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Induction of senescence pathways in Kindler syndrome primary keratinocytes.
[kindler syndrome]
Individuals
with
Kindler
syndrome
(
KS
)
have
loss
-of-function
mutations
in
the
FERMT
1
gene
that
encodes
the
focal
adhesion
component
kindlin-
1
.
The
major
clinical
manifestation
of
KS
is
epidermal
atrophy
(
premature
skin
ageing
)
.
This
phenotypic
feature
is
thought
to
be
related
to
the
decreased
proliferation
rate
of
KS
keratinocytes
;
nevertheless
,
molecular
mediators
of
such
abnormal
behaviour
have
not
been
fully
elucidated
.
To
investigate
how
kindlin-
1
deficiency
affects
the
proliferative
potential
of
primary
human
keratinocytes
.
We
serially
cultivated
nine
primary
KS
keratinocyte
strains
until
senescence
and
determined
their
lifespan
and
colony-forming
efficiency
(
CFE
)
at
each
serial
passage
.
The
expression
of
molecular
markers
of
stemness
and
cellular
senescence
were
investigated
by
immunoblotting
using
cell
extracts
of
primary
keratinocyte
cultures
from
patients
with
KS
and
healthy
donors
.
In
another
set
of
experiments
,
kindlin-
1
downregulation
in
normal
keratinocytes
was
obtained
by
small
interfering
RNA
(
siRNA
)
technology
.
We
found
that
KS
keratinocytes
exhibited
a
precocious
senescence
and
strongly
reduced
clonogenic
potential
.
Moreover
,
KS
cultures
showed
a
strikingly
increased
percentage
of
aborted
colonies
(
paraclones
)
already
at
early
passages
indicating
an
early
depletion
of
stem
cells
.
Immunoblotting
analysis
of
KS
keratinocyte
extracts
showed
reduced
levels
of
the
stemness
markers
p
63
and
Bmi-
1
,
upregulation
of
p
16
and
scant
amounts
of
hypophosphorylated
Rb
protein
,
which
indicated
cell
cycle-arrested
status
.
Treatment
of
normal
human
primary
keratinocytes
with
siRNA
targeting
kindlin-
1
proved
that
its
deficiency
was
directly
responsible
for
p
63
,
Bmi-
1
and
pRb
downregulation
and
p
16
induction
.
Our
data
directly
implicate
kindlin-
1
in
preventing
premature
senescence
of
keratinocytes
.
Diseases
Validation
Diseases presenting
"loss-of-function mutations"
symptom
achondroplasia
alpha-thalassemia
aromatase deficiency
child syndrome
cowden syndrome
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
erythropoietic protoporphyria
esophageal adenocarcinoma
familial hypocalciuric hypercalcemia
harlequin ichthyosis
hirschsprung disease
kallmann syndrome
kindler syndrome
lamellar ichthyosis
neonatal adrenoleukodystrophy
pendred syndrome
werner syndrome
x-linked adrenoleukodystrophy
This symptom has already been validated
