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CHD7, the gene mutated in CHARGE syndrome, regulates genes involved in neural crest cell guidance.
[kallmann syndrome]
Heterozygous
loss
of
function
mutations
in
CHD
7
(
chromodomain
helicase
DNA-binding
protein
7
)
lead
to
CHARGE
syndrome
,
a
complex
developmental
disorder
affecting
craniofacial
structures
,
cranial
nerves
and
several
organ
systems
.
Recently
,
it
was
demonstrated
that
CHD
7
is
essential
for
the
formation
of
multipotent
migratory
neural
crest
cells
,
which
migrate
from
the
neural
tube
to
many
regions
of
the
embryo
,
where
they
differentiate
into
various
tissues
including
craniofacial
and
heart
structures
.
So
far
,
only
few
CHD
7
target
genes
involved
in
neural
crest
cell
development
have
been
identified
and
the
role
of
CHD
7
in
neural
crest
cell
guidance
and
the
regulation
of
mesenchymal-epithelial
transition
are
unknown
.
Therefore
,
we
undertook
a
genome-
wide
microarray
expression
analysis
on
wild-
type
and
CHD
7
deficient
(
Chd
7
(
Whi
/
+
)
and
Chd
7
(
Whi
/
Whi
)
)
mouse
embryos
at
day
9
.
5
,
a
time
point
of
neural
crest
cell
migration
.
We
identified
98
differentially
expressed
genes
between
wild-
type
and
Chd
7
(
Whi
/
Whi
)
embryos
.
Interestingly
,
many
misregulated
genes
are
involved
in
neural
crest
cell
and
axon
guidance
such
as
semaphorins
and
ephrin
receptors
.
By
performing
knockdown
experiments
for
Chd
7
in
Xenopus
laevis
embryos
,
we
found
abnormalities
in
the
expression
pattern
of
Sema
3
a
,
a
protein
involved
in
the
pathogenesis
of
Kallmann
syndrome
,
in
vivo
.
In
addition
,
we
detected
non-synonymous
SEMA
3
A
variations
in
3
out
of
45
CHD
7
-
negative
CHARGE
patients
.
In
summary
,
we
discovered
for
the
first
time
that
Chd
7
regulates
genes
involved
in
neural
crest
cell
guidance
,
demonstrating
a
new
aspect
in
the
pathogenesis
of
CHARGE
syndrome
.
Furthermore
,
we
showed
for
Sema
3
a
a
conserved
regulatory
mechanism
across
different
species
,
highlighting
its
significance
during
development
.
Although
we
postulated
that
the
non-synonymous
SEMA
3
A
variants
which
we
found
in
CHD
7
-
negative
CHARGE
patients
alone
are
not
sufficient
to
produce
the
phenotype
,
we
suggest
an
important
modifier
role
for
SEMA
3
A
in
the
pathogenesis
of
this
multiple
malformation
syndrome
.
Diseases
Validation
Diseases presenting
"abnormalities in the expression pattern"
symptom
kallmann syndrome
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