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Phenotype-genotype relationships in PEX10-deficient peroxisome biogenesis disorder patients.
[neonatal adrenoleukodystrophy]
The
peroxisome
biogenesis
disorders
(
PBD
)
are
characterized
by
neural
,
hepatic
,
and
renal
deficiencies
,
severe
mental
retardation
,
and
are
often
lethal
.
These
disorders
are
genetically
and
phenotypically
heterogeneous
and
are
caused
by
defective
peroxisomal
protein
import
and
decreased
peroxisomal
metabolic
function
.
Mutations
in
PEX
10
have
been
identified
in
patients
from
complementation
group
7
(
CG
7
)
of
the
PBDs
and
we
report
here
an
analysis
of
the
genotypes
and
phenotypes
of
PEX
10
-
deficient
patients
.
All
four
PEX
10
-
deficient
Zellweger
Syndrome
(
ZS
)
patients
were
found
to
have
nonsense
,
frameshift
,
or
splice
site
mutations
that
remove
large
portions
of
the
PEX
10
coding
region
.
In
contrast
,
a
more
mildly
affected
PEX
10
-
deficient
neonatal
adrenoleukodystrophy
patient
expressed
a
PEX
10
allele
with
a
missense
mutation
,
H
290
Q
,
affecting
the
C-
terminal
zinc-binding
domain
of
the
PEX
10
product
.
These
results
support
the
hypothesis
that
severe
,
loss
-of-function
mutations
in
PEX
genes
cause
more
severe
clinical
phenotypes
,
whereas
mildly
affected
PBD
patients
have
PEX
gene
mutations
that
retain
residual
function
.
To
quantitate
the
effects
of
the
PEX
10
mutations
identified
here
and
elsewhere
we
employed
a
functional
complementation
assay
.
Surprisingly
,
we
observed
that
nonsense
and
frameshift
mutations
predicted
to
delete
the
C-
terminal
2
/
3
(
R
125
X
)
or
1
/
3
(
c
.
704
insA
)
of
the
protein
displayed
nearly
normal
PEX
10
activity
.
Even
more
surprising
,
we
found
that
the
unexpectedly
high
PEX
10
activity
displayed
by
these
cDNAs
could
be
eliminated
by
removing
or
mutating
segments
of
the
PEX
10
cDNA
downstream
of
the
mutations
.
Although
these
results
demonstrate
serious
flaws
in
the
PEX
10
functional
complementation
assay
,
they
do
suggest
that
the
C-
terminal
zinc-binding
domain
is
critical
for
PEX
10
function
.
Diseases
Validation
Diseases presenting
"decreased peroxisomal metabolic function"
symptom
neonatal adrenoleukodystrophy
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