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Spectrum of mutations of the AAAS gene in Allgrove syndrome: lack of mutations in six kindreds with isolated resistance to corticotropin.
[triple a syndrome]
Familial
glucocorticoid
deficiency
due
to
corticotropin
(
ACTH
)
resistance
consists
of
two
distinct
genetic
syndromes
that
are
both
inherited
as
autosomal
recessive
traits
:
isolated
ACTH
resistance
(
iACTHR
)
,
which
may
be
caused
by
inactivating
mutations
of
the
ACTH
receptor
(
the
MC
2
R
gene
)
or
mutations
in
an
as
yet
unknown
gene
(
s
)
,
and
Allgrove
syndrome
(
AS
)
.
The
latter
is
also
known
as
triple-
A
syndrome
(
MIM
231550
)
.
In
three
large
cohorts
of
AS
kindreds
,
the
disease
has
been
mapped
to
chromosome
12
;
most
recently
,
mutations
in
the
AAAS
gene
on
12
q
13
were
found
in
these
AS
families
.
AAAS
codes
for
the
WD-repeat
containing
ALADIN
(
for
alacrima
-
achalasia
-
adrenal
insufficiency
-neurologic
disorder
)
protein
.
We
investigated
families
with
iACTHR
(
n
=
4
)
and
AS
(
n
=
6
)
and
a
Bedouin
family
with
ACTHR
and
a
known
defect
of
the
TSH
receptor
.
Four
AS
families
were
of
mixed
extraction
from
Puerto
Rico
(
PR
)
;
most
of
the
remaining
six
families
were
Caucasian
families
from
North
America
(
NA
)
.
Sequencing
analysis
found
no
MC
2
R
genetic
defects
in
any
of
the
kindreds
.
No
iACTHR
kindreds
,
but
all
of
AS
families
,
had
AAAS
mutations
.
The
previously
reported
IVS
14
+
1
G--
>
A
splice
donor
mutation
was
found
in
all
PR
families
,
apparently
due
to
a
founder
effect
;
one
NA
kindred
was
heterozygous
for
this
mutation
.
In
the
latter
family
,
long
-range
PCR
failed
to
identify
a
deletion
or
other
rearrangements
of
the
AAAS
gene
.
No
other
heterozygote
or
transmitting
parent
had
any
phenotype
that
could
be
considered
part
of
AS
.
The
IVS
14
+
1
G--
>
A
mutation
results
in
a
premature
termination
of
the
predicted
protein
;
although
it
was
present
in
all
PR
families
(
in
the
homozygote
state
in
three
of
them
)
,
there
was
substantial
clinical
variation
between
them
.
One
PR
family
also
carried
a
novel
splice
donor
mutation
of
the
AAAS
gene
in
exon
11
,
IVS
11
+
1
G--
>
A
;
the
proband
was
a
compound
heterozygote
.
A
novel
point
mutation
,
43
C--
>
A
(
Gln
15
L
ys
)
,
in
exon
1
of
the
AAAS
gene
was
identified
in
the
homozygote
state
in
a
Canadian
AS
kindred
with
a
milder
AS
phenotype
.
The
predicted
amino
acid
substitution
in
this
family
is
located
in
a
sequence
that
may
participate
in
the
preservation
of
stability
of
ALADIN
beta
-strands
,
whereas
the
splicing
mutation
in
exon
11
may
interfere
with
the
formation
of
WD
repeats
in
this
molecule
.
We
conclude
that
1
)
AAAS
does
not
appear
to
be
frequently
mutated
in
families
with
iACTHR
;
2
)
AAAS
is
mutated
in
AS
families
from
PR
(
that
had
previously
been
mapped
to
12
q
13
)
and
NA
;
and
,
3
)
there
is
significant
clinical
variability
between
patients
with
the
same
AAAS
defect
.
Diseases
Validation
Diseases presenting
"defect of the tsh receptor"
symptom
triple a syndrome
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