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The T-Box transcription factor Tbx5 is required for the patterning and maturation of the murine cardiac conduction system.
[holt-oram syndrome]
We
report
a
critical
role
for
the
T
-
box
transcription
factor
Tbx
5
in
development
and
maturation
of
the
cardiac
conduction
system
.
We
find
that
Tbx
5
is
expressed
throughout
the
central
conduction
system
,
including
the
atrioventricular
bundle
and
bundle
branch
conduction
system
.
Tbx
5
haploinsufficiency
in
mice
(
Tbx
5
(
del
/
+
)
)
,
a
model
of
human
Holt-
Oram
syndrome
,
caused
distinct
morphological
and
functional
defects
in
the
atrioventricular
and
bundle
branch
conduction
systems
.
In
the
atrioventricular
canal
,
Tbx
5
haploinsufficiency
caused
a
maturation
failure
of
conduction
system
morphology
and
function
.
Electrophysiologic
testing
of
Tbx
5
(
del
/
+
)
mice
suggested
a
specific
atrioventricular
node
maturation
failure
.
In
the
ventricular
conduction
system
,
Tbx
5
haploinsufficiency
caused
patterning
defects
of
both
the
left
and
right
ventricular
bundle
branches
,
including
absence
or
severe
abnormalities
of
the
right
bundle
branch
.
Absence
of
the
right
bundle
branch
correlated
with
right
-
bundle-branch
block
by
ECG
.
Deficiencies
in
the
gap
junction
protein
gene
connexin
40
(
Cx
40
)
,
a
downstream
target
of
Tbx
5
,
did
not
account
for
morphologic
conduction
system
defects
in
Tbx
5
(
del
/
+
)
mice
.
We
conclude
that
Tbx
5
is
required
for
Cx
40
-
independent
patterning
of
the
cardiac
conduction
system
,
and
suggest
that
the
electrophysiologic
defects
in
Holt-
Oram
syndrome
reflect
a
developmental
abnormality
of
the
conduction
system
.