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Abnormal distribution of heterogeneous nuclear ribonucleoproteins in sporadic inclusion body myositis.
[inclusion body myositis]
Previous
histopathologic
studies
of
sporadic
inclusion
body
myositis
(
sIBM
)
identified
sarcoplasmic
aggregation
and
myonuclear
depletion
of
the
predominantly
nuclear
heterogeneous
nuclear
ribonucleoprotein
(
hnRNP
)
TDP-
43
in
sIBM
myofibers
.
Here
,
we
examined
sIBM
muscle
for
abnormalities
in
two
other
hnRNPs
hnRNPA
1
and
hnRNPA
2
B
1
,
mutations
in
which
cause
multisystem
proteinopathy
associated
with
rimmed-vacuolar
myopathies
.
Muscle
biopsy
specimens
from
13
patients
with
sIBM
and
13
patients
without
sIBM
(
dermatomyositis
N
=
3
,
polymyositis
N
=
3
,
muscular
dystrophy
N
=
3
,
motor
neuron
disease
N
=
2
,
non-neuromuscular
disease
N
=
2
)
underwent
immunohistochemistry
for
hnRNPA
1
,
hnRNPA
2
B
1
,
and
TDP-
43
.
Muscle
transcriptional
microarray
data
from
27
patients
with
sIBM
and
12
patients
without
neuromuscular
disease
was
analyzed
.
Depletion
of
hnRNPA
1
and
hnRNPA
2
B
1
was
present
in
15
%
and
7
%
of
sIBM
myonuclei
,
respectively
,
compared
with
1
%
and
0
%
of
myonuclei
in
non-
s
IBM
muscle
.
Sarcoplasmic
aggregates
of
hnRNPA
1
and
hnRNPA
2
B
1
distinct
from
TDP-
43
aggregates
were
also
found
in
sIBM
.
hnRNPA
1
and
hnRNPA
2
B
1
,
as
well
as
other
hnRNPs
,
gene
expression
was
unaltered
in
sIBM
compared
to
normal
muscle
.
Along
with
TDP-
43
,
other
hnRNPs
,
including
hnRNPA
1
and
hnRNPA
2
B
1
,
are
depleted
from
sIBM
myonuclei
at
the
protein
but
not
transcript
level
.
The
depletion
of
multiple
hnRNPs
from
sIBM
myonuclei
together
with
their
sarcoplasmic
aggregation
suggests
that
one
aspect
of
sIBM
pathophysiology
may
involve
abnormal
RNA
metabolism
that
includes
hyperassembly
of
ribonucleoprotein
granules
mediated
by
prion-like
domains
in
hnRNPs
,
evolving
into
pathological
aggregates
.
Diseases
Validation
Diseases presenting
"muscular dystrophy"
symptom
achondroplasia
adrenomyeloneuropathy
alpha-thalassemia
coats disease
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
focal myositis
inclusion body myositis
This symptom has already been validated