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Functional rescue of Kallmann syndrome-associated prokineticin receptor 2 (PKR2) mutants deficient in trafficking.
[kallmann syndrome]
Mutations
in
the
G
protein-coupled
prokineticin
receptor
2
(
PKR
2
)
are
known
to
cause
Kallmann
syndrome
and
idiopathic
hypogonadotropic
hypogonadism
manifesting
with
delayed
puberty
and
infertility
.
Some
of
the
mutant
receptors
are
not
routed
to
the
cell
surface
;
instead
,
they
are
trapped
in
the
cellular
secretory
pathway
.
The
cell-permeant
agonists
/
antagonists
have
been
used
to
rescue
some
membrane
receptors
that
are
not
targeted
onto
the
cell
membrane
.
Here
,
we
chose
three
disease-associated
mutations
(
W
178
S
,
G
234
D
,
and
P
290
S
)
,
which
all
resulted
in
retention
of
PKR
2
intracellularly
.
We
show
that
a
small
molecule
PKR
2
antagonist
(
A
457
)
dramatically
increased
cell
surface
expression
and
rescued
the
function
of
P
290
S
PKR
2
,
but
had
no
effect
on
W
178
S
and
G
234
D
PKR
2
.
Furthermore
,
we
also
tested
chemical
chaperone
glycerol
on
the
cell
surface
expression
and
function
of
PKR
2
mutants
.
Treatment
with
10
%
glycerol
significantly
increased
the
cell
surface
expression
and
signaling
of
P
290
S
and
W
178
S
PKR
2
.
These
data
demonstrate
that
some
Kallmann
syndrome
-associated
,
intracellularly
retained
mutant
PKR
2
receptors
can
be
functionally
rescued
,
suggesting
a
potential
treatment
strategy
for
patients
bearing
such
mutations
.
Diseases
Validation
Diseases presenting
"function of pkr2 mutants"
symptom
kallmann syndrome
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