Rare Diseases Symptoms Automatic Extraction
Home
A random Abstract
Our Project
Our Team
Effect of the calcimimetic R-568 [3-(2-chlorophenyl)-N-((1R)-1-(3-methoxyphenyl)ethyl)-1-propanamine] on correcting inactivating mutations in the human calcium-sensing receptor.
[familial hypocalciuric hypercalcemia]
Over
257
mutations
in
the
human
calcium-sensing
receptor
(
hCaSR
)
gene
have
been
reported
.
Heterozygous
inactivating
mutations
can
result
in
familial
hypocalciuric
hypercalcemia
(
FHH
)
,
whereas
homozygous
inactivating
mutations
can
cause
life-threatening
neonatal
severe
hyperparathyroidism
(
NSHPT
)
.
Activating
mutations
in
the
hCaSR
can
result
in
hypercalciuria
and
hypocalcemia
.
A
recent
publication
on
the
successful
treatment
of
a
patient
suffering
from
FHH
with
the
hCaSR
positive
allosteric
modulator
cinacalcet
prompted
our
interest
in
exploring
the
molecular
pharmacology
of
calcimimetics
to
correct
signaling
defects
associated
with
inactivating
hCaSR
mutations
.
We
prepared
11
mutant
hCaSRs
,
previously
identified
in
patients
suffering
from
NSHPT
or
FHH
,
and
tested
their
ability
to
couple
to
inositol
phosphate
accumulation
and
intracellular
calcium
mobilization
in
transiently
transfected
human
embryonic
kidney
293
and
Chines
hamster
ovary
cells
using
the
calcimimetic
R-
568
[
3
-
(
2
-
chlorophenyl
)
-
N-
(
(
1
R
)
-
1
-
(
3
-
methoxyphenyl
)
ethyl
)
-
1
-
propanamine
]
.
We
found
that
extracellular
Ca
(
2
+
)
was
significantly
less
potent
on
the
mutated
receptors
compared
with
wild-
type
hCaSR
.
However
,
R-
568
was
able
to
enhance
the
potency
of
extracellular
Ca
(
2
+
)
toward
the
mutant
hCaSRs
.
Furthermore
,
R-
568
increased
the
maximal
agonist
response
on
several
of
the
mutant
CaSRs
.
We
applied
a
novel
operational
model
of
allosteric
modulation
/
agonism
that
provided
a
common
mechanism
to
account
for
the
behavior
of
the
wild-
type
and
mutant
hCaSRs
.
The
data
provide
evidence
for
the
potential
use
of
calcimimetics
to
treat
diseases
such
as
FHH
and
NSHPT
where
severe
hypercalcemia
can
be
life-threatening
.
Diseases
Validation
Diseases presenting
"hypercalcemia"
symptom
carcinoma of the gallbladder
cushing syndrome
familial hypocalciuric hypercalcemia
kabuki syndrome
severe combined immunodeficiency
waldenström macroglobulinemia
This symptom has already been validated