Human RAG mutations: Biochemistry and clinical implications

Nature Reviews Immunology

Volumn 16, Issue 4, 2016, Pages 234-246

  Notarangelo, Luigi D ^a   Kim, Min Sung ^b   Walter, Jolan E ^a,c   Lee, Yu Nee ^a  

^a BOSTON CHILDREN S HOSPITAL   (United States)

^b NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES   (United States)

^c MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

INTERLEUKIN 4; INTERLEUKIN 5; RAG1 PROTEIN; RAG2 PROTEIN; DNA BINDING PROTEIN; HOMEODOMAIN PROTEIN; NUCLEAR PROTEIN; RAG-1 PROTEIN; RAG2 PROTEIN, HUMAN;

ADAPTIVE IMMUNITY; AUTOIMMUNITY; B LYMPHOCYTE; CELL INFILTRATION; CELL POPULATION; DISEASE SEVERITY; EOSINOPHILIA; ERYTHRODERMA; GENE MUTATION; GENE REARRANGEMENT; GENE STRUCTURE; GENETIC VARIABILITY; GENOTYPE PHENOTYPE CORRELATION; HEPATOSPLENOMEGALY; HUMAN; IMMUNE DYSREGULATION; IMMUNOCOMPETENCE; IMMUNOGLOBULIN DEFICIENCY; LYMPHADENOPATHY; MOLECULAR PATHOLOGY; NEXT GENERATION SEQUENCING; NONHUMAN; NONVIRAL GENE THERAPY; OMENN SYNDROME; PHENOTYPE; PRIORITY JOURNAL; PROTEIN DEFICIENCY; RADIOSENSITIVITY; REVIEW; SEVERE COMBINED IMMUNODEFICIENCY; T LYMPHOCYTE; GENE THERAPY; GENETICS; IMMUNOLOGIC DEFICIENCY SYNDROMES; IMMUNOLOGY; MUTATION; VDJ RECOMBINATION;

B-LYMPHOCYTES; DNA-BINDING PROTEINS; GENETIC THERAPY; HOMEODOMAIN PROTEINS; HUMANS; IMMUNOLOGIC DEFICIENCY SYNDROMES; MUTATION; NUCLEAR PROTEINS; PHENOTYPE; SEVERE COMBINED IMMUNODEFICIENCY; T-LYMPHOCYTES; V(D)J RECOMBINATION;

EID: 84961279265     PISSN: 14741733     EISSN: 14741741     Source Type: Journal    
DOI: 10.1038/nri.2016.28     Document Type: Review

References (103)

