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IMMUNOBIOLOGY
Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J
recombinase activity can cause either T-B–severe combined
immune deficiency or Omenn syndrome
Barbara Corneo, Despina Moshous, Tayfun Güngör, Nicolas Wulffraat, Pierre Philippet,
Françoise Le Deist, Alain Fischer, and Jean-Pierre de Villartay
Omenn syndrome (OS) is an inherited
disorder characterized by an absence of
circulating B cells and an infiltration of
the skin and the intestine by activated
oligoclonal T lymphocytes, indicating that
a profound defect in the lymphoid developmental program could be accountable
for this condition. Inherited mutations in
either the recombination activating genes
RAG1 or RAG2, resulting in partial V(D)J
recombinase activity, were shown to be responsible for OS. This study reports on the
characterization of new RAG1/2 gene mutations in a series of 9 patients with OS. Given
the occurrence of the same mutations in
patients with T-B–severe combined immune
deficiency or OS on 3 separate occasions,
the proposal is made that an additional
factor may be required in certain circumstances for the development of the Omenn
phenotype. The nature of this factor is
discussed. (Blood. 2001;97:2772-2776)
© 2001 by The American Society of Hematology
Introduction
The diversity of immunoglobulins and T-cell receptors (TCRs) is
mediated by the somatic recombination of genes encoding variable
(V), diversity (D), and joining (J) segments by a mechanism known
as V(D)J recombination.1 The RAG1 and RAG2 proteins, the
expression of which is restricted to immature lymphocytes, initiate
the reaction. The RAG1/2 complex introduces a DNA doublestrand break (dsb) in the recombination signal sequences (RSSs),
composed of conserved heptamer and nonamer separated by either
12 or 23 bp, that flank all V, D, and J segments.2-6 During the
subsequent steps, a nonlymphoid-specific machinery is responsible
for the repair of this DNA damage.7,8 Faulty V(D)J recombination
generally results in the arrest of both B- and T-cell development,
leading to severe combined immune deficiency (SCID). This was
documented in several settings including the targeted deletion of
the RAG1 and RAG2 genes,9,10 the inactivation of other known
components of the DNA repair machinery,11-15 as well as the
murine and equine SCID conditions in which the DNA-dependent
protein kinase (DNA-PKcs) encoding gene is mutated.16,17 A
similar condition exists in humans, characterized by a complete
absence of both B and T cells (T-B-SCID).18,19 We have previously
shown that 2 subsets can be individualized within this group of
patients depending on cell sensitivity to ionizing radiation.20,21 In
the first one (OMIM no. 601457) the initial phase of the V(D)J
recombination is impaired, owing to mutations in either the RAG1
or RAG2 gene,22,23 although cell sensitivity to radiation is normal.
The second subset (OMIM no. 602450), the affected gene of which
is not known yet,24 is characterized by a defect in DNA-break
repair as judged by the increased ␥-ray sensitivity and the inability
to rejoin coding ends during V(D)J recombination.25
Omenn syndrome (OS) (OMIM no. 603554) is yet another
SCID condition characterized by the early occurrence in life of
diffuse erythrodermia, hepatosplenomegaly, protracted diarrhea,
and failure to thrive.26,27 No circulating mature B cells are found in
these patients despite the usually high level of serum IgE. This is in
sharp contrast with the detection of a large number of poorly
functional, activated (HLA-DR⫹) T lymphocytes in blood, together
with eosinophils. These T cells, which are not of maternal origin,
produce TH2-type cytokines28-32 and infiltrate the skin, the gut, the
liver, and the spleen, causing a graft-versus-host (GVH)–like
disease.27,33-37 The T-cell population in patients with OS exhibits an
extremely restricted TCR heterogeneity34,36-38 in the periphery as
well as in the thymus,32 which is strongly suggestive of a defect in
the lymphoid developmental program. In addition, the finding in
the same kindred of siblings with either OS or T-B-SCID strengthened this hypothesis and suggested that an impaired V(D)J
recombination could be the underlying molecular defect in this
condition.27 Indeed, mutations in both RAG1 and RAG2 genes were
described in patients with OS.32,38-40 We report here the analysis of
RAG1/2 genes in a series of 9 OS patients. Three of these
mutations, causing OS in some patients, were also associated with
typical T-B-SCID condition in other patients. Altogether, this result
suggests that a low level of V(D)J recombination caused by a leaky
mutation in either RAG1 or RAG2 gene may not always be
sufficient to account for the Omenn condition.
