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Expression of human phenylalanine hydroxylase activity in T lymphocytes of classical phenylketonuria children by retroviral-mediated gene transfer.
[classical phenylketonuria]
Classical
phenylketonuria
(
PKU
)
is
a
metabolic
disorder
caused
by
mutations
in
the
phenylalanine
hydroxylase
(
PAH
)
gene
.
At
present
,
T
lymphocyte-directed
gene
therapy
is
the
only
means
for
which
a
safety
record
has
been
established
.
Thus
,
we
investigated
the
applicability
of
this
strategy
to
PKU
gene
therapy
.
We
first
looked
for
tetrahydrobiopterin
(
BH
4
)
and
dihydropteridine
reductase
(
DHPR
)
activity
,
which
are
required
for
the
phenylalanine
hydroxylation
reaction
and
BH
4
regeneration
,
respectively
,
in
T
cells
isolated
from
PKU
children
.
We
found
that
T
cells
contained
a
small
amount
of
biopterin
,
but
significant
DHPR
activity
,
and
that
the
intracellular
biopterin
content
could
be
increased
by
exogenous
BH
4
supplementation
.
Moreover
,
PKU
T
cells
were
capable
of
taking
up
phenylalanine
efficiently
and
effluxing
acquired
tyrosine
.
Finally
,
a
recombinant
retrovirus
containing
the
human
PAH
cDNA
was
constructed
and
used
to
transduce
isolated
PKU
T
cells
.
Viral-transduced
T
cells
produced
high
levels
of
PAH
activity
as
compared
to
control
mock-infected
T
cells
.
These
results
indicate
that
T
lymphocytes
express
all
that
is
required
for
synthesizing
/
replenishing
constituents
of
the
phenylalanine
hydroxylation
reaction
and
expressing
transduced
phenylalanine
hydroxylase
cDNA
.
Diseases
Validation
Diseases presenting
"small amount"
symptom
classical phenylketonuria
dystrophic epidermolysis bullosa
junctional epidermolysis bullosa
pleomorphic liposarcoma
pyruvate dehydrogenase deficiency
scrub typhus
systemic capillary leak syndrome
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