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Pharmacochaperone-mediated rescue of calcium-sensing receptor loss-of-function mutants.
[familial hypocalciuric hypercalcemia]
The
calcium
sensing
receptor
(
CaSR
)
is
a
Family
C
/
3
G
protein-coupled
receptor
that
translates
changes
in
extracellular
Ca
(
2
+
)
into
diverse
intracellular
signals
.
Loss
-of-function
mutations
in
human
CaSR
cause
familial
hypocalciuric
hypercalcemia
and
neonatal
severe
hyperparathyroidism
.
CaSR
must
navigate
a
number
of
endoplasmic
reticulum
quality
control
checkpoints
during
biosynthesis
,
including
a
conformational
/
functional
checkpoint
.
Here
we
examine
the
biosynthesis
of
25
CaSR
mutations
causing
familial
hypocalciuric
hypercalcemia
/
neonatal
severe
hyperparathyroidism
using
immunoprecipitation
,
biotinylation
,
and
functional
assays
.
We
define
classes
of
CaSR
mutants
based
on
their
biosynthetic
profile
.
Class
I
CaSR
mutants
are
not
rescued
to
the
plasma
membrane
.
To
dissect
the
organellar
compartments
that
class
I
mutants
can
access
,
we
engineered
a
cleavage
site
for
the
proprotein
convertase
furin
into
the
extracellular
domain
of
wild-
type
CaSR
and
class
I
mutants
.
Based
on
absence
or
presence
of
cleavage
fragments
,
we
find
most
mutants
are
degraded
from
the
endoplasmic
reticulum
(
no
furin-mediated
cleavage
)
,
whereas
others
access
the
Golgi
(
furin-mediated
cleavage
)
before
degradation
.
Class
II
CaSR
mutants
show
increased
expression
and
/
or
enhanced
plasma
membrane
localization
upon
treatment
with
MG
132
or
the
pharmacochaperone
NPS
R-
568
,
permitting
assay
of
functional
activity
.
Of
the
10
CaSR
mutants
that
exhibit
plasma
membrane
localization
,
only
two
did
not
show
enhanced
functional
activity
after
rescue
with
NPS
R-
568
.
The
established
approaches
can
be
used
with
current
and
newly
identified
CaSR
mutations
to
identify
the
location
of
biosynthetic
block
and
to
determine
the
likelihood
of
rescue
by
allosteric
agonists
.
Diseases
Validation
Diseases presenting
"loss-of-function mutations"
symptom
achondroplasia
alpha-thalassemia
aromatase deficiency
child syndrome
cowden syndrome
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
erythropoietic protoporphyria
esophageal adenocarcinoma
familial hypocalciuric hypercalcemia
harlequin ichthyosis
hirschsprung disease
kallmann syndrome
kindler syndrome
lamellar ichthyosis
neonatal adrenoleukodystrophy
pendred syndrome
werner syndrome
x-linked adrenoleukodystrophy
This symptom has already been validated