Rare Diseases Symptoms Automatic Extraction
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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
"myasthenia"
symptom
cystinuria
epidermolysis bullosa simplex
sneddon syndrome
This symptom has already been validated