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Rat model for dominant dystrophic epidermolysis bullosa: glycine substitution reduces collagen VII stability and shows gene-dosage effect.
[dystrophic epidermolysis bullosa]
Dystrophic
epidermolysis
bullosa
,
a
severely
disabling
hereditary
skin
fragility
disorder
,
is
caused
by
mutations
in
the
gene
coding
for
collagen
VII
,
a
specialized
adhesion
component
of
the
dermal-epidermal
junction
zone
.
Both
recessive
and
dominant
forms
are
known
;
the
latter
account
for
about
40
%
of
cases
.
Patients
with
dominant
dystrophic
epidermolysis
bullosa
exhibit
a
spectrum
of
symptoms
ranging
from
mild
localized
to
generalized
skin
manifestations
.
Individuals
with
the
same
mutation
can
display
substantial
phenotypic
variance
,
emphasizing
the
role
of
modifying
genes
in
this
disorder
.
The
etiology
of
dystrophic
epidermolysis
bullosa
has
been
known
for
around
two
decades
;
however
,
important
pathogenetic
questions
such
as
involvement
of
modifier
genes
remain
unanswered
and
a
causative
therapy
has
yet
to
be
developed
.
Much
of
the
failure
to
make
progress
in
these
areas
is
due
to
the
lack
of
suitable
animal
models
that
capture
all
aspects
of
this
complex
monogenetic
disorder
.
Here
,
we
report
the
first
rat
model
of
dominant
dystrophic
epidermolysis
bullosa
.
Affected
rats
carry
a
spontaneous
glycine
to
aspartic
acid
substitution
,
p
.
G
1867
D
,
within
the
main
structural
domain
of
collagen
VII
.
This
confers
dominant-negative
interference
of
protein
folding
and
decreases
the
stability
of
mutant
collagen
VII
molecules
and
their
polymers
,
the
anchoring
fibrils
.
The
phenotype
comprises
fragile
and
blister-prone
skin
,
scarring
and
nail
dystrophy
.
The
model
recapitulates
all
signs
of
the
human
disease
with
complete
penetrance
.
Homozygous
carriers
of
the
mutation
are
more
severely
affected
than
heterozygous
ones
,
demonstrating
for
the
first
time
a
gene
-dosage
effect
of
mutated
alleles
in
dystrophic
epidermolysis
bullosa
.
This
novel
viable
and
workable
animal
model
for
dominant
dystrophic
epidermolysis
bullosa
will
be
valuable
for
addressing
molecular
disease
mechanisms
,
effects
of
modifying
genes
,
and
development
of
novel
molecular
therapies
for
patients
with
dominantly
transmitted
skin
disease
.
Diseases
Validation
Diseases presenting
"spontaneous glycine"
symptom
dystrophic epidermolysis bullosa
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