Targeted Disruption of the Artemis Murine Counterpart Results in SCID and Defective V(D)J Recombination That Is Partially Corrected with Bone Marrow Transplantation

Li, Lanying; Salido, Eduardo; Zhou, Yungui; Bhattacharyya, Swati; Yannone, Steven M.; Dunn, Elizabeth; Meneses, Juanito J.; Feeney, Ann J.; Cowan, Morton J.

doi:10.4049/jimmunol.174.4.2420

Cited by 34 publications

(55 citation statements)

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“…Our original linkage study mapped the SCIDA genetic defect to chromosome 10p 13 and we subsequently identified a founder mutation in Artemis as the cause of SCIDA in Navajo and Apache Native Americans. 8,14 Surprisingly, this Artemis mutation was not found in the three T À B À NK þ SCID children from two related kindreds of Dine Indians in the Canadian Northwest Territories, a linguistically and genetically related people.…”

Section: Introductionmentioning

confidence: 99%

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A novel missense RAG-1 mutation results in T−B−NK+ SCID in Athabascan-speaking Dine Indians from the Canadian Northwest Territories

et al. 2008

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DNA double-strand repair factors in the non-homologous end joining (NHEJ) pathway resolve DNA double-strand breaks introduced by the recombination-activating gene (RAG) proteins during V(D)J recombination of T and B lymphocyte receptor genes. Defective NHEJ and subsequent failure of V(D)J recombination leads to severe combined immunodeficiency disease (SCID). We originally linked T À B À NK þ SCID in Athabascan-speaking Native Americans in the Southwestern US and Northwest Territories of Canada to chromosome 10. However, despite a common ancestry, the null mutation in the Artemis gene that we found to be causal in the SCID among the Navajo and Apache Indians was not present in the Dine Indians in the Northwest Territories. We now report a novel homozygous missense mutation (R776W) in RAG-1 in three children with T À B À NK þ SCID from two related families of Athabascan-speaking Dine Indians in the Canadian Northwest Territories. As expected, we found no increased sensitivity to ionizing radiation in patient fibroblasts. The impaired activity of this RAG-1 mutant in V(D)J recombination was confirmed by the EGFP-based V(D)J recombination assays. Overexpression of wild type RAG-1 in patient fibroblasts complemented V(D)J recombination, with recovery of both coding and signal joint formation. Our results indicate that the novel R776W missense mutation in RAG-1 is causal in the T À B À NK þ SCID phenotype in Athabascan-speaking Dine Indians from the Canadian Northwest Territories.

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Section: Introductionmentioning

confidence: 99%

“…The percentage of successful recombination was represented by the ratio of colonies grown on ampicillin and chloramphenicol (from recombined substrate only) vs ampicillin plates. 14 …”

Section: Egfp-based Inversional V(d)j Recombination Assaymentioning

confidence: 99%

A novel missense RAG-1 mutation results in T−B−NK+ SCID in Athabascan-speaking Dine Indians from the Canadian Northwest Territories

et al. 2008

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“…Mice that lack Rag1 (REFS 45,46), Rag2 (REFS 47,48), Zap70 (REFS 49-53), Il7ra 54 or Dclre1c 55,56 show a severe defect in the production of T cells. These knockout mouse models accurately represent the alleles associated with severe disease in humans, but do not reflect the complex clinical presentation associated with alternative alleles.…”

Section: Antinuclear Antibodiesmentioning

confidence: 99%

Unravelling the association of partial T-cell immunodeficiency and immune dysregulation

2008

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| Partial T-cell immunodeficiencies constitute a heterogeneous cluster of disorders characterized by an incomplete reduction in T-cell number or activity. The immune deficiency component of these diseases is less severe than that of the severe T-cell immunodeficiencies and therefore some ability to respond to infectious organisms is retained. Unlike severe T-cell immunodeficiencies, however, partial immunodeficiencies are commonly associated with hyper-immune dysregulation, including autoimmunity, inflammatory diseases and elevated IgE production. This causative association is counterintuitive -immune deficiencies are caused by loss-of-function changes to the T-cell component, whereas the coincident autoimmune symptoms are the consequence of gain-offunction changes. This Review details the genetic basis of partial T -cell immunodeficiencies and draws on recent advances in mouse models to propose mechanisms by which a reduction in T-cell numbers or function may disturb the population-dependent balance between activation and tolerance.

