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Relationship between enzyme properties and disease progression in Canavan disease.
[canavan disease]
Canavan
disease
(
CD
)
is
a
fatal
neurological
disorder
caused
by
defects
in
the
gene
that
encodes
for
a
critical
metabolic
enzyme
.
The
enzyme
aspartoacylase
catalyzes
the
deacetylation
of
N-
acetylaspartate
to
produce
acetate
required
for
fatty
acid
biosynthesis
in
the
brain
.
The
loss
of
aspartoacylase
activity
leads
to
the
demyelination
and
disrupted
brain
development
that
is
found
in
CD
patients
.
Sixteen
different
clinical
mutants
of
aspartoacylase
have
been
cloned
,
expressed
and
purified
to
examine
their
properties
and
the
relationship
between
enzyme
properties
and
disease
phenotype
.
In
contrast
to
numerous
cell
culture
studies
that
reported
virtually
complete
loss
of
function
,
each
of
these
purified
mutant
enzymes
was
found
to
have
measureable
catalytic
activity
.
However
,
the
activities
of
these
mutants
are
diminished
,
by
as
little
as
three-fold
to
greater
than
100
-
fold
when
compared
to
the
native
enzyme
.
Many
of
these
mutated
enzyme
forms
show
decreased
thermal
stability
and
an
increased
propensity
for
denaturation
upon
exposure
to
urea
,
but
only
four
of
the
16
mutants
examined
showed
both
diminished
thermal
and
diminished
conformational
stability
.
Significantly
,
each
of
these
lower
stability
mutants
are
responsible
for
the
more
severe
phenotypes
of
CD
,
while
patients
with
milder
forms
of
CD
have
aspartoacylase
mutants
with
generally
high
catalytic
activity
and
with
either
good
thermal
or
good
conformational
stability
.
These
results
suggest
that
the
loss
of
catalytic
function
and
the
accumulation
of
N-
acetylaspartate
in
Canavan
disease
is
at
least
partially
a
consequence
of
the
decreased
protein
stability
caused
by
these
mutations
.
Diseases
Validation
Diseases presenting
"different clinical mutants"
symptom
canavan disease
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