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A random Abstract
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Functional analysis of the novel TBX5 c.1333delC mutation resulting in an extended TBX5 protein.
[holt-oram syndrome]
Autosomal
dominant
Holt-
Oram
syndrome
(
HOS
)
is
caused
by
mutations
in
the
TBX
5
gene
and
is
characterized
by
congenital
heart
and
preaxial
radial
ray
upper
limb
defects
.
Most
of
the
TBX
5
mutations
found
in
patients
with
HOS
cause
premature
truncation
of
the
primary
TBX
5
transcript
.
TBX
5
missense
mutations
alter
the
three
-dimensional
structure
of
the
protein
and
result
in
failed
nuclear
localization
or
reduced
binding
to
target
DNA
.
In
this
study
we
present
our
functional
analyses
of
the
novel
and
unusual
c
.
1333
delC
mutation
found
in
a
patient
with
classical
HOS
.
The
functional
impact
of
this
novel
mutation
was
assessed
by
investigating
the
intracellular
localization
of
the
resulting
TBX
5
protein
and
its
ability
to
activate
the
expression
of
its
downstream
target
ANF
.
T
he
deletion
of
the
cytosine
is
the
first
TBX
5
frameshift
mutation
predicted
to
result
in
an
elongated
TBX
5
protein
with
74
miscoding
amino
acids
and
62
supernumerary
C-
terminal
amino
acids
.
The
c
.
1333
delC
mutation
affects
neither
the
nuclear
localization
,
nor
its
colocalization
with
SALL
4
,
but
severely
affects
the
activation
of
the
ANF
promoter
.
T
he
mutation
c
.
1333
delC
does
not
locate
within
functional
domains
,
but
impairs
the
activation
of
the
downstream
target
.
This
suggests
that
misfolding
of
the
protein
prevents
its
biological
function
.