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Functional associations of genetic variants involved in the clinical manifestation of erythropoietic protoporphyria in the Argentinean population.
[erythropoietic protoporphyria]
Combined
inheritance
of
genetic
variants
in
ferrochelatase
gene
(
FECH
)
are
implicated
in
clinical
manifestation
of
Erythropoietic
Protoporphyria
(
EPP
)
.
Identify
the
genetic
variants
in
FECH
gene
and
their
associations
in
the
expression
of
EPP
in
Argentina
.
Determine
the
allelic
frequency
of
polymorphic
variants
,
associations
in
cis
and
its
linkage
disequilibrium
.
The
FECH
gene
was
PCR-amplified
and
sequenced
.
Allelic
variants
of
intragenic
polymorphisms
were
identified
by
PCR
followed
by
sequencing
or
restriction
digestion
analysis
.
Residual
FECH
activity
was
determined
by
prokaryotic
expression
in
Escherichia
coli
JM
109
.
Data
were
analyzed
using
Haploview
and
Statistix
9
.
Ten
mutations
were
identified
:
three
novel
(
p
.
S
222
N
;
p
.
R
298
X
and
p
.
R
367
X
)
and
seven
already
known
(
g
.
12490
_
18067
del
;
p
.
R
115
X
;
p
.
I
186
T
;
c
.
580
_
584
delTACAG
;
c
.
598
+
1
G
>
T
;
p
.
Y
209
X
and
p
.
W
310
X
)
.
The
p
.
R
115
X
mutation
was
found
in
two
families
.
The
p
.
S
222
N
mutation
expressed
5
%
of
normal
activity
.
Only
individuals
who
inherited
a
mutation
combined
in
trans
to
a
low
expression
allele
c
.
1
-
251
G
,
c
.
68
-
23
T
,
and
c
.
315
-
48
C
,
showed
clinical
symptoms
.
The
absence
of
c
.
315
-
48
C
variant
was
sufficient
for
not
triggering
EPP
.
However
,
these
variants
showed
high
levels
of
cosegregation
and
GTC
haplotype
is
over-represented
in
EPP
patients
.
In
the
dominant
inheritance
form
of
EPP
,
c
.
3
15
-
48
C
variant
in
trans
to
the
mutated
allele
is
sufficient
to
trigger
the
disease
.
The
presence
of
GTC
haplotype
in
all
patients
with
dominant
EPP
could
be
due
to
the
high
level
of
cosegregation
of
c
.
315
-
48
C
with
c
.
1
-
251
G
and
c
.
68
-
23
T
variants
in
our
population
.
