200
Views
6
CrossRef citations to date
0
Altmetric
Review

Approaches to patients with variants in RAG genes: from diagnosis to timely treatment

, , &
Pages 1033-1046 | Received 22 May 2019, Accepted 17 Sep 2019, Published online: 10 Oct 2019

References

  • Schatz DG, Swanson PC. V(D)J recombination: mechanisms of initiation. Annu Rev Genet. 2011;45:167–202.
  • Tonegawa S. Somatic generation of antibody diversity. Nature. 1983;302(5909):575–581.
  • Gellert M. V(D)J recombination: RAG proteins, repair factors, and regulation. Annu Rev Biochem. 2002;71:101–132.
  • Yin FF, Bailey S, Innis CA, et al. Structure of the RAG1 nonamer binding domain with DNA reveals a dimer that mediates DNA synapsis. Nat Struct Mol Biol. 2009;16(5):499–508.
  • McBlane JF, van Gent DC, Ramsden DA, et al. Cleavage at a V(D)J recombination signal requires only RAG1 and RAG2 proteins and occurs in two steps. Cell. 1995;83(3):387–395.
  • Helmink BA, Sleckman BP. The response to and repair of RAG-mediated DNA double-strand breaks. Annu Rev Immunol. 2012;30:175–202.
  • Lin WC, Desiderio S. Cell cycle regulation of V(D)J recombination-activating protein RAG-2. Proc Natl Acad Sci U S A. 1994;91(7):2733–2737.
  • Notarangelo LD, Kim MS, Walter JE, et al. Human RAG mutations: biochemistry and clinical implications. Nat Rev Immunol. 2016;16(4):234–246.
  • Lee YN, Frugoni F, Dobbs K, et al. A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency. J Allergy Clin Immunol. 2014;133(4):1099–1108.
  • Tirosh I, Yamazaki Y, Frugoni F, et al. Recombination activity of human recombination-activating gene 2 (RAG2) mutations and correlation with clinical phenotype. J Allergy Clin Immunol. 2019 Feb;143(2):726-735. doi: 10.1016/j.jaci.2018.04.027.
  • Schuetz C, Pannicke U, Jacobsen EM, et al. Lesson from hypomorphic recombination-activating gene (RAG) mutations: why asymptomatic siblings should also be tested. J Allergy Clin Immunol. 2014;133(4):1211–1215.
  • IJspeert H, Driessen GJ, Moorhouse MJ, et al. Similar recombination-activating gene (RAG) mutations result in similar immunobiological effects but in different clinical phenotypes. J Allergy Clin Immunol. 2014;133(4):1124–1133.
  • Schwarz K, Gauss GH, Ludwig L, et al. RAG mutations in human B cell-negative SCID. Science. 1996;274(5284):97–99.
  • de Saint-Basile G, Le Deist F, de Villartay JP, et al. Restricted heterogeneity of T lymphocytes in combined immunodeficiency with hypereosinophilia (Omenn’s syndrome). J Clin Invest. 1991;87(4):1352–1359.
  • Rieux-Laucat F, Bahadoran P, Brousse N, et al. Highly restricted human T cell repertoire in peripheral blood and tissue-infiltrating lymphocytes in Omenn’s syndrome. J Clin Invest. 1998;102(2):312–321.
  • Villa A, Santagata S, Bozzi F, et al. Partial V(D)J recombination activity leads to Omenn syndrome. Cell. 1998;93(5):885–896.
  • Kuijpers TW, Ijspeert H, van Leeuwen EM, et al. Idiopathic CD4+ T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations. Blood. 2011;117(22):5892–5896.
  • Schuetz C, Huck K, Gudowius S, et al. An immunodeficiency disease with RAG mutations and granulomas. N Engl J Med. 2008;358(19):2030–2038.
  • Buchbinder D, Baker R, Lee YN, et al. Identification of patients with RAG mutations previously diagnosed with common variable immunodeficiency disorders. J Clin Immunol. 2015;35(2):119–124.
  • Geier CB, Piller A, Linder A, et al. Leaky RAG deficiency in adult patients with impaired antibody production against bacterial polysaccharide antigens. PLoS One. 2015;10(7):e0133220.
  • Lawless D, Geier CB, Farmer JR, et al. Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency. J Allergy Clin Immunol. 2018;141(6):2303–2306.
