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A mosaic activating mutation in AKT1 associated with the Proteus syndrome.
[proteus syndrome]
The
Proteus
syndrome
is
characterized
by
the
overgrowth
of
skin
,
connective
tissue
,
brain
,
and
other
tissues
.
It
has
been
hypothesized
that
the
syndrome
is
caused
by
somatic
mosaicism
for
a
mutation
that
is
lethal
in
the
nonmosaic
state
.
We
performed
exome
sequencing
of
DNA
from
biopsy
samples
obtained
from
patients
with
the
Proteus
syndrome
and
compared
the
resultant
DNA
sequences
with
those
of
unaffected
tissues
obtained
from
the
same
patients
.
We
confirmed
and
extended
an
observed
association
,
using
a
custom
restriction-enzyme
assay
to
analyze
the
DNA
in
158
samples
from
29
patients
with
the
Proteus
syndrome
.
We
then
assayed
activation
of
the
AKT
protein
in
affected
tissues
,
using
phosphorylation-
specific
antibodies
on
Western
blots
.
Of
29
patients
with
the
Proteus
syndrome
,
26
had
a
somatic
activating
mutation
(
c
.
49
G
→
A
,
p
.
Glu
17
Lys
)
in
the
oncogene
AKT
1
,
encoding
the
AKT
1
kinase
,
an
enzyme
known
to
mediate
processes
such
as
cell
proliferation
and
apoptosis
.
Tissues
and
cell
lines
from
patients
with
the
Proteus
syndrome
harbored
admixtures
of
mutant
alleles
that
ranged
from
1
%
to
approximately
50
%
.
Mutant
cell
lines
showed
greater
AKT
phosphorylation
than
did
control
cell
lines
.
A
pair
of
single
-cell
clones
that
were
established
from
the
same
starting
culture
and
differed
with
respect
to
their
mutation
status
had
different
levels
of
AKT
phosphorylation
.
T
he
Proteus
syndrome
is
caused
by
a
somatic
activating
mutation
in
AKT
1
,
proving
the
hypothesis
of
somatic
mosaicism
and
implicating
activation
of
the
PI
3
K-AKT
pathway
in
the
characteristic
clinical
findings
of
overgrowth
and
tumor
susceptibility
in
this
disorder
.
(
Funded
by
the
Intramural
Research
Program
of
the
National
Human
Genome
Research
Institute
.
)
.
Diseases
Validation
Diseases presenting
"then assayed activation of the akt protein"
symptom
proteus syndrome
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