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RAG1 Deficiency May Present Clinically as Selective IgA Deficiency

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Abstract

Background

Recombination-activating gene (RAG) 1 and 2 deficiency is seen in patients with severe combined immunodeficiency (SCID) and Omenn syndrome. However, the spectrum of the disease has recently expanded to include a milder phenotype.

Objective

We analyzed a 4-year-old boy who was initially given the diagnosis of selective immunoglobulin A deficiency (SIgAD) based on immunoglobulin serum levels without any opportunistic infections, rashes, hepatosplenomegaly, autoimmunity or granulomas. The patient was found to be infected with varicella zoster; however, the clinical course was not serious. He produced antiviral antibodies.

Methods

We performed lymphocyte phenotyping, quantification of T cell receptor excision circles (TRECs) and kappa deleting recombination excision circles (KRECs), an analysis of target sequences of RAG1 and 2, a whole-genome SNP array, an in vitro V(D)J recombination assay, a spectratype analysis of the CDR3 region and a flow cytometric analysis of the bone marrow.

Results

Lymphocyte phenotyping demonstrated that the ratio of CD4+ to CD8+ T cells was inverted and the majority of CD4+T cells expressed CD45RO antigens in addition to the almost complete lack of B cells. Furthermore, both TRECs and KRECs were absent. Targeted DNA sequencing and SNP array revealed that the patient carried a deletion of RAG1 and RAG2 genes on the paternally-derived chromosome 11, and two maternally-derived novel RAG1 missense mutations (E455K, R764H). In vitro analysis of recombination activity showed that both RAG1 mutant proteins had low, but residual function.

Conclusions

The current case further expands the phenotypic spectrum of mild presentations of RAG deficiency, and suggests that TRECs and KRECs are useful markers for detecting hidden severe, as well as mild, cases.

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Abbreviations

RAG:

Recombination-activating gene

SCID:

Severe combined immunodeficiency

SIgAD:

Selective immunoglobulin A deficiency

TRECs:

T cell receptor excision circles

sjKRECs:

signal joint immunoglobulin kappa deleting recombination excision circles

cjKRECs:

coding joint immunoglobulin kappa deleting recombination excision circles

PID:

Primary immunodeficiency

RAGD:

RAG deficiency

CVID:

Common variable immunodeficiency

BMT:

Bone marrow transplantation

LOH:

Loss of heterozygosity

GFP:

Green fluorescent protein

BM:

Bone marrow

TCR:

T cell receptor

FISH:

Fluorescence in situ hybridization

BAC:

Bacterial artificial chromosome

CID:

Combined immunodeficiency

VZV:

Varicella zoster virus

EBMT:

The European Group for Blood and Marrow Transplantation

References

  1. Hammarstrom L, Vorechovsky I, Webster D. Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol. 2000;120:225–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Asai E, Wada T, Sakakibara Y, Toga A, Toma T, Shimizu T, et al. Analysis of mutations and recombination activity in RAG-deficient patients. Clin Immunol. 2011;138:172–7.

    Article  CAS  PubMed  Google Scholar 

  3. Corneo B, Moshous D, Gungor T, Wulffraat N, Philippet P, Le Deist FL, 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;97:2772–6.

    Article  CAS  PubMed  Google Scholar 

  4. Villa A, Santagata S, Bozzi F, Giliani S, Frattini A, Imberti L, et al. Partial V(D)J recombination activity leads to Omenn syndrome. Cell. 1998;93:885–96.

    Article  CAS  PubMed  Google Scholar 

  5. Villa A, Notarangelo LD, Roifman CM. Omenn syndrome: inflammation in leaky severe combined immunodeficiency. J Allergy Clin Immunol. 2008;122:1082–6.

    Article  CAS  PubMed  Google Scholar 

  6. De Ravin SS, Cowen EW, Zarember KA, Whiting-Theobald NL, Kuhns DB, Sandler NG, et al. Hypomorphic Rag mutations can cause destructive midline granulomatous disease. Blood. 2010;116:1263–71.

