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Mammalian TBX1 preferentially binds and regulates downstream targets via a tandem T-site repeat.
[22q11.2 deletion syndrome]
Haploinsufficiency
or
mutation
of
TBX
1
is
largely
responsible
for
the
etiology
of
physical
malformations
in
individuals
with
velo-cardio-
facial
/
DiGeorge
syndrome
(
VCFS
/
DGS
/
22
q
11
.
2
deletion
syndrome
)
.
TBX
1
encodes
a
transcription
factor
protein
that
contains
an
evolutionarily
conserved
DNA
binding
domain
termed
the
T
-
box
that
is
shared
with
other
family
members
.
All
T
-
box
proteins
,
examined
so
far
,
bind
to
similar
but
not
identical
consensus
DNA
sequences
,
indicating
that
they
have
specific
binding
preferences
.
To
identify
the
TBX
1
specific
consensus
sequence
,
Systematic
Evolution
of
Ligands
by
Exponential
Enrichment
(
SELEX
)
was
performed
.
In
contrast
to
other
TBX
family
members
recognizing
palindrome
sequences
,
we
found
that
TBX
1
preferentially
binds
to
a
tandem
repeat
of
5
'
-
AGGTGTGAAGGTGTGA-
3
'
.
We
also
identified
a
second
consensus
sequence
comprised
of
a
tandem
repeat
with
a
degenerated
downstream
site
.
We
show
that
three
known
human
disease-causing
TBX
1
missense
mutations
(
F
148
Y
,
H
194
Q
and
G
310
S
)
do
not
alter
nuclear
localization
,
or
disrupt
binding
to
the
tandem
repeat
consensus
sequences
,
but
they
reduce
transcriptional
activity
in
cell
culture
reporter
assays
.
To
identify
Tbx
1
-
downstream
genes
,
we
performed
an
in
silico
genome
wide
analysis
of
potential
cis-acting
elements
in
DNA
and
found
strong
enrichment
of
genes
required
for
developmental
processes
and
transcriptional
regulation
.
We
found
that
TBX
1
binds
to
19
different
loci
in
vitro
,
which
may
correspond
to
putative
cis-acting
binding
sites
.
In
situ
hybridization
coupled
with
luciferase
gene
reporter
assays
on
three
gene
loci
,
Fgf
8
,
Bmper
,
Otog-
MyoD
,
show
that
these
motifs
are
directly
regulated
by
TBX
1
in
vitro
.
Collectively
,
the
present
studies
establish
new
insights
into
molecular
aspects
of
TBX
1
binding
to
DNA
.
This
work
lays
the
groundwork
for
future
in
vivo
studies
,
including
chromatin
immunoprecipitation
followed
by
next
generation
sequencing
(
ChIP-Seq
)
to
further
elucidate
the
molecular
pathogenesis
of
VCFS
/
DGS
.
Diseases
Validation
Diseases presenting
"wide analysis"
symptom
22q11.2 deletion syndrome
aniridia
cholangiocarcinoma
kabuki syndrome
proteus syndrome
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