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Linking genotypes database with locus-specific database and genotype-phenotype correlation in phenylketonuria.
[phenylketonuria]
The
wide
range
of
metabolic
phenotypes
in
phenylketonuria
is
due
to
a
large
number
of
variants
causing
variable
impairment
in
phenylalanine
hydroxylase
function
.
A
total
of
834
phenylalanine
hydroxylase
gene
variants
from
the
locus-
specific
database
PAHvdb
and
genotypes
of
4181
phenylketonuria
patients
from
the
BIOPKU
database
were
characterized
using
FoldX
,
SIFT
Blink
,
Polyphen-
2
and
SNPs
3
D
algorithms
.
Obtained
data
was
correlated
with
residual
enzyme
activity
,
patients
'
phenotype
and
tetrahydrobiopterin
responsiveness
.
A
descriptive
analysis
of
both
databases
was
compiled
and
an
interactive
viewer
in
PAHvdb
database
was
implemented
for
structure
visualization
of
missense
variants
.
We
found
a
quantitative
relationship
between
phenylalanine
hydroxylase
protein
stability
and
enzyme
activity
(
rs
=
0
.
479
)
,
between
protein
stability
and
allelic
phenotype
(
rs
=
-
0
.
458
)
,
as
well
as
between
enzyme
activity
and
allelic
phenotype
(
rs
=
0
.
799
)
.
Enzyme
stability
algorithms
(
FoldX
and
SNPs
3
D
)
,
allelic
phenotype
and
enzyme
activity
were
most
powerful
to
predict
patients
'
phenotype
and
tetrahydrobiopterin
response
.
Phenotype
prediction
was
most
accurate
in
deleterious
genotypes
(
≈
100
%
)
,
followed
by
homozygous
(
92
.
9
%
)
,
hemizygous
(
94
.
8
%
)
,
and
compound
heterozygous
genotypes
(
77
.
9
%
)
,
while
tetrahydrobiopterin
response
was
correctly
predicted
in
71
.
0
%
of
all
cases
.
To
our
knowledge
this
is
the
largest
study
using
algorithms
for
the
prediction
of
patients
'
phenotype
and
tetrahydrobiopterin
responsiveness
in
phenylketonuria
patients
,
using
data
from
the
locus-
specific
and
genotypes
database
.
European
Journal
of
Human
Genetics
advance
online
publication
,
18
June
2014
;
doi
:
10
.
1038
/
ejhg
.
2014
.
114
.
Diseases
Validation
Diseases presenting
"a large number of variants causing variable impairment in phenylalanine hydroxylase function"
symptom
phenylketonuria
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