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A random Abstract
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Nur7 is a nonsense mutation in the mouse aspartoacylase gene that causes spongy degeneration of the CNS.
[canavan disease]
Aspartoacylase
(
ASPA
)
is
an
oligodendrocyte-
restricted
enzyme
that
catalyzes
the
hydrolysis
of
neuronally
derived
N-
acetylaspartate
(
NAA
)
to
acetate
and
aspartic
acid
.
ASPA
deficiency
leads
to
the
fatal
childhood
autosomal
recessive
leukodystrophy
Canavan
disease
(
CD
)
.
Here
we
demonstrate
that
the
previously
described
ENU-induced
nur
7
mouse
mutant
is
caused
by
a
nonsense
mutation
,
Q
193
X
,
in
the
Aspa
gene
(
Aspa
(
nur
7
)
)
.
Homozygous
Aspa
(
nur
7
nur
7
)
mice
do
not
express
detectable
Aspa
protein
and
display
an
early
-onset
spongy
degeneration
of
CNS
myelin
with
increased
NAA
levels
similar
to
that
observed
in
CD
patients
.
In
addition
,
CNS
regions
rich
in
neuronal
cell
bodies
also
display
vacuolization
.
Interestingly
,
distinct
myelin
rich
areas
,
such
as
the
corpus
callosum
,
optic
nerve
,
and
spinal
cord
white
matter
appear
normal
in
Aspa
(
nur
7
/
nur
7
)
mice
.
Reduced
cerebroside
synthesis
has
been
demonstrated
in
CD
patients
and
animal
models
.
To
determine
the
potential
relevance
of
this
observation
in
disease
pathogenesis
,
we
generated
Aspa
(
nur
7
/
nur
7
)
mice
that
were
heterozygous
for
a
null
allele
of
the
gene
that
encodes
the
enzyme
UDP-galactose
:
ceramide
galactosyltransferase
(
Cgt
)
,
which
is
responsible
for
catalyzing
the
synthesis
of
the
abundant
myelin
galactolipids
.
Despite
reduced
amounts
of
cerebrosides
,
the
Aspa
(
nur
7
/
nur
7
)
;
Cgt
(
+
/
-
)
mice
were
not
more
severely
affected
than
the
Aspa
(
nur
7
)
mutants
,
suggesting
that
diminished
cerebroside
synthesis
is
not
a
major
contributing
factor
in
disease
pathogenesis
.
Furthermore
,
we
found
that
myelin
degeneration
leads
to
significant
axonal
loss
in
the
cerebellum
of
older
Aspa
(
nur
7
)
mutants
.
This
finding
suggests
that
axonal
pathology
caused
by
CNS
myelin
defects
may
underlie
the
neurological
disabilities
that
CD
patients
develop
at
late
stages
of
the
disease
.
Diseases
Validation
Diseases presenting
"leukodystrophy"
symptom
achondroplasia
adrenomyeloneuropathy
alexander disease
cadasil
canavan disease
carcinoma of the gallbladder
classical phenylketonuria
coats disease
fabry disease
gm1 gangliosidosis
krabbe disease
neonatal adrenoleukodystrophy
phenylketonuria
pyruvate dehydrogenase deficiency
wiskott-aldrich syndrome
x-linked adrenoleukodystrophy
zellweger syndrome
This symptom has already been validated