From the Dèveloppement Normal et pathologique du Système Immunitaire, Hôpital
Necker Enfants Malades, Paris, France; Division of Immunology/Haematology,
University Children’s Hospital, Zurich, Switzerland; Pediatric Immunology, Children’s
Hospital, Utrecht, The Netherlands; and Division of Pediatric, Immuno-hematology,
C. H. St Joseph–Espèrance, Montegnèe-Liège, Belgium.
Deutsche Forschungsgemeinschaft. B.C. is supported by scholarships from
ARC and Ligue Contre le Cancer.
Submitted September 18, 2000; accepted December 19, 2000.
Supported by institutional grants from Institut National de la Santè et de la
Recherche Mèdicale and Ministëre de l’Education Nationale de la Recherche
et de la Technologie, and grants from Association de Recherche sur le Cancer
(ARC), Association contre les myopathies (AFM) Commissariat l’Energie
Atomique (CEA-LRC 7V). D.M. is supported by scholarships from ARC and the
2772
B.C. and D.M. contributed equally to this work.
Reprints: Jean-Pierre de Villartay, INSERM U429, Hôpital Necker Enfants
Malades, 149 rue de Sèvres, 75015 Paris, France; e-mail: devillar@
infobiogen.fr.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
© 2001 by The American Society of Hematology
BLOOD, 1 MAY 2001 䡠 VOLUME 97, NUMBER 9
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BLOOD, 1 MAY 2001 䡠 VOLUME 97, NUMBER 9
RAG1/2 MUTATIONS IN OMENN SYNDROME AND T-B-SCID
2773
Table 1. Clinical and biologic characteristics of patients with Omenn syndrome
Patients
Sex
OM1
OM2
OM3
OM4
OM5
OM6
OM7
OM8
OM9
F
F
M
M
F
F
F
F
M
Age (mo)
Consanguinity
4
⫹
4
2
⫹
⫹
2.5
⫺
0.2
⫹
3
⫺
5
⫺
4
2
⫺
⫺
Lymph (/␮L)
8160
9500
19 500
3000
12 700
6000
1500
22 400
10 000
CD3 (/␮L)
6000
7700
17 000
2800
6800
4800
1000
18 400
7400
DR⫹ (/␮L)
1800
3700
12 000
nd
5100
nd
850
14 700
nd
CD19 (/␮L)
0
190
0
0
127
0
0
1380
(⫹)
1900
nd
90
380
nd
20 000
⬎1000
nd
nd
6700
500
nd
nd
CD56 (/␮L)*
nd
nd
IgE (KU/L)
215
⬎3000
38 300
64
Eosino (/␮L)
952
1390
10 700
3200
5600
60
0
nd
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
RAG1/2†
C2306T
G3030A
⌬T631
1)C1322T
⌬T631
1)G1533A
1)G1983A
1)⌬AA368
1)A1316G
mutations
L732F
R973H
T173FS
R404W
T173FS
Erythrodermia
2)⌬T2735
S875FS
Mutation in T cells
⫹
⫹
⫹
⫹
⫹
R474H
R624H
K86FS
R39G
2)G2301T
2)A3086G
2)T1111A
2)G1887A
G730F
K992E
Y333X
R229Q
nd
nd
nd
nd
nd indicates not determined; IgE, immunoglobulin E; X, nonsense; FS, frameshift.
*(⫹) functional NK activity in OM5.
†RAG1 mutations in OM1-8, RAG2 mutations in OM9.
Western blot
Patients, materials, and methods
Patients
Patients OM1 to OM9 are suffering from typical OS (Table 1) as defined
by early onset of diffuse erythrodermia, protracted diarrhea, eosinophilia, failure to thrive, and expansion of oligoclonal, activated,
patient-derived T lymphocytes.26,27 P27, P42, and P52 presented with a
typical phenotype of autosomal T-B-recessive SCID18 with no circulating B cells, no circulating T cells for P42, and few T cells of patient
origin in P27 and P52 (150/␮L in each case); natural killer (NK) cells
were present in all of them. Patient 42 and OM9 are siblings and were
described previously.27 Patients OM1, OM2, OM3, OM5, and P52 were
from consanguineous families. Informed consent was obtained from the
patients’ parents prior to this study.
