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Molecular and functional characterization of human pendrin and its allelic variants.
[pendred syndrome]
Pendrin
(
SLC
26
A
4
,
PDS
)
is
an
electroneutral
anion
exchanger
transporting
I
(
-
)
,
Cl
(
-
)
,
HCO
(
3
)
(
-
)
,
OH
(
-
)
,
SCN
(
-
)
and
formate
.
In
the
thyroid
,
pendrin
is
expressed
at
the
apical
membrane
of
the
follicular
epithelium
and
may
be
involved
in
mediating
apical
iodide
efflux
into
the
follicle
;
in
the
inner
ear
,
it
plays
a
crucial
role
in
the
conditioning
of
the
pH
and
ion
composition
of
the
endolymph
;
in
the
kidney
,
it
may
exert
a
role
in
pH
homeostasis
and
regulation
of
blood
pressure
.
Mutations
of
the
pendrin
gene
can
lead
to
syndromic
and
non-syndromic
hearing
loss
with
EVA
(
enlarged
vestibular
aqueduct
)
.
Functional
tests
of
mutated
pendrin
allelic
variants
found
in
patients
with
Pendred
syndrome
or
non-syndromic
EVA
(
ns-
EVA
)
revealed
that
the
pathological
phenotype
is
due
to
the
reduction
or
loss
of
function
of
the
ion
transport
activity
.
The
diagnosis
of
Pendred
syndrome
and
ns-
EVA
can
be
difficult
because
of
the
presence
of
phenocopies
of
Pendred
syndrome
and
benign
polymorphisms
occurring
in
the
general
population
.
As
a
consequence
,
defining
whether
or
not
an
allelic
variant
is
pathogenic
is
crucial
.
Recently
,
we
found
that
the
two
parameters
used
so
far
to
assess
the
pathogenic
potential
of
a
mutation
,
i
.
e
.
low
incidence
in
the
control
population
,
and
substitution
of
evolutionary
conserved
amino
acids
,
are
not
always
reliable
for
predicting
the
functionality
of
pendrin
allelic
variants
;
actually
,
we
identified
mutations
occurring
with
the
same
frequency
in
the
cohort
of
hearing
impaired
patients
and
in
the
control
group
of
normal
hearing
individuals
.
Moreover
,
we
identified
functional
polymorphisms
affecting
highly
conserved
amino
acids
.
As
a
general
rule
however
,
we
observed
a
complete
loss
of
function
for
all
truncations
and
amino
acid
substitutions
involving
a
proline
.
In
this
view
,
clinical
and
radiological
studies
should
be
combined
with
genetic
and
molecular
studies
for
a
definitive
diagnosis
.
In
performing
genetic
studies
,
the
possibility
that
the
mutation
could
affect
regions
other
than
the
pendrin
coding
region
,
such
as
its
promoter
region
and
/
or
the
coding
regions
of
functionally
related
genes
(
FOXI
1
,
KCNJ
10
)
,
should
be
taken
into
account
.
The
presence
of
benign
polymorphisms
in
the
population
suggests
that
genetic
studies
should
be
corroborated
by
functional
studies
;
in
this
context
,
the
existence
of
hypo-
functional
variants
and
possible
differences
between
the
I
(
-
)
/
Cl
(
-
)
and
Cl
(
-
)
/
HCO
(
3
)
(
-
)
exchange
activities
should
be
carefully
evaluated
.
Diseases
Validation
Diseases presenting
"loss of function for all truncations"
symptom
pendred syndrome
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