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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
"loss-of-function mutations"
symptom
achondroplasia
alpha-thalassemia
aromatase deficiency
child syndrome
cowden syndrome
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
erythropoietic protoporphyria
esophageal adenocarcinoma
familial hypocalciuric hypercalcemia
harlequin ichthyosis
hirschsprung disease
kallmann syndrome
kindler syndrome
lamellar ichthyosis
neonatal adrenoleukodystrophy
pendred syndrome
werner syndrome
x-linked adrenoleukodystrophy
This symptom has already been validated