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Impaired epidermal ceramide synthesis causes autosomal recessive congenital ichthyosis and reveals the importance of ceramide acyl chain length.
[lamellar ichthyosis]
The
barrier
function
of
the
human
epidermis
is
supposed
to
be
governed
by
lipid
composition
and
organization
in
the
stratum
corneum
.
Disorders
of
keratinization
,
namely
ichthyoses
,
are
typically
associated
with
disturbed
barrier
activity
.
Using
autozygosity
mapping
and
exome
sequencing
,
we
have
identified
a
homozygous
missense
mutation
in
CERS
3
in
patients
with
congenital
ichthyosis
characterized
by
collodion
membranes
at
birth
,
generalized
scaling
of
the
skin
,
and
mild
erythroderma
.
We
demonstrate
that
the
mutation
inactivates
ceramide
synthase
3
(
CerS
3
)
,
which
is
synthesized
in
skin
and
testis
,
in
an
assay
of
N-
acylation
with
C
2
6
-
CoA
,
both
in
patient
keratinocytes
and
using
recombinant
mutant
proteins
.
Moreover
,
we
show
a
specific
loss
of
ceramides
with
very
long
acyl
chains
from
C
2
6
up
to
C
3
4
in
terminally
differentiating
patient
keratinocytes
,
which
is
in
line
with
findings
from
a
recent
CerS
3
-
deficient
mouse
model
.
Analysis
of
reconstructed
patient
skin
reveals
disturbance
of
epidermal
differentiation
with
an
earlier
maturation
and
an
impairment
of
epidermal
barrier
function
.
Our
findings
demonstrate
that
synthesis
of
very
long
chain
ceramides
by
CerS
3
is
a
crucial
early
step
for
the
skin
barrier
formation
and
link
disorders
presenting
with
congenital
ichthyosis
to
defects
in
sphingolipid
metabolism
and
the
epidermal
lipid
architecture
.
Diseases
Validation
Diseases presenting
"crucial early step for the skin barrier formation"
symptom
lamellar ichthyosis
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