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Cellular localization of 17 natural mutant variants of ALADIN protein in triple A syndrome - shedding light on an unexpected splice mutation.
[triple a syndrome]
The
triple
A
syndrome
is
a
complex
and
multisystemic
autosomal
recessive
disease
with
the
3
main
symptoms
of
adrenal
insufficiency
,
alacrima
,
and
achalasia
accompanied
by
neurological
impairment
.
Mutations
in
the
AAAS
gene
on
chromosome
12
q
13
are
responsible
for
the
disorder
.
AAAS
encodes
a
protein
named
ALADIN
,
which
belongs
to
the
family
of
WD-repeat-containing
proteins
and
has
been
shown
to
localize
to
nuclear
pore
complexes
.
The
function
of
the
protein
is
not
clear
.
It
is
supposed
that
ALADIN
plays
an
important
role
in
RNA
and
(
or
)
protein
trafficking
between
the
nucleus
and
cytoplasm
.
With
transfection
experiments
,
we
analyzed
the
cellular
localization
of
the
wild-
type
and
17
natural
mutant
variants
(
9
missense
,
5
nonsense
,
3
frameshift
mutations
)
of
ALADIN
.
We
show
that
most
mutations
cause
mislocalization
of
the
mutant
ALADIN
proteins
in
the
cytoplasm
.
In
contrast
,
some
variants
with
mutations
located
at
the
N-
terminus
(
Q
15
K
,
L
25
P
)
and
3
artificial
C-
terminus
mutations
(
Q
490
X
,
R
493
X
,
and
V
497
X
)
remain
at
the
nuclear
pore
.
Using
a
patient
cell
line
,
we
show
that
the
mutation
43
C
>
A
in
exon
1
does
not
cause
a
missense
mutation
Q
15
K
but
,
rather
,
results
in
aberrant
splicing
.
Diseases
Validation
Diseases presenting
"c-terminus mutations"
symptom
triple a syndrome
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