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Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients.
[kabuki syndrome]
Kabuki
syndrome
(
KS
)
is
a
multiple
congenital
anomalies
syndrome
characterized
by
characteristic
facial
features
and
varying
degrees
of
mental
retardation
,
caused
by
mutations
in
KMT
2
D
/
MLL
2
and
KDM
6
A
/
UTX
genes
.
In
this
study
,
we
performed
a
mutational
screening
on
303
Kabuki
patients
by
direct
sequencing
,
MLPA
,
and
quantitative
PCR
identifying
133
KMT
2
D
,
62
never
described
before
,
and
four
KDM
6
A
mutations
,
three
of
them
are
novel
.
We
found
that
a
number
of
KMT
2
D
truncating
mutations
result
in
mRNA
degradation
through
the
nonsense-mediated
mRNA
decay
,
contributing
to
protein
haploinsufficiency
.
Furthermore
,
we
demonstrated
that
the
reduction
of
KMT
2
D
protein
level
in
patients
'
lymphoblastoid
and
skin
fibroblast
cell
lines
carrying
KMT
2
D
-
truncating
mutations
affects
the
expression
levels
of
known
KMT
2
D
target
genes
.
Finally
,
we
hypothesized
that
the
KS
patients
may
benefit
from
a
readthrough
therapy
to
restore
physiological
levels
of
KMT
2
D
and
KDM
6
A
proteins
.
To
assess
this
,
we
performed
a
proof-of-principle
study
on
14
KMT
2
D
and
two
KDM
6
A
nonsense
mutations
using
specific
compounds
that
mediate
translational
readthrough
and
thereby
stimulate
the
re
-expression
of
full-length
functional
proteins
.
Our
experimental
data
showed
that
both
KMT
2
D
and
KDM
6
A
nonsense
mutations
displayed
high
levels
of
readthrough
in
response
to
gentamicin
treatment
,
paving
the
way
to
further
studies
aimed
at
eventually
treating
some
Kabuki
patients
with
readthrough
inducers
.
Diseases
Validation
Diseases presenting
"contributing to protein haploinsufficiency"
symptom
kabuki syndrome
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