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
"common mechanism"
symptom
canavan disease
familial hypocalciuric hypercalcemia
focal myositis
gm1 gangliosidosis
waldenström macroglobulinemia
You can validate or delete this automatically detected symptom
Validate the Symptom
Delete the Symptom