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Targeted proteolysis of plectin isoform 1a accounts for hemidesmosome dysfunction in mice mimicking the dominant skin blistering disease EBS-Ogna.
[epidermolysis bullosa simplex]
Autosomal
recessive
mutations
in
the
cytolinker
protein
plectin
account
for
the
multisystem
disorders
epidermolysis
bullosa
simplex
(
EBS
)
associated
with
muscular
dystrophy
(
EBS-
MD
)
,
pyloric
atresia
(
EBS-
PA
)
,
and
congenital
myasthenia
(
EBS
-
CMS
)
.
In
contrast
,
a
dominant
missense
mutation
leads
to
the
disease
EBS
-Ogna
,
manifesting
exclusively
as
skin
fragility
.
We
have
exploited
this
trait
to
study
the
molecular
basis
of
hemidesmosome
failure
in
EBS
-Ogna
and
to
reveal
the
contribution
of
plectin
to
hemidesmosome
homeostasis
.
We
generated
EBS
-Ogna
knock-
in
mice
mimicking
the
human
phenotype
and
show
that
blistering
reflects
insufficient
protein
levels
of
the
hemidesmosome-associated
plectin
isoform
1
a
.
We
found
that
plectin
1
a
,
in
contrast
to
plectin
1
c
,
the
major
isoform
expressed
in
epidermal
keratinocytes
,
is
proteolytically
degraded
,
supporting
the
notion
that
degradation
of
hemidesmosome-anchored
plectin
is
spatially
controlled
.
Using
recombinant
proteins
,
we
show
that
the
mutation
renders
plectin
's
190
-
nm-
long
coiled-coil
rod
domain
more
vulnerable
to
cleavage
by
calpains
and
other
proteases
activated
in
the
epidermis
but
not
in
skeletal
muscle
.
Accordingly
,
treatment
of
cultured
EBS
-Ogna
keratinocytes
as
well
as
of
EBS
-Ogna
mouse
skin
with
calpain
inhibitors
resulted
in
increased
plectin
1
a
protein
expression
levels
.
Moreover
,
we
report
that
plectin
's
rod
domain
forms
dimeric
structures
that
can
further
associate
laterally
into
remarkably
stable
(
paracrystalline
)
polymers
.
We
propose
focal
self-association
of
plectin
molecules
as
a
novel
mechanism
contributing
to
hemidesmosome
homeostasis
and
stabilization
.
Diseases
Validation
Diseases presenting
"skeletal muscle"
symptom
cadasil
epidermolysis bullosa simplex
esophageal adenocarcinoma
focal myositis
hereditary cerebral hemorrhage with amyloidosis
inclusion body myositis
lamellar ichthyosis
neuralgic amyotrophy
pleomorphic liposarcoma
pyomyositis
pyruvate dehydrogenase deficiency
systemic capillary leak syndrome
well-differentiated liposarcoma
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