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Mutational analysis of the adaptor protein 2 sigma subunit (AP2S1) gene: search for autosomal dominant hypocalcemia type 3 (ADH3).
[familial hypocalciuric hypercalcemia]
Autosomal
dominant
hypocalcemia
(
ADH
)
types
1
and
2
are
due
to
calcium-sensing
receptor
(
CASR
)
and
G-
protein
subunit-α
11
(
GNA
11
)
gain-of-function
mutations
,
respectively
,
whereas
CASR
and
GNA
11
loss
-of-function
mutations
result
in
familial
hypocalciuric
hypercalcemia
(
FHH
)
types
1
and
2
,
respectively
.
Loss
-of-function
mutations
of
adaptor
protein-
2
sigma
subunit
(
AP
2
σ
2
)
,
encoded
by
AP
2
S
1
,
cause
FHH
3
,
and
we
therefore
sought
for
gain-of-function
AP
2
S
1
mutations
that
may
cause
an
additional
form
of
ADH
,
which
we
designated
ADH
3
.
T
he
objective
of
the
study
was
to
investigate
the
hypothesis
that
gain-of-function
AP
2
S
1
mutations
may
cause
ADH
3
.
The
sample
size
required
for
the
detection
of
at
least
one
mutation
with
a
greater
than
95
%
likelihood
was
determined
by
binomial
probability
analysis
.
Nineteen
patients
(
including
six
familial
cases
)
with
hypocalcemia
in
association
with
low
or
normal
serum
PTH
concentrations
,
consistent
with
ADH
,
but
who
did
not
have
CASR
or
GNA
11
mutations
,
were
ascertained
.
Leukocyte
DNA
was
used
for
sequence
and
copy
number
variation
analysis
of
AP
2
S
1
.
Binomial
probability
analysis
,
using
the
assumption
that
AP
2
S
1
mutations
would
occur
in
hypocalcemic
patients
at
a
prevalence
of
20
%
,
which
is
observed
in
FHH
patients
without
CASR
or
GNA
11
mutations
,
indicated
that
the
likelihood
of
detecting
at
least
one
AP
2
S
1
mutation
was
greater
than
95
%
and
greater
than
98
%
in
sample
sizes
of
14
and
19
hypocalcemic
patients
,
respectively
.
AP
2
S
1
mutations
and
copy
number
variations
were
not
detected
in
the
19
hypocalcemic
patients
.
The
absence
of
AP
2
S
1
abnormalities
in
hypocalcemic
patients
,
suggests
that
ADH
3
may
not
occur
or
otherwise
represents
a
rare
hypocalcemic
disorder
.
Diseases
Validation
Diseases presenting
"were ascertained"
symptom
familial hypocalciuric hypercalcemia
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