice mutation. We report the clinical
manifestations and laboratory findings of a
21-year-old male with HDR syndrome
resulting from a novel GATA3 mutation.
A 19-year-old male presented at the
Department of Endocrinology, First
Affiliated Hospital of Third Military
Medical University, Chongqing, China, in
March 2012 recurring limb twitches and
weakness, and a 2-year history of foamy
urine and renal dysfunction. He exhibited
spontaneously twitching limbs without loss
of consciousness, which ceased after a few
seconds and then recurred. The patient
started speaking with normal pronunciation
and clear articulation aged 1 year, but at
2 years of age was found to show a poor or
absent response to sound and was diagnosed
with mixed deafness at a local hospital.
Hearing was improved by use of a hearing
aid, and the patient could communicate
normally and go to school. Recurring limb
twitching (without loss of consciousness)
began following a fever when he was
2 years old, and was treated by parentally
administered calcium supplementation.
In 2010, the patient began to exhibit foamy
urine with no obvious cause, and his
serum creatinine level was substantially
elevated. Abdominal colour Doppler
ultrasonography revealed small kidneys
and calcification of the liver, and the patient
was diagnosed with chronic nephritis by the
The patient was the first child born to his
mother, and was the product of her first
pregnancy. He was delivered normally at full
term and weighed around 3 kg. His mental
and physical development was similar to
that of his peers, although he was not as tall.
His parents were not consanguineous.
The family medical history was
unremarkable, and the patient had no siblings.
Physical examination found that binaural
hearing was decreased, and the patient wore
a hearing aid. His teeth were irregularly
arranged, with dental fluorosis. His neck
was symmetrical and there was no palpable
mass. The thyroid, heart, lungs and
abdomen were normal. There was no obvious
oedema of the lower limbs. Chvostek’s sign
was negative; Trousseau’s sign was positive.
During the examination, while the patient
was conscious, he exhibited tetanic spasm
and involuntary dance-like movements of
the hands and feet; the symptoms ceased
spontaneously after a few seconds. The
interval between attacks varied from tens
of minutes to several hours.
Laboratory examinations revealed serum
calcium 1.86 mmol/l (normal range 2.1–
2.6 mmol/l), serum phosphate 1.71 mmol/l
(0.81–1.55 mmol/l), serum creatinine
215 mmol/l (40–97 mmol/l), serum urea
nitrogen 14.3 mmol/l (1.7–8.3 mmol/l), 24-h urine
protein 388 mg(10–150 mg) and intact
parathyroid hormone 9.96 pg/ml (15–65 pg/ml;
PTH Elecsys kit; Roche, Basel, Switzerland).
Kidney and urinary tract ultrasonography
indicated shrinkage and sparse blood flow in
both kidneys, without hydronephrosis, stone
or space-occupying lesions. Renal function
imaging indicated that the glomerular
filtration rate (GFR) of the left and right kidney
was 10.63 ml/min and 23.51 ml/min,
respectively, after correction for height and body
weight. Total GFR was 34.14 ml/min (normal
Figure 1. Computed tomography image of the brain and abdomen of a male patient with
hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR) syndrome showing multiple intracranial calcification
in the brain (a) and shrinkage in the kidneys (b).
lower limit 90.0 ml/min for both kidneys and
45.0 ml/min for a single kidney). Computed
tomography of the brain and abdomen found
substantial calcium deposits in the brain and
shrinkage in the kidneys (Figure 1).
Audiological examination indicated that the
patient had bilateral mixed deafness
The patient was admitted to hospital for
re-examination in November 2014. Genetic
analysis of GATA3 was performed using
DNA extracted from peripheral blood of
the patient and his parents, with their
consent. Direct sequencing of the exon encoding
region of GATA3 gene was performed, and a
comparison was made with the reference
sequence (NM_001002295.1 and
NG_015859.1). A de novo novel heterozygous
mutation in exon 2 of the GATA3 gene was
detected in the patient (c. 529 dupC [p.
