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Biochemical and folding defects in a RAG1 variant associated with Omenn syndrome.
[omenn syndrome]
The
RAG
1
and
RAG
2
proteins
are
required
to
assemble
mature
Ag
receptor
genes
in
developing
lymphocytes
.
Hypomorphic
mutations
in
the
gene
encoding
RAG
1
are
associated
with
Omenn
syndrome
,
a
primary
immunodeficiency
.
We
explored
the
biochemical
defects
resulting
from
a
mutation
identified
in
an
Omenn
syndrome
patient
which
generates
an
amino
acid
substitution
in
the
RAG
1
RING
finger
/
ubiquitin
ligase
domain
(
C
3
25
Y
in
murine
RAG
1
)
as
well
as
an
adjacent
substitution
(
P
326
G
)
.
RAG
1
C
3
25
Y
demonstrated
a
50
-
fold
reduction
in
recombination
activity
in
cultured
pro-
B
cells
despite
the
fact
that
its
expression
and
localization
to
the
nucleus
were
similar
to
the
wild-
type
protein
.
The
C
3
25
Y
substitution
severely
abrogated
ubiquitin
ligase
activity
of
the
purified
RAG
1
RING
finger
domain
,
and
the
tertiary
structure
of
the
domain
was
altered
.
The
P
326
G
substitution
also
abrogated
ubiquitin
ligase
activity
but
had
a
less
severe
effect
on
protein
folding
.
RAG
1
P
326
G
also
demonstrated
a
recombination
impairment
that
was
most
pronounced
when
RAG
1
levels
were
limiting
.
Thus
,
a
correctly
folded
RAG
1
RING
finger
domain
is
required
for
normal
V
(
D
)
J
recombination
,
and
RAG
1
ubiquitin
ligase
activity
can
contribute
when
the
protein
is
present
at
relatively
low
levels
.
Diseases
Validation
Diseases presenting
"severely abrogated ubiquitin ligase activity of the purified rag1 ring finger domain"
symptom
omenn syndrome
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