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Oxidative stress and apoptosis in homocystinuria patients with genetic remethylation defects.
[homocystinuria without methylmalonic aciduria]
Oxidative
stress
has
been
described
as
a
putative
disease
mechanism
in
pathologies
associated
with
an
elevation
of
homocysteine
.
An
increased
reactive
oxygen
species
(
ROS
)
production
and
apoptosis
rate
have
been
associated
with
several
disorders
of
cobalamin
metabolism
,
particularly
with
methylmalonic
aciduria
(
MMA
)
combined
with
homocystinuria
cblC
type
.
In
this
work
,
we
have
evaluated
several
parameters
related
to
oxidative
stress
and
apoptosis
in
fibroblasts
from
patients
with
homocystinuria
due
to
defects
in
the
MTR
,
MTRR
,
and
MTHFR
genes
involved
in
the
remethylation
pathway
of
homocysteine
.
We
have
also
evaluated
these
processes
by
knocking
down
the
MTRR
gene
in
cellular
models
,
and
complementation
by
transducing
the
wild-
type
gene
in
cblE
mutant
fibroblasts
.
All
cell
lines
showed
a
significant
increase
in
ROS
content
and
in
MnSOD
expression
level
,
and
also
a
higher
rate
of
apoptosis
with
similar
levels
to
the
ones
in
cblC
fibroblasts
.
The
amount
of
the
active
phosphorylated
forms
of
p
38
and
JNK
stress-kinases
was
also
increased
.
ROS
content
and
apoptosis
rate
increased
in
control
fibroblasts
and
in
a
glioblastoma
cell
line
by
shRNA-mediated
silencing
of
MTRR
gene
expression
.
In
contrast
,
wild-
type
MTRR
gene
corrected
mutant
cell
lines
showed
a
decrease
in
ROS
and
apoptosis
levels
.
To
the
best
of
our
knowledge
,
this
study
provides
the
first
evidence
that
an
impaired
remethylation
capacity
due
to
low
MTRR
and
MTR
activity
might
be
partially
responsible
for
stress
response
.
Diseases
Validation
Diseases presenting
"first evidence"
symptom
congenital adrenal hyperplasia
dentin dysplasia
esophageal adenocarcinoma
fabry disease
homocystinuria without methylmalonic aciduria
krabbe disease
liposarcoma
phenylketonuria
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