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Calcium-sensing-related gene mutations in hypercalcaemic hypocalciuric patients as differential diagnosis from primary hyperparathyroidism: detection of two novel inactivating mutations in an Italian population.
[familial hypocalciuric hypercalcemia]
Inactivating
mutations
of
the
calcium-sensing
receptor
(
CaSR
)
,
of
the
G-
protein
subunit
α
11
(
GNA
11
)
and
of
the
adaptor-related
protein
complex
2
,
sigma
1
subunit
(
AP
2
S
1
)
genes
are
responsible
for
familial
hypocalciuric
hypercalcaemia
(
FHH
)
.
The
aim
of
this
study
was
to
analyse
prevalence
and
pathogenicity
of
CaSR
,
GNA
11
and
AP
2
S
1
mutations
in
patients
with
an
FHH
phenotype
and
to
compare
them
with
a
sample
of
patients
with
primary
hyperparathyroidism
(
PHPT
)
in
order
to
identify
the
most
useful
laboratory
parameter
for
a
differential
diagnosis
.
Patients
with
an
FHH
phenotype
were
studied
with
polymerase
chain
reaction
amplification
and
direct
sequencing
of
the
entire
CaSR
,
GNA
11
and
AP
2
S
1
coding
sequences
.
Novel
mutations
were
introduced
in
a
Myc-tagged
human
wild-
type
(
WT
)
CaSR
cDNA-expressing
vector
,
and
functional
assay
was
performed
on
human
embryonic
kidney
cells
evaluating
expression
and
function
of
mutated
proteins
.
Among
16
FHH
patients
,
none
had
an
inactivating
GNA
11
or
AP
2
S
1
mutation
while
3
(
18
.
8
%
)
carried
a
CaSR
mutation
and
10
(
62
.
5
%
)
at
least
one
CaSR
polymorphism
.
Within
the
latter
group
,
7
of
10
patients
had
more
than
one
polymorphism
(
4
.
1
±
2
.
1
per
patient
)
.
Two
novel
CaSR
mutations
[
c
.
2120
A
>
T
(
E
707
V
)
and
c
.
2320
G
>
A
(
G
774
S
)
]
were
identified
:
the
E
707
V
mutation
prevented
CaSR
expression
(
western
blot
)
,
whereas
the
G
774
S
mutation
determined
a
reduced
receptor
sensitivity
to
calcium
(
IP
3
assay
)
.
PHPT
patients
showed
significantly
(
P
<
0
.
001
)
higher
serum
calcium
,
parathyroid
hormone
,
urinary
calcium
and
calcium
-creatinine
clearance
ratio
(
CCCR
)
and
significantly
lower
serum
phosphate
than
FHH
ones
.
FHH
should
be
clearly
differentiated
by
PHPT
to
avoid
unnecessary
surgery
:
CCCR
could
be
a
useful
screening
tool
while
genetic
analysis
should
include
the
two
novel
CaSR
mutations
herein
described
.
The
role
of
multiple
polymorphisms
deserves
further
investigation
in
patients
with
an
FHH
phenotype
.
Diseases
Validation
Diseases presenting
"urinary calcium"
symptom
adrenal incidentaloma
aromatase deficiency
cystinuria
familial hypocalciuric hypercalcemia
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