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Knocking-in the R142C mutation in transglutaminase 1 disrupts the stratum corneum barrier and postnatal survival of mice.
[lamellar ichthyosis]
Mutations
in
the
gene
encoding
transglutaminase
1
(
TG
1
)
are
responsible
for
various
types
of
autosomal
recessive
congenital
ichthyosis
(
ARCI
)
,
such
as
lamellar
ichthyosis
(
LI
)
,
congenital
ichthyosiform
erythroderma
(
CIE
)
and
some
minor
variants
of
ARCI
.
A
point
mutation
of
R
143
C
in
the
β-sandwich
domain
of
TG
1
has
been
often
identified
in
patients
with
LI
or
CIE
.
To
elucidate
the
effect
of
that
point
mutation
on
skin
barrier
structures
and
functions
,
we
generated
mice
with
a
point
mutation
of
R
142
C
,
which
corresponds
to
the
R
143
C
mutation
in
human
TG
1
.
A
mouse
line
with
the
R
142
C
point
mutation
in
TG
1
was
established
using
a
gene
targeting
technique
and
the
Cre-lox
P
system
.
The
skin
phenotypes
were
analyzed
in
homozygous
mutant
Tgm
1
(
R
142
C
/
R
142
C
)
mice
.
In
the
skin
of
Tgm
1
(
R
142
C
/
R
142
C
)
mice
,
expression
of
the
mutant
transcripts
was
comparable
with
wild-
type
or
Tgm
1
(
+
/
R
142
C
)
mice
.
However
,
the
amount
of
mutated
protein
in
the
skin
was
markedly
decreased
in
Tgm
1
(
R
142
C
/
R
142
C
)
mice
,
and
the
TG
1
activity
of
Tgm
1
(
R
142
C
/
R
142
C
)
keratinocytes
was
almost
lost
.
Tgm
1
(
R
142
C
/
R
142
C
)
mice
exhibited
morphological
and
functional
skin
barrier
defects
and
neonatal
lethality
.
The
stratum
corneum
of
those
mice
lacked
cornified
envelopes
,
and
loricrin
,
the
major
structural
component
,
failed
to
assemble
at
the
corneocyte
cell
periphery
.
Tgm
1
(
R
142
C
/
R
142
C
)
mice
showed
a
marked
increase
in
transepidermal
water
loss
and
their
skin
was
easily
permeable
to
toluidine
blue
dye
.
The
intercellular
lipid
lamellar
structures
of
the
stratum
corneum
were
irregular
and
the
13
-
nm
periodic
X-
ray
diffractions
from
the
stratum
corneum
lipid
molecules
were
lost
in
vivo
.
From
these
results
,
we
suggest
that
the
R
142
C
mutation
of
TG
1
reduces
the
enzyme
stability
which
is
indispensable
for
development
of
the
stratum
corneum
and
skin
barrier
function
and
for
postnatal
survival
of
mice
.
Diseases
Validation
Diseases presenting
"mutation in tg1"
symptom
lamellar ichthyosis
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