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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
"axonal loss in the cerebellum"
symptom
canavan disease
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