Progress in Retinal and Eye Research,
Journal Year:
2020,
Volume and Issue:
81, P. 100883 - 100883
Published: July 28, 2020
Fuchs
endothelial
corneal
dystrophy
(FECD)
is
a
common
cause
for
heritable
visual
loss
in
the
elderly.
Since
first
description
of
an
association
between
FECD
and
polymorphisms
situated
within
transcription
factor
4
(TCF4)
gene,
genetic
molecular
studies
have
implicated
intronic
CTG
trinucleotide
repeat
(CTG18.1)
expansion
as
causal
variant
majority
patients.
To
date,
several
non-mutually
exclusive
mechanisms
been
proposed
that
drive
and/or
exacerbate
onset
disease.
These
include
(i)
TCF4
dysregulation;
(ii)
toxic
gain-of-function
from
repeat-containing
RNA;
(iii)
repeat-associated
non-AUG
dependent
(RAN)
translation;
(iv)
somatic
instability
CTG18.1.
However,
relative
contribution
these
disease
pathogenesis
currently
unknown.
In
this
review,
we
summarise
research
implicating
pathogenesis,
define
phenotype-genotype
correlations
CTG18.1
expansion,
provide
update
on
tools
are
available
to
study
Furthermore,
ongoing
international
efforts
develop
novel
expansion-mediated
therapeutics
highlighted
forward-thinking
perspective
key
unanswered
questions
remain
field.
Journal of Biological Chemistry,
Journal Year:
2020,
Volume and Issue:
295(13), P. 4134 - 4170
Published: Feb. 15, 2020
Expansions
of
simple
tandem
repeats
are
responsible
for
almost
50
human
diseases,
the
majority
which
severe,
degenerative,
and
not
currently
treatable
or
preventable.
In
this
review,
we
first
describe
molecular
mechanisms
repeat-induced
toxicity,
is
connecting
link
between
repeat
expansions
pathology.
We
then
survey
alternative
DNA
structures
that
formed
by
expandable
review
evidence
formation
these
at
core
instability.
Next,
consequences
presence
long
structure-forming
level:
somatic
intergenerational
instability,
fragility,
mutagenesis.
discuss
reasons
gender
bias
in
instability
tissue
specificity
also
known
pathways
replication,
transcription,
repair,
chromatin
state
interact
thereby
promote
possible
persistence
disease-causing
genome.
suggesting
a
payoff
advantages
having
abundant
simple-sequence
eukaryotic
genome
function
evolvability.
Finally,
two
unresolved
fundamental
questions:
(i)
why
does
behavior
differ
model
systems
pedigrees,
(ii)
can
use
current
knowledge
on
to
cure
expansion
diseases?
Science,
Journal Year:
2021,
Volume and Issue:
373(6562), P. 1468 - 1473
Published: Sept. 23, 2021
The
sequencing
of
the
human
genome
has
allowed
study
genetic
architecture
common
diseases:
number
genomic
variants
that
contribute
to
risk
disease
and
their
joint
frequency
effect
size
distribution.
Common
diseases
are
polygenic,
with
many
loci
contributing
phenotype,
cumulative
burden
alleles
determines
individual
in
conjunction
environmental
factors.
Most
occur
noncoding
regions
regulating
cell-
context-specific
gene
expression.
Although
sizes
most
small,
effects
individuals,
quantified
as
a
polygenic
(risk)
score,
can
identify
people
at
increased
disease,
thereby
facilitating
prevention
or
early
intervention.
Nature Genetics,
Journal Year:
2024,
Volume and Issue:
56(3), P. 383 - 394
Published: Jan. 30, 2024
Abstract
Brain
region-specific
degeneration
and
somatic
expansions
of
the
mutant
Huntingtin
(
mHTT
)
CAG
tract
are
key
features
Huntington’s
disease
(HD).
However,
relationships
among
expansions,
death
specific
cell
types
molecular
events
associated
with
these
processes
not
established.
Here,
we
used
fluorescence-activated
nuclear
sorting
(FANS)
deep
profiling
to
gain
insight
into
properties
human
striatum
cerebellum
in
HD
control
donors.
arise
at
striatal
medium
spiny
neurons
(MSNs),
cholinergic
interneurons
cerebellar
Purkinje
neurons,
ATXN3
MSNs
from
SCA3
higher
levels
MSH2
MSH3
(forming
MutSβ),
which
can
inhibit
nucleolytic
excision
slip-outs
by
FAN1.
Our
data
support
a
model
necessary
but
may
be
sufficient
for
identify
transcriptional
changes
toxicity.