RAG1 and RAG2 gene sequencing and cloning
The RAG1 gene coding sequence was amplified by polymerase chain
reaction (PCR) on genomic DNA obtained from whole blood using
R1F7B 5⬘-CGGGATCCTTATAAGATACATCAGTGGG-3⬘ and R1R6X
5⬘-GCTCTAGAGCCCCATACACAGCAGTAA-3⬘ primers and the expand high fidelity PCR reaction system (Roche Molecular Biochemicals,
Meylan, France) according to the manufacturer’s recommendations.
Nucleotide primers were chosen on the HuRAG1 sequence from Schatz
and colleagues.2 The RAG2 coding sequence was amplified as previously described.23 PCR products were directly sequenced using internal
primers and the dRhodamine terminator cycle sequencing kit (Applied
Biosystems, Warrington, United Kingdom). For V(D)J recombination
assays, RAG1 and RAG2 PCR products were subcloned together with a
c-myc epitope as BamHI-XbaI fragments in pcDNA1.1 vector (Invitrogen,
Groningen, The Netherlands).
Figure 1. Structure of the human RAG1 protein and localization of missense mutations causing OS. Mutations are from
Villa and colleagues38 (black on gray), Wada and coworkers39
(white on black), and this report (black on white). All the mutations
are located within the active core (amino acids 384-1009) of the
protein and some of them involve the homeodomain or one of the
RAG2 interaction domains.49 Many of the mutations map close to
the 3 acidic residues (DDE) defining the catalytic site of RAG1.
Wild-type (wt) and mutated RAG1 expression constructs were transfected
into 293T cells by conventional CaPO4 precipitation. Forty-eight hours
after transfection, cells were lyzed in 500 ␮L lysis buffer, 10 mM Tris (pH
8, 1% NP-40, 10 mM NaCl, 0.2 mM phenylmethylsulfonyl fluoride
[PMSF]) and spun 2 minutes at 15 000 rpm as described.41 The nuclear
fractions were solubilized in nuclear lysis buffer (10 mM Tris [pH 8], 1%
NP-40, 0.4 mM NaCl, 20 mM HEPES, 0.2 mM PMSF, 10 ␮g/mL pepstatin
and aprotinin) and clarified by centrifugation 15 minutes at 15 000g. The
pellet representing the insoluble fraction was resuspended in 100 ␮L 2 ⫻
Laemmli loading buffer and sonicated. Then, 10 ␮L was loaded on 8%
sodium dodecyl sulfate (SDS)–polyacrylamide gel. After transfer, RAG1
proteins were detected by Western blot with an anti-myc antibody (clone
9E10, Santa Cruz Biotechnology, Santa Cruz, CA).
V(D)J recombination assay
The V(D)J recombination assay was carried out in fibroblasts as described
previously.25 Briefly, 5 ⫻ 106 exponentially simian virus 40 (SV40)–
transformed fibroblasts were electroporated in 400 ␮L complete culture
medium (RPMI 1640, 10% fetal calf serum [FCS]) with 6 ␮g RAG1 and 4.8
␮g RAG2 encoding plasmids, carrying either the wt or the mutated
sequences, together with 2.5 ␮g pHRecCJ, pHRecSJ, or pH2V14CJ (see
below) V(D)J extrachromosomal substrates. Following transfection and
recovery of the extrachromosomal constructs, the V(D)J recombination
frequency was assessed by plating bacteria on X-Gal containing plates.
