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Novel mutations in the PEX2 gene of four unrelated 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
.
Common
to
PBDs
are
liver
disease
,
variable
neurodevelopmental
delay
,
retinopathy
and
perceptive
deafness
.
PBD
patients
belonging
to
complementation
group
10
(
CG
10
)
have
mutations
in
the
PEX
2
gene
(
PXMP
3
)
,
which
codes
for
a
protein
(
PEX
2
)
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
four
PBD
patients
belonging
to
CG
10
.
Sequence
analysis
of
their
PEX
2
genes
revealed
4
different
mutations
,
3
of
which
have
not
been
reported
before
.
Two
of
the
patients
had
homozygous
mutations
leading
to
truncated
proteins
lacking
both
transmembrane
domains
and
the
zinc-binding
domain
.
These
mutations
correlated
well
with
their
severe
phenotypes
.
The
third
patient
had
a
homozygous
mutation
leading
to
the
absence
of
the
zinc-binding
domain
(
W
223
X
)
and
the
fourth
patient
had
a
homozygous
mutation
leading
to
the
change
of
the
second
cysteine
residue
of
the
zinc-binding
domain
(
C
2
47
R
)
.
Surprisingly
,
the
patient
lacking
the
domain
had
a
mild
phenotype
,
whereas
the
C
2
47
R
patient
had
a
severe
phenotype
.
This
might
be
due
to
an
increased
instability
of
PEX
2
due
to
the
R
for
C
substitution
or
to
a
dominant
negative
effect
on
interacting
proteins
.
Diseases
Validation
Diseases presenting
"truncated proteins lacking both transmembrane domains"
symptom
neonatal adrenoleukodystrophy
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