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Novel inactivating mutations of the calcium-sensing receptor: the calcimimetic NPS R-568 improves signal transduction of mutant receptors.
[familial hypocalciuric hypercalcemia]
Inactivating
mutations
in
the
calcium-sensing
receptor
(
CaSR
)
gene
cause
neonatal
severe
hyperparathyroidism
and
familial
hypocalciuric
hypercalcemia
(
FHH
)
.
The
aims
of
the
present
study
were
the
functional
characterization
of
novel
mutations
of
the
CaSR
found
in
FHH
patients
,
the
comparison
of
in
vitro
receptor
function
with
clinical
parameters
,
and
the
effect
of
the
allosteric
calcimimetic
NPS
R-
568
on
the
signaling
of
mutant
receptors
.
Wild-
type
and
mutant
CaSRs
(
W
530
G
,
C
5
68
Y
,
W
718
X
,
M
734
R
,
L
849
P
,
Q
926
R
,
and
D
1005
N
)
were
expressed
in
human
embryonic
kidney
293
cells
.
Receptor
signaling
was
studied
by
measuring
intracellular
free
calcium
in
response
to
different
concentrations
of
extracellular
calcium
(
[
Ca
(
2
+
)
]
(
o
)
)
.
Four
CaSR
mutations
(
C
5
68
Y
,
W
718
X
,
M
734
R
,
and
L
849
P
)
demonstrated
a
complete
lack
of
a
[
Ca
(
2
+
)
]
(
o
)
-
induced
cytosolic
Ca
(
2
+
)
response
up
to
30
mm
[
Ca
(
2
+
)
]
(
o
)
,
whereas
the
CaSR
mutants
W
530
G
,
Q
926
R
,
and
D
1005
N
retained
some
sensitivity
to
[
Ca
(
2
+
)
]
(
o
)
.
There
was
no
significant
relation
between
the
in
vitro
calcium
sensitivity
,
serum
calcium
,
and
intact
PTH
levels
in
the
patients
.
Patients
with
C-
terminal
CaSR
mutations
had
a
calcium
to
creatine
ratio
above
the
established
diagnostic
threshold
of
0
.
01
for
FHH
.
The
calcimimetic
NPS
R-
568
enhanced
the
responsiveness
to
[
Ca
(
2
+
)
]
(
o
)
in
CaSR
mutants
of
the
extracellular
domain
(
W
530
G
and
C
5
68
Y
)
as
well
as
the
intracellular
C-
terminal
domain
(
Q
926
R
and
D
1005
N
)
.
Therefore
,
calcimimetics
might
offer
medical
treatment
for
symptomatic
FHH
patients
,
and
more
important
,
for
patients
with
neonatal
severe
hyperparathyroidism
that
harbor
calcimimetic-sensitive
CaSR
mutants
.
Diseases
Validation
Diseases presenting
"human embryonic kidney"
symptom
familial hypocalciuric hypercalcemia
pendred syndrome
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