V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations

Villa, Anna; Sobacchi, Cristina; Notarangelo, Luigi D.; Bozzi, Fabio; Abinun, Mario; Abrahamsen, Tore G.; Arkwright, Peter D.; Baniyash, Michal; Brooks, Edward G.; Conley, Mary Ellen; Cortés, Patricia; Duse, Marzia; Fasth, Anders; Filipovich, Alexandra M.; Infante, Anthony J.; Jones, Alison; Mazzolari, Evelina; Müller, Susanna; Pašić, Srdjan; Rechavi, Gideon; Sacco, Maria Grazia; Santagata, Sandro; Schroeder, Marlis L.; Seger, Reinhard; Strina, Dario; Ugazio, Alberto G.; Väliaho, Jouni; Vihinen, Mauno; Vogler, Larry B.; Ochs, Hans D.; Vezzoni, Paolo; Friedrich, Wilhelm; Schwarz, Klaus

doi:10.1182/blood.v97.1.81

Cited by 310 publications

(315 citation statements)

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“…The G1095A mutation, resulting in a C328Y substitution, was identified in a 3-month-old patient presenting with some of the clinical features of OS, including skin rash, pneumonia, lymphadenopathy, and hepatomegaly (7). Although this patient displayed a severe reduction in circulating B lymphocytes (Ͻ1% of total lymphocytes), the overall immunological phenotype differed in several respects from the typical OS profile.…”

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confidence: 94%

“…OS features a specific spectrum of clinical manifestations including erythroderma, lymphadenopathy, and frequent severe infections (1,2). Mutations in RAG1 and RAG2 and less frequently in the DCLRE1C gene, encoding the Artemis protein, or other loci have been identified in OS patients (3)(4)(5)(6)(7). The RAG1 and RAG2 proteins constitute a lymphoid-specific endonuclease required for the development of both B and T lymphocytes (8 -11).…”

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confidence: 99%

“…The mRAG1 core can also support development of both B and T cells in the mouse, but total V(D)J recombination is reduced and aberrant recombination is increased (21,22). Although the majority of the missense mutations in the human RAG1 (hRAG1) gene associated with OS result in amino acid substitutions in the core, at least three have been found in the N-TR (7,23).…”

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confidence: 99%

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Biochemical and Folding Defects in a RAG1 Variant Associated with Omenn Syndrome

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Anand

Bhattacharyya

et al. 2007

The Journal of Immunology

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The RAG1 and RAG2 proteins are required to assemble mature Ag receptor genes in developing lymphocytes. Hypomorphic mutations in the gene encoding RAG1 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 RAG1 RING finger/ubiquitin ligase domain (C325Y in murine RAG1) as well as an adjacent substitution (P326G). RAG1 C325Y 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 C325Y substitution severely abrogated ubiquitin ligase activity of the purified RAG1 RING finger domain, and the tertiary structure of the domain was altered. The P326G substitution also abrogated ubiquitin ligase activity but had a less severe effect on protein folding. RAG1 P326G also demonstrated a recombination impairment that was most pronounced when RAG1 levels were limiting. Thus, a correctly folded RAG1 RING finger domain is required for normal V(D)J recombination, and RAG1 ubiquitin ligase activity can contribute when the protein is present at relatively low levels.

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confidence: 94%

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Biochemical and Folding Defects in a RAG1 Variant Associated with Omenn Syndrome

Simkus

Anand

Bhattacharyya

et al. 2007

The Journal of Immunology

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“…About 30% of human SCID cases arise from a defect in V(D)J recombination (Table 1), leading to an early arrest of both B and T lymphocytes. This T-B-SCID condition can be either the result of deleterious mutations in the Rag1 and Rag2 genes (Villa et al, 2001), affecting the initiation of the V(D)J recombination, or else impinge on the DNA repair phase of the V(D)J recombination reaction. In the latter case, the immune deficiency is accompanied by an increased cellular sensitivity to ionizing radiation (IR) (RS-SCIDs), a condition resembling the murine scid situation.…”

Section: V(d)j Recombination Deficiencies In Humans: Rs-scids and Scimentioning

confidence: 99%

V(D)J and immunoglobulin class switch recombinations: a paradigm to study the regulation of DNA end-joining

