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Consequences of two different amino-acid substitutions at the same codon in KRT14 indicate definitive roles of structural distortion in epidermolysis bullosa simplex pathogenesis.
[epidermolysis bullosa simplex]
Numerous
inherited
diseases
develop
due
to
missense
mutations
,
leading
to
an
amino-acid
substitution
.
Whether
an
amino-acid
change
is
pathogenic
depends
on
the
level
of
deleterious
effects
caused
by
the
amino-acid
alteration
.
We
show
an
example
of
different
structural
and
phenotypic
consequences
caused
by
two
individual
amino-acid
changes
at
the
same
position
.
Epidermolysis
bullosa
simplex
(
EBS
)
is
a
genodermatosis
resulting
from
KRT
5
or
KRT
14
mutations
.
Mutation
analysis
of
an
EBS
family
revealed
that
affected
individuals
were
heterozygous
for
a
,
to
our
knowledge
,
previously
unreported
mutation
of
c
.
1237
G
>
C
(
p
.
Ala
413
Pro
)
in
KRT
14
.
Interestingly
,
2
of
100
unrelated
normal
controls
were
heterozygous
,
and
1
of
the
100
was
homozygous
for
a
different
mutation
in
this
position
,
c
.
1237
G
>
A
(
p
.
Ala
413
Thr
)
.
In
silico
modeling
of
the
protein
demonstrated
deleterious
structural
effects
from
proline
substitution
but
not
from
threonine
substitution
.
In
vitro
transfection
studies
revealed
a
significantly
larger
number
of
keratin-clumped
cells
in
HaCaT
cells
transfected
with
mutant
KRT
14
complementary
DNA
(
cDNA
)
harboring
p
.
Ala
413
Pro
than
those
transfected
with
wild-
type
KRT
14
cDNA
or
mutant
KRT
14
cDNA
harboring
p
.
Ala
413
Thr
.
These
results
show
that
changes
in
two
distinct
amino
acids
at
a
locus
are
destined
to
elicit
different
phenotypes
due
to
the
degree
of
structural
distortion
resulting
from
the
amino-acid
alterations
.
Diseases
Validation
Diseases presenting
"unrelated normal controls"
symptom
aniridia
child syndrome
epidermolysis bullosa simplex
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