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Calcium-sensing receptor (CASR) mutations in hypercalcemic states: studies from a single endocrine clinic over three years.
[familial hypocalciuric hypercalcemia]
Inactivating
mutations
of
the
calcium-sensing
receptor
(
CASR
)
are
implicated
in
different
hypercalcemic
syndromes
,
including
familial
hypocalciuric
hypercalcemia
(
FHH
)
,
primary
hyperparathyroidism
(
PHPT
)
,
and
familial
isolated
hyperparathyroidism
(
FIHP
)
.
However
,
molecular
diagnostics
applied
to
large
nonselected
hypercalcemic
cohorts
from
a
single
center
have
not
been
reported
.
Our
objective
was
to
describe
the
prevalence
,
type
,
and
potential
pathogenicity
of
CASR
mutations
in
a
series
of
cases
with
FHH
(
n
=
17
)
,
PHPT
(
n
=
165
)
,
and
FIHP
(
n
=
3
)
and
controls
(
n
=
198
)
presenting
at
a
single
endocrine
clinic
.
All
were
prospectively
evaluated
at
the
"
Casa
Sollievo
della
Sofferenza
"
Hospital
in
southern
Italy
over
a
3
-
yr
period
.
CASR
screening
was
conducted
by
denaturing
HPLC
.
The
variant
CASRs
were
functionally
characterized
by
transient
transfection
studies
in
kidney
cells
in
vitro
.
A
single
novel
missense
variant
was
identified
in
one
PHPT
case
.
However
,
in
FHH
probands
,
mutations
were
found
in
eight
of
17
(
47
%
)
.
With
a
hypercalcemic
family
member
,
mutation
detection
rate
in
FHH
rose
to
seven
of
eight
(
87
%
)
,
whereas
only
one
of
nine
sporadic
cases
was
positive
,
and
none
of
the
three
FIHP
cases
had
detectable
CASR
mutations
.
Five
missense
variant
CASRs
,
identified
in
control
subjects
,
performed
as
wild
type
in
functional
assays
,
whereas
the
missense
mutant
CASRs
identified
in
the
FHH
patients
,
and
in
the
one
PHPT
case
,
exhibited
significant
impairment
.
A
novel
intronic
mutation
(
IVS
4
-
19
a--
>
c
)
found
in
one
FHH
family
,
created
an
abnormally
spliced
product
in
an
in
vitro
minigene
assay
.
CASR
testing
,
with
functional
analysis
,
provides
critical
confirmatory
evidence
in
the
differential
diagnosis
of
hypercalcemic
states
.
Diseases
Validation
Diseases presenting
"provides critical confirmatory evidence in the differential diagnosis of hypercalcemic states"
symptom
familial hypocalciuric hypercalcemia
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