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Molecular damage in Fabry disease: Characterization and prediction of alpha-galactosidase A pathological mutations.
[fabry disease]
Loss
-of-function
mutations
of
the
enzyme
alpha-galactosidase
A
(
GLA
)
causes
Fabry
disease
(
FD
)
,
that
is
a
rare
and
potentially
fatal
disease
.
Identification
of
these
pathological
mutations
by
sequencing
is
important
because
it
allows
an
early
treatment
of
the
disease
.
However
,
before
taking
any
treatment
decision
,
if
the
mutation
identified
is
unknown
,
we
first
need
to
establish
if
it
is
pathological
or
not
.
General
bioinformatic
tools
(
PolyPhen-
2
,
SIFT
,
Condel
,
etc
.
)
can
be
used
for
this
purpose
,
but
their
performance
is
still
limited
.
Here
we
present
a
new
tool
,
specifically
derived
for
the
assessment
of
GLA
mutations
.
We
first
compared
mutations
of
this
enzyme
known
to
cause
FD
with
neutral
sequence
variants
,
using
several
structure
and
sequence
properties
.
Then
,
we
used
these
properties
to
develop
a
family
of
prediction
methods
adapted
to
different
quality
requirements
.
Trained
and
tested
on
a
set
of
known
Fabry
mutations
,
our
methods
have
a
performance
(
Matthews
correlation
:
0
.
56
-
0
.
72
)
comparable
or
better
than
that
of
the
more
complex
method
,
Polyphen-
2
(
Matthews
correlation
:
0
.
61
)
,
and
better
than
those
of
SIFT
(
Matthews
correl
.
:
0
.
54
)
and
Condel
(
Matthews
correl
.
:
0
.
51
)
.
This
result
is
validated
in
an
independent
set
of
65
pathological
mutations
,
for
which
our
method
displayed
the
best
success
rate
(
91
.
0
%
,
87
.
7
%
,
and
73
.
8
%
,
for
our
method
,
PolyPhen-
2
and
SIFT
,
respectively
)
.
These
data
confirmed
that
our
specific
approach
can
effectively
contribute
to
the
identification
of
pathological
mutations
in
GLA
,
and
therefore
enhance
the
use
of
sequence
information
in
the
identification
of
undiagnosed
Fabry
patients
.
Proteins
2014
;
©
2014
Wiley
Periodicals
,
Inc
.
Diseases
Validation
Diseases presenting
"complex method"
symptom
cholangiocarcinoma
fabry disease
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