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Methylome repatterning in a mouse model of Maternal PKU Syndrome.
[phenylketonuria]
Maternal
PKU
Syndrome
(
MPKU
)
is
an
embryopathy
resulting
from
in
utero
phenylalanine
(
PHE
)
toxicity
secondary
to
maternal
phenylalanine
hydroxylase
deficient
phenylketonuria
(
PKU
)
.
Clinical
phenotypes
in
MPKU
include
mental
retardation
,
microcephaly
,
in
utero
growth
restriction
,
and
congenital
heart
defects
.
Numerous
in
utero
toxic
exposures
alter
DNA
methylation
in
the
fetus
.
The
PAH
(
enu
2
)
mouse
is
a
model
of
classical
PKU
while
offspring
born
of
hyperphenylalaninemic
dams
model
MPKU
.
We
investigated
offspring
of
PAH
(
enu
2
)
dams
to
determine
if
altered
patterns
of
DNA
methylation
occurred
in
response
to
in
utero
PHE
exposure
.
As
neurologic
deficit
is
the
most
prominent
MPKU
phenotype
,
methylome
patterns
were
assessed
in
brain
tissue
using
methylated
DNA
immunoprecipitation
and
paired-end
sequencing
.
Brain
tissues
were
assessed
in
E
18
.
5
-
19
fetuses
of
PHE
unrestricted
PAH
(
enu
2
)
dams
,
PHE
restricted
PAH
(
enu
2
)
dams
,
and
heterozygous
(
wt
/
enu
2
)
control
dams
.
Extensive
methylome
repatterning
was
observed
in
offspring
of
hyperphenylalaninemic
dams
while
the
offspring
of
PHE
restricted
dams
displayed
attenuated
methylome
repatterning
.
Methylation
within
coding
regions
was
dominated
by
noncoding
RNA
genes
.
Differential
methylation
of
promoters
targeted
protein
coding
genes
.
To
assess
the
impact
of
methylome
repatterning
on
gene
expression
,
brain
tissue
in
experimental
and
control
animals
were
queried
with
microarrays
assessing
expression
of
microRNAs
and
protein
coding
genes
.
Altered
expression
of
methylome-modified
microRNAs
and
protein
coding
genes
was
extensive
in
offspring
of
hyperphenylalaninemic
dams
while
minimal
changes
were
observed
in
offspring
of
PHE
restricted
dams
.
Several
genes
displaying
significantly
reduced
expression
have
roles
in
neurological
function
or
genetic
disease
with
neurological
phenotypes
.
These
data
indicate
in
utero
PHE
toxicity
alters
DNA
methylation
in
the
brain
which
has
downstream
impact
upon
gene
expression
.
Altered
gene
expression
may
contribute
to
pathophysiology
of
neurologic
presentation
in
MPKU
.
Diseases
Validation
Diseases presenting
"mental retardation"
symptom
achondroplasia
alexander disease
alpha-thalassemia
aniridia
aromatase deficiency
canavan disease
classical phenylketonuria
coats disease
cohen syndrome
cowden syndrome
cystinuria
dentin dysplasia
familial hypocalciuric hypercalcemia
homocystinuria without methylmalonic aciduria
hydrocephalus with stenosis of the aqueduct of sylvius
kabuki syndrome
kallmann syndrome
lamellar ichthyosis
lymphangioleiomyomatosis
monosomy 21
phenylketonuria
primary hyperoxaluria type 1
proteus syndrome
pyruvate dehydrogenase deficiency
sneddon syndrome
triple a syndrome
wolf-hirschhorn syndrome
zellweger syndrome
This symptom has already been validated