1. Schatz, D. G., Oettinger, M. A. & Baltimore, D. The V(D)J recombination activating gene, RAG-1. Cell 59, 1035-1048 (1989).
2. Oettinger, M. A., Schatz, D. G., Gorka, C. & Baltimore, D. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 248, 1517-1523 (1990).
3. Mombaerts, P. et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68, 869-877 (1992).
4. Shinkai, Y. et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68, 855-867 (1992).
5. Schwarz, K. et al. RAG mutations in human B cell-negative SCID. Science 274, 97-99 (1996).
6. Villa, A. et al. Partial V(D)J recombination activity leads to Omenn syndrome. Cell 93, 885-896 (1998).
7. de Saint-Basile, G. et al. Restricted heterogeneity of T lymphocytes in combined immunodeficiency with hypereosinophilia (Omenn's syndrome). J. Clin. Invest. 87, 1352-1359 (1991).
8. Rieux-Laucat, F. et al. Highly restricted human T cell repertoire in peripheral blood and tissue-infiltrating lymphocytes in Omenn's syndrome. J. Clin. Invest. 102, 312-321 (1998).
9. Schuetz, C. et al. An immunodeficiency disease with RAG mutations and granulomas. N. Engl. J. Med. 358, 2030-2038 (2008).
10. Kim, M. S., Lapkouski, M., Yang, W. & Gellert, M. Crystal structure of the V(D)J recombinase RAG1-RAG2. Nature 518, 507-511 (2015).
11. Shetty, K. & Schatz, D. G. Recruitment of RAG1 and RAG2 to chromatinized DNA during V(D)J recombination. Mol. Cell. Biol. 35, 3701-3713 (2015).
12. Ru, H. et al. Molecular mechanism of V(D)J recombination from synaptic RAG1-RAG2 complex structures. Cell 163, 1138-1152 (2015).
13. Fischer, A., Notarangelo, L. D., Neven, B., Cavazzana, M. & Puck, J. M. Severe combined immunodeficiencies and related disorders. Nat. Rev. Disease Primers http://dx.doi.org/10.1038/nrdp.2015.61 (2015).
14. Pai, S. Y. et al. Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N. Engl. J. Med. 371, 434-446 (2014).
15. Nicolas, N. et al. A human severe combined immunodeficiency (SCID) condition with increased sensitivity to ionizing radiations and impaired V(D)J rearrangements defines a new DNA recombination/repair deficiency. J. Exp. Med. 188, 627-634 (1998).
16. Bosma, G. C., Custer, R. P. & Bosma, M. J. A severe combined immunodeficiency mutation in the mouse. Nature 301, 527-530 (1983).
17. Fulop, G. M. & Phillips, R. A. The scid mutation in mice causes a general defect in DNA repair. Nature 347, 479-482 (1990).
18. Woodbine, L., Gennery, A. R. & Jeggo, P. A. The clinical impact of deficiency in DNA non-homologous end-joining. DNA Repair (Amst.) 16, 84-96 (2014).
19. Omenn, G. S. Familial reticuloendotheliosis with eosinophilia. N. Engl. J. Med. 273, 427-432 (1965).
20. Schandene, L. et al. T helper type 2-like cells and therapeutic effects of interferon-γ in combined immunodeficiency with hypereosinophilia (Omenn's syndrome). Eur. J. Immunol. 23, 56-60 (1993).
21. Chilosi, M. et al. CD30 cell expression and abnormal soluble CD30 serum accumulation in Omenn's syndrome: evidence for a T helper 2-mediated condition. Eur. J. Immunol. 26, 329-334 (1996).
22. Signorini, S. et al. Intrathymic restriction and peripheral expansion of the T-cell repertoire in Omenn syndrome. Blood 94, 3468-3478 (1999).
23. Villa, A. et al. V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. Blood 97, 81-88 (2001).
24. Shearer, W. T. et al. Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience. J. Allergy Clin. Immunol. 133, 1092-1098 (2014).
25. de Villartay, J. P. et al. A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. J. Clin. Invest. 115, 3291-3299 (2005).
26. Ehl, S. et al. A variant of SCID with specific immune responses and predominance of γδ T cells. J. Clin. Invest. 115, 3140-3148 (2005).
27. Kwan, A. et al. Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA 312, 729-738 (2014).
28. Al-Herz, W. & Al-Mousa, H. Combined immunodeficiency: the Middle East experience. J. Allergy Clin. Immunol. 131, 658-660 (2013).
29. Corneo, B. et al. 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. Blood 97, 2772-2776 (2001).
