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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
"obesity"
symptom
acute rheumatic fever
adrenal incidentaloma
aniridia
aromatase deficiency
carcinoma of the gallbladder
cohen syndrome
congenital adrenal hyperplasia
cushing syndrome
cystinuria
esophageal adenocarcinoma
esophageal carcinoma
esophageal squamous cell carcinoma
familial hypocalciuric hypercalcemia
familial mediterranean fever
heparin-induced thrombocytopenia
kabuki syndrome
monosomy 21
phenylketonuria
primary hyperoxaluria type 1
sneddon syndrome
werner syndrome
wolf-hirschhorn syndrome
x-linked adrenoleukodystrophy
This symptom has already been validated