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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
"deficient patients"
symptom
aniridia
classical phenylketonuria
congenital toxoplasmosis
erythropoietic protoporphyria
homocystinuria without methylmalonic aciduria
neonatal adrenoleukodystrophy
omenn syndrome
phenylketonuria
pyruvate dehydrogenase deficiency
severe combined immunodeficiency
zellweger syndrome
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