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Efficiency of translation termination in humans is highly dependent upon nucleotides in the neighbourhood of a (premature) termination codon.
[junctional epidermolysis bullosa]
Spontaneous
read-through
of
a
premature
termination
codon
(
PTC
)
has
so
far
not
been
observed
in
patients
carrying
nonsense
mutations
.
This
report
describes
a
patient
with
junctional
epidermolysis
bullosa
who
was
expected
to
die
because
of
compound
heterozygous
nonsense
mutations
in
the
gene
LAMA
3
(
R
943
X
/
R
1159
X
)
,
but
was
rescued
by
spontaneous
read-through
of
the
R
943
X
allele
.
FACS
analysis
of
cells
carrying
various
PTCs
surrounded
by
their
natural
neighbouring
codons
revealed
significant
reporter
gene
expression
despite
the
PTC
only
for
this
patient
's
genetic
context
.
Gene
expression
could
be
abolished
by
replacing
the
first
or
third
nucleotide
before
,
or
one
of
the
two
nucleotides
following
the
PTC
.
Site-directed
mutagenesis
was
used
to
identify
genotypes
allowing
PTC
read-through
.
The
genetic
context
of
the
LAMA
3
mutation
R
943
X
is
close
to
a
hypothetical
consensus
sequence
for
maximum
PTC
read-through
.
Bioinformatic
analysis
showed
that
this
consensus
sequence
is
present
in
four
sequences
from
the
NCBI
reference
database
,
each
of
which
contains
another
in
-frame
termination
codon
three
or
four
codons
apart
.
This
indicates
strong
selective
pressure
against
leaky
termination
codons
in
the
human
genome
.
This
patient
's
mutated
full
length
mRNA
escaped
nonsense-mediated
decay
,
leading
to
LAMA
3
mRNA
levels
similar
to
those
of
a
healthy
control
,
and
full
length
laminin
α
3
could
be
detected
in
culture
supernatant
of
the
patient
's
keratinocytes
.
Immunofluorescence
analyses
of
skin
biopsies
and
continuous
clinical
improvement
of
the
patient
's
condition
suggested
accumulation
of
intact
laminin-
332
in
the
epidermal
basement
membrane
.
These
findings
provide
important
clues
for
the
prediction
of
PTC
read-through
in
human
genetic
disease
.
Diseases
Validation
Diseases presenting
"premature termination codon"
symptom
aniridia
dystrophic epidermolysis bullosa
junctional epidermolysis bullosa
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