Arg177profs*126]). The mutation was
absent from both of his parents and an
unrelated patient with primary
hypoparathyroidism (Figure 3). This de novo frameshift
mutation resulted in a premature stop codon
after a new 126 amino acid sequence.
The patient and his parents provided
written informed consent to report this
case, and the report was approved by the
ethics committee of the First Affiliated
Hospital of Third Military Medical
University, Chongqing, China.
Since GATA3 was first identified, 51
mutations have been described in patients with
HDR syndrome.10 Mutations can be
stratified into three categories according to
function: (i) GATA3 truncation/deletion or ZnF2
deletion, causing loss of DNA binding
ability (90% of mutations); (ii) ZnF1 deletion,
reducing GATA3 DNA binding affinity; (iii)
GATA3 protein conformational changes or
loss of interaction with FOG.11,12 Mutations
can include total gene deletion, nonsense
mutation, intragene deletion, intragene
insertion and splice mutation.13 The
mutation identified in our patient was a novel
heterozygous mutation in exon 2 of GATA3,
c. 529dupC (p. Arg177profs*126), a
frameshift mutation resulting in a premature stop
codon, and therefore a truncated protein
lacking both ZnF1 and ZnF2.
Our patient demonstrated the typical
triad of HDR syndrome, including recurrent
Figure 3. Gene sequencing of GATA3 (GATA binding protein 3) in: (a) a 21-year-old male patient with
hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR) syndrome; (b) the patient’s father;
(c) the patient’s mother; and (d) an unrelated patient with primary hypoparathyroidism. Arrow indicates a de
novo, heterozygous c.529dupC mutation in the patient.
intracranial calcification, and calcification of the
right liver, all caused by
hypoparathyroidism. Patients with HDR syndrome can
experience epileptic seizures, stiffness, limb
spasms, cerebral infarctions and recurrent
kidney stones.14 Post mortem examination
found hypoplasia or complete absence of
parathyroid glands in some patients with
HDR syndrome.15 Oral vitamin D and
calcium supplementation can be useful in
treating this disease, by improving calcium
absorption and correcting hypocalcaemia
caused by increased renal excretion of
calcium. The recurrent limb twitching in the
present case may be due to the lack of
regular vitamin D supplementation.
Hearing loss in patients with HDR
syndrome is bilateral, symmetrical
sensorineural deafness.16 The degree of hearing
loss and the age of onset vary, however. Our
patient exhibited mixed deafness, which was
successfully ameliorated by the use of a
hearing aid. Hearing damage is not
progressive in HDR syndrome.17
Kidney manifestations of HDR syndrome
vary, and can include diffuse proliferative
glomerulonephritis or focal segmental
glomerular sclerosis, with most patients eventually
developing renal failure.18 In the present case,
the main symptoms of renal dysplasia were
increased creatinine and urea nitrogen,
reduced bilateral renal filtration function,
shrinkage and sparse blood-flow signals in
both kidneys. Ultrasonography
examinations performed 2 years apart revealed a
degree of progression and aggravation of
renal dysfunction in our patient.
In conclusion, our patient exhibited
the typical triad of HDR syndrome.
Gene sequencing discovered a novel
mutation in exon 2 of GATA3 (*c. 529dupC [p.
Arg177profs*126]), resulting in GATA3
haploinsufficiency. Further study is required
to understand the functional and structural
changes of proteins involved in this disorder
and their associations with phenotypic
spectrum. Deafness is the characteristic
manifestation of HDR syndrome, and patients
with deafness and twitch should receive
audiometry, serum calcium, phosphorus
and parathyroid hormone tests, as well as
renal radiographic examinations. The
prognosis of these patients is usually associated
with renal function. The protection of renal
function should therefore be the focus of
treatment in HDR syndrome in order to
prolong the survival time of patients.
Declaration of conflicting interest
This work was supported by research grants from
the National Natural Science Foundation of
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