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A novel loss-of-function mutation, Gln459Arg, of the calcium-sensing receptor gene associated with apparent autosomal recessive inheritance of familial hypocalciuric hypercalcemia.
[familial hypocalciuric hypercalcemia]
Mutations
that
inactivate
one
allele
of
the
gene
encoding
the
calcium
sensing
receptor
(
CaSR
)
cause
autosomal
dominant
familial
hypocalciuric
hypercalcemia
(
FHH
)
,
whereas
homozygous
mutations
cause
neonatal
severe
hyperparathyroidism
.
We
describe
the
identification
and
biochemical
characterization
of
a
novel
CASR
gene
mutation
that
caused
apparent
autosomal
recessive
FHH
in
an
extended
consanguineous
kindred
.
The
study
design
involved
direct
sequence
analysis
of
the
CaSR
gene
,
clinical
and
biochemical
analyses
of
patients
,
and
in
vitro
immunobiochemical
studies
of
the
mutant
CaSR
.
A
novel
inactivating
mutation
(
Q
459
R
)
was
identified
in
exon
4
of
both
alleles
of
the
CASR
in
the
proband
,
who
presented
with
asymptomatic
hypercalcemia
and
hypocalciuria
at
age
2
yr
.
The
proband
's
parents
were
heterozygous
for
the
Q
459
R
mutation
consistent
with
autosomal
recessive
inheritance
of
FHH
.
Among
13
family
members
that
were
studied
,
eight
subjects
were
heterozygous
for
the
Q
459
R
mutation
and
five
had
normal
genotypes
.
All
heterozygous
subjects
were
asymptomatic
and
normocalcemic
apart
from
one
subject
who
was
mildly
hypercalcemic
.
The
Q
459
R
mutant
CaSR
was
normally
expressed
at
the
cell
membrane
but
retained
only
30
-
50
%
of
the
calcium
-dependent
activity
of
the
wild-
type
CaSR
.
We
identified
a
novel
loss
-of-function
Q
459
R
mutation
in
the
CASR
gene
that
exhibits
mildly
reduced
sensitivity
to
calcium
and
that
is
associated
with
apparent
autosomal
recessive
transmission
of
FHH
.
This
study
demonstrates
the
importance
of
genetic
testing
in
FHH
to
distinguish
between
de
novo
and
inherited
mutations
of
the
CASR
gene
and
assist
in
management
decisions
.