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Evidence that unrestricted legumain activity is involved in disturbed epidermal cornification in cystatin M/E deficient mice.
[harlequin ichthyosis]
Homozygosity
for
Cst
6
null
alleles
causes
the
phenotype
of
the
ichq
mouse
,
which
is
a
model
for
human
harlequin
ichthyosis
(
OMIM
242500
)
,
a
genetically
heterogeneous
group
of
keratinization
disorders
.
Here
we
report
evidence
for
the
mechanism
by
which
deficiency
of
the
cysteine
protease
inhibitor
cystatin
M
/
E
(
the
Cst
6
gene
product
)
leads
to
disturbed
cornification
,
impaired
barrier
function
and
dehydration
.
Absence
of
cystatin
M
/
E
causes
unrestricted
activity
of
its
target
protease
legumain
in
hair
follicles
and
epidermis
,
which
is
the
exact
location
where
cystatin
M
/
E
is
normally
expressed
.
Analysis
of
stratum
corneum
proteins
revealed
a
strong
decrease
of
soluble
loricrin
monomers
in
skin
extracts
of
ichq
mice
,
although
normal
levels
of
loricrin
were
present
in
the
stratum
granulosum
and
stratum
corneum
of
ichq
mice
,
as
shown
by
immunohistochemistry
.
This
suggested
a
premature
or
enhanced
crosslinking
of
loricrin
monomers
in
ichq
mice
by
transglutaminase
3
(
TGase
3
)
.
In
these
mice
,
we
indeed
found
strongly
increased
levels
of
TGase
3
that
was
processed
into
its
activated
30
and
47
kDa
subunits
,
compared
to
wild-
type
mice
.
This
study
shows
that
cystatin
M
/
E
and
legumain
form
a
functional
dyad
in
epidermis
in
vivo
.
Disturbance
of
this
protease-antiprotease
balance
causes
increased
enzyme
activity
of
TGase
3
that
could
explain
the
observed
abnormal
cornification
.
Diseases
Validation
Diseases presenting
"functional dyad in epidermis"
symptom
harlequin ichthyosis
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