V␤14-RSS sequence analysis and cloning
V␤14 RSS sequences were PCR-amplified from genomic DNA using
V14-F1 5⬘-CAGCCCCAACCAGACCTCT-3⬘ and V14-R1 5⬘-CTGCCCAACTTTGAAACCTCA-3⬘ primers and directly sequenced using dRhodamine terminator cycle sequencing kit. pH2V14CJ construct was derived
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2774
BLOOD, 1 MAY 2001 䡠 VOLUME 97, NUMBER 9
CORNEO et al
Table 2. In vitro V(D)J recombination assay with RAG1 mutants causing Omenn syndrome
pHRecCJ (coding joints)
pHRecSJ (signal joints)
RAG1
Blue col
Total
R(⫻ 10⫺3)*
Blue col
Total
Wild type
39
11 800
9.9
560
53 360
10.5
0
66 500
⬍ 0.01
0
930 000
⬍ 0.001
L732F
R(⫻ 10⫺3)†
R973H
0
66 000
⬍ 0.01
1
17 220
0.06
⌬T631
24
44 320
1.6
42
36 000
1.16
R404W
0
64 000
⬍ 0.01
0
876 000
⬍ 0.001
S875FS3
0
117 000
⬍ 0.008
1
36 960
0.03
R474H
8
78 300
0.30
0
24 400
⬍ 0.04
G720C
0
27 000
⬍ 0.03
0
22 000
⬍ 0.04
R624H
0
117 000
⬍ 0.008
0
7000
⬍ 0.14
K992E
0
31 500
⬍ 0.03
0
15 000
⬍ 0.06
K86FS
0
19 840
⬍ 0.05
0
15 400
⬍ 0.06
Y333X
1
67 800
0.04
0
27 600
⬍ 0.03
FS indicates frameshift mutation; X, nonsense mutation.
*R (coding joints) ⫽ 3 ⫻ (Blue col)/(Total) ⫻ 1000.
†R (signal joints) ⫽ (Blue col)/(Total) ⫻ 1000.
from pHRecCJ by replacing the RSS-23 (SalI-EcoRI) with that of V␤14
obtained by annealing the following oligos: 5⬘-AATTCCAAGCTTATCGATACCGTCGAGTGTTTTTGTGCAGAGAGCAGCTGGCTGTGCAACACTGTGGATAAACTGCTGGCACAGG-3⬘ and 5⬘-TCGACCTGTGCCAGCAGTTTATCCACAGTGTTGCACAGCCAGCTGCTCTCTGCACAAAAACACTCGACGGTATCGATAAGCTTGG-3⬘. The V␤14RSS oligos include 19 V␤14-encoding nucleotides (in bold) upstream of the
RSS heptamer motif, because coding bases flanking the RSSs were found to
modify the V(D)J recombination efficiency in the context of particular
RAG1 mutations.42,43
Results
RAG1 mutations in OS
The RAG1 and RAG2 genes were analyzed by genomic sequencing
in a series of 9 patients with typical characteristics of OS including
a high number of T lymphocytes (1500-22 400/␮L) bearing
HLA-DR activation marker, an almost complete absence of
circulating B cells, a hypereosinophilia in 7 of 9 cases and an
erythrodermia in all cases (Table 1). Eleven mutations in RAG1 and
2 mutations in RAG2 were found either as homozygous or
compound heterozygous. The mutations were always found inherited from both parents. In OM3, OM5, and OM8, mutations were
either nonsense (Y333X in OM8) or involved deletion of one
(⌬T631 in OM3 and OM5) or 2 (⌬AA368 in OM8) nucleotides
resulting in a frameshift and the appearance of premature stop
codons early in the coding sequence, before the active core of the
protein (amino acids 384-1009).44-46 These mutations are, in theory,
not compatible with any activity of the RAG1 protein and should
have resulted in a complete T-B-SCID phenotype when present on
both chromosomes, which is the case for OM3 and OM5.
Altogether, the homozygous ⌬T631 mutation was found in 3
siblings of OM3 family, in OM5, in another unrelated patient (data
not shown) as well as in a recently described OS patient.40 All these
OS patients originate from the Mediterranean border. To explain
the “leaky” V(D)J recombination phenotype in these patients, one
has to assume that the premature stop codon generated by the
⌬T631 mutation is bypassed by an alternative translation initiation
through a downstream AUG codon, giving rise to an N-terminal
truncated protein still containing the entire active core domain.
Translation reinitiation is not unprecedented and has previously
been described in mammalian cells to abrogate nonsense-mediated
messenger RNA (mRNA) decay.47 Noordzij and colleagues recently demonstrated that a natural alternative translation initiation
site exists in human RAG1, at position 202, that leads to a
N-terminal truncated protein of 100 kd.40 They demonstrated that
this alternative AUG codon allows for the production of a truncated
RAG1 in the context of the ⌬T631 mutation protein, albeit at a very
low level when compared to full-length wt RAG1. In case of OM4,
the premature stop codon resulting from the ⌬T2735 mutation
almost certainly corresponds to a null RAG1 allele because it is
located within the active core. The Omenn phenotype likely results
from the missense mutation (R404W) on the other allele in
this patient.
