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ALADINI482S causes selective failure of nuclear protein import and hypersensitivity to oxidative stress in triple A syndrome.
[triple a syndrome]
Triple
A
syndrome
is
an
autosomal
recessive
neuroendocrinological
disease
caused
by
mutations
in
a
gene
that
encodes
546
amino
acid
residues
.
The
encoded
protein
is
the
nucleoporin
ALADIN
,
a
component
of
nuclear
pore
complex
(
NPC
)
.
We
identified
a
mutant
ALADIN
(
I
482
S
)
that
fails
to
target
NPC
and
investigated
the
consequences
of
mistargeting
using
cultured
fibroblasts
(
I
482
Sf
)
from
a
patient
with
triple
A
syndrome
.
ALADIN
(
I
482
S
)
affected
a
karyopherin-alpha
/
beta
-mediated
import
pathway
and
decreased
nuclear
accumulations
of
aprataxin
(
APTX
)
,
a
repair
protein
for
DNA
single
-strand
breaks
(
SSBs
)
,
and
of
DNA
ligase
I
in
I
482
Sf
.
This
decrease
was
restored
by
wild-
type
ALADIN
.
ALADIN
(
I
482
S
)
had
no
effect
on
imports
of
M
9
/
kap-
beta
2
,
BIB
/
kap-
beta
3
,
histone
H
1
/
importin
7
,
the
ubiquitin
conjugating
enzyme
UbcM
2
/
importin
11
,
or
the
spliceosome
protein
U
1
A
,
indicating
that
ALADIN
(
I
482
S
)
selectively
impaired
transport
of
discrete
import
complexes
through
NPC
.
Cell
survival
assay
showed
hypersensitivity
of
I
482
Sf
to
l-buthionine-
(
S
,
R
)
-
sulfoximine
(
BSO
)
,
a
glutathione-depleting
agent
.
BSO
decreased
nuclear
APTX
and
ligase
I
levels
in
I
482
Sf
and
normal
control
fibroblasts
,
but
increased
SSBs
only
in
I
482
Sf
.
These
observations
implied
that
I
482
Sf
are
hypersensitive
to
BSO
and
no
longer
sufficiently
repair
SSBs
.
Consistent
with
this
notion
,
I
482
Sf
transfected
with
both
APTX
and
ligase
I
had
increased
resistance
to
BSO
,
whereas
I
482
Sf
transfected
with
LacZ
vector
remained
hypersensitive
to
BSO
.
We
propose
that
oxidative
stress
aggravates
nuclear
import
failure
,
which
is
already
compromised
in
patient
cells
.
Consequent
DNA
damage
,
beyond
the
limited
capacity
of
DNA
repair
proteins
,
i
.
e
.
,
APTX
and
ligase
I
,
may
participate
in
triggering
cell
death
.
Diseases
Validation
Diseases presenting
"single-strand breaks"
symptom
triple a syndrome
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