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X-Linked thrombocytopenia causing mutations in WASP (L46P and A47D) impair T cell chemotaxis.
[wiskott-aldrich syndrome]
Mutation
in
the
Wiskott-
Aldrich
syndrome
Protein
(
WASP
)
causes
Wiskott-
Aldrich
syndrome
(
WAS
)
,
X-
linked
thrombocytopenia
(
XLT
)
and
X-
linked
congenital
neutropenia
(
XLN
)
.
The
majority
of
missense
mutations
causing
WAS
and
XLT
are
found
in
the
WH
1
(
WASP
Homology
)
domain
of
WASP
,
known
to
mediate
interaction
with
WIP
(
WASP
Interacting
Protein
)
and
CIB
1
(
Calcium
and
Integrin
Binding
)
.
We
analyzed
two
WASP
missense
mutants
(
L
46
P
and
A
47
D
)
causing
XLT
for
their
effects
on
T
cell
chemotaxis
.
Both
mutants
,
WASPRL
46
P
and
WASPRA
47
D
(
S
1
-
WASP
shRNA
resistant
)
expressed
well
in
JurkatWASP-KD
T
cells
(
WASP
knockdown
)
,
however
expression
of
these
two
mutants
did
not
rescue
the
chemotaxis
defect
of
JurkatWASP-KD
T
cells
towards
SDF-
1
α
.
In
addition
JurkatWASP-KD
T
cells
expressing
these
two
WASP
mutants
were
found
to
be
defective
in
T
cell
polarization
when
stimulated
with
SDF-
1
α
.
WASP
exists
in
a
closed
conformation
in
the
presence
of
WIP
,
however
both
the
mutants
(
WASPRL
46
P
and
WASPRA
47
D
)
were
found
to
be
in
an
open
conformation
as
determined
in
the
bi
-molecular
complementation
assay
.
WASP
protein
undergoes
proteolysis
upon
phosphorylation
and
this
turnover
of
WASP
is
critical
for
T
cell
migration
.
Both
the
WASP
mutants
were
found
to
be
stable
and
have
reduced
tyrosine
phosphorylation
after
stimulation
with
SDF-
1
α
.
Thus
our
data
suggest
that
missense
mutations
WASPRL
46
P
or
WASPRA
47
D
affect
the
activity
of
WASP
in
T
cell
chemotaxis
probably
by
affecting
the
turnover
of
the
protein
.
