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Self-improvement of keratinocyte differentiation defects during skin maturation in ABCA12-deficient harlequin ichthyosis model mice.
[lamellar ichthyosis]
Harlequin
ichthyosis
(
HI
)
is
caused
by
loss
-of-function
mutations
in
the
keratinocyte
lipid
transporter
ABCA
12
.
The
patients
often
die
in
the
first
1
or
2
weeks
of
life
,
although
HI
survivors
'
phenotypes
improve
within
several
weeks
after
birth
.
In
order
to
clarify
the
mechanisms
of
phenotypic
recovery
,
we
studied
grafted
skin
and
keratinocytes
from
Abca
12
-
disrupted
(
Abca
12
(
-
/
-
)
)
mice
showing
abnormal
lipid
transport
.
Abca
12
(
-
/
-
)
neonatal
epidermis
showed
significantly
reduced
total
ceramide
amounts
and
aberrant
ceramide
composition
.
Immunofluorescence
and
immunoblotting
of
Abca
12
(
-
/
-
)
neonatal
epidermis
revealed
defective
profilaggrin
/
filaggrin
conversion
and
reduced
protein
expression
of
the
differentiation-
specific
molecules
,
loricrin
,
kallikrein
5
,
and
transglutaminase
1
,
although
their
mRNA
expression
was
up-regulated
.
In
contrast
,
Abca
12
(
-
/
-
)
skin
grafts
kept
in
a
dry
environment
exhibited
dramatic
improvements
in
all
these
abnormalities
.
Increased
transepidermal
water
loss
,
a
parameter
representing
barrier
defect
,
was
remarkably
decreased
in
grafted
Abca
12
(
-
/
-
)
skin
.
Ten
-passage
sub-cultured
Abca
12
(
-
/
-
)
keratinocytes
showed
restoration
of
intact
ceramide
distribution
,
differentiation-
specific
protein
expression
and
profilaggrin
/
filaggrin
conversion
,
which
were
defective
in
primary
-cultures
.
Using
cDNA
microarray
analysis
,
lipid
transporters
including
four
ATP-binding
cassette
transporters
were
up-regulated
after
sub-culture
of
Abca
12
(
-
/
-
)
keratinocytes
compared
with
primary
-culture
.
These
results
indicate
that
disrupted
keratinocyte
differentiation
during
the
fetal
development
is
involved
in
the
pathomechanism
of
HI
and
,
during
maturation
,
Abca
12
(
-
/
-
)
epidermal
keratinocytes
regain
normal
differentiation
processes
.
This
restoration
may
account
for
the
skin
phenotype
improvement
observed
in
HI
survivors
.
Diseases
Validation
Diseases presenting
"exhibited dramatic improvements in all these abnormalities"
symptom
harlequin ichthyosis
lamellar ichthyosis
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