    Article  PubMed Central  PubMed  Google Scholar 

  7. de Villartay JP, Lim A, Al-Mousa H, Dupont S, Dechanet-Merville J, Coumau-Gatbois E, et al. A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. J Clin Invest. 2005;115:3291–9.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Ehl S, Schwarz K, Enders A, Duffner U, Pannicke U, Kuhr J, et al. A variant of SCID with specific immune responses and predominance of gamma delta T cells. J Clin Invest. 2005;115:3140–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Schuetz C, Huck K, Gudowius S, Megahed M, Feyen O, Hubner B, et al. An immunodeficiency disease with RAG mutations and granulomas. N Engl J Med. 2008;358:2030–8.

    Article  CAS  PubMed  Google Scholar 

  10. De Ravin SS, Cowen EW, Zarember KA, Whiting-Theobald NL, Kuhns DB, Sandler NG, et al. Hypomorphic Rag mutations can cause destructive midline granulomatous disease. Blood. 2010;116:1263–71.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Niehues T, Perez-Becker R, Schuetz C. More than just SCID–the phenotypic range of combined immunodeficiencies associated with mutations in therecombinase activating genes (RAG) 1 and 2. Clin Immunol. 2010;135:183–92.

    Article  CAS  PubMed  Google Scholar 

  12. Morinishi Y, Imai K, Nakagawa N, Sato H, Horiuchi K, Ohtsuka Y, et al. Identification of severe combined immunodeficiency by T-cell receptor excision circles quantification using neonatal guthrie cards. J Pediatr. 2009;155:829–33.

    Article  CAS  PubMed  Google Scholar 

  13. Nakagawa N, Imai K, Kanegane H, Sato H, Yamada M, Kondoh K, et al. Quantification of kappa-deleting recombination excision circles in Guthrie cards for the identification of early B-cell maturation defects. J Allergy Clin Immunol. 2011;128:223–5.

    Article  CAS  PubMed  Google Scholar 

  14. Kamae C, Nakagawa N, Sato H, Honma K, Mitsuiki N, Ohara O, et al. Common variable immunodeficiency classification by quantifying T-cell receptor and immunoglobulin kappa-deleting recombination excision circles. J Allergy Clin Immunol. 2013;131:1437–40.

    Article  PubMed  Google Scholar 

  15. Lee YN, Frugoni F, Dobbs K, Walter JE, Giliani S, Gennery AR, et al. A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency. J Allergy Clin Immunol. 2014;133:1099–108.

    Article  CAS  PubMed  Google Scholar 

  16. Nomura K, Kanegane H, Karasuyama H, Tsukada S, Agematsu K, Murakami G, et al. Genetic defect in human X-linked agammaglobulinemia impedes a maturational evolution of pro-B cells into a later stage of pre-B cells in the B-cell differentiation pathway. Blood. 2000;96:610–7.

    CAS  PubMed  Google Scholar 

  17. Currier JR, Robinson MA. Spectratype/immunoscope analysis of the expressed TCR repertoire. Curr Protoc Immunol. 2001; Chapter 10:Unit 10 28.

  18. Ng PC, Henikoff S. SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31:3812–4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Villa A, Sobacchi C, Notarangelo LD, Bozzi F, Abinun M, Abrahamsen TG, et al. V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. Blood. 2001;97:81–8.

    Article  CAS  PubMed  Google Scholar 

  20. Kumaki S, Villa A, Asada H, Kawai S, Ohashi Y, Takahashi M, et al. Identification of anti-herpes simplex virus antibody-producing B cells in a patient with an atypical RAG1 immunodeficiency. Blood. 2001;98:1464–8.

    Article  CAS  PubMed  Google Scholar 

  21. Kuijpers TW, Ijspeert H, van Leeuwen EM, Jansen MH, Hazenberg MD, Weijer KC, et al. Idiopathic CD4+ T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations. Blood. 2011;117:5892–6.