  • Farmer JR, Foldvari Z, Ujhazi B, et al. Outcomes and treatment strategies for autoimmunity and hyperinflammation in patients with RAG deficiency. J Allergy Clin Immunol Pract. 2019 Jul-Aug;7(6):1970-1985.e4. doi: 10.1016/j.jaci.2018.04.027.
  • Walter JE, Rosen LB, Csomos K, et al. Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency. J Clin Invest. 2015;125(11):4135–4148.
  • Cassani B, Poliani PL, Marrella V, et al. Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome. J Exp Med. 2010;207(7):1525–1540.
  • Giliani S, Bonfim C, de Saint Basile G, et al. Omenn syndrome in an infant with IL7RA gene mutation. J Pediatr. 2006;148(2):272–274.
  • Walter JE, Rucci F, Patrizi L, et al. Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency. J Exp Med. 2010;207(7):1541–1554.
  • Milner JD, Fasth A, Etzioni A. Autoimmunity in severe combined immunodeficiency (SCID): lessons from patients and experimental models. J Clin Immunol. 2008;28(Suppl 1):S29–33.
  • Cassani B, Poliani PL, Moratto D, et al. Defect of regulatory T cells in patients with Omenn syndrome. J Allergy Clin Immunol. 2010;125(1):209–216.
  • Rowe JH, Stadinski BD, Henderson LA, et al. Abnormalities of T-cell receptor repertoire in CD4(+) regulatory and conventional T cells in patients with RAG mutations: implications for autoimmunity. J Allergy Clin Immunol. 2017;140(6):1739–43 e7.
  • Henderson LA, Frugoni F, Hopkins G, et al. Expanding the spectrum of recombination-activating gene 1 deficiency: a family with early-onset autoimmunity. J Allergy Clin Immunol. 2013;132(4):969–71 e1–2.
  • Arkwright PD, Abinun M, Cant AJ. Autoimmunity in human primary immunodeficiency diseases. Blood. 2002;99(8):2694–2702.
  • Villa A, Notarangelo LD, Roifman CM. Omenn syndrome: inflammation in leaky severe combined immunodeficiency. J Allergy Clin Immunol. 2008;122(6):1082–1086.
  • Stenson PD, Ball EV, Mort M, et al. Human Gene Mutation Database (HGMD): 2003 update. Hum Mutat. 2003;21(6):577–581.
  • Cirillo E, Giardino G, Gallo V, et al. Severe combined immunodeficiency – an update. Ann N Y Acad Sci. 2015;1356:90–106.
  • Pai SY, Logan BR, Griffith LM, et al. Transplantation outcomes for severe combined immunodeficiency, 2000–2009. N Engl J Med. 2014;371(5):434–446.
  • Heimall J, Logan BR, Cowan MJ, et al. Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: a PIDTC natural history study. Blood. 2017;130(25):2718–2727.
  • Kwan A, Abraham RS, Currier R, et al. Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA. 2014;312(7):729–738.
  • Dorsey MJ, Dvorak CC, Cowan MJ, et al. Treatment of infants identified as having severe combined immunodeficiency by means of newborn screening. J Allergy Clin Immunol. 2017;139(3):733–742.
  • Corneo B, Moshous D, Gungor T, 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. 2001;97(9):2772–2776.
  • Wada T, Yasui M, Toma T, et al. Detection of T lymphocytes with a second-site mutation in skin lesions of atypical X-linked severe combined immunodeficiency mimicking Omenn syndrome. Blood. 2008;112(5):1872–1875.
  • Roifman CM, Zhang J, Atkinson A, et al. Adenosine deaminase deficiency can present with features of Omenn syndrome. J Allergy Clin Immunol. 2008;121(4):1056–1058.
  • Turul T, Tezcan I, Artac H, et al. Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency. Eur J Pediatr. 2009;168(1):87–93.
  • Ege M, Ma Y, Manfras B, et al. Omenn syndrome due to ARTEMIS mutations. Blood. 2005;105(11):4179–4186.
  • Grunebaum E, Bates A, Roifman CM. Omenn syndrome is associated with mutations in DNA ligase IV. J Allergy Clin Immunol. 2008;122(6):1219–1220.
  • Gennery AR, Slatter MA, Rice J, et al. Mutations in CHD7 in patients with CHARGE syndrome cause T-B + natural killer cell + severe combined immune deficiency and may cause Omenn-like syndrome. Clin Exp Immunol. 2008;153(1):75–80.
