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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
"hearing loss"
symptom
22q11.2 deletion syndrome
achondroplasia
adrenomyeloneuropathy
alexander disease
benign recurrent intrahepatic cholestasis
canavan disease
cohen syndrome
congenital toxoplasmosis
dentinogenesis imperfecta
fabry disease
familial mediterranean fever
heparin-induced thrombocytopenia
hirschsprung disease
holt-oram syndrome
homocystinuria without methylmalonic aciduria
hydrocephalus with stenosis of the aqueduct of sylvius
kabuki syndrome
kallmann syndrome
neonatal adrenoleukodystrophy
pendred syndrome
von hippel-lindau disease
wolf-hirschhorn syndrome
This symptom has already been validated
