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Epidermal-specific defect of GPI anchor in Pig-a null mice results in Harlequin ichthyosis-like features.
[harlequin ichthyosis]
We
previously
demonstrated
that
the
epidermal-
specific
glycosylphosphatidylinositol
(
GPI
)
-
anchor-
deficient
mice
,
generated
by
Pig-a
gene
disruption
(
Pig-a
null
mice
)
,
exhibited
wrinkled
and
dry
skin
with
hyperkeratosis
and
abnormal
differentiation
,
and
they
died
within
a
few
days
after
birth
.
Here
,
we
investigated
the
basis
for
the
early
demise
of
these
animals
,
and
the
potential
role
of
epidermal
structural
and
biochemical
abnormalities
.
The
rapid
demise
of
these
animals
was
associated
with
both
diminished
epidermal
permeability
barrier
function
and
decreased
stratum
corneum
(
SC
)
water
content
.
The
barrier
abnormality
could
be
attributed
abnormal
internal
contents
of
lamellar
bodies
,
with
a
downstream
failure
to
generate
normal
extracellular
lamellar
bilayers
in
the
SC
.
Moreover
,
processing
profilaggrin
to
its
monomeric
form
was
impaired
in
Pig-a
null
mouse
epidermis
,
while
levels
of
the
differentiation-
specific
proteins
,
involucrin
,
loricrin
and
profilaggrin
were
normal
.
Failure
of
filaggrin
processing
was
accompanied
by
decreased
activity
of
protein
phosphatase
2
A
,
an
enzyme
involved
in
profilaggrin
to
filaggrin
processing
.
Thus
,
these
studies
demonstrate
a
critical
role
for
GPI
anchor
and
GPI
-anchored
proteins
in
divergent
arms
of
epidermal
terminal
differentiation
.
While
the
permeability
barrier
abnormality
can
be
attributed
to
defects
in
the
lamellar
body
secretory
system
,
the
hydration
abnormality
is
,
in
part
,
due
to
lack
of
availability
of
filaggrin
-derived
proteolytic
products
.
Finally
,
since
the
dual
abnormalities
in
the
lamellar
body
secretory
system
and
filaggrin
processing
resemble
two
key
features
of
human
Harlequin
ichthyosis
,
Pig-a
null
mice
could
provide
an
appropriate
analog
for
further
studies
of
this
disease
.
Diseases
Validation
Diseases presenting
"lack of availability of filaggrin-derived proteolytic products"
symptom
harlequin ichthyosis
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