  • Dalal I, Tabori U, Bielorai B, et al. Evolution of a T-B- SCID into an Omenn syndrome phenotype following parainfluenza 3 virus infection. Clin Immunol. 2005;115(1):70–73.
  • Ehl S, Schwarz K, Enders A, et al. A variant of SCID with specific immune responses and predominance of gamma delta T cells. J Clin Invest. 2005;115(11):3140–3148.
  • de Villartay JP, Lim A, Al-Mousa H, et al. A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. J Clin Invest. 2005;115(11):3291–3299.
  • De Ravin SS, Cowen EW, Zarember KA, et al. Hypomorphic Rag mutations can cause destructive midline granulomatous disease. Blood. 2010;116(8):1263–1271.
  • Lee YN, Frugoni F, Dobbs K, et al. Characterization of T and B cell repertoire diversity in patients with RAG deficiency. Sci Immunol. 2016;1:6.
  • Dutmer CM, Asturias EJ, Smith C, et al. Late onset hypomorphic RAG2 deficiency presentation with fatal vaccine-strain VZV infection. J Clin Immunol. 2015;35(8):754–760.
  • Goda V, Malik A, Kalmar T, et al. Partial RAG deficiency in a patient with varicella infection, autoimmune cytopenia, and anticytokine antibodies. J Allergy Clin Immunol Pract. 2018;6(5):1769–71 e2.
  • Chen K, Wu W, Mathew D, et al. Autoimmunity due to RAG deficiency and estimated disease incidence in RAG1/2 mutations. J Allergy Clin Immunol. 2014;133(3):880–2 e10.
  • Reiff A, Bassuk AG, Church JA, 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. 2013;33(8):1289–1292.
  • Delmonte OM, Schuetz C, Notarangelo LD. RAG deficiency: two genes, many diseases. J Clin Immunol. 2018;38(6):646–655.
  • Dorna MB, Barbosa PFA, Rangel-Santos A, et al. Combined immunodeficiency with late-onset progressive hypogammaglobulinemia and normal B cell count in a patient with RAG2 deficiency. Front Pediatr. 2019;7:122.
  • Berland A, Rosain J, Kaltenbach S, et al. PROMIDISalpha: a T-cell receptor alpha signature associated with immunodeficiencies caused by V(D)J recombination defects. J Allergy Clin Immunol. 2019;143(1):325–34 e2.
  • Thwaites DT, Carter C, Lawless D, et al. A novel RAG1 mutation reveals a critical in vivo role for HMGB1/2 during V(D)J recombination. Blood. 2018;133(8):820-829.
  • Kato T, Crestani E, Kamae C, et al. RAG1 deficiency may present clinically as selective IgA deficiency. J Clin Immunol. 2015;35(3):280–288.
  • Abolhassani H, Wang N, Aghamohammadi A, et al. A hypomorphic recombination-activating gene 1 (RAG1) mutation resulting in a phenotype resembling common variable immunodeficiency. J Allergy Clin Immunol. 2014;134(6):1375–1380.
  • Kamae C, Nakagawa N, Sato H, et al. Common variable immunodeficiency classification by quantifying T-cell receptor and immunoglobulin kappa-deleting recombination excision circles. J Allergy Clin Immunol. 2013;131(5):1437–40 e5.
  • Abraham RS, Recher M, Giliani S, et al. Adult-onset manifestation of idiopathic T-cell lymphopenia due to a heterozygous RAG1 mutation. J Allergy Clin Immunol. 2013;131(5):1421–1423.
  • Dvorak CC, Haddad E, Buckley RH, et al. The genetic landscape of severe combined immunodeficiency in the United States and Canada in the current era (2010–2018). J Allergy Clin Immunol. 2019;143(1):405–407.
  • Kumanovics A, Lee YN, Close DW, et al. Estimated disease incidence of RAG1/2 mutations: a case report and querying the exome aggregation consortium. J Allergy Clin Immunol. 2017;139(2):690–2 e3.
  • Al-Herz W, Massaad MJ, Chou J, et al. DNA recombination defects in Kuwait: clinical, immunologic and genetic profile. Clin Immunol. 2018;187:68–75.
  • Al-Herz W, Notarangelo LD, Sadek A, et al. Combined immunodeficiency in the United States and Kuwait: comparison of patients’ characteristics and molecular diagnosis. Clin Immunol. 2015;161(2):170–173.
