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Quantitative analysis of WRN exonuclease activity by isotope dilution mass spectrometry.
[werner syndrome]
Werner
syndrome
is
a
disorder
characterized
by
a
premature
aging
phenotype
.
The
disease
is
caused
by
mutations
in
the
WRN
gene
which
encodes
a
DNA
helicase
/
exonuclease
which
is
involved
in
multiple
aspects
of
DNA
metabolism
.
Current
methods
mostly
rely
on
radiometric
techniques
to
assess
WRN
exonuclease
activity
.
Here
we
present
an
alternative
,
quantitative
approach
based
on
non-radioactive
isotope
dilution
mass
spectrometry
(
LC
-
MS
/
MS
)
.
A
oligoduplex
substrate
mimicking
the
telomeric
sequence
was
used
for
method
development
.
Released
nucleotides
,
which
correlate
with
the
degree
of
oligoduplex
degradation
,
were
dephosphorylated
,
purified
,
and
quantified
by
LC
-
MS
/
MS
.
Heavy-isotope-labeled
internal
standards
were
used
to
account
for
technical
variability
.
The
method
was
validated
in
terms
of
reproducibility
,
time-course
and
concentration-dependency
of
the
reaction
.
As
shown
in
this
study
,
the
LC
-
MS
/
MS
method
can
assess
exonuclease
activity
of
WRN
mutants
,
WRN
's
substrate
and
strand
specificity
,
and
modulatory
effects
of
WRN
interaction
partners
and
posttranslational
modifications
.
Moreover
,
it
can
be
used
to
analyze
the
selectivity
and
processivity
of
WRN
exonuclease
and
allows
the
screening
of
small
molecules
for
WRN
exonuclease
inhibitors
.
Importantly
,
this
approach
can
easily
be
adapted
to
study
nucleases
other
than
WRN
.
This
is
of
general
interest
,
because
exonucleases
are
key
players
in
DNA
metabolism
and
aging
mechanisms
.
Diseases
Validation
Diseases presenting
"small molecules"
symptom
epidermolysis bullosa simplex
erythropoietic protoporphyria
fabry disease
gm1 gangliosidosis
krabbe disease
phenylketonuria
werner syndrome
x-linked adrenoleukodystrophy
zellweger syndrome
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