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Biochemical analyses are instrumental in identifying the impact of mutations on holo and/or apo-forms and on the region(s) of alanine:glyoxylate aminotransferase variants associated with primary hyperoxaluria type I.
[primary hyperoxaluria type 1]
Primary
Hyperoxaluria
Type
I
(
PH
1
)
is
a
disorder
of
glyoxylate
metabolism
caused
by
mutations
in
the
human
AGXT
gene
encoding
liver
peroxisomal
alanine
:
glyoxylate
aminotransferase
(
AGT
)
,
a
pyridoxal
5
'
-
phosphate
(
PLP
)
dependent
enzyme
.
Previous
investigations
highlighted
that
,
although
PH
1
is
characterized
by
a
significant
variability
in
terms
of
enzymatic
phenotype
,
the
majority
of
the
pathogenic
variants
are
believed
to
share
both
structural
and
functional
defects
,
as
mainly
revealed
by
data
on
AGT
activity
and
expression
level
in
crude
cellular
extracts
.
However
,
the
knowledge
of
the
defects
of
the
AGT
variants
at
a
protein
level
is
still
poor
.
We
therefore
performed
a
side-
by
-side
comparison
between
normal
AGT
and
nine
purified
recombinant
pathogenic
variants
in
terms
of
catalytic
activity
,
coenzyme
binding
mode
and
affinity
,
spectroscopic
features
,
oligomerization
,
and
thermal
stability
of
both
the
holo-
and
apo-forms
.
Notably
,
we
chose
four
variants
in
which
the
mutated
residues
are
located
in
the
large
domain
of
AGT
either
within
the
active
site
and
interacting
with
the
coenzyme
or
in
its
proximity
,
and
five
variants
in
which
the
mutated
residues
are
distant
from
the
active
site
either
in
the
large
or
in
the
small
domain
.
Overall
,
this
integrated
analysis
of
enzymatic
activity
,
spectroscopic
and
stability
information
is
used
to
(
i
)
reassess
previous
data
obtained
with
crude
cellular
extracts
,
(
ii
)
establish
which
form
(
s
)
(
i
.
e
.
holoenzyme
and
/
or
apoenzyme
)
and
region
(
s
)
(
i
.
e
.
active
site
microenvironment
,
large
and
/
or
small
domain
)
of
the
protein
are
affected
by
each
mutation
,
and
(
iii
)
suggest
the
possible
therapeutic
approach
for
patients
bearing
the
examined
mutations
.
Diseases
Validation
Diseases presenting
"hyperoxaluria"
symptom
cystinuria
neonatal adrenoleukodystrophy
primary hyperoxaluria type 1
This symptom has already been validated