30. Ijspeert, H. et al. Similar recombination-activating gene (RAG) mutations result in similar immunobiological effects but in different clinical phenotypes. J. Allergy Clin. Immunol. 133, 1124-1133 (2014).
31. Dalal, I. et al. Evolution of a T-B-SCID into an Omenn syndrome phenotype following parainfluenza 3 virus infection. Clin. Immunol. 115, 70-73 (2005).
32. Wada, T. et al. Oligoclonal expansion of T lymphocytes with multiple second-site mutations leads to Omenn syndrome in a patient with RAG1-deficient severe combined immunodeficiency. Blood 106, 2099-2101 (2005).
33. De Ravin, S. S. et al. Hypomorphic Rag mutations can cause destructive midline granulomatous disease. Blood 116, 1263-1271 (2010).
34. Avila, E. M. et al. Highly variable clinical phenotypes of hypomorphic RAG1 mutations. Pediatrics 126, e1248-e1252 (2010).
35. Henderson, L. A. et al. Expanding the spectrum of recombination-activating gene 1 deficiency: a family with early-onset autoimmunity. J. Allergy Clin. Immunol. 132, 969-971 (2013).
36. Walter, J. E. et al. Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency. J. Clin. Invest. 125, 4135-4148 (2015).
37. Sharapova, S. O. et al. Late-onset combined immune deficiency associated to skin granuloma due to heterozygous compound mutations in RAG1 gene in a 14 years old male. Hum. Immunol. 74, 18-22 (2013).
38. Patiroglu, T. et al. Atypical severe combined immunodeficiency caused by a novel homozygous mutation in Rag1 gene in a girl who presented with pyoderma gangrenosum: a case report and literature review. J. Clin. Immunol. 34, 792-795 (2014).
39. Chen, K. et al. Autoimmunity due to RAG deficiency and estimated disease incidence in RAG1/2 mutations. J. Allergy Clin. Immunol. 133, 880-882 (2014).
40. Buchbinder, D. et al. Identification of patients with RAG mutations previously diagnosed with common variable immunodeficiency disorders. J. Clin. Immunol. 35, 119-124 (2015).
41. + T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations. Blood 117, 5892-5896 (2011).
42. Abolhassani, H. et al. A hypomorphic recombination-activating gene 1 (RAG1) mutation resulting in a phenotype resembling common variable immunodeficiency. J. Allergy Clin. Immunol. 134, 1375-1380 (2014).
43. Kato, T. et al. RAG1 deficiency may present clinically as selective IgA deficiency. J. Clin. Immunol. 35, 280-288 (2015).
44. Geier, C. B. et al. Leaky RAG deficiency in adult patients with impaired antibody production against bacterial polysaccharide antigens. PLoS ONE 10, e0133220 (2015).
45. Chou, J. et al. A novel homozygous mutation in recombination activating gene 2 in 2 relatives with different clinical phenotypes: Omenn syndrome and hyper-IgM syndrome. J. Allergy Clin. Immunol. 130, 1414-1416 (2012).
46. Reiff, A. et al. Exome sequencing reveals RAG1 mutations in a child with autoimmunity and sterile chronic multifocal osteomyelitis evolving into disseminated granulomatous disease. J. Clin. Immunol. 33, 1289-1292 (2013).
47. Kuo, T. C. & Schlissel, M. S. Mechanisms controlling expression of the RAG locus during lymphocyte development. Curr. Opin. Immunol. 21, 173-178 (2009).
48. Landree, M. A., Wibbenmeyer, J. A. & Roth, D. B. Mutational analysis of RAG1 and RAG2 identifies three catalytic amino acids in RAG1 critical for both cleavage steps of V(D)J recombination. Genes Dev. 13, 3059-3069 (1999).
49. Kim, D. R., Dai, Y., Mundy, C. L., Yang, W. & Oettinger, M. A. Mutations of acidic residues in RAG1 define the active site of the V(D)J recombinase. Genes Dev. 13, 3070-3080 (1999).
50. Bellon, S. F., Rodgers, K. K., Schatz, D. G., Coleman, J. E. & Steitz, T. A. Crystal structure of the RAG1 dimerization domain reveals multiple zinc-binding motifs including a novel zinc binuclear cluster. Nat. Struct. Biol. 4, 586-591 (1997).
51. Matthews, A. G. et al. RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombination. Nature 450, 1106-1110 (2007).
52. Cortes, P., Ye, Z. S. & Baltimore, D. RAG-1 interacts with the repeated amino acid motif of the human homologue of the yeast protein SRP1. Proc. Natl Acad. Sci. USA 91, 7633-7637 (1994).
