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Keratin gene mutations in disorders of human skin and its appendages.
[epidermolysis bullosa simplex]
Keratins
,
the
major
structural
protein
of
all
epithelia
are
a
diverse
group
of
cytoskeletal
scaffolding
proteins
that
form
intermediate
filament
networks
,
providing
structural
support
to
keratinocytes
that
maintain
the
integrity
of
the
skin
.
Expression
of
keratin
genes
is
usually
regulated
by
differentiation
of
the
epidermal
cells
within
the
stratifying
squamous
epithelium
.
Amongst
the
54
known
functional
keratin
genes
in
humans
,
about
22
different
genes
including
,
the
cornea
,
hair
and
hair
follicle-
specific
keratins
have
been
implicated
in
a
wide
range
of
hereditary
diseases
.
The
exact
phenotype
of
each
disease
usually
reflects
the
spatial
expression
level
and
the
types
of
mutated
keratin
genes
,
the
location
of
the
mutations
and
their
consequences
at
sub-cellular
levels
as
well
as
other
epigenetic
and
/
or
environmental
factors
.
The
identification
of
specific
pathogenic
mutations
in
keratin
disorders
formed
the
basis
of
our
understanding
that
led
to
re
-classification
,
improved
diagnosis
with
prognostic
implications
,
prenatal
testing
and
genetic
counseling
in
severe
keratin
genodermatoses
.
Molecular
defects
in
cutaneous
keratin
genes
encoding
for
keratin
intermediate
filaments
(
KIFs
)
causes
keratinocytes
and
tissue-
specific
fragility
,
accounting
for
a
large
number
of
genetic
disorders
in
human
skin
and
its
appendages
.
These
diseases
are
characterized
by
keratinocytes
fragility
(
cytolysis
)
,
intra-epidermal
blistering
,
hyperkeratosis
,
and
keratin
filament
aggregation
in
severely
affected
tissues
.
Examples
include
epidermolysis
bullosa
simplex
(
EBS
;
K
5
,
K
14
)
,
keratinopathic
ichthyosis
(
KPI
;
K
1
,
K
2
,
K
10
)
i
.
e
.
epidermolytic
ichthyosis
(
EI
;
K
1
,
K
10
)
and
ichthyosis
bullosa
of
Siemens
(
IBS
;
K
2
)
,
pachyonychia
congenita
(
PC
;
K
6
a
,
K
6
b
,
K
16
,
K
17
)
,
epidermolytic
palmo-
plantar
keratoderma
(
EPPK
;
K
9
,
(
K
1
)
)
,
monilethrix
(
K
81
,
K
83
,
K
86
)
,
ectodermal
dysplasia
(
ED
;
K
85
)
and
steatocystoma
multiplex
.
These
keratins
also
have
been
identified
to
have
roles
in
apoptosis
,
cell
proliferation
,
wound
healing
,
tissue
polarity
and
remodeling
.
This
review
summarizes
and
discusses
the
clinical
,
ultrastructural
,
molecular
genetics
and
biochemical
characteristics
of
a
broad
spectrum
of
keratin-related
genodermatoses
,
with
special
clinical
emphasis
on
EBS
,
EI
and
PC
.
We
also
highlight
current
and
emerging
model
tools
for
prognostic
future
therapies
.
Hopefully
,
disease
modeling
and
in
-depth
understanding
of
the
molecular
pathogenesis
of
the
diseases
may
lead
to
the
development
of
novel
therapies
for
several
hereditary
cutaneous
diseases
.
Diseases
Validation
Diseases presenting
"hyperkeratosis"
symptom
child syndrome
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
harlequin ichthyosis
lamellar ichthyosis
malignant atrophic papulosis
oral submucous fibrosis
papillon-lefèvre syndrome
proteus syndrome
triple a syndrome
This symptom has already been validated