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Defective lipid remodeling of GPI anchors in peroxisomal disorders, Zellweger syndrome, and rhizomelic chondrodysplasia punctata.
[zellweger syndrome]
Many
cell
surface
proteins
in
mammalian
cells
are
anchored
to
the
plasma
membrane
via
glycosylphosphatidylinositol
(
GPI
)
.
The
predominant
form
of
mammalian
GPI
contains
1
-
alkyl-
2
-
acyl
phosphatidylinositol
(
PI
)
,
which
is
generated
by
lipid
remodeling
from
diacyl
PI
.
The
conversion
of
diacyl
PI
to
1
-
alkyl-
2
-
acyl
PI
occurs
in
the
ER
at
the
third
intermediate
in
the
GPI
biosynthetic
pathway
.
This
lipid
remodeling
requires
the
alkyl-phospholipid
biosynthetic
pathway
in
peroxisome
.
Indeed
,
cells
defective
in
dihydroxyacetone
phosphate
acyltransferase
(
DHAP-AT
)
or
alkyl-
DHAP
synthase
express
only
the
diacyl
form
of
GPI
-anchored
proteins
.
A
defect
in
the
alkyl-phospholipid
biosynthetic
pathway
causes
a
peroxisomal
disorder
,
rhizomelic
chondrodysplasia
punctata
(
RCDP
)
,
and
defective
biogenesis
of
peroxisomes
causes
Zellweger
syndrome
,
both
of
which
are
lethal
genetic
diseases
with
multiple
clinical
phenotypes
such
as
psychomotor
defects
,
mental
retardation
,
and
skeletal
abnormalities
.
Here
,
we
report
that
GPI
lipid
remodeling
is
defective
in
cells
from
patients
with
Zellweger
syndrome
having
mutations
in
the
peroxisomal
biogenesis
factors
PEX
5
,
PEX
16
,
and
PEX
19
and
in
cells
from
patients
with
RCDP
types
1
,
2
,
and
3
caused
by
mutations
in
PEX
7
,
DHAP-AT
,
and
alkyl-
DHAP
synthase
,
respectively
.
Absence
of
the
1
-
alkyl-
2
-
acyl
form
of
GPI
-anchored
proteins
might
account
for
some
of
the
complex
phenotypes
of
these
two
major
peroxisomal
disorders
.
Diseases
Validation
Diseases presenting
"mental retardation"
symptom
achondroplasia
alexander disease
alpha-thalassemia
aniridia
aromatase deficiency
canavan disease
classical phenylketonuria
coats disease
cohen syndrome
cowden syndrome
cystinuria
dentin dysplasia
familial hypocalciuric hypercalcemia
homocystinuria without methylmalonic aciduria
hydrocephalus with stenosis of the aqueduct of sylvius
kabuki syndrome
kallmann syndrome
lamellar ichthyosis
lymphangioleiomyomatosis
monosomy 21
phenylketonuria
primary hyperoxaluria type 1
proteus syndrome
pyruvate dehydrogenase deficiency
sneddon syndrome
triple a syndrome
wolf-hirschhorn syndrome
zellweger syndrome
This symptom has already been validated