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G protein-coupled receptor mutations and human genetic disease.
[familial hypocalciuric hypercalcemia]
Genetic
variations
in
G
protein-coupled
receptor
genes
(
GPCRs
)
disrupt
GPCR
function
in
a
wide
variety
of
human
genetic
diseases
.
In
vitro
strategies
and
animal
models
have
been
used
to
identify
the
molecular
pathologies
underlying
naturally
occurring
GPCR
mutations
.
Inactive
,
overactive
,
or
constitutively
active
receptors
have
been
identified
that
result
in
pathology
.
These
receptor
variants
may
alter
ligand
binding
,
G
protein
coupling
,
receptor
desensitization
and
receptor
recycling
.
Receptor
systems
discussed
include
rhodopsin
,
thyrotropin
,
parathyroid
hormone
,
melanocortin
,
follicle-stimulating
hormone
(
FSH
)
,
luteinizing
hormone
,
gonadotropin-releasing
hormone
(
GNRHR
)
,
adrenocorticotropic
hormone
,
vasopressin
,
endothelin-β
,
purinergic
,
and
the
G
protein
associated
with
asthma
(
GPRA
or
neuropeptide
S
receptor
1
(
NPSR
1
)
)
.
The
role
of
activating
and
inactivating
calcium-sensing
receptor
(
CaSR
)
mutations
is
discussed
in
detail
with
respect
to
familial
hypocalciuric
hypercalcemia
(
FHH
)
and
autosomal
dominant
hypocalemia
(
ADH
)
.
The
CASR
mutations
have
been
associated
with
epilepsy
.
Diseases
caused
by
the
genetic
disruption
of
GPCR
functions
are
discussed
in
the
context
of
their
potential
to
be
selectively
targeted
by
drugs
that
rescue
altered
receptors
.
Examples
of
drugs
developed
as
a
result
of
targeting
GPCRs
mutated
in
disease
include
:
calcimimetics
and
calcilytics
,
therapeutics
targeting
melanocortin
receptors
in
obesity
,
interventions
that
alter
GNRHR
loss
from
the
cell
surface
in
idiopathic
hypogonadotropic
hypogonadism
and
novel
drugs
that
might
rescue
the
P
2
RY
12
receptor
congenital
bleeding
phenotype
.
De
-orphanization
projects
have
identified
novel
disease-associated
receptors
,
such
as
NPSR
1
and
GPR
35
.
The
identification
of
variants
in
these
receptors
provides
genetic
reagents
useful
in
drug
screens
.
Discussion
of
the
variety
of
GPCRs
that
are
disrupted
in
monogenic
Mendelian
disorders
provides
the
basis
for
examining
the
significance
of
common
pharmacogenetic
variants
.
Diseases
Validation
Diseases presenting
"asthma"
symptom
allergic bronchopulmonary aspergillosis
cutaneous mastocytosis
erdheim-chester disease
familial hypocalciuric hypercalcemia
lamellar ichthyosis
lymphangioleiomyomatosis
pendred syndrome
This symptom has already been validated