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Premature terminal differentiation and a reduction in specific proteases associated with loss of ABCA12 in Harlequin ichthyosis.
[harlequin ichthyosis]
One
of
the
primary
functions
of
skin
is
to
form
a
defensive
barrier
against
external
infections
and
water
loss
.
Disrupted
barrier
function
underlies
the
most
severe
and
often
lethal
form
of
recessive
congenital
ichthyosis
,
harlequin
ichthyosis
(
HI
)
.
HI
is
associated
with
mutations
in
the
gene
that
encodes
the
ABC
transporter
protein
,
ABCA
12
.
We
have
investigated
the
morphological
and
biochemical
alterations
associated
with
abnormal
epidermal
differentiation
and
barrier
formation
in
HI
epidermis
.
An
in
vitro
model
of
HI
skin
using
human
keratinocytes
retrovirally
transduced
with
shRNA
targeting
ABCA
12
in
a
three
-dimensional
,
organotypic
co
-culture
(
OTCC
)
system
has
also
been
developed
.
A
robust
reduction
in
ABCA
12
expression
had
a
dramatic
effect
on
keratinocyte
differentiation
and
morphology
comparable
with
that
observed
in
HI
skin
,
including
a
thicker
epidermis
and
abnormal
lipid
content
with
a
reduction
in
nonpolar
lipids
.
As
seen
in
HI
epidermis
,
proteins
that
are
normally
expressed
in
late
differentiation
were
highly
dysregulated
in
the
ABCA
12
-
ablated
OTCC
system
.
These
proteins
were
expressed
in
the
stratum
basale
and
also
in
the
stratum
spinosum
,
indicative
of
a
premature
terminal
differentiation
phenotype
.
Expression
of
the
proteases
kallikrein
5
and
cathepsin
D
was
dramatically
reduced
in
both
HI
epidermis
and
the
OTCC
model
.
These
data
suggest
that
ABCA
12
is
a
key
molecule
in
regulating
keratinocyte
differentiation
and
transporting
specific
proteases
associated
with
desquamation
.
Diseases
Validation
Diseases presenting
"mutations in the gene that encodes the abc transporter protein"
symptom
harlequin ichthyosis
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