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Molecular expression and characterization of erythroid-specific 5-aminolevulinate synthase gain-of-function mutations causing X-linked protoporphyria.
[erythropoietic protoporphyria]
X-
linked
protoporphyria
(
XLP
)
(
MIM
300752
)
is
a
recently
recognized
erythropoietic
porphyria
due
to
gain-of-function
mutations
in
the
erythroid-
specific
aminolevulinate
synthase
gene
(
ALAS
2
)
.
Previously
,
two
exon
11
small
deletions
,
c
.
1699
_
1670
ΔAT
(
ΔAT
)
and
c
.
1706
_
1709
ΔAGTG
(
ΔAGTG
)
,
that
prematurely
truncated
or
elongated
the
ALAS
2
polypeptide
,
were
reported
to
increase
enzymatic
activity
20
-
to
40
-
fold
,
causing
the
erythroid
accumulation
of
protoporphyrins
,
cutaneous
photosensitivity
and
liver
disease
.
The
mutant
ΔAT
and
ΔAGTG
ALAS
2
enzymes
,
two
novel
mutations
,
c
.
1734
ΔG
(
ΔG
)
and
c
.
1642
C
>
T
(
p
.
Q
548
X
)
,
and
an
engineered
deletion
c
.
1670
-
1671
TC
>
GA
p
.
F
5
57
X
were
expressed
,
and
their
purified
enzymes
were
characterized
.
Wild-
type
and
ΔAGTG
enzymes
exhibited
similar
amounts
of
54
-
and
52
-
kDa
polypeptides
on
sodium
dodecyl
sulfate-polyacrylamide
gel
electrophoresis
(
SDS
-PAGE
)
,
whereas
the
ΔAT
and
p
.
F
5
57
X
had
only
52
-
kDa
polypeptides
.
Compared
to
the
purified
wild-
type
enzyme
,
ΔAT
,
ΔAGTG
and
Q
548
X
enzymes
had
increased
specific
activities
that
were
only
1
.
8
-
,
3
.
1
-
and
1
.
6
-
fold
,
respectively
.
Interestingly
,
binding
studies
demonstrated
that
the
increased
activity
Q
548
X
enzyme
did
not
bind
to
succinyl-
CoA
synthetase
.
The
elongated
ΔG
enzyme
had
wild-
type
specific
activity
,
kinetics
and
thermostability
;
twice
the
wild-
type
purification
yield
(
56
versus
25
%
)
;
and
was
primarily
a
54
-
kDa
form
,
suggesting
greater
stability
in
vivo
.
On
the
basis
of
studies
of
mutant
enzymes
,
the
maximal
gain-of
function
region
spanned
57
amino
acids
between
533
and
580
.
Thus
,
these
ALAS
2
gain-of-function
mutations
increased
the
specific
activity
(
ΔAT
,
ΔAGTG
and
p
.
Q
548
X
)
or
stability
(
ΔG
)
of
the
enzyme
,
thereby
leading
to
the
increased
erythroid
protoporphyrin
accumulation
causing
XLP
.
Diseases
Validation
Diseases presenting
"small deletions"
symptom
alpha-thalassemia
cadasil
erythropoietic protoporphyria
kabuki syndrome
oligodontia
wolf-hirschhorn syndrome
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