Frontiers in Cell and Developmental Biology,
Год журнала:
2022,
Номер
10
Опубликована: Окт. 25, 2022
The
human
DEAD-box
protein
DDX3X
is
an
RNA
remodelling
enzyme
that
has
been
implicated
in
various
aspects
of
metabolism.
In
addition,
like
many
proteins,
it
non-conventional
functions
are
independent
its
enzymatic
activity,
e.g.,
acts
as
adaptor
molecule
innate
immune
signalling
pathways.
linked
to
several
diseases.
For
example,
somatic
mutations
were
identified
cancers,
and
de
novo
germline
cause
a
neurodevelopmental
condition
now
termed
‘DDX3X
syndrome’.
also
important
host
factor
different
viral
infections,
where
can
have
pro-or
anti-viral
effects
depending
on
the
specific
virus.
regulation
translation
initiation
for
mRNA
transcripts
likely
central
cellular
function
DDX3X,
yet
questions
regarding
exact
targets
mechanisms
action
remain
unanswered.
this
review,
we
explore
current
knowledge
about
DDX3X’s
physiological
summarise
interactions
with
machinery.
A
role
translational
reprogramming
during
stress
emerging,
may
be
involved
granule
formation
mediating
non-canonical
initiation.
Finally,
discuss
DDX3X-mediated
infections.
Dysregulation
contributes
involvement
disease
pathophysiology.
Thus,
better
understanding
regulating
important,
so
potentially
develop
therapeutic
strategies
overcoming
negative
dysregulation.
Mutations
in
the
RNA
helicase,
DDX3X
,
are
a
leading
cause
of
Intellectual
Disability
and
present
as
syndrome,
neurodevelopmental
disorder
associated
with
cortical
malformations
autism.
Yet,
cellular
molecular
mechanisms
by
which
controls
development
largely
unknown.
Here,
using
mouse
model
Ddx3x
loss-of-function
we
demonstrate
that
directs
translational
cell
cycle
control
neural
progenitors,
underlies
precise
corticogenesis.
First,
show
brain
is
sensitive
to
dosage;
complete
loss
from
progenitors
causes
microcephaly
females,
whereas
hemizygous
males
heterozygous
females
reduced
neurogenesis
without
marked
microcephaly.
In
addition,
sexually
dimorphic,
its
paralog,
Ddx3y
compensates
for
developing
male
neocortex.
Using
live
imaging
promotes
neuronal
generation
regulating
both
duration
neurogenic
divisions.
Finally,
use
ribosome
profiling
vivo
discover
repertoire
translated
transcripts
including
those
DDX3X-dependent
essential
neurogenesis.
Our
study
reveals
invaluable
new
insights
into
etiology
implicating
dysregulated
progenitor
dynamics
translation
pathogenic
mechanisms.
Nature Communications,
Год журнала:
2023,
Номер
14(1)
Опубликована: Дек. 6, 2023
Loss-of-function
of
DDX3X
is
a
leading
cause
neurodevelopmental
disorders
(NDD)
in
females.
also
somatically
mutated
cancer
driver
gene
proposed
to
have
tumour
promoting
and
suppressing
effects.
We
perform
saturation
genome
editing
DDX3X,
testing
vitro
the
functional
impact
12,776
nucleotide
variants.
identify
3432
functionally
abnormal
variants,
three
distinct
classes.
train
machine
learning
classifier
variants
NDD-relevance.
This
has
at
least
97%
sensitivity
99%
specificity
detect
pathogenic
for
NDD,
substantially
out-performing
silico
predictors,
resolving
up
93%
uncertain
significance.
Moreover,
functionally-abnormal
can
account
almost
all
excess
nonsynonymous
somatic
mutations
seen
DDX3X-driven
cancers.
Systematic
maps
variant
effects
generated
experimentally
tractable
cell
types
potential
transform
clinical
interpretation
both
germline
disease-associated
variation.
Communications Biology,
Год журнала:
2023,
Номер
6(1)
Опубликована: Март 31, 2023
Abstract
Non-obstructive
azoospermia,
the
absence
of
sperm
in
ejaculate
due
to
disturbed
spermatogenesis,
represents
most
severe
form
male
infertility.
De
novo
microdeletions
Y-chromosomal
AZFa
region
are
one
few
well-established
genetic
causes
for
NOA
and
routinely
analysed
diagnostic
workup
affected
men.
So
far,
it
is
unclear
which
three
genes
located
chromosomal
indispensible
germ
cell
maturation.
Here
we
present
four
different
likely
pathogenic
loss-of-function
variants
gene
DDX3Y
identified
by
analysing
exome
sequencing
data
more
than
1,600
infertile
Three
patients
underwent
testicular
extraction
revealed
typical
Sertoli
cell-only
phenotype.
One
was
proven
be
de
novo.
Consequently,
key
spermatogenic
factor
screening
should
included
workflow.
