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A random Abstract
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Cellular processing of the amyloidogenic cystatin C variant of hereditary cerebral hemorrhage with amyloidosis, Icelandic type.
[hereditary cerebral hemorrhage with amyloidosis]
An
important
gap
in
our
understanding
of
the
pathogenesis
of
the
amyloidoses
is
the
identification
of
the
cellular
events
that
lead
from
synthesis
of
an
amyloid
precursor
protein
to
its
conversion
to
the
amyloid
fiber
subunit
.
We
address
this
question
by
characterizing
the
effects
of
an
amyloidogenic
mutation
on
the
intracellular
processing
of
its
protein
product
.
The
protein
,
a
mutant
of
the
cysteine
protease
inhibitor
cystatin
C
,
is
the
amyloid
precursor
protein
in
Hereditary
Cerebral
Hemorrhage
with
Amyloidosis
--
Icelandic
type
(
HCHWA
-
I
)
.
The
amyloid
fibers
are
composed
of
mutant
cystatin
C
(
L
68
Q
)
that
lacks
the
first
10
amino
acids
.
We
have
previously
shown
that
processing
of
wild-
type
cystatin
C
entails
formation
of
a
transient
intracellular
dimer
that
dissociates
prior
to
secretion
,
such
that
extracellular
cystatin
C
is
monomeric
.
We
report
here
that
the
cystatin
C
mutation
engenders
several
alterations
in
its
intracellular
trafficking
.
It
forms
a
stable
intracellular
dimer
that
is
partially
retained
in
the
endoplasmic
reticulum
and
degraded
.
The
bulk
of
mutant
cystatin
C
that
is
secreted
does
not
dissociate
and
is
secreted
as
an
inactive
dimer
.
Thus
,
formation
of
the
stable
mutant
cystatin
C
dimer
is
an
early
event
in
the
pathogenesis
of
this
disease
.
Diseases
Validation
Diseases presenting
"amyloidosis"
symptom
cadasil
fabry disease
familial mediterranean fever
hereditary cerebral hemorrhage with amyloidosis
lymphangioleiomyomatosis
phenylketonuria
systemic capillary leak syndrome
triple a syndrome
waldenström macroglobulinemia
This symptom has already been validated