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A phenylalanine hydroxylase amino acid polymorphism with implications for molecular diagnostics.
[classical phenylketonuria]
Mutations
in
the
gene
encoding
phenylalanine
hydroxylase
(
PAH
,
EC
1
.
14
.
16
.
1
)
are
associated
with
various
degrees
of
hyperphenylalaninemia
,
including
classical
phenylketonuria
(
PKU
)
.
We
examined
the
PAH
gene
in
a
Brazilian
PKU
family
of
African
origin
and
identified
three
missense
variants
,
R
252
W
(
c
.
754
C
-
-
>
T
)
,
K
274
E
(
c
.
820
A
-
-
>
G
)
,
and
I
318
T
(
c
.
953
T
-
-
>
C
)
,
the
two
latter
of
which
were
transmitted
in
cis
.
Expression
analyses
in
two
different
in
vitro
systems
showed
that
I
318
T
is
associated
with
profoundly
decreased
enzyme
activity
,
whereas
the
enzyme
activity
of
K
274
E
is
indistinguishable
from
that
of
the
wild-
type
protein
.
Detailed
kinetic
analyses
of
PAH
expressed
in
E
.
coli
showed
that
the
K
274
E
mutant
protein
has
kinetic
properties
similar
to
that
of
the
wild-
type
protein
.
Population
studies
have
suggested
that
the
K
274
E
variant
occurs
on
approximately
4
%
of
African-
American
PAH
alleles
,
whereas
the
neonatal
screening
incidence
of
PKU
among
African
Americans
is
only
1
:
100
,
000
.
This
is
to
our
knowledge
the
first
demonstration
of
a
PAH
missense
variant
with
no
apparent
association
to
PAH
deficiency
.
Awareness
of
this
common
variant
may
be
helpful
to
laboratories
that
perform
molecular
diagnosis
of
PAH
deficiency
in
populations
of
African
origin
.
Diseases
Validation
Diseases presenting
"first demonstration"
symptom
alexander disease
classical phenylketonuria
systemic capillary leak syndrome
werner syndrome
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