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Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer.
[harlequin ichthyosis]
Harlequin
ichthyosis
(
HI
)
is
a
devastating
skin
disorder
with
an
unknown
underlying
cause
.
Abnormal
keratinocyte
lamellar
granules
(
LGs
)
are
a
hallmark
of
HI
skin
.
ABCA
12
is
a
member
of
the
ATP-binding
cassette
transporter
family
,
and
members
of
the
ABCA
subfamily
are
known
to
have
closely
related
functions
as
lipid
transporters
.
ABCA
3
is
involved
in
lipid
secretion
via
LGs
from
alveolar
type
II
cells
,
and
missense
mutations
in
ABCA
12
have
been
reported
to
cause
lamellar
ichthyosis
type
2
,
a
milder
form
of
ichthyosis
.
Therefore
,
we
hypothesized
that
HI
might
be
caused
by
mutations
that
lead
to
serious
ABCA
12
defects
.
We
identify
5
distinct
ABCA
12
mutations
,
either
in
a
compound
heterozygous
or
homozygous
state
,
in
patients
from
4
HI
families
.
All
the
mutations
resulted
in
truncation
or
deletion
of
highly
conserved
regions
of
ABCA
12
.
Immunoelectron
microscopy
revealed
that
ABCA
12
localized
to
LGs
in
normal
epidermal
keratinocytes
.
We
confirmed
that
ABCA
12
defects
cause
congested
lipid
secretion
in
cultured
HI
keratinocytes
and
succeeded
in
obtaining
the
recovery
of
LG
lipid
secretion
after
corrective
gene
transfer
of
ABCA
12
.
We
concluded
that
ABCA
12
works
as
an
epidermal
keratinocyte
lipid
transporter
and
that
defective
ABCA
12
results
in
a
loss
of
the
skin
lipid
barrier
,
leading
to
HI
.
Our
findings
not
only
allow
DNA-based
early
prenatal
diagnosis
but
also
suggest
the
possibility
of
gene
therapy
for
HI
.
Diseases
Validation
Diseases presenting
"skin disorder"
symptom
aniridia
congenital adrenal hyperplasia
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
harlequin ichthyosis
junctional epidermolysis bullosa
kindler syndrome
lamellar ichthyosis
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