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Iron availability modulates aberrant splicing of ferrochelatase through the iron- and 2-oxoglutarate dependent dioxygenase Jmjd6 and U2AF(65.).
[erythropoietic protoporphyria]
Erythropoietic
protoporphyria
(
EPP
)
results
from
partial
deficiency
of
ferrochelatase
(
FECH
)
.
Genetically
,
EPP
patients
differ
from
asymptomatic
mutation
carriers
at
the
unmutated
FECH
allele
,
the
expression
of
which
is
modulated
by
single
nucleotide
polymorphism
IVS
3
-
48
C
/
T
.
The
IVS
3
-
48
C
genotype
,
which
is
present
among
patients
,
leads
to
correct
splicing
of
60
%
of
the
pre-m
RNA
and
to
alternative
splicing
of
40
%
,
the
latter
mRNA-product
being
destroyed
by
nonsense-mediated
decay
.
An
IVS
3
-
48
T
genotype
generates
80
%
correct
and
20
%
aberrant
products
.
Our
study
demonstrated
that
under
iron
deficient
conditions
,
the
aberrant
splice
product
was
increased
to
56
%
and
50
%
of
total
FECH
mRNA
in
erythroleukemic
K
562
and
lymphoblastoid
cell
lines
,
respectively
,
both
being
homozygous
for
IVS
3
-
48
T
.
Concomitantly
,
FECH
protein
was
decreased
.
Iron
deficiency
had
less
effect
on
the
FECH
splice
ratio
in
an
IVS
3
-
48
C
/
C
lymphoblastoid
cell
line
.
Effects
similar
to
iron
deficiency
were
generated
by
siRNA
knockdown
of
either
splicing
factor
U
2
AF
(
65
)
or
Fe
(
II
)
-
and
2
-
oxoglutarate-dependent
dioxygenase
Jumonji
domain-containing
protein
6
(
Jmjd
6
)
,
which
interacts
with
U
2
AF
(
65
)
by
lysyl-hydroxylation
.
Based
on
these
results
,
we
propose
that
the
availability
of
iron
,
a
co
-
factor
of
Jmjd
6
,
modulates
U
2
AF
(
65
)
-
lysyl-hydroxylation
.
This
in
turn
,
influences
the
relative
amounts
of
correct
and
aberrant
FECH
mRNA
splice
products
and
thus
,
regulates
the
FECH
enzyme
activity
.
Diseases
Validation
Diseases presenting
"single nucleotide polymorphism"
symptom
cadasil
dystrophic epidermolysis bullosa
erythropoietic protoporphyria
esophageal adenocarcinoma
esophageal carcinoma
kabuki syndrome
monosomy 21
oligodontia
primary effusion lymphoma
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