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Distinct expression and function of alternatively spliced Tbx5 isoforms in cell growth and differentiation.
[holt-oram syndrome]
Mutations
in
the
T
-
box
transcription
factor
Tbx
5
cause
Holt-
Oram
syndrome
,
an
autosomal
dominant
disease
characterized
by
a
wide
spectrum
of
cardiac
and
upper
limb
defects
with
variable
expressivity
.
Tbx
5
haploinsufficiency
has
been
suggested
to
be
the
underlying
mechanism
,
and
experimental
models
are
consistent
with
a
dosage-sensitive
requirement
for
Tbx
5
in
heart
development
.
Here
,
we
report
that
Tbx
5
levels
are
regulated
through
alternative
splicing
that
generates
,
in
addition
to
the
known
518
-
amino-acid
protein
,
a
C-
terminal
truncated
isoform
.
This
shorter
isoform
retains
the
capacity
to
bind
DNA
,
but
its
interaction
with
Tbx
5
collaborators
such
as
GATA-
4
is
altered
.
In
vivo
,
the
two
spliced
isoforms
are
oppositely
regulated
in
a
temporal
and
growth
factor
-dependent
manner
and
are
present
in
distinct
DNA-binding
complexes
.
The
expression
of
the
long
isoform
correlates
with
growth
stimulation
,
and
its
reexpression
in
postnatal
transgenic
mouse
hearts
promotes
hypertrophy
.
Conversely
,
the
upregulation
of
the
short
but
not
the
long
isoform
in
C
2
C
12
myoblasts
leads
to
growth
arrest
and
cell
death
.
The
results
provide
novel
insight
into
posttranscriptional
Tbx
5
regulation
and
point
to
an
important
role
not
only
in
cell
differentiation
but
also
in
cell
proliferation
and
organ
growth
.
The
data
may
help
analyze
genotype-phenotype
relations
in
patients
with
Holt-
Oram
syndrome
.
Diseases
Validation
Diseases presenting
"heart development"
symptom
holt-oram syndrome
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