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A random Abstract
Our Project
Our Team
A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency.
[omenn syndrome]
The
recombination-activating
gene
(
RAG
)
1
/
2
proteins
play
a
critical
role
in
the
development
of
T
and
B
cells
by
initiating
the
VDJ
recombination
process
that
leads
to
generation
of
a
broad
T
-
cell
receptor
(
TCR
)
and
B-
cell
receptor
repertoire
.
Pathogenic
mutations
in
the
RAG
1
/
2
genes
result
in
various
forms
of
primary
immunodeficiency
,
ranging
from
T
(
-
)
B
(
-
)
severe
combined
immune
deficiency
to
delayed
-onset
disease
with
granuloma
formation
,
autoimmunity
,
or
both
.
It
is
not
clear
what
contributes
to
such
heterogeneity
of
phenotypes
.
We
sought
to
investigate
the
molecular
basis
for
phenotypic
diversity
presented
in
patients
with
various
RAG
1
mutations
.
We
have
developed
a
flow
cytometry-based
assay
that
allows
analysis
of
RAG
recombination
activity
based
on
green
fluorescent
protein
expression
and
have
assessed
the
induction
of
the
Ighc
locus
rearrangements
in
mouse
Rag
1
(
-
/
-
)
pro-
B
cells
reconstituted
with
wild-
type
or
mutant
human
RAG
1
(
hRAG
1
)
using
deep
sequencing
technology
.
Here
we
demonstrate
correlation
between
defective
recombination
activity
of
hRAG
1
mutant
proteins
and
severity
of
the
clinical
and
immunologic
phenotype
and
provide
insights
on
the
molecular
mechanisms
accounting
for
such
phenotypic
diversity
.
Using
a
sensitive
assay
to
measure
the
RAG
1
activity
level
of
79
mutations
in
a
physiologic
setting
,
we
demonstrate
correlation
between
recombination
activity
of
RAG
1
mutants
and
the
severity
of
clinical
presentation
and
show
that
RAG
1
mutants
can
induce
specific
abnormalities
of
the
VDJ
recombination
process
.
Diseases
Validation
Diseases presenting
"immunodeficiency"
symptom
adrenal incidentaloma
allergic bronchopulmonary aspergillosis
cushing syndrome
dracunculiasis
hirschsprung disease
hodgkin lymphoma, classical
homocystinuria without methylmalonic aciduria
kabuki syndrome
legionellosis
malignant atrophic papulosis
oculocutaneous albinism
omenn syndrome
papillon-lefèvre syndrome
primary effusion lymphoma
primary hyperoxaluria type 1
pyomyositis
severe combined immunodeficiency
sneddon syndrome
werner syndrome
wiskott-aldrich syndrome
wolf-hirschhorn syndrome
x-linked adrenoleukodystrophy
This symptom has already been validated