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Involvement of DNMT3B in the pathogenesis of Hirschsprung disease and its possible role as a regulator of neurogenesis in the human enteric nervous system.
[hirschsprung disease]
Hirschsprung
disease
(
OMIM
142623
)
is
a
neurocristopathy
attributed
to
a
failure
of
cell
proliferation
or
migration
and
/
or
failure
of
the
enteric
precursors
along
the
gut
to
differentiate
during
embryonic
development
.
Although
some
genes
involved
in
this
pathology
are
well
characterized
,
many
aspects
remain
poorly
understood
.
In
this
study
,
we
aimed
to
identify
novel
genes
implicated
in
the
pathogenesis
of
Hirschsprung
disease
.
We
compared
the
expression
patterns
of
genes
involved
in
human
stem
cell
pluripotency
between
enteric
precursors
from
controls
and
Hirschsprung
disease
patients
.
We
further
evaluated
the
role
of
DNMT
3
B
in
the
context
of
Hirschsprung
disease
by
inmunocytochemistry
,
global
DNA
methylation
assays
,
and
mutational
screening
.
Seven
differentially
expressed
genes
were
identified
.
We
focused
on
DNMT
3
B
,
which
encodes
a
DNA
methyltransferase
that
performs
de
novo
DNA
methylation
during
embryonic
development
.
DNMT
3
B
mutational
analysis
in
our
Hirschsprung
disease
series
revealed
the
presence
of
potentially
pathogenic
mutations
(
p
.
Gly
25
Arg
,
p
.
Arg
190
Cys
,
and
p
.
Gly
198
Trp
)
.
DNMT
3
B
may
be
regulating
enteric
nervous
system
development
through
DNA
methylation
in
the
neural
crest
cells
,
suggesting
that
aberrant
methylation
patterns
could
have
a
relevant
role
in
Hirschsprung
disease
.
Moreover
,
the
synergistic
effect
of
mutations
in
both
DNMT
3
B
and
other
Hirschsprung
disease
-related
genes
may
be
contributing
to
a
more
severe
phenotype
in
our
Hirschsprung
disease
patients
.