PLoS Genetics,
Journal Year:
2024,
Volume and Issue:
20(12), P. e1011502 - e1011502
Published: Dec. 5, 2024
Primary
angle
closure
glaucoma
(PACG)
affects
more
than
20
million
people
worldwide,
with
an
increased
prevalence
in
south-east
Asia.
In
a
prior
haplotype-based
Genome
Wide
Association
Study
(GWAS),
we
identified
novel
CNTNAP5
genic
region,
significantly
associated
PACG.
the
current
study,
have
extended
our
perception
of
involvement
glaucomatous
neurodegeneration
zebrafish
model,
through
investigating
phenotypic
consequences
pertinent
to
retinal
degeneration
upon
knockdown
cntnap5
by
translation-blocking
morpholinos.
While
was
successfully
validated
using
antibody,
immunofluorescence
followed
western
blot
analyses
cntnap5-morphant
(MO)
revealed
expression
acetylated
tubulin
indicative
perturbed
cytoarchitecture
layers.
Moreover,
significant
loss
Nissl
substance
is
observed
neuro-retinal
layers
cntnap5-MO
eye,
indicating
neurodegeneration.
Additionally,
spontaneous
movement
behavioural
analysis,
lower
average
distance
traversed
light
phase
compared
mismatch-controls,
whereas
no
difference
dark
phase,
corroborating
vision
zebrafish.
This
study
provides
first
direct
functional
evidence
putative
role
visual
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Dec. 29, 2024
Abstract
Most
genetic
risk
variants
linked
to
ocular
diseases
are
non-protein
coding
and
presumably
contribute
disease
through
dysregulation
of
gene
expression,
however,
deeper
understanding
their
mechanisms
action
has
been
impeded
by
an
incomplete
annotation
the
transcriptional
regulatory
elements
across
different
retinal
cell
types.
To
address
this
knowledge
gap,
we
carried
out
single-cell
multiomics
assays
investigate
chromatin
accessibility,
DNA
methylome
3D
architecture
in
human
retina,
macula,
pigment
epithelium
(RPE)/choroid.
We
identified
420,824
unique
candidate
characterized
states
23
sub-classes
cells.
Comparative
analysis
landscapes
between
mouse
retina
cells
further
revealed
both
evolutionarily
conserved
divergent
gene-regulatory
programs.
Leveraging
rapid
advancements
deep-learning
techniques,
developed
sequence-based
predictors
interpret
non-coding
diseases.
Our
study
establishes
retina-wide,
transcriptome,
epigenome,
genome
atlases,
provides
a
resource
for
studying
programs
relevant
ABSTRACT
Genome-wide
association
studies
(GWAS)
have
established
a
key
role
of
dysfunctional
immune
response
in
the
etiology
Age-related
Macular
Degeneration
(AMD).
However,
cells
constitute
small
proportion
retina,
and
their
AMD
is
not
completely
resolved.
Here
we
develop
an
explainable
machine
learning
pipeline
using
transcriptome
data
453
donor
retinas,
identifying
81
genes
distinguishing
from
controls
with
AUC-ROC
0.80
(CI
0.70-0.92).
These
show
enrichment
for
pathways
involved
response,
complement
extracellular
matrix
connected
to
known
through
co-expression
networks
gene
expression
correlation.
The
majority
these
were
enriched
within
retinal
glial
cells,
particularly
microglia
astrocytes.
Their
was
further
strengthened
by
cellular
deconvolution,
which
identified
distinct
differences
astrocytes
between
normal
AMD.
We
corroborated
findings
independent
single-cell
data,
where
several
candidate
exhibited
differential
expression.
Finally,
integration
AMD-GWAS
common
regulatory
variant,
rs4133124
at
PLCG2
,
as
novel
AMD-association.
Collectively,
our
study
provides
molecular
insights
into
recurring
theme
dysfunction
highlights
significance
cell
important
determinant
progression.
Human Molecular Genetics,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Nov. 12, 2024
Genome-wide
association
studies
have
uncovered
mostly
non-coding
variants
at
over
60
genetic
loci
linked
to
susceptibility
for
age-related
macular
degeneration
(AMD).
To
ascertain
the
causal
gene
PILRB/PILRA
locus,
we
used
a
CRISPR
strategy
produce
germline
deletions
in
mouse
paired
immunoglobin-like
type
2
receptor
(Pilr)
genes
that
encode
highly
related
activating
(PILRB)
and
inhibitory
(PILRA)
receptors.
We
show
combined
loss
of
Pilrb1
Pilrb2,
but
not
Pilra,
leads
an
early
relatively
stationary
defect
as
electroretinography
(ERG)
amplitudes
Pilrb1/2-/-
mice
exhibit
marked
reduction
postnatal
day
15
do
additional
significant
decrease
3
12-months.
No
alterations
are
evident
Müller
glia,
microglia,
bipolar,
amacrine
horizontal
cells
based
on
immunohistochemistry
using
cell-type
specific
markers.
PILRB
immunostaining
is
specifically
detected
proximal
part
photoreceptor
outer
segment.
Reduced
expression
select
calcium-regulated
phototransduction
synapse-associated
proteins,
including
GCAP1
2,
PDE6b,
AIPL1,
PSD95,
CTBP1
indicates
dysregulation
calcium
homeostasis
possible
mechanism
retinal
phenotype
mice.
Our
suggest
novel
function
photoreceptors
PILRB,
PILRA,
with
AMD
pathogenesis.
PLoS Genetics,
Journal Year:
2024,
Volume and Issue:
20(12), P. e1011502 - e1011502
Published: Dec. 5, 2024
Primary
angle
closure
glaucoma
(PACG)
affects
more
than
20
million
people
worldwide,
with
an
increased
prevalence
in
south-east
Asia.
In
a
prior
haplotype-based
Genome
Wide
Association
Study
(GWAS),
we
identified
novel
CNTNAP5
genic
region,
significantly
associated
PACG.
the
current
study,
have
extended
our
perception
of
involvement
glaucomatous
neurodegeneration
zebrafish
model,
through
investigating
phenotypic
consequences
pertinent
to
retinal
degeneration
upon
knockdown
cntnap5
by
translation-blocking
morpholinos.
While
was
successfully
validated
using
antibody,
immunofluorescence
followed
western
blot
analyses
cntnap5-morphant
(MO)
revealed
expression
acetylated
tubulin
indicative
perturbed
cytoarchitecture
layers.
Moreover,
significant
loss
Nissl
substance
is
observed
neuro-retinal
layers
cntnap5-MO
eye,
indicating
neurodegeneration.
Additionally,
spontaneous
movement
behavioural
analysis,
lower
average
distance
traversed
light
phase
compared
mismatch-controls,
whereas
no
difference
dark
phase,
corroborating
vision
zebrafish.
This
study
provides
first
direct
functional
evidence
putative
role
visual
