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Tbx5-dependent rheostatic control of cardiac gene expression and morphogenesis.
[holt-oram syndrome]
Dominant
mutations
in
the
T
-
box
transcription
factor
gene
TBX
5
cause
Holt-
Oram
syndrome
(
HOS
)
,
an
inherited
human
disease
characterized
by
upper
limb
malformations
and
congenital
heart
defects
(
CHDs
)
of
variable
severity
.
We
hypothesize
that
minor
alterations
in
the
dosage
of
Tbx
5
directly
influences
severity
of
CHDs
.
Using
a
mouse
allelic
series
,
we
show
a
sensitive
inverse
correlation
between
Tbx
5
dosage
and
abnormal
cardiac
morphogenesis
and
gene
expression
.
The
CHDs
found
in
mice
harbouring
a
hypomorphic
allele
of
Tbx
5
(
Tbx
5
(
lox
/
+
)
mice
)
are
less
pronounced
than
those
found
in
Tbx
5
haploinsufficient
mice
(
Tbx
5
(
del
/
+
)
)
,
and
homozygous
hypomorphic
(
Tbx
5
(
lox
/
lox
)
)
embryos
have
noticeably
more
advanced
cardiac
development
than
Tbx
5
null
(
Tbx
5
(
del
/
del
)
)
embryos
.
Examination
of
target
gene
expression
across
the
allelic
series
uncovers
very
fine
sensitivity
across
the
range
of
Tbx
5
dosages
,
in
which
some
genes
respond
dramatically
differently
to
only
15
%
differences
in
Tbx
5
mRNA
levels
.
This
analysis
was
expanded
to
a
genome-
wide
level
,
which
uncovered
a
Tbx
5
dosage-sensitive
genetic
program
involving
a
network
of
cardiac
transcription
factors
,
developmentally
important
cell-cell
signaling
molecules
,
and
ion
channel
proteins
.
These
results
indicate
an
exquisite
sensitivity
of
the
developing
heart
to
Tbx
5
dosage
and
provide
significant
insight
into
the
transcriptional
and
cellular
mechanisms
that
are
disrupted
in
CHDs
.