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Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome.
[kabuki syndrome]
Kabuki
syndrome
is
caused
by
haploinsufficiency
for
either
of
two
genes
that
promote
the
opening
of
chromatin
.
If
an
imbalance
between
open
and
closed
chromatin
is
central
to
the
pathogenesis
of
Kabuki
syndrome
,
agents
that
promote
chromatin
opening
might
have
therapeutic
potential
.
We
have
characterized
a
mouse
model
of
Kabuki
syndrome
with
a
heterozygous
deletion
in
the
gene
encoding
the
lysine-
specific
methyltransferase
2
D
(
Kmt
2
d
)
,
leading
to
impairment
of
methyltransferase
function
.
In
vitro
reporter
alleles
demonstrated
a
reduction
in
histone
4
acetylation
and
histone
3
lysine
4
trimethylation
(
H
3
K
4
me
3
)
activity
in
mouse
embryonic
fibroblasts
from
Kmt
2
d
(
+
/
βGeo
)
mice
.
These
activities
were
normalized
in
response
to
AR
-
42
,
a
histone
deacetylase
inhibitor
.
In
vivo
,
deficiency
of
H
3
K
4
me
3
in
the
dentate
gyrus
granule
cell
layer
of
Kmt
2
d
(
+
/
βGeo
)
mice
correlated
with
reduced
neurogenesis
and
hippocampal
memory
defects
.
These
abnormalities
improved
upon
postnatal
treatment
with
AR
-
42
.
Our
work
suggests
that
a
reversible
deficiency
in
postnatal
neurogenesis
underlies
intellectual
disability
in
Kabuki
syndrome
.
Diseases
Validation
Diseases presenting
"postnatal treatment"
symptom
congenital toxoplasmosis
kabuki syndrome
megacystis-microcolon-intestinal hypoperistalsis syndrome
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