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ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria.
[erythropoietic protoporphyria]
Mutations
in
the
uroporphyrinogen
III
synthase
(
UROS
)
gene
cause
congenital
erythropoietic
porphyria
(
CEP
)
,
an
autosomal-recessive
inborn
error
of
erythroid
heme
biosynthesis
.
Clinical
features
of
CEP
include
dermatologic
and
hematologic
abnormalities
of
variable
severity
.
The
discovery
of
a
new
type
of
erythroid
porphyria
,
X-
linked
dominant
protoporphyria
(
XLDPP
)
,
which
results
from
increased
activity
of
5
-
aminolevulinate
synthase
2
(
ALAS
2
)
,
the
rate-controlling
enzyme
of
erythroid
heme
synthesis
,
led
us
to
hypothesize
that
the
CEP
phenotype
may
be
modulated
by
sequence
variations
in
the
ALAS
2
gene
.
We
genotyped
ALAS
2
in
4
unrelated
CEP
patients
exhibiting
the
same
C
7
3
R
/
P
248
Q
UROS
genotype
.
The
most
severe
of
the
CEP
patients
,
a
young
girl
,
proved
to
be
heterozygous
for
a
novel
ALAS
2
mutation
:
c
.
1757
A
>
T
in
exon
11
.
This
mutation
is
predicted
to
affect
the
highly
conserved
and
penultimate
C-
terminal
amino
acid
of
ALAS
2
(
Y
586
)
.
The
rate
of
5
-
aminolevulinate
release
from
Y
586
F
was
significantly
increased
over
that
of
wild-
type
ALAS
2
.
The
contribution
of
the
ALAS
2
gain-of-function
mutation
to
the
CEP
phenotype
underscores
the
importance
of
modifier
genes
underlying
CEP
.
We
propose
that
ALAS
2
gene
mutations
should
be
considered
not
only
as
causative
of
X-
linked
sideroblastic
anemia
(
XLSA
)
and
XLDPP
but
may
also
modulate
gene
function
in
other
erythropoietic
disorders
.
Diseases
Validation
Diseases presenting
"abnormalities of variable severity"
symptom
erythropoietic protoporphyria
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