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Novel mutations in the PEX12 gene of patients with a peroxisome biogenesis disorder.
[neonatal adrenoleukodystrophy]
The
peroxisome
biogenesis
disorders
(
PBDs
)
form
a
genetically
and
clinically
heterogeneous
group
of
disorders
due
to
defects
in
at
least
11
distinct
genes
.
The
prototype
of
this
group
of
disorders
is
Zellweger
syndrome
(
ZS
)
,
with
neonatal
adrenoleukodystrophy
(
NALD
)
and
infantile
Refsum
disease
(
IRD
)
as
milder
variants
.
Liver
disease
,
variable
neurodevelopmental
delay
,
retinopathy
and
perceptive
deafness
are
common
to
PBDs
.
PBD
patients
belonging
to
complementation
group
3
(
CG
3
)
have
mutations
in
the
PEX
12
gene
,
which
codes
for
a
protein
(
PEX
12
)
that
contains
two
transmembrane
domains
,
and
a
zinc-binding
domain
considered
to
be
important
for
its
interaction
with
other
proteins
of
the
peroxisomal
protein
import
machinery
.
We
report
on
the
identification
of
five
PBD
patients
belonging
to
CG
3
.
Sequence
analysis
of
their
PEX
12
genes
revealed
five
different
mutations
,
four
of
which
have
not
been
reported
before
.
Four
of
the
patients
have
mutations
that
disrupt
the
translation
frame
and
/
or
create
an
early
termination
codon
in
the
PEX
12
open
reading
frame
predicted
to
result
in
truncated
protein
products
,
lacking
at
least
the
COOH-terminal
zinc-binding
domain
.
All
these
patients
display
the
more
severe
phenotypes
(
ZS
or
NALD
)
.
The
fifth
patient
expresses
two
PEX
12
alleles
capable
of
encoding
a
protein
that
does
contain
the
zinc-binding
domain
and
displayed
a
milder
phenotype
(
IRD
)
.
The
three
biochemical
markers
measured
in
fibroblasts
(
DHAPAT
activity
,
C
2
6
:
0
beta
-oxidation
and
pristanic
acid
beta
-oxidation
)
also
correlated
with
the
genotypes
.
Thus
,
the
genotypes
of
our
CG
3
patients
show
a
good
correlation
with
the
biochemical
and
clinical
phenotype
of
the
patients
.