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Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3.
[familial hypocalciuric hypercalcemia]
Adaptor
protein-
2
(
AP
2
)
,
a
central
component
of
clathrin-coated
vesicles
(
CCVs
)
,
is
pivotal
in
clathrin-mediated
endocytosis
,
which
internalizes
plasma
membrane
constituents
such
as
G
protein-coupled
receptors
(
GPCRs
)
.
AP
2
,
a
heterotetramer
of
α
,
β
,
μ
and
σ
subunits
,
links
clathrin
to
vesicle
membranes
and
binds
to
tyrosine-
and
dileucine-based
motifs
of
membrane-associated
cargo
proteins
.
Here
we
show
that
missense
mutations
of
AP
2
σ
subunit
(
AP
2
S
1
)
affecting
Arg
15
,
which
forms
key
contacts
with
dileucine-based
motifs
of
CCV
cargo
proteins
,
result
in
familial
hypocalciuric
hypercalcemia
type
3
(
FHH
3
)
,
an
extracellular
calcium
homeostasis
disorder
affecting
the
parathyroids
,
kidneys
and
bone
.
We
found
AP
2
S
1
mutations
in
>
20
%
of
cases
of
FHH
without
mutations
in
calcium
-sensing
GPCR
(
CASR
)
,
which
cause
FHH
1
.
AP
2
S
1
mutations
decreased
the
sensitivity
of
CaSR-expressing
cells
to
extracellular
calcium
and
reduced
CaSR
endocytosis
,
probably
through
loss
of
interaction
with
a
C-
terminal
CaSR
dileucine-based
motif
,
whose
disruption
also
decreased
intracellular
signaling
.
Thus
,
our
results
identify
a
new
role
for
AP
2
in
extracellular
calcium
homeostasis
.
Diseases
Validation
Diseases presenting
"whose disruption also decreased intracellular signaling"
symptom
familial hypocalciuric hypercalcemia
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