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Two novel mutations of the calcium-sensing receptor gene affecting the same amino acid position lead to opposite phenotypes and reveal the importance of p.N802 on receptor activity.
[familial hypocalciuric hypercalcemia]
Gain-of-function
mutations
of
the
calcium-sensing
receptor
(
CASR
)
gene
have
been
identified
in
patients
with
sporadic
or
familial
autosomal
dominant
hypocalcemia
(
ADH
)
.
Inactivating
mutations
of
the
CASR
gene
cause
familial
hypocalciuric
hypercalcemia
(
FHH
)
.
Here
,
we
report
two
novel
CASR
mutations
affecting
the
same
amino
acid
(
p
.
N
802
)
;
one
causes
ADH
and
the
other
atypical
FHH
.
T
he
first
patient
,
an
11
-
year
-old
girl
suffering
from
hypocalcemia
,
developed
nephrocalcinosis
when
she
was
only
5
years
old
.
The
second
patient
is
a
30
-
year
-old
woman
who
presented
with
mild
hypercalcemia
.
PCR
amplification
of
CASR
coding
exons
and
direct
sequencing
of
PCR
products
were
used
to
identify
mutations
.
Site-directed
mutagenesis
was
used
to
generate
mutated
CASR
cDNAs
in
an
expression
plasmid
.
Using
the
MAPK
assay
system
and
transient
transfection
of
Cos
-
7
cells
with
wild-
type
(
WT
)
and
mutated
CASR
,
we
studied
the
responses
of
these
mutated
receptors
to
extracellular
Ca
(
2
+
)
and
to
the
negative
allosteric
CASR
modulator
,
NPS
2143
.
T
wo
heterozygous
missense
mutations
(
p
.
N
802
I
and
p
.
N
802
S
)
affecting
a
residue
in
the
sixth
transmembrane
domain
of
CASR
were
identified
.
In
functional
tests
,
the
response
of
the
p
.
N
802
S
mutant
to
calcium
was
typical
of
an
inactivating
mutation
.
However
,
the
p
.
N
802
I
mutant
had
70
%
of
the
maximally
stimulated
WT
receptor
activity
even
in
the
absence
of
extracellular
calcium
.
This
constitutive
activity
was
only
partially
inhibited
by
the
inhibitor
,
NPS
2143
.
T
he
asparagine
at
amino
acid
position
802
appears
to
be
essential
for
the
activity
of
the
CASR
protein
and
is
implicated
in
the
mechanism
of
CASR
signaling
.
Diseases
Validation
Diseases presenting
"mild hypercalcemia"
symptom
familial hypocalciuric hypercalcemia
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