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Deficiency of ferritin heavy-chain nuclear import in triple a syndrome implies nuclear oxidative damage as the primary disease mechanism.
[triple a syndrome]
Triple
A
syndrome
is
a
rare
autosomal
recessive
disorder
characterized
by
ACTH-resistant
adrenal
failure
,
alacrima
,
achalasia
,
and
progressive
neurological
manifestations
.
The
majority
of
cases
are
associated
with
mutations
in
the
AAAS
gene
,
which
encodes
a
novel
,
60
-
kDa
WD-repeat
nuclear
pore
protein
,
alacrima
-
achalasia
-
adrenal
insufficiency
neurological
disorder
(
ALADIN
)
of
unknown
function
.
Our
aim
was
to
elucidate
the
functional
role
of
ALADIN
by
determining
its
interacting
protein
partners
using
the
bacterial
two
-hybrid
(
B
2
-
H
)
technique
.
Nonidentical
cDNA
fragments
were
identified
from
both
a
HeLa
S-
3
cell
and
human
cerebellar
cDNA
library
that
encoded
the
full-length
ferritin
heavy
chain
protein
(
FTH
1
)
.
This
interaction
was
confirmed
by
both
co
-immunoprecipitation
and
fluorescence
lifetime
imaging
microscopy-fluorescence
resonance
energy
transfer
studies
.
Immunoblotting
showed
that
fibroblasts
from
triple
A
patients
(
with
known
AAAS
mutations
)
lack
nuclear
FTH
1
,
suggesting
that
the
nuclear
translocation
of
FTH
1
is
defective
.
Cells
transfected
with
FTH
1
and
visualized
by
confocal
microscopy
had
very
little
nuclear
FTH
1
,
but
when
cotransfected
with
AAAS
,
FTH
1
is
readily
visible
in
the
nuclei
.
Therefore
,
FTH
1
nuclear
translocation
is
enhanced
when
ALADIN
is
coexpressed
in
these
cells
.
In
addition
to
its
well
known
iron
storage
role
,
FTH
1
has
been
shown
to
protect
the
nucleus
from
oxidative
damage
.
Apoptosis
of
neuronal
cells
induced
by
hydrogen
peroxide
was
significantly
reduced
by
transfection
of
AAAS
or
by
FTH
1
or
maximally
by
both
genes
together
.
Taken
together
,
this
work
offers
a
plausible
mechanism
for
the
progressive
clinical
features
of
triple
A
syndrome
.
Diseases
Validation
Diseases presenting
"fth1 has been shown to protect the nucleus from oxidative damage"
symptom
triple a syndrome
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