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A mouse model of harlequin ichthyosis delineates a key role for Abca12 in lipid homeostasis.
[harlequin ichthyosis]
Harlequin
Ichthyosis
(
HI
)
is
a
severe
and
often
lethal
hyperkeratotic
skin
disease
caused
by
mutations
in
the
ABCA
12
transport
protein
.
In
keratinocytes
,
ABCA
12
is
thought
to
regulate
the
transfer
of
lipids
into
small
intracellular
trafficking
vesicles
known
as
lamellar
bodies
.
However
,
the
nature
and
scope
of
this
regulation
remains
unclear
.
As
part
of
an
original
recessive
mouse
ENU
mutagenesis
screen
,
we
have
identified
and
characterised
an
animal
model
of
HI
and
showed
that
it
displays
many
of
the
hallmarks
of
the
disease
including
hyperkeratosis
,
loss
of
barrier
function
,
and
defects
in
lipid
homeostasis
.
We
have
used
this
model
to
follow
disease
progression
in
utero
and
present
evidence
that
loss
of
Abca
12
function
leads
to
premature
differentiation
of
basal
keratinocytes
.
A
comprehensive
analysis
of
lipid
levels
in
mutant
epidermis
demonstrated
profound
defects
in
lipid
homeostasis
,
illustrating
for
the
first
time
the
extent
to
which
Abca
12
plays
a
pivotal
role
in
maintaining
lipid
balance
in
the
skin
.
To
further
investigate
the
scope
of
Abca
12
's
activity
,
we
have
utilised
cells
from
the
mutant
mouse
to
ascribe
direct
transport
functions
to
the
protein
and
,
in
doing
so
,
we
demonstrate
activities
independent
of
its
role
in
lamellar
body
function
.
These
cells
have
severely
impaired
lipid
efflux
leading
to
intracellular
accumulation
of
neutral
lipids
.
Furthermore
,
we
identify
Abca
12
as
a
mediator
of
Abca
1
-
regulated
cellular
cholesterol
efflux
,
a
finding
that
may
have
significant
implications
for
other
diseases
of
lipid
metabolism
and
homeostasis
,
including
atherosclerosis
.
Diseases
Validation
Diseases presenting
"profound defects in lipid"
symptom
harlequin ichthyosis
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