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MicroRNA 218 mediates the effects of Tbx5a over-expression on zebrafish heart development.
[holt-oram syndrome]
tbx
5
,
a
member
of
the
T
-
box
gene
family
,
encodes
one
of
the
key
transcription
factors
mediating
vertebrate
heart
development
.
Tbx
5
function
in
heart
development
appears
to
be
exquisitely
sensitive
to
gene
dosage
,
since
both
haploinsufficiency
and
gene
duplication
generate
the
cardiac
abnormalities
associated
with
Holt-
Oram
syndrome
(
HOS
)
,
a
highly
penetrant
autosomal
dominant
disease
characterized
by
congenital
heart
defects
of
varying
severity
and
upper
limb
malformation
.
It
is
suggested
that
tight
integration
of
microRNAs
and
transcription
factors
into
the
cardiac
genetic
circuitry
provides
a
rich
and
robust
array
of
regulatory
interactions
to
control
cardiac
gene
expression
.
Based
on
these
considerations
,
we
performed
an
in
silico
screening
to
identify
microRNAs
embedded
in
genes
highly
sensitive
to
Tbx
5
dosage
.
Among
the
identified
microRNAs
,
we
focused
our
attention
on
miR-
218
-
1
that
,
together
with
its
host
gene
,
slit
2
,
is
involved
in
heart
development
.
We
found
correlated
expression
of
tbx
5
and
miR-
218
during
cardiomyocyte
differentiation
of
mouse
P
19
CL
6
cells
.
In
zebrafish
embryos
,
we
show
that
both
Tbx
5
and
miR-
218
dysregulation
have
a
severe
impact
on
heart
development
,
affecting
early
heart
morphogenesis
.
Interestingly
,
down-regulation
of
miR-
218
is
able
to
rescue
the
heart
defects
generated
by
tbx
5
over-expression
supporting
the
notion
that
miR-
218
is
a
crucial
mediator
of
Tbx
5
in
heart
development
and
suggesting
its
possible
involvement
in
the
onset
of
heart
malformations
.
Diseases
Validation
Diseases presenting
"limb malformation"
symptom
holt-oram syndrome
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