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Tbx5-dependent pathway regulating diastolic function in congenital heart disease.
[holt-oram syndrome]
At
the
end
of
every
heartbeat
,
cardiac
myocytes
must
relax
to
allow
filling
of
the
heart
.
Impaired
relaxation
is
a
significant
factor
in
heart
failure
,
but
all
pathways
regulating
the
cardiac
relaxation
apparatus
are
not
known
.
Haploinsufficiency
of
the
T
-
box
transcription
factor
Tbx
5
in
mouse
and
man
causes
congenital
heart
defects
(
CHDs
)
as
part
of
Holt-
Oram
syndrome
(
HOS
)
.
Here
,
we
show
that
haploinsufficiency
of
Tbx
5
in
mouse
results
in
cell-autonomous
defects
in
ventricular
relaxation
.
Tbx
5
dosage
modulates
expression
of
the
sarco
(
endo
)
plasmic
reticulum
Ca
(
2
+
)
-
ATPase
isoform
2
a
encoded
by
Atp
2
a
2
and
Tbx
5
haploinsufficiency
in
ventricular
myocytes
results
in
impaired
Ca
(
2
+
)
uptake
dynamics
and
Ca
(
2
+
)
transient
prolongation
.
We
also
demonstrate
that
Tbx
5
can
activate
the
Atp
2
a
2
promoter
.
Furthermore
,
we
find
that
patients
with
HOS
have
significant
diastolic
filling
abnormalities
.
These
results
reveal
a
direct
genetic
pathway
that
regulates
cardiac
diastolic
function
,
implying
that
patients
with
structural
CHDs
may
have
clinically
important
underlying
anomalies
in
heart
function
that
merit
treatment
.
Diseases
Validation
Diseases presenting
"direct genetic pathway"
symptom
holt-oram syndrome
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