Seven of the RAG1 gene mutations (Figure 1) were single
nucleotide changes leading to amino acid substitutions (L732F,
R973H, R404W, R474H, G720C, R624H, and K992E) (singleletter amino acid codes). All these mutations are located in the core
region of RAG1. To formally exclude the possibility that these
mutations could represent polymorphisms, we performed V(D)J
recombination assays in fibroblasts with mutated RAG1 constructs
(Table 2). The recombination frequencies obtained were dramatically reduced compared to those obtained with the wt RAG1
plasmid for all the mutations tested except for the ⌬T631 (see
above). This was true when using reporter construct specific for
either the coding (pHRecCJ) or the signal (pHRecSJ) joint
formation. Missense mutations did not result in unstable proteins as
judged by Western blot analysis (Figure 2). One mutation (R404W)
is located within the homeodomain of RAG1,48 a region involved
in DNA binding and previously associated with other mutations in
patients with OS.38 R973H and K992E missense mutations are
located in one of the 2 domains of RAG1 previously shown to be
required for a proper interaction with RAG2.49 Finally, it is
interesting to note that none of the mutations described to date in
OS patients directly affect the 3 recently defined acidic residues
(D603, D711, and E965) composing the catalytic active site of the
protein.50-52 However, 10 of them are located close to these
residues, whereas the others are clustered in the homeodomain,
therefore sharpening the critical regions of RAG1. The emergence
of few T cell clones in OS patients could have theoretically been
Figure 2. Western blot analysis of RAG1 mutants. The wt and RAG1 mutants were
expressed in 293T cells and revealed by Western blot using an anti-myc antibody.
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BLOOD, 1 MAY 2001 䡠 VOLUME 97, NUMBER 9
RAG1/2 MUTATIONS IN OMENN SYNDROME AND T-B-SCID
2775
Table 3. The same mutation in RAG1 or RAG2 can cause severe combined immune deficiency or Omenn syndrome
Patients
Phenotype
OS2*
P27
OM3/5
P52
OM9†
P42†
Omenn
SCID
Omenn
SCID
Omenn
SCID
150
6300
0
0
0
T lymphocyte (/␮L)
150
B lymphocyte (/␮L)
0
Mutation
19 500/12 700
0/0
0
RAG1
RAG1
RAG2
(R561H)
(⌬T631)
(R39G, R229Q)
OS indicates Omenn syndrome; SCID, severe combined immune deficiency.
*OS2 was described in Villa and colleagues.38
†OM9 and P42 are two previously described siblings presenting OS and SCID conditions, respectively.27
the result of the reversion of the RAG1 gene mutations in precursor
cells as previously described in another SCID condition.53 DNA
sequence analysis of purified T cells from patients OM1 through
OM5 revealed the presence of the RAG1 mutations on both alleles,
ruling out the possibility of a reversion and therefore attesting that
residual V(D)J activity in the context of “leaky” RAG1 mutations
was responsible for the emergence of few T-cell clones in these
patients. This is also likely to be true for B lymphocytes because
OS patients secrete immunoglobulins (hyper IgE), although the
reason for an absence of detectable B cells in the periphery is not
yet fully understood.
Some RAG1/2 mutations can cause both OS and T-B-SCID
We have previously described a family with both T-B-SCID (P42)
and OS (OM9) affected siblings.27 Two identical compound
heterozygous mutations in the RAG2 gene (R39G and R229Q)
were found in these 2 patients (Tables 1 and 3). R229Q substitution
was previously described in another OS patient32 as well as in a
T-B-SCID patient bearing a RAG1 deletion on the other allele.22
The V(D)J recombination assay using RAG2 expression plasmid
harboring these mutations clearly established their deleterious
effect on recombination in vitro (Corneo et al23 and data not
shown). Altogether, RAG2-R229Q mutation is equally associated
with OS (2 of 4 cases) and T-B-SCID (2 of 4 cases). In addition, the
RAG1 ⌬T631 mutation, present in several OS patients, was also
responsible for the SCID phenotype in P52 (Table 3). Interestingly,
the presence of few autologous T cells (150/␮L) in this patient,
which attests for the leakiness of the mutation, was not accompanied by the clinical and biologic manifestations of OS. Lastly, we
found the same homozygous RAG1-R561H missense mutation,
first identified in the OS patient OS2 described by Villa and
coworkers,38 in a T-B-SCID patient (P27 in Table 3) who had also
very few circulating autologous T lymphocytes (150/␮L) without
OS manifestation. These 3 observations clearly demonstrate that
residual V(D)J recombinase activity in the context of mutated
RAG1 or RAG2 proteins may not always be sufficient to cause the
OS phenotype, leaving the possibility for the existence of additional factors required for the development of OS. Because OS is
caused by “leaky” mutations, which are by essence variables, one
can imagine that depending on the degree of leakiness, an
additional factor may or may not be required for full OS phenotype
expression. A precise survey of RAG1 and RAG2 mutations in new
T-B-SCID patients and OS should clarify this issue in the future.
