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In silico analysis of all point mutations on the 2B domain of K5/K14 causing epidermolysis bullosa simplex: a genotype-phenotype correlation.
[epidermolysis bullosa simplex]
Epidermolysis
bullosa
simplex
(
EBS
)
is
a
genodermatosis
caused
by
mutations
in
keratins
5
and
14
(
K
5
and
K
14
)
,
which
leads
to
fragility
of
basal
keratinocytes
and
eventually
epidermal
cytolysis
and
blistering
.
Depending
upon
the
severity
of
symptoms
,
EBS
is
classified
into
three
major
subtypes
.
In
order
of
increasing
severity
these
classes
are
EBS
,
localized
(
EBS-loc
)
,
EBS
,
other
generalized
(
EBS
,
gen-non
DM
)
,
and
EBS
,
Dowling-
Meara
(
EBS
-
DM
)
.
We
have
searched
and
assembled
36
previously
reported
point
mutations
located
on
the
2
B
domain
of
K
5
/
K
14
in
order
to
investigate
the
effects
of
point
mutations
.
By
performing
a
comprehensive
in
silico
analysis
we
determine
the
underlying
relationship
between
the
mutation
and
its
phenotypic
effects
.
Our
result
showed
that
all
pathogenic
point
mutations
exert
their
dominant
negative
effect
on
the
K
5
/
K
14
coiled-coil
heterodimer
complex
by
altering
interchain
interaction
,
leading
to
the
changes
in
stability
and
assembly
competence
of
the
heterodimer
complex
.
The
physico-chemical
properties
of
substituted
amino
acid
and
location
of
the
mutation
are
also
deeply
correlated
with
disease
severity
.
In
addition
,
we
found
a
SNP
previously
reported
as
non-pathogenic
(
K
14
p
.
M
338
R
)
that
likely
affects
the
stability
of
the
dimer
structure
due
to
the
loss
of
interchain
interaction
and
steric
clashes
.
Overall
,
our
finding
demonstrates
the
significance
of
in
silico
characterization
of
EBS
severity
and
would
allow
for
accurate
genetic
counseling
and
prenatal
diagnosis
.
Diseases
Validation
Diseases presenting
"basal keratinocytes"
symptom
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
harlequin ichthyosis
junctional epidermolysis bullosa
kindler syndrome
lamellar ichthyosis
severe combined immunodeficiency
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