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Modeling the effect of 3 missense AGXT mutations on dimerization of the AGT enzyme in primary hyperoxaluria type 1.
[primary hyperoxaluria type 1]
Mutations
of
the
AGXT
gene
encoding
the
alanine
:
glyoxylate
aminotransferase
liver
enzyme
(
AGT
)
cause
primary
hyperoxaluria
type
1
(
PH
1
)
.
Here
we
report
a
molecular
modeling
study
of
selected
missense
AGXT
mutations
:
the
common
Gly
170
Arg
and
the
recently
described
Gly
47
A
rg
and
Ser
81
Leu
variants
,
predicted
to
be
pathogenic
using
standard
criteria
.
Taking
advantage
of
the
refined
3
D
structure
of
AGT
,
we
computed
the
dimerization
energy
of
the
wild-
type
and
mutated
proteins
.
M
olecular
modeling
predicted
that
Gly
47
A
rg
affects
dimerization
with
a
similar
effect
to
that
shown
previously
for
Gly
170
A
rg
through
classical
biochemical
approaches
.
In
contrast
,
no
effect
on
dimerization
was
predicted
for
Ser
81
Leu
.
Therefore
,
this
probably
demonstrates
pathogenic
properties
via
a
different
mechanism
,
similar
to
that
described
for
the
adjacent
Gly
82
G
lu
mutation
that
affects
pyridoxine
binding
.
This
study
shows
that
the
molecular
modeling
approach
can
contribute
to
evaluating
the
pathogenicity
of
some
missense
variants
that
affect
dimerization
.
However
,
in
silico
studies--aimed
to
assess
the
relationship
between
structural
change
and
biological
effects--require
the
integrated
use
of
more
than
1
tool
.
Diseases
Validation
Diseases presenting
"hyperoxaluria"
symptom
cystinuria
neonatal adrenoleukodystrophy
primary hyperoxaluria type 1
This symptom has already been validated