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In vitro functional studies of rare CYP21A2 mutations and establishment of an activity gradient for nonclassic mutations improve phenotype predictions in congenital adrenal hyperplasia.
[congenital adrenal hyperplasia]
A
detailed
genotype-phenotype
evaluation
is
presented
by
studying
the
enzyme
activities
of
five
rare
amino
acid
substitutions
(
Arg
233
G
ly
,
Ala
265
S
er
,
Arg
341
T
rp
,
Arg
366
C
ys
and
Met
473
Ile
)
identified
in
the
CYP
21
A
2
gene
in
patients
investigated
for
Congenital
adrenal
hyperplasia
(
CAH
)
.
To
investigate
whether
the
mutations
identified
in
the
CYP
21
A
2
gene
are
disease
causing
and
to
establish
a
gradient
for
the
degree
of
enzyme
impairment
to
improve
prediction
of
patient
phenotype
.
The
CYP
21
A
2
genes
of
seven
patients
investigated
for
CAH
were
sequenced
and
five
mutations
were
identified
.
The
mutant
proteins
were
expressed
in
vitro
in
COS
-
1
cells
,
and
the
enzyme
activities
towards
the
two
natural
substrates
were
determined
to
verify
the
disease-causing
state
of
the
mutations
.
The
in
vitro
activities
of
these
rare
mutations
were
also
compared
with
the
activities
of
four
mutations
known
to
cause
nonclassic
CAH
(
Pro
30
L
eu
,
Val
281
L
eu
,
Pro
453
S
er
and
Pro
482
S
er
)
in
addition
to
an
in
silico
structural
evaluation
of
the
novel
mutants
.
To
verify
the
disease-causing
state
of
novel
mutations
.
F
ive
CYP
21
A
2
mutations
were
identified
(
Arg
233
G
ly
,
Ala
265
S
er
,
Arg
341
T
rp
,
Arg
366
C
ys
and
Met
473
Ile
)
.
All
mutant
proteins
exhibited
enzyme
activities
above
5
%
,
and
four
mutations
were
classified
as
nonclassic
and
one
as
a
normal
variant
.
By
comparing
the
investigated
protein
changes
with
four
common
mutations
causing
nonclassic
CAH
,
a
gradient
for
the
degree
of
enzyme
impairment
could
be
established
.
Studying
rare
mutations
in
CAH
increases
our
knowledge
regarding
the
molecular
mechanisms
that
render
a
mutation
pathogenic
.
It
also
improves
phenotype
predictions
and
genetic
counselling
for
future
generations
.
Diseases
Validation
Diseases presenting
"congenital adrenal hyperplasia"
symptom
adrenal incidentaloma
aromatase deficiency
congenital adrenal hyperplasia
cushing syndrome
phenylketonuria
This symptom has already been validated