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X-linked adrenoleukodystrophy: molecular and functional analysis of the ABCD1 gene in Argentinean patients.
[x-linked adrenoleukodystrophy]
X-
linked
adrenoleukodystrophy
(
X-
ALD
)
is
an
inherited
metabolic
disease
associated
with
mutations
in
the
ABCD
1
gene
that
encodes
an
ATP-binding
cassette
transporter
protein
,
ALDP
.
The
disease
is
characterized
by
increased
concentrations
of
very
long
-chain
fatty
acids
(
VLCFAs
)
in
plasma
and
in
adrenal
,
testicular
and
nervous
tissues
,
due
to
a
defect
in
peroxisomal
VLCFA
β-oxidation
.
In
the
present
study
,
we
analyzed
10
male
patients
and
17
female
carriers
from
10
unrelated
pedigrees
with
X-
ALD
from
Argentina
.
By
sequencing
the
ABCD
1
we
detected
9
different
mutations
,
8
of
which
were
novel
.
These
new
mutations
were
verified
by
a
combination
of
methods
that
included
both
functional
(
western
blot
and
peroxisomal
VLCFA
β-oxidation
)
and
bioinformatics
analysis
.
The
spectrum
of
novel
mutations
consists
of
3
frameshift
(
p
.
Ser
284
fs
*
16
,
p
.
Glu
380
Argfs
*
21
and
p
.
Thr
254
Argfs
*
82
)
;
a
deletion
(
p
.
Ser
572
_
Asp
575
del
)
;
a
splicing
mutation
(
c
.
1081
+
5
G
>
C
)
and
3
missense
mutations
(
p
.
A
la
341
A
sp
,
p
.
His
420
Pro
and
p
.
Tyr
547
Cys
)
.
In
one
patient
2
changes
were
found
:
a
known
missense
(
p
.
His
669
Arg
)
and
an
unpublished
amino
acid
substitution
(
p
.
Ala
19
S
er
)
.
In
vitro
studies
suggest
that
p
.
Ala
19
S
er
is
a
polymorphism
.
Moreover
,
we
identified
two
novel
intronic
polymorphisms
and
two
amino
acid
polymorphisms
.
In
conclusion
,
this
study
extends
the
spectrum
of
mutation
in
X-
ALD
and
facilitates
the
identification
of
heterozygous
females
.