53. Deng, Z., Liu, H. & Liu, X. RAG1-mediated ubiquitylation of histone H3 is required for chromosomal V(D)J recombination. Cell Res. 25, 181-192 (2015).
54. Liu, Y., Subrahmanyam, R., Chakraborty, T., Sen, R. & Desiderio, S. A plant homeodomain in RAG-2 that binds hypermethylated lysine 4 of histone H3 is necessary for efficient antigen-receptor-gene rearrangement. Immunity 27, 561-571 (2007).
55. Shimazaki, N., Tsai, A. G. & Lieber, M. R. H3K4me3 stimulates the V(D)J RAG complex for both nicking and hairpinning in trans in addition to tethering in cis: implications for translocations. Mol. Cell 34, 535-544 (2009).
56. Jiang, H. et al. Ubiquitylation of RAG-2 by Skp2-SCF links destruction of the V(D)J recombinase to the cell cycle. Mol. Cell 18, 699-709 (2005).
57. Branzei, D. & Foiani, M. Regulation of DNA repair throughout the cell cycle. Nat. Rev. Mol. Cell Biol. 9, 297-308 (2008).
58. Lee, Y. N. et al. A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency. J. Allergy Clin. Immunol. 133, 1099-1108 (2014).
59. Mo, X., Bailin, T. & Sadofsky, M. J. A. C-terminal region of RAG1 contacts the coding DNA during V(D)J recombination. Mol. Cell. Biol. 21, 2038-2047 (2001).
60. Wong, S. Y., Lu, C. P. & Roth, D. B. A. RAG1 mutation found in Omenn syndrome causes coding flank hypersensitivity: a novel mechanism for antigen receptor repertoire restriction. J. Immunol. 181, 4124-4130 (2008).
61. Santagata, S. et al. N-terminal RAG1 frameshift mutations in Omenn's syndrome: internal methionine usage leads to partial V(D)J recombination activity and reveals a fundamental role in vivo for the N-terminal domains. Proc. Natl Acad. Sci. USA 97, 14572-14577 (2000).
62. Simkus, C., Anand, P., Bhattacharyya, A. & Jones, J. M. Biochemical and folding defects in a RAG1 variant associated with Omenn syndrome. J. Immunol. 179, 8332-8340 (2007).
63. Couedel, C. et al. Analysis of mutations from SCID and Omenn syndrome patients reveals the central role of the Rag2 PHD domain in regulating V(D)J recombination. J. Clin. Invest. 120, 1337-1344 (2010).
64. Itan, Y. et al. The human gene damage index as a gene-level approach to prioritizing exome variants. Proc. Natl Acad. Sci. USA 112, 13615-13620 (2015).
65. Noordzij, J. G. et al. The immunophenotypic and immunogenotypic B-cell differentiation arrest in bone marrow of RAG-deficient SCID patients corresponds to residual recombination activities of mutated RAG proteins. Blood 100, 2145-2152 (2002).
66. Yu, X. et al. Human syndromes of immunodeficiency and dysregulation are characterized by distinct defects in T-cell receptor repertoire development. J. Allergy Clin. Immunol. 133, 1109-1115 (2014).
67. Wesemann, D. R. et al. Immature B cells preferentially switch to IgE with increased direct Sμ to S∈ recombination. J. Exp. Med. 208, 2733-2746 (2011).
68. Cassani, B. et al. Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome. J. Exp. Med. 207, 1525-1540 (2010).
69. Walter, J. E. et al. Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency. J. Exp. Med. 207, 1541-1554 (2010).
70. Anderson, M. S. et al. Projection of an immunological self shadow within the thymus by the Aire protein. Science 298, 1395-1401 (2002).
71. + regulatory T cells in human thymus. Nature 436, 1181-1185 (2005).
72. Akiyama, T., Tateishi, R., Akiyama, N., Yoshinaga, R. & Kobayashi, T. J. Positive and negative regulatory mechanisms for fine-tuning cellularity and functions of medullary thymic epithelial cells. Front. Immunol. 6, 461 (2015).
73. Cavadini, P. et al. AIRE deficiency in thymus of 2 patients with Omenn syndrome. J. Clin. Invest. 115, 728-732 (2005).
74. Poliani, P. L. et al. Early defects in human T-cell development severely affect distribution and maturation of thymic stromal cells: possible implications for the pathophysiology of Omenn syndrome. Blood 114, 105-108 (2009).
75. Rucci, F. et al. Abnormalities of thymic stroma may contribute to immune dysregulation in murine models of leaky severe combined immunodeficiency. Front. Immunol. 2, 15 (2011).
