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Cowden syndrome-related mutations in PTEN associate with enhanced proteasome activity.
[cowden syndrome]
Germline
mutations
in
PTEN
have
been
described
in
a
spectrum
of
syndromes
that
are
collectively
known
as
PTEN
hamartoma
tumor
syndrome
(
PHTS
)
.
In
addition
to
being
mutated
in
the
germline
in
PHTS
,
somatic
loss
-of-function
PTEN
mutations
are
seen
in
a
wide
range
of
sporadic
human
tumors
.
Here
,
we
show
evidence
of
upregulated
proteasome
activity
in
PHTS-derived
lymphoblasts
,
Pten
knock-
in
mice
and
cell
lines
expressing
missense
and
nonsense
PTEN
mutations
.
Notably
,
elevated
nuclear
proteasome
activity
occurred
in
cells
expressing
the
nuclear
mislocalized
PTEN
-K
62
R
mutant
,
whereas
elevated
cytosolic
proteasome
activity
was
observed
in
cells
expressing
the
cytosolic-predominant
mutant
PTEN
(
M
3
M
4
and
C
136
R
)
.
Treatment
with
proteasome
inhibitor
MG-
132
was
able
to
restore
both
nonsense
and
missense
mutant
PTEN
protein
levels
in
vitro
.
PHTS
patients
with
destabilizing
PTEN
mutations
and
proteasome
hyperactivity
are
more
susceptible
to
develop
neurologic
symptoms
such
as
mental
retardation
and
autism
than
mutation
-
positive
patients
with
normal
proteasome
activity
.
A
detailed
molecular
and
functional
analysis
shows
that
PTEN
mutants
most
likely
cause
proteasome
hyperactivity
via
2
different
mechanisms
,
namely
,
induction
of
proteotoxic
stress
and
loss
of
protein
phosphatase
activity
.
These
results
provide
novel
insights
into
the
cellular
functions
of
PTEN
and
reveal
molecular
mechanisms
whereby
PTEN
mutations
increase
proteasome
activity
and
lead
to
neurologic
phenotypes
.
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