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Abnormal mitoferrin-1 expression in patients with erythropoietic protoporphyria.
[erythropoietic protoporphyria]
Most
patients
with
erythropoietic
protoporphyria
have
deficient
ferrochelatase
(
FECH
)
activity
due
to
changes
in
FECH
DNA
.
We
evaluated
seven
patients
with
erythropoietic
protoporphyria
phenotype
in
whom
abnormalities
of
FECH
DNA
were
not
found
by
conventional
analysis
.
The
major
focus
was
mitoferrin-
1
(
MFRN
1
)
,
the
mitochondrial
transporter
of
Fe
used
for
heme
formation
by
FECH
and
for
2
Fe
2
S
cluster
synthesis
,
which
is
critical
to
FECH
activity
/
stability
.
Four
patients
had
a
deletion
in
ALAS
2
that
causes
enzyme
gain-of-function
,
resulting
in
increased
formation
of
protoporphyrin
;
one
had
a
heterozygous
major
deletion
in
FECH
DNA
.
All
had
an
abnormal
transcript
of
MFRN
1
in
messenger
RNA
extracted
from
blood
leukocytes
and
/
or
liver
tissue
.
The
abnormal
transcript
contained
an
insert
of
intron
2
that
had
a
stop
codon
.
The
consequences
of
abnormal
MFRN
1
expression
were
examined
using
zebrafish
and
yeast
MFRN-
deficient
strains
and
cultured
lymphoblasts
from
the
patients
.
Abnormal
human
MFRN
1
complementary
DNA
showed
loss
-of-function
in
zebrafish
and
yeast
mutants
,
whereas
normal
human
MFRN
1
complementary
DNA
rescued
both
.
Using
cultured
lymphoblasts
,
quantitative
reverse
transcription
polymerase
chain
reaction
showed
increased
formation
of
abnormal
transcript
that
was
accompanied
by
decreased
formation
of
normal
transcript
and
reduced
FECH
activity
in
patients
compared
to
normal
lines
.
A
positive
correlation
coefficient
(
0
.
75
)
was
found
between
FECH
activity
and
normal
MFRN
1
messenger
RNA
in
lymphoblasts
.
However
,
no
obvious
cause
for
increased
formation
of
abnormal
transcript
was
identified
in
MFRN
1
exons
and
splice
junctions
.
Abnormal
MFRN
1
expression
can
contribute
to
erythropoietic
protoporphyria
phenotype
in
some
patients
,
probably
by
causing
a
reduction
in
FECH
activity
.
Diseases
Validation
Diseases presenting
"increased formation of abnormal transcript"
symptom
erythropoietic protoporphyria
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