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Instability of the amyloidogenic cystatin C variant of hereditary cerebral hemorrhage with amyloidosis, Icelandic type.
[hereditary cerebral hemorrhage with amyloidosis]
A
cystatin
C
variant
with
L
68
Q
substitution
and
a
truncation
of
10
NH
2
-
terminal
residues
is
the
major
constituent
of
the
amyloid
deposited
in
the
cerebral
vasculature
of
patients
with
the
Icelandic
form
of
hereditary
cerebral
hemorrhage
with
amyloidosis
(
HCHWA
-
I
)
.
Variant
and
wild
type
cystatin
C
production
,
processing
,
secretion
,
and
clearance
were
studied
in
human
cell
lines
stably
overexpressing
the
cystatin
C
genes
.
Immunoblot
and
mass
spectrometry
analyses
demonstrated
monomeric
cystatin
C
in
cell
homogenates
and
culture
media
.
While
cystatin
C
formed
concentration-dependent
dimers
,
the
HCHWA
-
I
variant
dimerized
at
lower
concentrations
than
the
wild
type
protein
.
Amino-terminal
sequence
analysis
revealed
that
the
variant
and
normal
proteins
produced
and
secreted
are
the
full-length
cystatin
C
.
Pulse-chase
experiments
demonstrated
similar
levels
of
normal
and
variant
cystatin
C
production
and
secretion
.
However
,
the
secreted
variant
cystatin
C
exhibited
an
increased
susceptibility
to
a
serine
protease
in
conditioned
media
and
in
human
cerebrospinal
fluid
,
explaining
its
depletion
from
the
cerebrospinal
fluid
of
HCHWA
-
I
patients
.
Thus
,
the
amino
acid
substitution
may
induce
unstable
cystatin
C
with
intact
inhibitory
activity
and
predisposition
to
self-aggregation
and
amyloid
fibril
formation
.
Diseases
Validation
Diseases presenting
"type cystatin"
symptom
hereditary cerebral hemorrhage with amyloidosis
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