Novel RAG2 Mutation in a Patient with Leaky Severe Combined Immunodeficiency
Abstract
T and B lymphocytes development and function are highly dependent on Recombination Activating Genes (RAG) 1 and 2. RAG mutations result in different degrees of T and B cell impaired function, broad clinical manifestations, and immunological manifestations. Pathogenic mutations cause severe combined immunodeficiency (SCID) phenotype, while hypomorphic mutations are responsible for leaky or partial SCID.
Here, we described a 4-year-old girl who had a persistent diarrhea, recurrent infection, and vomiting. Although physicians were suspicious about autoimmune enteropathy, her molecular report showed a homozygous and novel RAG2 mutation in its core domain. The number of CD4 T cells and IgA level were lower than normal ranges. Lack of IgA brought about different GI complications. Our patient died finally because of liver and gallbladder failure.
1. Geha RS, Notarangelo LD, Casanova JL, Chapel H, Conley ME, Fischer A, et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol. 2007;120(4):776-94.
2. Puck JM, Group SNSW. Population-based newborn screening for severe combined immunodeficiency: steps toward implementation. J Allergy Clin Immunol. 2007;120(4):760-8.
3. Rezaei N, Pourpak Z, Aghamohammadi A, Farhoudi A, Movahedi M, Gharagozlou M, et al. Consanguinity in primary immunodeficiency disorders; the report from Iranian Primary Immunodeficiency Registry. Am J Reprod Immunol. 2006;56(2):145-51.
4. Schwarz K, Gauss GH, Ludwig L, Pannicke U, Li Z, Lindner D, et al. RAG mutations in human B cell-negative SCID. Science. 1996;274(5284):97-9.
5. Sponzilli I, Notarangelo LD. Severe combined immunodeficiency (SCID): from molecular basis to clinical management. Acta Biomed. 2011;82(1):5-13.
6. Notarangelo LD, Kim MS, Walter JE, Lee YN. Human RAG mutations: biochemistry and clinical implications. Nat Rev Immunol. 2016;16(4):234-46.
7. 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(8):1263-71.
8. Niehues T, Perez-Becker R, Schuetz C. More than just SCID--the phenotypic range of combined immunodeficiencies associated with mutations in the recombinase activating genes (RAG) 1 and 2. Clin Immunol. 2010;135(2):183-92.
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(19):2030-8.
10. Walter JE, Rosen LB, Csomos K, Rosenberg JM, Mathew D, Keszei M, et al. Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency. J Clin Invest. 2015;125(11):4135-48.
11. Chou J, Hanna-Wakim R, Tirosh I, Kane J, Fraulino D, Lee YN, 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. 2012;130(6):1414-6.
12. Ktiouet S, Bertrand Y, Rival-Tringali AL, Kanitakis J, Malcus C, Poitevin F, et al. Omenn syndrome due to mutation of the RAG2 gene. J Eur Acad Dermatol Venereol. 2009;23(12):1449-51.
13. 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(2):172-7.
14. 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(1):81-8.
15. Tabori U, Mark Z, Amariglio N, Etzioni A, Golan H, Biloray B, et al. Detection of RAG mutations and prenatal diagnosis in families presenting with either T-B- severe combined immunodeficiency or Omenn's syndrome. Clin Genet. 2004;65(4):322-6.
16. Poliani PL, Facchetti F, Ravanini M, Gennery AR, Villa A, Roifman CM, 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. 2009;114(1):105-8.
17. Dalal I, Tasher D, Somech R, Etzioni A, Garti BZ, Lev D, et al. Novel mutations in RAG1/2 and ADA genes in Israeli patients presenting with T-B-SCID or Omenn syndrome. Clin Immunol. 2011;140(3):284-90.
18. Sobacchi C, Marrella V, Rucci F, Vezzoni P, Villa A. RAG-dependent primary immunodeficiencies. Hum Mutat. 2006;27(12):1174-84.
19. Safaei S, Pourpak Z, Moin M, Houshmand M. IL7R and RAG1/2 genes mutations/polymorphisms in patients with SCID. Iran J Allergy Asthma Immunol. 2011;10(2):129-32.
20. Gomez CA, Ptaszek LM, Villa A, Bozzi F, Sobacchi C, Brooks EG, et al. Mutations in conserved regions of the predicted RAG2 kelch repeats block initiation of V(D)J recombination and result in primary immunodeficiencies. Mol Cell Biol. 2000;20(15):5653-64.
21. 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(9):2772-6.
22. Lev A, Simon AJ, Trakhtenbrot L, Goldstein I, Nagar M, Stepensky P, et al. Characterizing T cells in SCID patients presenting with reactive or residual T lymphocytes. Clin Dev Immunol. 2012;2012:261470.
23. 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(6):2145-52.
24. Alsmadi O, Al-Ghonaium A, Al-Muhsen S, Arnaout R, Al-Dhekri H, Al-Saud B, et al. Molecular analysis of T-B-NK+ severe combined immunodeficiency and Omenn syndrome cases in Saudi Arabia. BMC Med Genet. 2009;10:116.
