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Identification of Novel Functional Null Allele of SLC26A4 Associated with Enlarged Vestibular Aqueduct and Its Possible Implication.
[pendred syndrome]
Mutations
in
the
SLC
26
A
4
gene
,
which
encodes
pendrin
,
cause
congenital
hearing
loss
as
a
manifestation
of
Pendred
syndrome
(
PS
)
with
an
iodide
organification
defect
or
nonsyndromic
enlarged
vestibular
aqueduct
(
NSEVA
,
DFNB
4
)
.
There
have
been
reports
of
differences
between
PS
and
NSEVA
,
including
their
auditory
phenotypes
and
molecular
genetic
bases
.
For
appropriate
genetic
diagnosis
and
counseling
,
it
is
important
to
functionally
characterize
SLC
26
A
4
variants
.
In
this
study
,
we
identified
and
evaluated
a
novel
null
mutation
of
SLC
26
A
4
and
report
our
method
of
assessing
the
pathogenic
potential
of
mutations
in
SLC
26
A
4
,
one
of
the
most
frequent
causative
genes
of
deafness
in
humans
.
A
3
-
year
-old
female
with
progressive
sensorineural
hearing
loss
and
her
parents
were
recruited
.
They
underwent
clinical
,
audiological
,
radiological
and
genetic
evaluations
,
which
revealed
that
the
female
patient
had
an
enlarged
vestibular
aqueduct
and
an
incomplete
partition
type
II
anomaly
in
the
cochlea
bilaterally
.
Sanger
sequencing
of
the
SLC
26
A
4
gene
was
also
performed
.
For
a
confirmatory
genetic
diagnosis
,
we
first
characterized
the
anion
/
base
exchange
ability
of
mutant
pendrin
products
in
HEK
293
cells
and
,
if
necessary
,
evaluated
whether
the
mutant
pendrin
traffics
to
the
plasma
membrane
in
COS
-
7
cells
.
We
also
expressed
a
null
function
mutant
,
p
.
H
723
R
,
and
a
previously
documented
polymorphism
,
p
.
P
542
R
,
as
controls
.
The
pure
tone
average
was
66
dB
HL
in
the
right
ear
and
75
dB
HL
in
the
left
ear
.
Sequencing
of
SLC
26
A
4
revealed
a
known
pathogenic
mutation
(
p
.
H
723
R
)
and
a
novel
missense
variant
(
p
.
V
510
D
)
as
a
compound
heterozygote
.
When
we
expressed
the
p
.
V
510
D
mutant
pendrin
in
mammalian
cells
,
the
rate
constants
for
Cl
(
-
)
/
HCO
3
(
-
)
exchange
were
10
.
96
±
4
.
79
%
compared
with
those
of
wild-
type
pendrin
.
This
figure
was
comparable
to
that
of
p
.
H
723
R
,
indicating
p
.
V
510
D
to
be
another
pathogenic
mutation
with
a
null
function
.
The
p
.
V
510
D
pendrin
product
was
shown
to
be
entrapped
in
the
endoplasmic
reticulum
(
ER
)
at
24
-
30
h
after
transfection
,
and
not
trafficked
to
the
plasma
membrane
in
COS
-
7
cells
,
suggesting
retention
in
the
ER
and
abnormal
trafficking
as
the
pathogenic
mechanism
.
This
was
similar
to
p
.
H
723
R
,
which
is
a
null
function
founder
mutant
in
this
population
but
is
a
candidate
variant
for
future
drug
therapy
to
rescue
the
abnormal
cell
trafficking
.
Impaired
cellular
trafficking
due
to
ER
retention
and
abolished
exchange
activity
of
the
newly
detected
p
.
V
510
D
indicates
the
pathogenic
potential
of
this
variant
.
These
missense
variants
may
be
good
candidate
variants
for
drug
therapy
if
the
intrinsic
exchange
activity
is
not
damaged
by
the
change
.
©
2014
S
.
Karger
AG
,
Basel
.
Diseases
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Diseases presenting
"progressive sensorineural hearing loss"
symptom
pendred syndrome
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