76. Marrella, V. et al. Anti-CD3∈ mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn syndrome: therapeutic implications. Blood 120, 1005-1014 (2012).
77. Marrella, V. et al. A hypomorphic R229Q Rag2 mouse mutant recapitulates human Omenn syndrome. J. Clin. Invest. 117, 1260-1269 (2007).
78. Meager, A. et al. Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med. 3, e289 (2006).
79. Cassani, B. et al. Defect of regulatory T cells in patients with Omenn syndrome. J. Allergy Clin. Immunol. 125, 209-216 (2010).
80. Matangkasombut, P. et al. Lack of iNKT cells in patients with combined immune deficiency due to hypomorphic RAG mutations. Blood 111, 271-274 (2008).
81. Jankovic, M., Casellas, R., Yannoutsos, N., Wardemann, H. & Nussenzweig, M. C. RAGs and regulation of autoantibodies. Annu. Rev. Immunol. 22, 485-501 (2004).
82. Lesley, R. et al. Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity 20, 441-453 (2004).
83. Thien, M. et al. Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches. Immunity 20, 785-798 (2004).
84. Borghesi, L. et al. B lineage-specific regulation of V(D)J recombinase activity is established in common lymphoid progenitors. J. Exp. Med. 199, 491-502 (2004).
85. Pilbeam, K. et al. The ontogeny and fate of NK cells marked by permanent DNA rearrangements. J. Immunol. 180, 1432-1441 (2008).
86. Karo, J. M., Schatz, D. G. & Sun, J. C. The RAG recombinase dictates functional heterogeneity and cellular fitness in natural killer cells. Cell 159, 94-107 (2014).
87. Schuetz, C. et al. SCID patients with ARTEMIS versus RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID. Blood 123, 281-289 (2014).
88. Hacein-Bey-Abina, S. et al. Efficacy of gene therapy for X-linked severe combined immunodeficiency. N. Engl. J. Med. 363, 355-364 (2010).
89. Hacein-Bey-Abina, S. et al. A modified γ-retrovirus vector for X-linked severe combined immunodeficiency. N. Engl. J. Med. 371, 1407-1417 (2014).
90. Aiuti, A. et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N. Engl. J. Med. 360, 447-458 (2009).
91. Candotti, F. et al. Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans. Blood 120, 3635-3646 (2012).
92. Pike-Overzet, K. et al. Correction of murine Rag1 deficiency by self-inactivating lentiviral vector-mediated gene transfer. Leukemia 25, 1471-1483 (2011).
93. Lagresle-Peyrou, C. et al. Long-term immune reconstitution in RAG-1-deficient mice treated by retroviral gene therapy: a balance between efficiency and toxicity. Blood 107, 63-72 (2006).
94. van Til, N. P. et al. Recombination-activating gene 1 (Rag1)-deficient mice with severe combined immunodeficiency treated with lentiviral gene therapy demonstrate autoimmune Omenn-like syndrome. J. Allergy Clin. Immunol. 133, 1116-1123 (2014).
95. -/- mice: sustained correction of the immunodeficiency. Blood 100, 3942-3949 (2002).
96. van Til, N. P. et al. Correction of murine Rag2 severe combined immunodeficiency by lentiviral gene therapy using a codon-optimized RAG2 therapeutic transgene. Mol. Ther. 20, 1968-1980 (2012).
97. Feeney, A. J., Goebel, P. & Espinoza, C. R. Many levels of control of V gene rearrangement frequency. Immunol. Rev. 200, 44-56 (2004).
98. Teng, G. et al. RAG represents a widespread threat to the lymphocyte genome. Cell 162, 751-765 (2015).
99. Hesse, J. E., Lieber, M. R., Gellert, M. & Mizuuchi, K. Extrachromosomal DNA substrates in pre-B cells undergo inversion or deletion at immunoglobulin V-(D)-J joining signals. Cell 19, 775-783 (1987).
100. Gauss, G. H. & Lieber, M. R. Unequal signal and coding joint formation in human V(D)J recombination. Mol. Cell. Biol. 13, 3900-3906 (1987).
101. Liang, H. E. et al. The "dispensable" portion of RAG2 is necessary for efficient V-to-DJ rearrangement during B and T cell development. Immunity 17, 639-651 (2002).
102. Bredemeyer, A. L. et al. ATM stabilizes DNA double-strand-break complexes during V(D)J recombination. Nature 442, 466-470 (2006).
103. Rigoni, R. et al. Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects. J. Exp. Med. 213, 355-375 (2016).