25. Corneo B, Moshous D, Callebaut I, de Chasseval R, Fischer A, de Villartay JP. Three-dimensional clustering of human RAG2 gene mutations in severe combined immune deficiency. J Biol Chem. 2000;275(17):12672-5.
26. Meshaal S, El Hawary R, Elsharkawy M, Mousa RK, Farid RJ, Abd Elaziz D, et al. Mutations in Recombination Activating Gene 1 and 2 in patients with severe combined immunodeficiency disorders in Egypt. Clin Immunol. 2015;158(2):167-73.
27. Sadeghi-Shabestari M, Vesal S, Jabbarpour-Bonyadi M, de Villatay J, Fischer A, Rezaei N. Novel RAG2 mutation in a patient with T-B-severe combined immunodeficiency and disseminated BCG disease. J Investig Allergol Clin Immunol. 2009;19(6):494-6.
28. Shen J, Jiang L, Gao Y, Ou R, Yu S, Yang B, et al. A novel RAG1 mutation in a compound heterozygous status in a child with Omenn syndrome. Front Genet. 2019;10:913.
29. Khan TA, Iqbal A, Rahman H, Cabral-Marques O, Ishfaq M, Muhammad N. Novel RAG1 mutation and the occurrence of mycobacterial and Chromobacterium violaceum infections in a case of leaky SCID. Microb pathog. 2017;109:114-9.
30. Szaflarska A, Rutkowska-Zapała M, Kotula M, Gruca A, Grabowska A, Lenart M, et al. Mutation c. 256_257delAA in RAG1 gene in polish children with severe combined immunodeficiency: diversity of clinical manifestations. Arch Immunol Ther Exp. 2016;64:177-83.
31. Miao J, Ying B, Li R, Tollefson AE, Spencer JF, Wold WS, et al. Characterization of an N-terminal non-core domain of RAG1 gene disrupted Syrian hamster model generated by CRISPR Cas9. Viruses. 2018;10(5):243.
32. Castagnoli R, Delmonte OM, Calzoni E, Notarangelo LD. Hematopoietic stem cell transplantation in primary immunodeficiency diseases: current status and future perspectives. Frontiers in pediatrics. 2019;7:295.
33. Buckley RH. Transplantation of hematopoietic stem cells in human severe combined immunodeficiency: longterm outcomes. Immunol Res. 2011;49:25-43.
34. Vertès AA. The potential of cytotherapeutics in hematologic reconstitution and in the treatment and prophylaxis of graft-versus-host disease. Chapter I: current practice and remaining unmet medical needs. Regen Med. 2015;10(3):331-43.
2. Puck JM, Group SNSW. Population-based newborn screening for severe combined immunodeficiency: steps toward implementation. J Allergy Clin Immunol. 2007;120(4):760-8.
3. Rezaei N, Pourpak Z, Aghamohammadi A, Farhoudi A, Movahedi M, Gharagozlou M, et al. Consanguinity in primary immunodeficiency disorders; the report from Iranian Primary Immunodeficiency Registry. Am J Reprod Immunol. 2006;56(2):145-51.
4. Schwarz K, Gauss GH, Ludwig L, Pannicke U, Li Z, Lindner D, et al. RAG mutations in human B cell-negative SCID. Science. 1996;274(5284):97-9.
5. Sponzilli I, Notarangelo LD. Severe combined immunodeficiency (SCID): from molecular basis to clinical management. Acta Biomed. 2011;82(1):5-13.
6. Notarangelo LD, Kim MS, Walter JE, Lee YN. Human RAG mutations: biochemistry and clinical implications. Nat Rev Immunol. 2016;16(4):234-46.
7. 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(8):1263-71.
8. Niehues T, Perez-Becker R, Schuetz C. More than just SCID--the phenotypic range of combined immunodeficiencies associated with mutations in the recombinase activating genes (RAG) 1 and 2. Clin Immunol. 2010;135(2):183-92.
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(19):2030-8.
10. Walter JE, Rosen LB, Csomos K, Rosenberg JM, Mathew D, Keszei M, et al. Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency. J Clin Invest. 2015;125(11):4135-48.
11. Chou J, Hanna-Wakim R, Tirosh I, Kane J, Fraulino D, Lee YN, 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. 2012;130(6):1414-6.
12. Ktiouet S, Bertrand Y, Rival-Tringali AL, Kanitakis J, Malcus C, Poitevin F, et al. Omenn syndrome due to mutation of the RAG2 gene. J Eur Acad Dermatol Venereol. 2009;23(12):1449-51.
13. 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(2):172-7.
14. 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(1):81-8.
15. Tabori U, Mark Z, Amariglio N, Etzioni A, Golan H, Biloray B, et al. Detection of RAG mutations and prenatal diagnosis in families presenting with either T-B- severe combined immunodeficiency or Omenn's syndrome. Clin Genet. 2004;65(4):322-6.