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“…Similarly, NHEJ factor gene inactivation in mice results in a profound impaired B-and T-cell development. [8][9][10][11][12][13][14] After completion of V(D)J recombination, mature immunoglobulin M ϩ (IgM ϩ ) B cells migrate to secondary lymphoid organs, where the immune B-cell repertoire is further shaped by 2 independent processes: somatic hypermutation and class switch recombination (CSR), which enhances the affinity and modifies the effector function of antibodies, respectively, without altering their antigenic specificity. CSR results in the replacement of the IgM constant region (C) with one of the downstream C H gene (␥, ⑀, or ␣) by a recombination mechanism between large repetitive switch (S) regions located upstream each constant region (except ␦), allowing for the fusion of the 2 S regions and excision of intervening DNA.…”

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Reduced immunoglobulin class switch recombination in the absence of Artemis

Rivera-Munoz

Soulas-Sprauel

Guyader

et al. 2009

Blood

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IntroductionThe large diversity of antigen receptors on T and B cells is provided in lymphoid organs by different mechanisms. The first one, the V(D)J recombination, allows for the somatic rearrangement of V (variable), D (diversity), and J (joining) gene loci into V(D)J segments coding for the variable antigen recognition domain of B-cell receptors and T-cell receptors. 1,2 This process is initiated by Rag (recombination acting gene) 1 and 2 endonuclease, which introduces DNA double-strand breaks (DSBs) between V, D, and J coding segments and flanking recombination signal sequences, thereby generating hairpin-sealed DNA coding ends on the chromosome and blunt signal ends excised from the chromosome. The repair of the DSBs is then ensured by the general DNA repair machinery, composed of at least 7 known factors of the nonhomologous end-joining (NHEJ) pathway: Ku70, Ku80, DNA-PKcs, Artemis (Art), XRCC4, Cernunnos/XLF, and DNA ligase IV. The DSB is recognized by the Ku70/Ku80 heterodimer, which recruits DNA-PKcs to form the DNA-PK complex. DNA-PKcs, a DNA-dependent PI3 kinase, recruits and activates Artemis by a phosphorylation process. Artemis is a 5Ј-3Ј exonuclease, which acquires an endonucleolytic activity on 5Ј and 3Ј overhangs as well as DNA hairpins on activation by DNA-PKcs in vitro whose function during V(D)J recombination is to open the hairpin-sealed coding ends. 3 Mutations in genes coding for NHEJ factors are responsible for the onset of various types of severe combined immunodeficiencies (SCID) in humans. [4][5][6][7] NHEJ represents the major DNA-DSB repair pathway in mammalian cells, and these patients present a cellular hypersensitivity to ionizing radiations (radiosensitive, RS-SCID). Similarly, NHEJ factor gene inactivation in mice results in a profound impaired B-and T-cell development. [8][9][10][11][12][13][14] After completion of V(D)J recombination, mature immunoglobulin M ϩ (IgM ϩ ) B cells migrate to secondary lymphoid organs, where the immune B-cell repertoire is further shaped by 2 independent processes: somatic hypermutation and class switch recombination (CSR), which enhances the affinity and modifies the effector function of antibodies, respectively, without altering their antigenic specificity. CSR results in the replacement of the IgM constant region (C) with one of the downstream C H gene (␥, ⑀, or ␣) by a recombination mechanism between large repetitive switch (S) regions located upstream each constant region (except ␦), allowing for the fusion of the 2 S regions and excision of intervening DNA. 15,16 The B-cell-specific activation-induced cytidine deaminase factor (AID) initiates the CSR reaction by deaminating cytidine residues to uracil within S regions in a transcriptiondependent manner, leading to DNA breaks in the 2 opposite strands of DNA. 17,18 Much experimental evidence supports the generation of DSBs during CSR, 15 although the exact molecular mechanism by which the initial AID-mediated DNA lesion is further processed to DNA-DSB is not yet fully understood. 19 As NHEJ r...

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Targeted Disruption of the Artemis Murine Counterpart Results in SCID and Defective V(D)J Recombination That Is Partially Corrected with Bone Marrow Transplantation

Cited by 34 publications

References 25 publications

A novel missense RAG-1 mutation results in T−B−NK+ SCID in Athabascan-speaking Dine Indians from the Canadian Northwest Territories

A novel missense RAG-1 mutation results in T−B−NK+ SCID in Athabascan-speaking Dine Indians from the Canadian Northwest Territories

Unravelling the association of partial T-cell immunodeficiency and immune dysregulation

Reduced immunoglobulin class switch recombination in the absence of Artemis

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