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Identification of three distinct peroxisomal protein import defects in patients with peroxisome biogenesis disorders.
[neonatal adrenoleukodystrophy]
Zellweger
syndrome
,
neonatal
adrenoleukodystrophy
,
infantile
Refsum
's
disease
,
and
classical
rhizomelic
chondrodysplasia
punctata
are
lethal
genetic
disorders
caused
by
defects
in
peroxisome
biogenesis
.
We
report
here
a
characterization
of
the
peroxisomal
matrix
protein
import
capabilities
of
fibroblasts
from
62
of
these
peroxisome
biogenesis
disorder
patients
representing
all
ten
known
complementation
groups
.
Using
an
immunofluorescence
microscopy
assay
,
we
identified
three
distinct
peroxisomal
protein
import
defects
among
these
patients
.
Type
-
1
cells
have
a
specific
inability
to
import
proteins
containing
the
PTS
1
peroxisomal
targeting
signal
,
type
-
2
cells
have
a
specific
defect
in
import
of
proteins
containing
the
PTS
2
signal
,
and
type
-
3
cells
exhibit
a
loss
of
,
or
reduction
in
,
the
import
of
both
PTS
1
and
PTS
2
proteins
.
Considering
that
the
common
cellular
phenotype
of
Zellweger
syndrome
,
neonatal
adrenoleukodystrophy
and
infantile
Refsum
's
disease
has
been
proposed
to
be
a
complete
defect
in
peroxisomal
matrix
protein
import
,
the
observation
that
85
%
(
40
/
47
)
of
the
type
-
3
cell
lines
imported
a
low
but
detectable
amount
of
both
PTS
1
and
PTS
2
proteins
was
surprising
.
Furthermore
,
different
cell
lines
with
the
type
-
3
defect
exhibited
a
broad
spectrum
of
different
phenotypes
;
some
showed
a
complete
absence
of
matrix
protein
import
while
others
contained
50
-
100
matrix
protein-containing
peroxisomes
per
cell
.
We
also
noted
certain
relationships
between
the
import
phenotypes
and
clinical
diagnoses
:
both
type
-
1
cell
lines
were
from
neonatal
adrenoleukodystrophy
patients
,
all
13
type
-
2
cell
lines
were
from
classical
rhizomelic
chondrodysplasia
punctata
patients
,
and
the
type
-
3
import
defect
was
found
in
the
vast
majority
of
Zellweger
syndrome
(
22
/
22
)
,
neonatal
adrenoleukodytrophy
(
17
/
19
)
,
and
infantile
Refsum
's
disease
(
7
/
7
)
patients
.
Our
finding
that
all
type
-
1
cell
lines
were
from
the
second
complementation
group
(
CG
2
)
,
all
13
type
-
2
cell
lines
were
from
CG
11
,
and
that
cells
from
the
eight
remaining
complementation
groups
only
exhibit
the
type
-
3
defect
indicates
that
mutations
in
particular
genes
give
rise
to
the
different
types
of
peroxisomal
protein
import
defects
.
This
hypothesis
is
further
supported
by
correlations
between
certain
complementation
groups
and
particular
type
-
3
subphenotypes
:
all
patient
cell
lines
belonging
to
CG
3
and
CG
10
showed
a
complete
absence
of
peroxisomal
matrix
protein
import
while
those
from
CG
6
,
CG
7
,
and
CG
8
imported
some
peroxisomal
matrix
proteins
.
However
,
the
fact
that
cell
lines
from
within
particular
complementation
groups
(
CG
1
,
CG
4
)
could
have
different
matrix
protein
import
characteristics
suggests
that
allelic
heterogeneity
also
plays
an
important
role
in
generating
different
import
phenotypes
in
certain
patients
.
(
ABSTRACT
TRUNCATED
AT
400
WORDS
)
Diseases
Validation
Diseases presenting
"defects in peroxisome biogenesis"
symptom
neonatal adrenoleukodystrophy
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