International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(4), С. 2053 - 2053
Опубликована: Фев. 8, 2024
Heterozygous
variants
in
the
Poly(U)
Binding
Splicing
Factor
60kDa
gene
(PUF60)
have
been
associated
with
Verheij
syndrome,
which
has
key
features
of
coloboma,
short
stature,
skeletal
abnormalities,
developmental
delay,
palatal
and
congenital
heart
kidney
defects.
Here,
we
report
five
novel
patients
from
unrelated
families
PUF60-related
disorders
exhibiting
genetic
clinical
findings
three
truncating
variants,
one
splice-site
variant
likely
reduced
protein
expression,
missense
variant.
Protein
modeling
patient's
PUF60
AlphaFold
structure
revealed
a
loss
polar
bonds
to
surrounding
residues.
Neurodevelopmental
were
present
all
patients,
variability
speech,
motor,
cognitive,
social-emotional
behavioral
features.
Novel
phenotypic
expansions
included
movement
as
well
immunological
recurrent
respiratory,
urinary
ear
infections,
atopic
diseases,
skin
abnormalities.
We
discuss
role
immunity
without
infection
based
on
recent
organismic
cellular
studies.
As
our
showed
less-severe
phenotypes
than
classical
particularly
absence
such
coloboma
or
propose
reclassification
neurodevelopmental
multi-system
involvement.
These
will
aid
counseling
families.
Serine
peptidase
inhibitor,
Kazal
type
1
(SPINK1),
a
56-amino-acid
protein
in
its
mature
form,
was
among
the
first
pancreatic
enzymes
to
be
extensively
characterized
biochemically
and
functionally.
Synthesized
primarily
acinar
cells
traditionally
known
as
secretory
trypsin
SPINK1
protects
pancreas
by
inhibiting
prematurely
activated
trypsin.
Since
2000,
interest
has
resurged
following
discovery
of
genetic
variants
linked
chronic
pancreatitis
(CP).
This
review
provides
historical
overview
SPINK1's
discovery,
function,
gene
structure
before
examining
key
findings.
We
highlight
three
with
well-characterized
pathogenic
mechanisms:
c.-4141G
>
T,
causative
enhancer
variant
studied
p.Asn34Ser
(c.101A
G),
which
disrupts
PTF1L-binding
site
within
an
evolutionarily
conserved
HNF1A-PTF1L
cis-regulatory
module;
c.194
+
2T
C,
canonical
5′
splice
GT
GC
that
retains
10%
wild-type
transcript
production;
Alu
insertion
3′-untranslated
region,
causes
complete
loss
function
forming
extended
double-stranded
RNA
structures
pre-existing
elements
deep
intronic
regions.
emphasize
integration
full-length
splicing
assay
(FLGSA)
SpliceAI's
predictive
capabilities,
establishing
disease
for
impact
all
possible
coding
prospectively
determined.
Findings
from
both
mouse
models
association
studies
support
sentinel
acute
event
(SAPE)
model,
explains
progression
CP.
Additionally,
may
contribute
increased
risk
ductal
adenocarcinoma
(PDAC).
Finally,
we
discuss
therapeutic
potential
SPINK1,
particularly
through
adeno-associated
virus
8
(AAV8)-mediated
overexpression
strategy
treating
preventing
pancreatitis,
areas
future
research.
Most
mRNA
splicing
occurs
co-transcriptionally,
but
it
is
unclear
how
factors
accurately
select
exons
for
inclusion.
Using
CUT&RUN
profiling
in
K562
cells,
we
demonstrate
that
three
factors-SF3B1,
U2AF1,
and
U2AF2-bind
near
active
promoters
of
intron-containing
intronless
genes,
implying
their
association
with
the
general
transcriptional
machinery.
RNase
A
treatment
reduces
factor
binding
at
promoters,
indicating
these
proteins
interact
nascent
transcripts.
Strikingly,
U2AF2
protein
also
accumulates
throughout
gene
bodies
requires
histone
H3-lysine36
trimethylation
not
transcripts
or
persistent
RNA
polymerase
II.
Chromatin-bound
preferentially
binds
to
highly
expressed,
exon-dense
greater
occupancy
skipped
after
knockdown,
suggesting
enhances
exon
selection
accuracy.
U2AF2-targeted
genes
include
those
encoding
factors,
where
improves
accuracy
efficiency.
Our
findings
provide
a
mechanistic
basis
homeostatic
regulation
efficient
co-transcriptional
by
chromatin-bound
U2AF2.
Wiley Interdisciplinary Reviews - RNA,
Год журнала:
2024,
Номер
15(2)
Опубликована: Март 1, 2024
Abstract
Disruptions
in
spatiotemporal
gene
expression
can
result
atypical
brain
function.
Specifically,
autism
spectrum
disorder
(ASD)
is
characterized
by
abnormalities
pre‐mRNA
splicing.
Abnormal
splicing
patterns
have
been
identified
the
brains
of
individuals
with
ASD,
and
mutations
factors
found
to
contribute
neurodevelopmental
delays
associated
ASD.
Here
we
review
studies
that
shed
light
on
importance
observed
ASD
explored
intricate
relationship
between
revealing
how
disruptions
may
underlie
pathogenesis.
We
provide
an
overview
research
regarding
all
place
a
special
emphasis
five
specific
factors—HNRNPH2,
NOVA2,
WBP4,
SRRM2,
RBFOX1—known
impact
ASD‐related
genes.
In
discussion
molecular
mechanisms
influenced
these
factors,
lay
groundwork
for
deeper
understanding
ASD's
complex
etiology.
Finally,
discuss
potential
benefit
unraveling
connection
development
more
precise
diagnostic
tools
targeted
therapeutic
interventions.
This
article
categorized
under:
RNA
Disease
Development
>
Evolution
Genomics
Ribonucleoprotein
Computational
Analyses
RNA‐Based
Catalysis
Splicing
Translation
