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Identification and functional characterization of a novel mutation in the calcium-sensing receptor gene in familial hypocalciuric hypercalcemia: modulation of clinical severity by vitamin D status.
[familial hypocalciuric hypercalcemia]
Familial
hypocalciuric
hypercalcemia
(
FHH
)
is
a
benign
condition
associated
with
heterogeneous
inactivating
mutations
in
the
calcium-sensing
receptor
(
CASR
)
gene
.
The
objective
of
the
study
was
to
identify
and
characterize
a
CASR
mutation
in
a
moderately
hypercalcemic
,
hyperparathyroid
individual
and
his
family
and
assess
the
influence
of
vitamin
D
status
on
the
clinical
expression
of
the
defect
.
We
studied
a
kindred
with
FHH
,
in
which
the
proband
(
a
34
-
yr
-old
male
)
was
initially
diagnosed
with
primary
hyperparathyroidism
due
to
frankly
elevated
serum
PTH
levels
.
CASR
gene
mutation
analysis
was
performed
on
genomic
DNA
of
the
proband
and
family
members
.
The
mutant
CASR
was
functionally
characterized
by
transient
transfection
studies
in
kidney
cells
in
vitro
.
A
novel
heterozygous
mutation
(
F
180
C
,
TTC
>
TGC
)
in
exon
4
of
the
CASR
gene
was
identified
.
Although
the
mutant
receptor
was
expressed
normally
at
the
cell
surface
,
it
was
unresponsive
with
respect
to
intracellular
signaling
(
MAPK
activation
)
to
increases
in
extracellular
calcium
concentrations
.
The
baby
daughter
of
the
proband
presented
with
neonatal
hyperparathyroidism
with
markedly
elevated
PTH
.
Vitamin
D
supplementation
of
both
the
proband
and
the
baby
resulted
in
reduction
of
serum
PTH
levels
to
the
normal
range
.
The
serum
calcium
level
remained
at
a
constant
and
moderately
elevated
level
.
The
identification
of
a
novel
CASR
gene
mutation
established
the
basis
of
the
hypercalcemia
in
the
kindred
.
Concomitant
vitamin
D
deficiency
modulates
the
severity
of
the
presentation
of
FHH
.