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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
"dehydration"
symptom
aniridia
esophageal carcinoma
familial hypocalciuric hypercalcemia
harlequin ichthyosis
homocystinuria without methylmalonic aciduria
junctional epidermolysis bullosa
lamellar ichthyosis
systemic capillary leak syndrome
This symptom has already been validated