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Identification of the molecular defect in patients with peroxisomal mosaicism using a novel method involving culturing of cells at 40 degrees C: implications for other inborn errors of metabolism.
[neonatal adrenoleukodystrophy]
The
peroxisome
biogenesis
disorders
(
PBDs
)
,
which
comprise
Zellweger
syndrome
(
ZS
)
,
neonatal
adrenoleukodystrophy
,
and
infantile
Refsum
disease
(
IRD
)
,
represent
a
spectrum
of
disease
severity
,
with
ZS
being
the
most
severe
,
and
IRD
the
least
severe
disorder
.
The
PBDs
are
caused
by
mutations
in
one
of
the
at
least
12
different
PEX
genes
encoding
proteins
involved
in
the
biogenesis
of
peroxisomes
.
We
report
the
biochemical
characteristics
and
molecular
basis
of
a
subset
of
atypical
PBD
patients
.
These
patients
were
characterized
by
abnormal
peroxisomal
plasma
metabolites
,
but
otherwise
normal
to
very
mildly
abnormal
peroxisomal
parameters
in
cultured
skin
fibroblasts
,
including
a
mosaic
catalase
immunofluorescence
pattern
in
fibroblasts
.
Since
this
latter
feature
made
standard
complementation
analysis
impossible
,
we
developed
a
novel
complementation
technique
in
which
fibroblasts
were
cultured
at
40
degrees
C
,
which
exacerbates
the
defect
in
peroxisome
biogenesis
.
Using
this
method
,
we
were
able
to
assign
eight
patients
to
complementation
group
3
(
CG
3
)
,
followed
by
the
identification
of
a
single
homozygous
c
.
959
C
>
T
(
p
.
S
320
F
)
mutation
in
their
PEX
12
gene
.
We
also
investigated
various
peroxisomal
biochemical
parameters
in
fibroblasts
at
30
degrees
C
,
37
degrees
C
,
and
40
degrees
C
,
and
found
that
all
parameters
showed
a
temperature-dependent
behavior
.
The
principle
of
culturing
cells
at
elevated
temperatures
to
exacerbate
the
defect
in
peroxisome
biogenesis
,
and
thereby
preventing
certain
mutations
from
being
missed
,
may
well
have
a
much
wider
applicability
for
a
range
of
different
inborn
errors
of
metabolism
.
Diseases
Validation
Diseases presenting
"but otherwise normal to very mildly abnormal peroxisomal parameters in cultured skin fibroblasts"
symptom
neonatal adrenoleukodystrophy
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