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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
"c"
symptom
adrenomyeloneuropathy
alexander disease
cadasil
coats disease
cohen syndrome
dedifferentiated liposarcoma
epidermolysis bullosa simplex
erythropoietic protoporphyria
familial hypocalciuric hypercalcemia
gm1 gangliosidosis
homocystinuria without methylmalonic aciduria
junctional epidermolysis bullosa
kallmann syndrome
oligodontia
papillon-lefèvre syndrome
phenylketonuria
pyruvate dehydrogenase deficiency
von hippel-lindau disease
x-linked adrenoleukodystrophy
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