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Colocalization of kindlin-1, kindlin-2, and migfilin at keratinocyte focal adhesion and relevance to the pathophysiology of Kindler syndrome.
[kindler syndrome]
Kindler
syndrome
(
KS
)
results
from
pathogenic
loss
-of-function
mutations
in
the
KIND
1
gene
,
which
encodes
kindlin-
1
,
a
focal
adhesion
and
actin
cytoskeleton-related
protein
.
How
and
why
abnormalities
in
kindlin-
1
disrupt
keratinocyte
cell
biology
in
KS
,
however
,
is
not
yet
known
.
In
this
study
,
we
identified
two
previously
unreported
binding
proteins
of
kindlin-
1
:
kindlin-
2
and
migfilin
.
Co
-immunoprecipitation
and
confocal
microscopy
studies
show
that
these
three
proteins
bind
to
each
other
and
colocalize
at
focal
adhesion
in
HaCaT
cells
and
normal
human
keratinocytes
.
Moreover
,
loss
-of-function
mutations
in
KIND
1
result
in
marked
variability
in
kindlin-
1
immunolabeling
in
KS
skin
,
which
is
mirrored
by
similar
changes
in
kindlin-
2
and
migfilin
immunoreactivity
.
Kindlin-
1
,
however
,
may
function
independently
of
kindlin-
2
and
migfilin
,
as
loss
of
kindlin-
1
expression
in
HaCaT
keratinocytes
by
RNA
interference
and
in
KS
keratinocytes
does
not
affect
KIND
2
or
FBLIM
1
(
migfilin
)
gene
expression
or
kindlin-
2
and
migfilin
protein
localization
.
In
addition
to
identifying
protein-binding
partners
for
kindlin-
1
,
this
study
also
highlights
that
KIND
1
gene
expression
and
kindlin-
1
protein
labeling
are
not
always
reduced
in
KS
,
findings
that
are
relevant
to
the
accurate
laboratory
diagnosis
of
this
genodermatosis
by
skin
immunohistochemistry
.
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