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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
"high levels"
symptom
22q11.2 deletion syndrome
adrenal incidentaloma
allergic bronchopulmonary aspergillosis
alpha-thalassemia
aromatase deficiency
cadasil
canavan disease
classical phenylketonuria
congenital adrenal hyperplasia
congenital toxoplasmosis
cutaneous mastocytosis
cystinuria
dentin dysplasia
dentinogenesis imperfecta
dracunculiasis
dystrophic epidermolysis bullosa
erythropoietic protoporphyria
gm1 gangliosidosis
hereditary cerebral hemorrhage with amyloidosis
holt-oram syndrome
homocystinuria without methylmalonic aciduria
kabuki syndrome
kallmann syndrome
liposarcoma
papillon-lefèvre syndrome
phenylketonuria
primary effusion lymphoma
primary hyperoxaluria type 1
scrub typhus
severe combined immunodeficiency
systemic capillary leak syndrome
triple a syndrome
von hippel-lindau disease
werner syndrome
wiskott-aldrich syndrome
wolf-hirschhorn syndrome
x-linked adrenoleukodystrophy
zellweger syndrome
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