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A RAG1 mutation found in Omenn syndrome causes coding flank hypersensitivity: a novel mechanism for antigen receptor repertoire restriction.
[omenn syndrome]
Hypomorphic
RAG
mutants
with
severely
reduced
V
(
D
)
J
recombination
activity
cause
Omenn
Syndrome
(
OS
)
,
an
immunodeficiency
with
features
of
immune
dysregulation
and
a
restricted
TCR
repertoire
.
Precisely
how
RAG
mutants
produce
autoimmune
and
allergic
symptoms
has
been
unclear
.
Current
models
posit
that
the
severe
recombination
defect
restricts
the
number
of
lymphocyte
clones
,
a
few
of
which
are
selected
upon
Ag
exposure
.
We
show
that
murine
RAG
1
R
972
Q
,
corresponding
to
an
OS
mutation
,
renders
the
recombinase
hypersensitive
to
selected
coding
sequences
at
the
hairpin
formation
step
.
Other
RAG
1
OS
mutants
tested
do
not
manifest
this
sequence
sensitivity
.
These
new
data
support
a
novel
mechanism
for
OS
:
by
selectively
impairing
recombination
at
certain
coding
flanks
,
a
RAG
mutant
can
cause
primary
repertoire
restriction
,
as
opposed
to
a
more
random
,
limited
repertoire
that
develops
secondary
to
severely
diminished
recombination
activity
.
Diseases
Validation
Diseases presenting
"severely diminished recombination activity"
symptom
omenn syndrome
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