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Calcium-sensing receptor sequencing in 21 patients with idiopathic or familial parathyroid disorder: pitfalls and characterization of a novel I32 V loss-of-function mutation.
[familial hypocalciuric hypercalcemia]
The
calcium-sensing
receptor
(
CaSR
)
is
a
G-
protein-coupled
receptor
with
a
crucial
role
in
calcium
homeostasis
.
Mutations
in
the
CaSR
gene
may
lead
to
specific
parathyroid
disorders
due
to
either
gain-of-function
(
autosomal
dominant
hypercalciuric
hypocalcemia
;
ADHH
)
or
loss
-of-function
(
familial
hypocalciuric
hypercalcemia
;
FHH
)
.
Our
aim
was
to
evaluate
CaSR
mutations
as
a
cause
of
disease
in
selected
patients
.
We
identified
and
recruited
patients
with
phenotypes
suggestive
of
CaSR-related
parathyroid
disorders
.
DNA
was
extracted
,
and
CaSR
gene
was
sequenced
.
Live-ratiometric
measurements
of
intracellular
[
Ca
(
2
+
)
]
and
Western
blot
assays
for
evaluation
of
MAPK
phosphorylation
in
response
to
changes
in
extracellular
[
Ca
(
2
+
)
]
were
performed
in
transiently
transfected
HEK-
293
T
cells
to
functionally
characterize
mutants
.
A
total
of
21
patients
were
evaluated
,
seven
of
them
with
idiopathic
hypoparathyroidism
(
suspected
ADHH
)
and
14
with
hyperparathyroidism
(
suspected
FHH
)
.
In
the
latter
group
two
patients
were
found
to
harbor
missense
mutations
:
a
novel
heterozygous
I
32
V
mutation
in
a
female
index
case
and
a
sporadic
known
R
185
Q
mutation
in
a
1
-
year
-old
girl
.
In-vitro
functional
studies
showed
that
I
32
V
is
an
inactivating
mutation
.
In
our
study
,
most
patients
had
normal
CaSR
sequencing
.
This
suggests
that
phenotypic
pitfalls
may
occur
at
time
of
patients
'
selection
for
CaSR
sequencing
.
In
one
patient
with
strong
positive
pre-test
probability
based
on
both
familial
history
and
appropriate
phenotype
,
a
novel
I
32
V
mutation
leading
to
FHH
was
identified
and
characterized
.
In
cases
of
familial
parathyroid
disorders
,
CaSR
sequencing
should
be
performed
,
but
if
negative
,
one
should
consider
involvement
of
alternative
genes
or
mechanisms
.
Diseases
Validation
Diseases presenting
"casr sequencing should be performed"
symptom
familial hypocalciuric hypercalcemia
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