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A truncating mutation in the laminin-332α chain highlights the role of the LG45 proteolytic domain in regulating keratinocyte adhesion and migration.
[junctional epidermolysis bullosa]
Altered
function
of
laminin-
332
(
α
3
β
3
γ
2
)
consequent
to
mutations
in
the
LAMA
3
,
LAMB
3
and
LAMC
2
genes
causes
junctional
epidermolysis
bullosa
non-
Herlitz
(
JEB
-nH
)
.
JEB
-nH
patients
suffer
from
skin
blistering
and
have
an
increased
risk
of
developing
aggressive
skin
carcinomas
in
adulthood
.
Laminin-
332
is
proteolytically
processed
and
its
extracellular
mature
form
lacks
the
α
3
chain
C-
terminal
globules
4
and
5
(
LG
45
)
.
The
LG
45
tandem
has
cell
adhesion
and
protumorigenic
properties
.
However
,
mutations
that
affect
this
domain
are
very
rare
and
their
functional
effects
in
patients
have
not
been
explored
to
date
.
To
characterize
molecularly
an
adult
patient
with
JEB
-nH
and
altered
laminin-
332
expression
presenting
multiple
skin
carcinomas
,
and
to
analyse
LG
45
-
mediated
biological
functions
using
keratinocytes
from
the
patient
.
A
mutational
search
in
laminin-
332
genes
was
performed
by
hetero-duplex
analysis
.
LAMA
3
mRNA
and
laminin-
332
protein
levels
in
patient
keratinocytes
were
investigated
by
real-time
reverse
transcriptase
polymerase
chain
reaction
and
radioimmunoprecipitation
assay
,
respectively
.
Keratinocyte
migration
was
examined
by
scratch
and
Boyden
chamber
assays
.
We
identified
a
homozygous
LAMA
3
mutation
,
p
.
Leu
1648
TrpfsX
32
,
which
truncates
the
last
45
amino
acids
of
the
carboxyl
terminal
LG
5
subdomain
.
Gene
expression
studies
revealed
that
the
mutant
transcripts
were
stable
and
even
increased
,
precursor
laminin-
332
molecules
were
retained
intracellularly
and
the
amount
of
mature
extracellular
heterotrimers
was
reduced
to
about
50
%
.
Finally
,
the
patient
's
keratinocytes
migrated
faster
than
normal
keratinocytes
.
Structural
disruption
of
LG
5
highlights
the
critical
functions
of
the
LG
45
proteolytic
region
in
precursor
laminin-
332
secretion
and
keratinocyte
adhesion
and
migration
.
Perturbation
of
LG
45
function
might
explain
the
non-
aggressive
behaviour
of
carcinomas
in
this
patient
.
Diseases
Validation
Diseases presenting
"increased risk of developing aggressive skin carcinomas in adulthood"
symptom
junctional epidermolysis bullosa
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