Progress in Retinal and Eye Research,
Год журнала:
2020,
Номер
81, С. 100883 - 100883
Опубликована: Июль 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.
Human Molecular Genetics,
Год журнала:
2020,
Номер
29(15), С. 2551 - 2567
Опубликована: Июль 4, 2020
The
expanded
HTT
CAG
repeat
causing
Huntington's
disease
(HD)
exhibits
somatic
expansion
proposed
to
drive
the
rate
of
onset
by
eliciting
a
pathological
process
that
ultimately
claims
vulnerable
cells.
To
gain
insight
into
in
humans,
we
performed
comprehensive
quantitative
analyses
~50
central
nervous
system
(CNS)
and
peripheral
postmortem
tissues
from
seven
adult-onset
one
juvenile-onset
HD
individual.
We
also
assessed
ATXN1
brain
regions
an
individual
with
neurologically
pathologically
distinct
disorder,
spinocerebellar
ataxia
type
1
(SCA1).
Our
findings
reveal
similar
profiles
tissue
instability
all
individuals,
which,
notably,
were
apparent
SCA1
was
observed
tissues,
but
different
degrees,
multiple
cortical
neostriatum
tending
have
greatest
CNS,
liver
periphery.
These
patterns
indicate
propensities
for
contributed
locus-independent
trans-factors
demonstrate
per
se
is
not
sufficient
cause
cell
or
disease-specific
pathology.
Rather,
pathology
may
reflect
toxic
processes
triggered
lengths
across
types
diseases.
find
length-dependent
propensity
reflected
cerebrospinal
fluid.
data
cells
be
useful
source
measure
biomarker
assays
therapeutic
efforts,
prompting
efforts
dissect
underlying
mechanisms
differ
between
Journal of Huntington s Disease,
Год журнала:
2021,
Номер
10(1), С. 35 - 51
Опубликована: Фев. 9, 2021
Historically,
Huntington’s
disease
(HD;
OMIM
#143100)
has
played
an
important
role
in
the
enormous
advances
human
genetics
seen
over
past
four
decades.
This
familial
neurodegenerative
disorder
involves
variable
onset
followed
by
consistent
worsening
of
characteristic
abnormal
movements
along
with
cognitive
decline
and
psychiatric
disturbances.
HD
was
first
autosomal
for
which
genetic
defect
assigned
to
a
position
on
chromosomes
using
only
linkage
analysis
common
DNA
polymorphisms.
discovery
set
off
multitude
similar
studies
other
diseases,
while
gene,
later
renamed
HTT,
its
vicinity
chromosome
4p16.3
then
acted
as
proving
ground
development
technologies
clone
sequence
genes
based
upon
their
genomic
location,
growing
momentum
such
fueling
Human
Genome
Project.
The
identification
gene
not
yet
led
effective
treatment,
but
continued
genotype-phenotype
relationships
large
subject
populations,
at
HTT
locus
subsequently
genome-wide,
provided
insights
into
pathogenesis
that
divide
course
two
sequential,
mechanistically
distinct
components.
Journal of Huntington s Disease,
Год журнала:
2021,
Номер
10(1), С. 75 - 94
Опубликована: Фев. 9, 2021
DNA
mismatch
repair
(MMR)
is
a
highly
conserved
genome
stabilizing
pathway
that
corrects
replication
errors,
limits
chromosomal
rearrangements,
and
mediates
the
cellular
response
to
many
types
of
damage.
Counterintuitively,
MMR
also
involved
in
generation
mutations,
as
evidenced
by
its
role
causing
somatic
triplet
repeat
expansion
Huntington’s
disease
(HD)
other
neurodegenerative
disorders.
In
this
review,
we
discuss
current
state
mechanistic
knowledge
review
roles
key
enzymes
pathway.
We
present
evidence
for
mutagenic
function
CAG
consider
hypotheses
have
been
proposed.
Understanding
may
shed
light
on
potential
avenues
therapeutic
intervention
HD.
Progress in Retinal and Eye Research,
Год журнала:
2020,
Номер
81, С. 100883 - 100883
Опубликована: Июль 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.
