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Functional analysis of novel TBX5 T-box mutations associated with Holt-Oram syndrome.
[holt-oram syndrome]
Holt-
Oram
syndrome
(
HOS
)
is
a
heart
/
hand
syndrome
clinically
characterized
by
upper
limb
and
cardiac
malformations
.
Mutations
in
T
-
box
transcription
factor
5
(
TBX
5
)
underlie
this
syndrome
,
the
majority
of
which
lead
to
premature
stops
.
In
this
study
,
we
present
our
functional
analyses
of
five
(
novel
)
missense
TBX
5
mutations
identified
in
HOS
patients
,
most
of
whom
presented
with
severe
cardiac
malformations
.
Functional
characterization
of
mutant
proteins
shows
a
dramatic
loss
of
DNA-binding
capacity
,
as
well
as
diminished
binding
to
known
cardiac
interaction
partners
NKX
2
-
5
and
GATA
4
.
The
disturbance
of
these
interactions
leads
to
a
loss
of
function
,
as
measured
by
the
reduced
activation
of
Nppa
and
FGF
10
in
rat
heart
derived
cells
,
although
with
variable
severity
.
Two
out
of
the
five
mutations
are
peculiar
:
one
,
p
.
H
220
del
,
is
associated
with
additional
extra
-
cardiac
defects
,
perhaps
by
interfering
with
other
T
-
box
dependant
pathways
,
and
another
,
p
.
I
106
V
,
leads
to
limb
defects
only
,
which
is
supported
by
its
normal
interaction
with
cardiac
-
specific
interaction
partners
.
Overall
,
our
data
are
consistent
with
the
hypothesis
that
these
novel
missense
mutations
in
TBX
5
lead
to
functional
haploinsufficiency
and
result
in
a
reduced
transcriptional
activation
of
target
genes
,
which
is
likely
central
to
the
pathogenesis
of
HOS
.
Diseases
Validation
Diseases presenting
"known cardiac interaction partners"
symptom
holt-oram syndrome
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