16. Poliani PL, Facchetti F, Ravanini M, Gennery AR, Villa A, Roifman CM, 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. 2009;114(1):105-8.
17. Dalal I, Tasher D, Somech R, Etzioni A, Garti BZ, Lev D, et al. Novel mutations in RAG1/2 and ADA genes in Israeli patients presenting with T-B-SCID or Omenn syndrome. Clin Immunol. 2011;140(3):284-90.
18. Sobacchi C, Marrella V, Rucci F, Vezzoni P, Villa A. RAG-dependent primary immunodeficiencies. Hum Mutat. 2006;27(12):1174-84.
19. Safaei S, Pourpak Z, Moin M, Houshmand M. IL7R and RAG1/2 genes mutations/polymorphisms in patients with SCID. Iran J Allergy Asthma Immunol. 2011;10(2):129-32.
20. Gomez CA, Ptaszek LM, Villa A, Bozzi F, Sobacchi C, Brooks EG, et al. Mutations in conserved regions of the predicted RAG2 kelch repeats block initiation of V(D)J recombination and result in primary immunodeficiencies. Mol Cell Biol. 2000;20(15):5653-64.
21. 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(9):2772-6.
22. Lev A, Simon AJ, Trakhtenbrot L, Goldstein I, Nagar M, Stepensky P, et al. Characterizing T cells in SCID patients presenting with reactive or residual T lymphocytes. Clin Dev Immunol. 2012;2012:261470.
23. 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(6):2145-52.
24. Alsmadi O, Al-Ghonaium A, Al-Muhsen S, Arnaout R, Al-Dhekri H, Al-Saud B, et al. Molecular analysis of T-B-NK+ severe combined immunodeficiency and Omenn syndrome cases in Saudi Arabia. BMC Med Genet. 2009;10:116.
25. Corneo B, Moshous D, Callebaut I, de Chasseval R, Fischer A, de Villartay JP. Three-dimensional clustering of human RAG2 gene mutations in severe combined immune deficiency. J Biol Chem. 2000;275(17):12672-5.
26. Meshaal S, El Hawary R, Elsharkawy M, Mousa RK, Farid RJ, Abd Elaziz D, et al. Mutations in Recombination Activating Gene 1 and 2 in patients with severe combined immunodeficiency disorders in Egypt. Clin Immunol. 2015;158(2):167-73.
27. Sadeghi-Shabestari M, Vesal S, Jabbarpour-Bonyadi M, de Villatay J, Fischer A, Rezaei N. Novel RAG2 mutation in a patient with T-B-severe combined immunodeficiency and disseminated BCG disease. J Investig Allergol Clin Immunol. 2009;19(6):494-6.
28. Shen J, Jiang L, Gao Y, Ou R, Yu S, Yang B, et al. A novel RAG1 mutation in a compound heterozygous status in a child with Omenn syndrome. Front Genet. 2019;10:913.
29. Khan TA, Iqbal A, Rahman H, Cabral-Marques O, Ishfaq M, Muhammad N. Novel RAG1 mutation and the occurrence of mycobacterial and Chromobacterium violaceum infections in a case of leaky SCID. Microb pathog. 2017;109:114-9.
30. Szaflarska A, Rutkowska-Zapała M, Kotula M, Gruca A, Grabowska A, Lenart M, et al. Mutation c. 256_257delAA in RAG1 gene in polish children with severe combined immunodeficiency: diversity of clinical manifestations. Arch Immunol Ther Exp. 2016;64:177-83.
31. Miao J, Ying B, Li R, Tollefson AE, Spencer JF, Wold WS, et al. Characterization of an N-terminal non-core domain of RAG1 gene disrupted Syrian hamster model generated by CRISPR Cas9. Viruses. 2018;10(5):243.
32. Castagnoli R, Delmonte OM, Calzoni E, Notarangelo LD. Hematopoietic stem cell transplantation in primary immunodeficiency diseases: current status and future perspectives. Frontiers in pediatrics. 2019;7:295.
33. Buckley RH. Transplantation of hematopoietic stem cells in human severe combined immunodeficiency: longterm outcomes. Immunol Res. 2011;49:25-43.
34. Vertès AA. The potential of cytotherapeutics in hematologic reconstitution and in the treatment and prophylaxis of graft-versus-host disease. Chapter I: current practice and remaining unmet medical needs. Regen Med. 2015;10(3):331-43.
| Files | ||
| Issue | Vol 4, No 4 (2021) | |
| Section | Case Report | |
| DOI | https://doi.org/10.18502/igj.v4i4.12758 | |
| Keywords | ||
| RAG2 Combined Immunodeficiency Severe Combined Immunodeficiency Primary Immunodeficiency IgA Deficiency | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Pashangzadeh S, Yazdani R, Delavari S, Abolhassani H, Parvaneh N. Novel RAG2 Mutation in a Patient with Leaky Severe Combined Immunodeficiency. Immunol Genet J. 2021;4(4):203-210.
