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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
"skin biopsies"
symptom
cadasil
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
fabry disease
harlequin ichthyosis
junctional epidermolysis bullosa
kindler syndrome
malignant atrophic papulosis
neonatal adrenoleukodystrophy
omenn syndrome
pyruvate dehydrogenase deficiency
sneddon syndrome
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