    Article  CAS  PubMed  Google Scholar 

  22. Henderson LA, Frugoni F, Hopkins G, de Boer H, Pai SY, Lee YN, et al. Expanding the spectrum of recombination-activating gene 1 deficiency: a family with early-onset autoimmunity. J Allergy Clin Immunol. 2014;132:969–71. e1-2.

    Article  Google Scholar 

  23. Moshous D, Callebaut I, de Chasseval R, Corneo B, Cavazzana-Calvo M, Le Deist F, et al. Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell. 2001;105:177–86.

    Article  CAS  PubMed  Google Scholar 

  24. Shiow LR, Paris K, Akana MC, Cyster JG, Sorensen RU, Puck JM. Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a Coronin-1A mutation and a chromosome 16p11.2 deletion. Clin Immunol. 2009;131:24–30.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Sheehan WJ, Delmonte OM, Miller DT, Roberts AE, Bonilla FA, Morra M, et al. Novel presentation of Omenn syndrome in association with aniridia. J Allergy Clin Immunol. 2009;123:966–9.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Agematsu K, Nagumo H, Hokibara S, Mori T, Wada T, Yachie A, et al. Complete arrest from pro- to pre-B cells in a case of B cell-negative severe combined immunodeficiency (SCID) without recombinase activating gene (RAG) mutations. Clin Exp Immunol. 2001;124:461–4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Noordzij JG, de Bruin-Versteeg S, Verkaik NS, Vossen JM, de Groot R, Bernatowska E, 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. 2002;100:2145–52.

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by NIH grant P01AI076210, a grant from the Jeffrey Modell Foundation (to LDN), the Ministry of Defense; the Ministry of Education, Culture, Sports, Science, and Technology; the Ministry of Health, Labor, and Welfare; and the Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics. We would like to thank Ms. Kaori Tomita and Ms. Kimiko Gasa for their skillful technical assistance.

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Authors and Affiliations

  1. Department of Pediatrics, National Defense Medical College, Tokorozawa, Saitama, Japan

    Tamaki Kato, Chikako Kamae, Kenichi Honma, Kohsuke Imai & Shigeaki Nonoyama

  2. Division of Immunology, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USA

    Elena Crestani & Luigi D. Notarangelo

  3. Department of Hemato-oncology/Regeneration Medicine, Kanagawa Children’s Medical Center, Yokohama, Kanagawa, Japan

    Tomoko Yokosuka

  4. Department of Pediatrics, Yokohama Rosai Hospital, Yokohama, Kanagawa, Japan

    Takeshi Ikegawa

  5. Department of Pediatrics, University of Toyama, Toyama, Japan

    Naonori Nishida & Hirokazu Kanegane

  6. Department of Pediatrics, Tokyo Medical and Dental University (TMDU), 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

    Hirokazu Kanegane, Tomohiro Morio & Kohsuke Imai

  7. Department of Pediatrics, Kanazawa University, Kanazawa, Ishikawa, Japan

    Taizo Wada & Akihiro Yachie

  8. Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan

    Osamu Ohara

  9. Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Chiba, Japan

    Osamu Ohara

Authors
  1. Tamaki Kato
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  2. Elena Crestani
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  3. Chikako Kamae
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  4. Kenichi Honma
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  5. Tomoko Yokosuka
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  6. Takeshi Ikegawa
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  7. Naonori Nishida
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  8. Hirokazu Kanegane
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  9. Taizo Wada
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  10. Akihiro Yachie
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  11. Osamu Ohara
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  12. Tomohiro Morio
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  13. Luigi D. Notarangelo
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  14. Kohsuke Imai
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  15. Shigeaki Nonoyama
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Corresponding author

Correspondence to Kohsuke Imai.

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Kato, T., Crestani, E., Kamae, C. et al. RAG1 Deficiency May Present Clinically as Selective IgA Deficiency. J Clin Immunol 35, 280–288 (2015). https://doi.org/10.1007/s10875-015-0146-4

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  • DOI: https://doi.org/10.1007/s10875-015-0146-4

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