  • Strauss KA, Puffenberger EG, Bunin N, et al. Clinical application of DNA microarrays: molecular diagnosis and HLA matching of an Amish child with severe combined immune deficiency. Clin Immunol. 2008;128(1):31–38.
  • Neven B, Perot P, Bruneau J, et al. Cutaneous and visceral chronic granulomatous disease triggered by a rubella virus vaccine strain in children with primary immunodeficiencies. Clin Infect Dis. 2017;64(1):83–86.
  • Thwaites DT, Carter C, Lawless D, et al. A novel RAG1 mutation reveals a critical in vivo role for HMGB1/2 during V(D)J recombination. Blood. 2019;133(8):820–829.
  • Geier CB, Farmer JR, Foldvari Z, et al. Vasculitis as a major morbidity factor in patients with hypomorphic RAG mutations. J Allergy Clin Immunol. 2019;143(2):AB116.
  • Schuetz C, Neven B, Dvorak CC, et al. SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID. Blood. 2014;123(2):281–289.
  • Antoine C, Muller S, Cant A, et al. Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968–99. Lancet. 2003;361(9357):553–560.
  • Gennery AR, Slatter MA, Grandin L, et al. Transplantation of hematopoietic stem cells and long-term survival for primary immunodeficiencies in Europe: entering a new century, do we do better? J Allergy Clin Immunol. 2010;126(3):602–10 e1–11.
  • Haddad E, Logan BR, Griffith LM, et al. SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery. Blood. 2018;132(17):1737–1749.
  • Ege MJ, Schuetz C, Jacobsen EM, et al. Late thymic deficiency after HLA-haploidentical hematopoietic stem cell transplantation for severe combined immunodeficiency. J Allergy Clin Immunol. 2019;143(4):1623–6 e13.
  • Cavazzana-Calvo M, Carlier F, Le Deist F, et al. Long-term T-cell reconstitution after hematopoietic stem-cell transplantation in primary T-cell-immunodeficient patients is associated with myeloid chimerism and possibly the primary disease phenotype. Blood. 2007;109(10):4575–4581.
  • Dobbs K, Tabellini G, Calzoni E, et al. Natural killer cells from patients with recombinase-activating gene and non-homologous end joining gene defects comprise a higher frequency of CD56(bright) NKG2A(+++) cells, and yet display increased degranulation and higher perforin content. Front Immunol. 2017;8:798.
  • Karo JM, Schatz DG, Sun JC. The RAG recombinase dictates functional heterogeneity and cellular fitness in natural killer cells. Cell. 2014;159(1):94–107.
  • Westermann-Clark E, Grossi A, Fioredda F, et al. RAG deficiency with ALPS features successfully treated with TCRalphabeta/CD19 cell depleted haploidentical stem cell transplant. Clin Immunol. 2018;187:102–103.
  • John T, Walter JE, Schuetz C, et al. Unrelated hematopoietic cell transplantation in a patient with combined immunodeficiency with granulomatous disease and autoimmunity secondary to RAG deficiency. J Clin Immunol. 2016;36(7):725–732.
  • Lagresle-Peyrou C, Yates F, Malassis-Seris M, et al. Long-term immune reconstitution in RAG-1-deficient mice treated by retroviral gene therapy: a balance between efficiency and toxicity. Blood. 2006;107(1):63–72.
  • van Til NP, van der Velden G, De Boer H, et al. 661. Lentiviral gene therapy of RAG severe combined immunodeficiency. Mol Ther. 2013;21:S252.
  • Yates F, Malassis-Seris M, Stockholm D, et al. Gene therapy of RAG-2-/- mice: sustained correction of the immunodeficiency. Blood. 2002;100(12):3942–3949.
  • van Til NP, Sarwari R, Visser TP, 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. 2014;133(4):1116–1123.
  • Ott de Bruin L, Yang W, Capuder K, et al. Rapid generation of novel models of RAG1 deficiency by CRISPR/Cas9-induced mutagenesis in murine zygotes. Oncotarget. 2016;7(11):12962–12974.
  • Pike-Overzet K, Baum C, Bredius RGM, et al. Successful RAG1-SCID gene therapy depends on the level of RAG1 expression. J Allergy Clin Immunol. 2014;134(1):242–243.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.