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Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP).
[erythropoietic protoporphyria]
Frameshift
mutations
in
the
last
coding
exon
of
the
5
-
aminolevulinate
synthase
(
ALAS
)
2
gene
were
described
to
activate
the
enzyme
causing
increased
levels
of
zinc-
and
metal-free
protoporphyrin
in
patients
with
X-
linked
dominant
protoporphyria
(
XLDPP
)
.
Only
two
such
so
-called
gain-of-function
mutations
have
been
reported
since
the
description
of
XLDPP
in
2008
.
In
this
study
of
four
newly
identified
XLDPP
families
,
we
identified
two
novel
ALAS
2
gene
mutations
,
a
nonsense
p
.
Q
548
X
and
a
frameshift
c
.
1651
-
1677
del
26
bp
,
along
with
a
known
mutation
(
delAGTG
)
found
in
two
unrelated
families
.
Of
relevance
,
a
de
novo
somatic
and
germinal
mosaicism
was
present
in
a
delAGTG
family
.
Such
a
phenomenon
may
explain
the
high
proportion
of
this
mutation
in
XLDPP
worldwide
.
Enhancements
of
over
3
-
and
14
-
fold
in
the
catalytic
rate
and
specificity
constant
of
purified
recombinant
XLDPP
variants
in
relation
to
those
of
wild-
type
ALAS
2
confirmed
the
gain
of
function
ascribed
to
these
enzymes
.
The
fact
that
both
p
.
Q
548
X
and
c
.
1651
-
1677
del
26
bp
are
located
in
close
proximity
and
upstream
from
the
two
previously
described
mutations
led
us
to
propose
the
presence
of
a
large
gain-of-function
domain
within
the
C-
terminus
of
ALAS
2
.
To
test
this
hypothesis
,
we
generated
four
additional
nonsense
mutants
(
p
.
A
539
X
,
p
.
G
544
X
,
p
.
G
576
X
and
p
.
V
583
X
)
surrounding
the
human
XLDPP
mutations
and
defined
an
ALAS
2
gain-of-function
domain
with
a
minimal
size
of
33
amino
acids
.
The
identification
of
this
gain-of-function
domain
provides
important
information
on
the
enzymatic
activity
of
ALAS
2
,
which
was
proposed
to
be
constitutively
inhibited
,
either
directly
or
indirectly
,
through
its
own
C-
terminus
.
Diseases
Validation
Diseases presenting
"previously described mutations"
symptom
erythropoietic protoporphyria
fabry disease
homocystinuria without methylmalonic aciduria
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