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CGI-58 is an alpha/beta-hydrolase within lipid transporting lamellar granules of differentiated keratinocytes.
[harlequin ichthyosis]
CGI-
58
is
the
causative
molecule
underlying
Dorfman-
Chanarin
syndrome
,
a
neutral
lipid
storage
disease
exhibiting
apparent
clinical
features
of
ichthyosis
.
CGI-
58
,
associated
with
triacylglycerol
hydrolysis
,
has
an
alpha
/
beta
-hydrolase
fold
and
is
also
known
as
the
alpha
/
beta
-hydrolase
domain-containing
protein
5
.
The
purpose
of
this
study
was
to
elucidate
the
function
of
CGI-
58
and
the
pathogenic
mechanisms
of
ichthyosis
in
Dorfman-
Chanarin
syndrome
.
Using
an
anti-
CGI-
58
antibody
,
we
found
CGI-
58
to
be
expressed
in
the
upper
epidermis
,
predominantly
in
the
granular
layer
cells
,
as
well
as
in
neurons
and
hepatocytes
.
Immunoelectron
microscopy
revealed
that
CGI-
58
was
also
localized
to
the
lamellar
granules
(
LGs
)
,
which
are
lipid
transport
and
secretion
granules
found
in
keratinocytes
.
CGI-
58
expression
was
markedly
reduced
in
the
epidermis
of
patients
with
harlequin
ichthyosis
,
demonstrating
defective
LG
formation
.
In
cultured
keratinocytes
,
CGI-
58
expression
was
mildly
up-regulated
under
high
Ca
(
2
+
)
conditions
and
markedly
up-regulated
in
three
-dimensional
,
organotypic
cultures
.
In
the
developing
human
epidermis
,
CGI-
58
immunostaining
was
observed
at
an
estimated
gestational
age
of
49
days
,
and
CGI-
58
mRNA
expression
was
up-regulated
concomitantly
with
both
epidermal
stratification
and
keratinocyte
differentiation
.
CGI-
58
knockdown
reduced
expression
of
keratinocyte
differentiation
/
keratinization
markers
in
cultured
human
keratinocytes
.
Our
results
indicate
that
CGI-
58
is
expressed
and
packaged
into
LGs
during
keratinization
and
likely
plays
crucial
role
(
s
)
in
keratinocyte
differentiation
and
LG
lipid
metabolism
,
contributing
to
skin
lipid
barrier
formation
.
Diseases
Validation
Diseases presenting
"ichthyosis"
symptom
child syndrome
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
harlequin ichthyosis
hirschsprung disease
junctional epidermolysis bullosa
kallmann syndrome
lamellar ichthyosis
This symptom has already been validated