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A novel mutation of human liver alanine:glyoxylate aminotransferase causes primary hyperoxaluria type 1: immunohistochemical quantification and subcellular distribution.
[primary hyperoxaluria type 1]
A
novel
alanine
:
glyoxylate
aminotransferase
(
AGT
)
mutation
involved
in
primary
hyperoxaluria
type
1
(
PH
1
)
was
studied
in
Japanese
patients
.
Two
mutations
in
exon
7
,
c
.
751
T
>
A
and
c
.
752
G
>
A
,
lead
to
a
W
251
K
amino
acid
substitution
.
Proband
1
(
patient
1
)
was
homozygous
for
the
W
251
K
mutation
allele
(
DDBJ
Accession
No
.
AB
292648
)
,
and
AGT
-
specific
activity
in
the
patient
's
liver
was
very
low
.
To
reveal
the
cause
of
the
low
enzymatic
activity
,
the
intracellular
localization
of
AGT
(
W
251
K
)
was
studied
using
immunohistochemistry
and
immunoelectron
microscopy
.
The
latter
analysis
showed
that
patient
2
had
only
one
-
fifth
of
the
normal
AGT
expression
per
catalase
,
suggesting
impairment
of
AGT
(
W
251
K
)
dependent
transport
into
peroxisomes
.
Peroxisomal
transport
of
human
AGT
is
believed
to
be
dependent
on
the
presence
of
the
type
1
peroxisomal
targeting
sequence
.
The
C-
terminal
tripeptide
of
AGT
,
KKL
is
necessary
for
peroxisomal
targeting
.
In
cultured
cells
,
EGFP-
AGT
(
W
251
K
)
localized
both
in
the
peroxisome
and
cytosol
.
These
results
were
consistent
with
the
data
obtained
from
liver
analysis
of
patient
2
.
The
subcellular
distribution
of
AGT
(
W
251
K
)
and
the
results
from
a
random
mutagenesis
study
suggest
that
KKL
is
necessary
for
peroxisomal
targeting
of
human
AGT
,
but
additional
signal
other
than
KKL
may
be
necessary
.