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Connexin 40, a target of transcription factor Tbx5, patterns wrist, digits, and sternum.
[holt-oram syndrome]
Haploinsufficiency
of
T
-
box
transcription
factor
5
(
TBX
5
)
causes
human
Holt-
Oram
syndrome
(
HOS
)
,
a
developmental
disorder
characterized
by
skeletal
and
heart
malformations
.
Mice
carrying
a
Tbx
5
null
allele
(
Tbx
5
(
+
/
Delta
)
)
have
malformations
in
digits
,
wrists
,
and
sternum
joints
,
regions
where
Tbx
5
is
expressed
.
We
demonstrate
that
mice
deficient
in
connexin
40
(
Cx
40
)
,
a
Tbx
5
-
regulated
gap
junction
component
,
shared
axial
and
appendicular
skeletal
malformations
with
Tbx
5
(
+
/
Delta
)
mice
.
Although
no
role
in
skeleton
patterning
has
been
described
for
gap
junctions
,
we
demonstrate
here
that
Cx
40
is
involved
in
formation
of
specific
joints
,
as
well
as
bone
shape
.
Even
a
50
%
reduction
in
either
Tbx
5
or
Cx
40
produces
bone
abnormalities
,
demonstrating
their
crucial
control
over
skeletal
development
.
Further
,
we
demonstrate
that
Tbx
5
exerts
in
part
its
key
regulatory
role
in
bone
growth
and
maturation
by
controlling
via
Cx
40
the
expression
of
Sox
9
(
a
transcription
factor
essential
for
chondrogenesis
and
skeleton
growth
)
.
Our
study
strongly
suggests
that
Cx
40
deficiency
accounts
for
many
skeletal
malformations
in
HOS
and
that
Tbx
5
regulation
of
Cx
40
plays
a
critical
role
in
the
exquisite
developmental
patterning
of
the
forelimbs
and
sternum
.
Diseases
Validation
Diseases presenting
"deficiency accounts"
symptom
holt-oram syndrome
severe combined immunodeficiency
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