Discussion
Hypothesis for an additional factor involved
in the development of OS
If “leaky” mutations in RAG1 or RAG2 are not solely responsible
for the development of OS, what could be the additional factor(s)
required to switch from T-B-SCID to OS? Two important characteristics of T cells from OS patients have to be considered in trying to
address this issue. First, despite the important restriction in the
T-cell repertoire in OS patients, some TCR-V␤ such as V␤14 are
often represented at high frequency in these patients.36 This finding
could suggest that V␤14 is preferentially rearranged in the context
of suboptimal recombinase activity in OS patients. To test this
hypothesis we first cloned the V␤14 RSS (together with 19
nucleotides of the flanking V␤14 coding sequence) in the pHRecCJ
V(D)J reporter plasmid and performed the V(D)J recombination
assay with either wt RAG1 or mutated forms of RAG1 (Table 4).
The pH2V14CJ reporter construct did not show a higher in vitro
recombination frequency over pHRecCJ when using wt RAG1/2.
Moreover, this construct was not rearranged in the context of the
Omenn-specific mutated RAG1 or RAG2 proteins. We also ruled
out the possibility, by DNA sequencing, of a polymorphism in the
V␤14 RSS that would be specifically present in OS patients and
would render this V␤ prone to V(D)J recombination in the context
of “leaky” RAG1/2 mutations (data not shown). The second
striking peculiarity of the few T-cell clones present in OS patients is
their continuous in vivo activation and their presence in tissues
such as skin and gut, thus causing GVH-like disease.32,33,36 We and
others proposed that in the context of a defective T-cell developmental program, few emerging T cells, already present in the thymus,32
could expand in the absence of retrocontrol by other populations of
T lymphocytes.27 One challenging hypothesis would be that a
particular antigen, present in some OS patients but not in
T-B-SCID patients, triggers the few clones emerging in these
patients leading to their expansion and constant activation in
vivo. This antigenic hypothesis is further strengthened by the
Table 4. In vitro V(D)J recombination assay with V␤14–recombination signal sequences
pHRecCJ
pH2V14CJ
RAG1
wt
wt
R973H
L732F
R404Q
wt
wt
RAG2
wt
wt
wt
wt
wt
R39G
R229Q
Blue col
Total
R(⫻ 10⫺2)*
270
9
0
0
0
0
0
37 800
7800
34 500
20 700
88 800
156 000
117 000
2.1
0.1
⬍ 0.002
⬍ 0.004
⬍ 0.001
⬍ 0.0006
⬍ 0.0008
wt indicates wild type.
*R (coding joints) ⫽ 3 ⫻ (Blue col)/(Total) ⫻ 10.
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BLOOD, 1 MAY 2001 䡠 VOLUME 97, NUMBER 9
CORNEO et al
fact that several TCR characteristics, such as the nature of the
V␤ segment as well as the length and amino acid composition of
the CDR3 loop, observed in OS patients are recurrent.32,36 These
clones would otherwise die in the absence of the specific
antigen. Although the exact nature of this putative “Omenn”
antigen is at present totally unknown, one can assume that it
should be present in the epithelia of the skin and the gut, the 2
major sites of infiltration by activated T cells in OS patients.
This antigen could either be genetically encoded (autoantigen)
or provided by the environment (exoantigen).
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From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
2001 97: 2772-2776
doi:10.1182/blood.V97.9.2772
Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J
recombinase activity can cause either T-B−severe combined immune
deficiency or Omenn syndrome
Barbara Corneo, Despina Moshous, Tayfun Güngör, Nicolas Wulffraat, Pierre Philippet, Françoise Le Deist,
Alain Fischer and Jean-Pierre de Villartay
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