et al. 2007

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The immune system is the site of intense DNA damage/ modification, which occur during the development and maturation of B and T lymphocytes. V(D)J recombination is initiated by the Rag1 and Rag2 proteins and the formation of a DNA double-strand break (DNA dsb). This DNA lesion is repaired through the use of the nonhomologous end-joining (NHEJ) pathway, several factors of which have been identified through the survey of immunodeficient conditions in humans and mice. Upon antigenic recognition in secondary lymphoid organs, mature B cells further diversify their repertoire through class switch recombination (CSR). CSR is a region-specific rearrangement process triggered by the activation-induced cytidine deaminase factor and also proceeds through the introduction of DNA dsb. However, unlike V(D)J recombination, CSR does not rely strictly on NHEJ for the repair of the DNA lesion. Instead, CSR, but not V(D)J recombination, requires the major factors of the DNA damage response. V(D)J recombination and CSR thus represent an interesting paradigm to study the regulation among the various DNA repair pathways. Oncogene (2007) 26, 7780-7791; doi:10.1038/sj.onc.1210875 Keywords: V(D)J recombination; class switch recombination; SCID; Artemis; Cernunnos; NHEJ V(D)J recombination and CSR: two rearrangement processes that shape the immune system repertoire B and T lymphocytes respond to foreign pathogens through specialized antigenic receptors, the B-cell receptor and T-cell receptor, respectively. The required diversity of these receptors is ensured by the V(D)J recombination process (Figure 1) which assembles previously scattered Variable (V), Diversity (D) and Joining (J) encoding gene segments through a specialized somatic DNA rearrangement mechanism (Tonegawa, 1983). The reaction is initiated by the lymphoid-specific factors, Rag1 and Rag2, which recognize recombination signal sequences (RSS) that flank all V, D and J gene units and introduce a DNA dsb at the border of the RSS (see Dudley et al. (2005) for a review on V(D)J recombination). The resulting DNA double-strand break (DNA dsb) is resolved by the ubiquitous DNA repair machinery known as non-homologous end-joining (NHEJ). The convergent efforts of scientists in the immunology and DNA repair fields were decisive in defining the various actors and molecular mechanisms of this DNA repair pathway over the years as will be discussed below.The terminal maturation of B lymphocytes, which occurs in germinal centres of secondary lymphoid organs upon antigen recognition, is accompanied by two additional molecular processing of immunoglobulin genes that increase the efficiency of the humoral response: (1) the class switch recombination (CSR, Figure 2) exchanges the immunoglobulin (Ig) constant region (CH), thus modifying the function of the Ig without altering its antigenic specificity (Manis et al., 2002b) and (2) somatic hypermutations are introduced in the Ig variable domains, thus increasing their affinity for antigen (Papavasiliou and Schatz, 2002). These two events ar...

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“…In the first set, mutations in either Rag1 or Rag2 genes [17] hamper initiation of V(D)J recombination, hence causing an early block of B and T cell maturation similar to the situation of Rag1 and Rag2 knockout (KO) mice [18,19]. The other group of patients does not harbor Rag1/2 mutations but instead resembles the murine scid condition since the alymphocytosis is accompanied by an increased cellular sensitivity to ionizing radiations, thus revealing a major defect in DNA repair in these radiosensitive SCID (RS-SCID) patients [20].…”

Section: Human Radiosensitive Scidmentioning

confidence: 99%

DNA repair and the immune system: From V(D)J recombination to aging lymphocytes

et al. 2007

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B and T lymphocytes are exposed to various genotoxic stresses during their life, which originate from programmed molecular mechanisms during their development and maturation or are secondary to cellular metabolism during acute phases of cell proliferation and activation during immune responses. How lymphocytes handle these multiple genomic assault has become a focus of interest over the years, perhaps beginning with the identification of the murine scid model in the early 80s when it was recognized that DNA repair deficiencies had profound consequences on the immune system. In this respect, the immune system represents an ideal model to study DNA damage responses (DDR) and the survey of immune deficiency conditions in humans or the development of specific animal models provided many major contributions in our understanding of the various biochemical pathways at play during DDR in general. Although the role of DNA repair in the early phases of B and T cell development has been analyzed thoroughly, the role of these functions in various aspects of the mature immune system (homeostasis, immunological memory, ageing) is less well understood. Lastly, the analysis of DNA repair in the immune system has provided many insights in the more general understanding of cancer. IntroductionAll living organisms are exposed to endogenous and environmental genotoxic stresses causing DNA injuries. Among these lesions, DNA double-strand breaks (DNAdsb) are considered as the most harmful. Unrepaired DNA damage can lead to mutation, cancer, or cell death. Several cellular responses are triggered, in what is called the DNA damage response (DDR), to handle DNA lesions (Fig. 1). The purpose of this review is not to go in the depth of the various biochemical pathways that constitute the DDR, as this aspect has been covered elsewhere [1], but rather to discuss, in an historical way, how the immune system depends on these pathways on one hand, and how studies of the immune system have been instrumental in the better understanding of some of these pathways, in particular the non-homologous end joining (NHEJ) pathway. Indeed, the immune system is the place of many genotoxic stresses that happen at various time points during the development and maturation of lymphocytes (Fig. 2). These DNA We discuss here the links that exist between the immune system and the DDR with the standpoint of the lymphocyte lifespan, from birth to ageing, and discuss the consequences of DNA repair defects on the integrity of the immune system. Development of the immune system V(D)J recombinationB and T lymphocytes respond to foreign pathogens through specialized antigenic receptors, the BCR and TCR, respectively. The required diversity of these receptors is ensured by the V(D)J recombination process (Fig. 3), which assembles previously scattered variable (V), diversity (D), and joining (J) encoding gene segments through a specialized somatic DNA rearrangement mechanism [2]. The reaction is initiated by the lymphoid-specific factors Rag1 and Rag2, which specifically...

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V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations

Cited by 310 publications

References 31 publications

Biochemical and Folding Defects in a RAG1 Variant Associated with Omenn Syndrome

Biochemical and Folding Defects in a RAG1 Variant Associated with Omenn Syndrome

V(D)J and immunoglobulin class switch recombinations: a paradigm to study the regulation of DNA end-joining

DNA repair and the immune system: From V(D)J recombination to aging lymphocytes

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