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The triple A syndrome is due to mutations in ALADIN, a novel member of the nuclear pore complex.
[triple a syndrome]
The
triple
A
syndrome
(
MIM
#
231550
)
is
a
rare
autosomal
recessive
disorder
characterized
by
adrenocorticotropic
hormone
(
ACTH
)
resistant
adrenal
failure
,
achalasia
,
alacrima
,
and
a
variety
of
neurological
and
dermatological
features
.
The
triple
A
syndrome
is
caused
by
mutations
in
the
AAAS
gene
,
which
encodes
a
protein
known
as
ALADIN
(
ALacrima
Achalasia
aDrenal
Insufficiency
Neurologic
disorder
)
.
ALADIN
is
a
new
WD-repeat
protein
that
has
no
significant
homology
to
any
previously
identified
WD-repeat
protein
.
It
has
been
shown
that
it
colocalizes
with
nuclear
pore
complexes
(
NPCs
)
,
a
finding
that
strongly
suggests
an
involvement
of
ALADIN
in
nucleocytoplasmic
transport
.
An
investigation
of
110
families
with
triple
A
syndrome
disclosed
mutation
hot
spots
including
Q
15
K
(
exon
1
)
,
and
S
293
P
(
exon
8
)
,
which
occur
in
17
and
21
families
from
different
geographical
regions
,
respectively
.
The
variable
phenotype
of
all
patients
can
not
be
correlated
with
the
localization
and
the
nature
of
the
ALADIN
mutations
.
Thus
,
modifying
genes
/
factors
may
be
involved
in
the
progression
of
this
neurodegenerative
disease
.
The
lack
of
AAAS
mutations
in
eight
patients
and
negative
linkage
to
chromosome
12
q
13
in
three
families
are
suggestive
of
genetic
heterogeneity
.
To
examine
the
cellular
localization
of
ALADIN
mutants
causing
triple
A
syndrome
,
we
investigated
nine
different
ALADIN-mutants
:
2
nonsense
(
W
84
X
,
Q
456
X
)
,
2
frameshift
(
F
157
fsX
171
,
G
397
fsX
414
)
and
5
point
mutations
(
Q
15
K
,
L
25
P
,
H
160
R
,
S
263
P
,
L
381
R
)
by
transfection
experiments
with
green
fluorescence
protein
.
Mutants
were
predominantly
localized
in
the
cytoplasm
,
but
also
found
in
the
nucleus
indicating
that
ALADIN
is
essential
for
NPC
targeting
.
To
investigate
physiological
functions
of
ALADIN
in
vivo
,
we
generated
and
analysed
Aaas-
/
-
knockout
mice
by
homologous
recombination
in
embryonic
stem
cells
.
Surprisingly
,
required
animals
lack
any
gross
abnormality
in
adrenal
and
nervous
system
function
.
Further
studies
have
to
investigate
the
role
of
ALADIN
at
NPCs
and
to
identify
interacting
proteins
.
Functional
analyses
of
ALADIN
may
permit
further
understanding
of
its
role
for
adrenocortical
function
and
neurodevelopment
.
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