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X-linked sideroblastic anemia due to carboxyl-terminal ALAS2 mutations that cause loss of binding to the β-subunit of succinyl-CoA synthetase (SUCLA2).
[erythropoietic protoporphyria]
Mutations
in
the
erythroid-
specific
aminolevulinic
acid
synthase
gene
(
ALAS
2
)
cause
X-
linked
sideroblastic
anemia
(
XLSA
)
by
reducing
mitochondrial
enzymatic
activity
.
Surprisingly
,
a
patient
with
the
classic
XLSA
phenotype
had
a
novel
exon
11
mutation
encoding
a
recombinant
enzyme
(
p
.
Met
567
Val
)
with
normal
activity
,
kinetics
,
and
stability
.
Similarly
,
both
an
expressed
adjacent
XLSA
mutation
,
p
.
Ser
568
Gly
,
and
a
mutation
(
p
.
Phe
557
T
er
)
lacking
the
31
carboxyl-terminal
residues
also
had
normal
or
enhanced
activity
,
kinetics
,
and
stability
.
Because
ALAS
2
binds
to
the
β
subunit
of
succinyl-
CoA
synthetase
(
SUCLA
2
)
,
the
mutant
proteins
were
tested
for
their
ability
to
bind
to
this
protein
.
Wild
type
ALAS
2
bound
strongly
to
a
SUCLA
2
affinity
column
,
but
the
adjacent
XLSA
mutant
enzymes
and
the
truncated
mutant
did
not
bind
.
In
contrast
,
vitamin
B
6
-
responsive
XLSA
mutations
p
.
Arg
452
Cys
and
p
.
A
rg
452
H
is
,
with
normal
in
vitro
enzyme
activity
and
stability
,
did
not
interfere
with
binding
to
SUCLA
2
but
instead
had
loss
of
positive
cooperativity
for
succinyl-
CoA
binding
,
an
increased
K
(
m
)
for
succinyl-
CoA
,
and
reduced
vitamin
B
6
affinity
.
Consistent
with
the
association
of
SUCLA
2
binding
with
in
vivo
ALAS
2
activity
,
the
p
.
Met
567
GlufsX
2
mutant
protein
that
causes
X-
linked
protoporphyria
bound
strongly
to
SUCLA
2
,
highlighting
the
probable
role
of
an
ALAS
2
-
succinyl-
CoA
synthetase
complex
in
the
regulation
of
erythroid
heme
biosynthesis
.
Diseases
Validation
Diseases presenting
"erythroid-specific aminolevulinic acid synthase gene"
symptom
erythropoietic protoporphyria
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