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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
"broad spectrum"
symptom
adrenomyeloneuropathy
cushing syndrome
cystinuria
dentinogenesis imperfecta
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
focal myositis
hereditary cerebral hemorrhage with amyloidosis
hodgkin lymphoma, classical
kabuki syndrome
kallmann syndrome
krabbe disease
neonatal adrenoleukodystrophy
omenn syndrome
pendred syndrome
pleomorphic liposarcoma
triple a syndrome
waldenström macroglobulinemia
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