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Distinct properties of wild-type and the amyloidogenic human cystatin C variant of hereditary cerebral hemorrhage with amyloidosis, Icelandic type.
[hereditary cerebral hemorrhage with amyloidosis]
Variant
human
cystatin
C
(
L
68
Q
)
is
an
amyloidogenic
protein
.
It
deposits
in
the
cerebral
vasculature
of
Icelandic
patients
with
cerebral
amyloid
angiopathy
,
leading
to
stroke
.
Wild-
type
and
variant
cystatin
C
are
cysteine
proteinase
inhibitors
which
form
concentration
dependent
inactive
dimers
;
however
,
variant
cystatin
C
dimerizes
at
lower
concentrations
and
has
an
increased
susceptibility
to
a
serine
protease
.
We
studied
the
effect
of
the
L
68
Q
amino
acid
substitution
on
cystatin
C
properties
,
utilizing
full
length
cystatin
C
purified
in
mild
conditions
from
media
of
cells
stably
transfected
with
either
the
wild-
type
or
variant
cystatin
C
genes
.
The
variant
cystatin
C
forms
fibrils
in
vitro
detectable
by
electron
microscopy
in
conditions
in
which
the
wild-
type
protein
forms
amorphous
aggregates
.
We
also
show
by
circular
dichroism
,
steady-
state
fluorescence
and
Fourier-transformed
infrared
spectroscopy
that
the
amino
acid
substitution
modifies
cystatin
C
structure
by
destabilizing
alpha-helical
structures
and
exposing
the
tryptophan
residue
to
a
more
polar
environment
,
yielding
a
more
unfolded
molecule
.
These
spectral
changes
demonstrate
that
variant
cystatin
C
has
a
three
-dimensional
structure
different
from
that
of
the
wild-
type
protein
.
The
structural
differences
between
variant
and
wild-
type
cystatin
C
account
for
the
susceptibility
of
the
variant
protein
to
unfolding
,
proteolysis
and
fibrillogenesis
.
Diseases
Validation
Diseases presenting
"leading to stroke"
symptom
hereditary cerebral hemorrhage with amyloidosis
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