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Archetypal Arg169Cys mutation in NOTCH3 does not drive the pathogenesis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy via a loss-of-function mechanism.
[cadasil]
Cerebral
autosomal
dominant
arteriopathy
with
subcortical
infarcts
and
leucoencephalopathy
,
the
most
common
heritable
small
vessel
disease
of
the
brain
,
is
caused
by
dominant
mutations
in
the
NOTCH
3
receptor
that
stereotypically
lead
to
age-dependent
Notch
3
ECD
deposition
in
the
vessels
.
NOTCH
3
loss
of
function
has
been
demonstrated
for
few
mutations
.
However
,
whether
this
finding
applies
to
all
mutations
and
whether
a
loss
-of-function
mechanism
drives
the
manifestations
of
the
disease
remain
yet
unknown
.
This
study
investigated
the
in
vivo
functionality
of
the
Arg
169
C
ys
archetypal
mutation
.
We
used
mice
with
constitutive
or
conditional
reduction
of
NOTCH
3
activity
,
mice
harboring
the
Arg
169
C
ys
mutation
at
the
endogenous
Notch
3
locus
(
Notch
3
Arg
170
C
ys
)
,
and
mice
overexpressing
the
Arg
169
C
ys
NOTCH
3
mutant
(
TgPAC-Notch
3
R
169
C
)
on
either
a
Notch
3
wild-
type
or
a
null
background
.
NOTCH
3
activity
was
monitored
in
the
brain
arteries
by
measuring
the
expression
of
NOTCH
3
target
genes
using
real-time
polymerase
chain
reaction
.
Notch
3
ECD
deposits
were
assessed
by
immunohistochemistry
.
Brain
parenchyma
was
analyzed
for
vacuolation
and
myelin
debris
in
the
white
matter
and
infarcts
.
We
identified
a
subset
of
genes
appropriate
to
detect
NOTCH
3
haploinsufficiency
in
the
adult
.
Expression
of
these
genes
was
unaltered
in
Notch
3
Arg
170
C
ys
mice
,
despite
marked
Notch
3
ECD
deposits
.
Elimination
of
wild-
type
NOTCH
3
did
not
influence
the
onset
and
burden
of
white
matter
lesions
in
20
-
month
-old
TgPAC-Notch
3
R
169
C
mice
,
and
20
-
month
-old
Notch
3
-
null
mice
exhibited
neither
infarct
nor
white
matter
changes
.
These
data
provide
strong
evidence
that
cerebral
autosomal
dominant
arteriopathy
with
subcortical
infarcts
and
leucoencephalopathy
can
develop
without
impairment
of
NOTCH
3
signaling
and
argue
against
a
loss
of
NOTCH
3
function
as
a
general
driving
mechanism
for
white
matter
lesions
in
cerebral
autosomal
dominant
arteriopathy
with
subcortical
infarcts
and
leucoencephalopathy
.