Clinical and laboratory phenotypes of severe combined immunodeficiencies with mutations in RAG1/RAG2 genes



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Abstract

Background. The RAG1 and RAG2 proteins are key players in the V(D)J recombination process leading to the assembly of antigen receptor genes. Defects in RAG1/RAG2 genes are caused to different phenotypes of severe combined immunodeficiencies (SCID). Objective — to determine the clinical and laboratory manifestations in patients with RAG1 / RAG2 mutations from one single center, to identify the phenotype-genotype correlations. Materials and methods. We described 4 children with RAG1 mutations. Diagnosis of SCID was confirmed by criteria’s of European society of immunodeficiencies (ESID). Results. In two patients we observed Omenn syndrome, in 1 — classic T -B -NK + SCID, in 1 — «sof» T +B -NK + SCID. One patient with Omenn syndrome and patient with «soft» SCID had same RAG1 mutations. Conclusions. RAG 1 / RAG2 mutations are caused to severe life-threatening combined immunodeficiency, requiring radical therapy. We found no genotype-phenotype correlations in patients with RAG1 defects.

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About the authors

I V Kondratenko

Russian Children's Clinical Hospital, Moscow; Russian National Scientific Medical University, Moscow

Email: ikondratenko@rambler.ru

O E Pashchenko

Russian National Scientific Medical University, Moscow

Y A Rodina

Russian Children's Clinical Hospital, Moscow

M V Belevtcev

Institute of Children's Oncology, Hematology and Immunology, Minsk, Belarus

den M Van

Institute for Bioethics, Health Ethics and Philosophy, Department of Caring Sciences, University of Maastricht, Maastricht, the Netherlands

A A Bologov

Russian Children's Clinical Hospital, Moscow; Russian National Scientific Medical University, Moscow

References

  1. Fausto Cossu. Genetics of SCID. Ital. J. Pediatr. 2010, v. 36, p. 76.
  2. Villa A., Sobacchi C., Notarangelo L.D. et al. V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. Blood. 2001, v. 97, p. 81-88.
  3. 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, v. 135 (2), p. 183-192.
  4. Catharina Schuetz, Kirsten Huck, Sonja Gudowius et al. An Immunodeficiency Disease with RAG Mutations and Granulomas. N. Engl. J. Med. 2008, v. 358, p. 2030-2038.
  5. De Villartay J., Lim A., Al-Mousa H. et al. A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. J. Clin. Invest. 2005, November 1, v. 115 (11), p. 3291-3299.
  6. Ярилин А.А. Основы иммунологии. М., «Медицина». 1999.
  7. Хаитов Р.М., Игнатьева Г.А., Сидорович И.Г. Иммунология. М., «Медицина». 2000.
  8. Cristlow S.E., Bowater R.P., Jackson S.P. Mammalian DNA double strand break repair protein XRCC4 interacts with DNA-ligase IV. Curr. Biol. 1997, v. 7, p. 588-598.
  9. Dudasova Z., Chovanec M. Artemis, a novel guardian of the genome. Neoplasma. 2003, v. 50, p. 311-318.
  10. Villa A., Santagata S., Bozzi F. et al. Partial V(D)J recombination activity leads to Omenn syndrome. Cell. 1998, v. 93, p. 885-896.
  11. Villa A., Santagata S., Bozzi F. et al. Omenn syndrome: a disorder of Rag1 and Rag2 genes. J. Clin. Immunol. 1999, v. 19, p. 87-97.
  12. 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, v. 97, p. 2772-2776.
  13. De Ravin S., Cowen E., Zarember K. et al. Hypomorphic Rag mutations can cause destructive midline granulomatous disease. Blood. 2010, August 26, v. 116 (8), p. 1263-1271.
  14. Al-Herz W., Bousfiha A., Casanova J. et al. Primary Immunodeficiency Diseases: an update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency. Frontiers in Immunology. 2011.
  15. Gelfand E.W., Dosch H.M. Diagnostics and classification of severe combined immunodeficiency diseases. Birth Defects. 1983, v. 19, p. 65-72.
  16. Bucley R.H., Schiff R.I., Markett M.L. et al. Human severe combined immunodeficiency: genetic, phenotypic and functional diversity in one hundred eight patients. J. Pediatr. 1997, v. 130, p. 378-387.
  17. Omenn G.S., Familial reticuloendotheliosis with eosinophilia. N. Engl. J. Med. 1965, v. 273, p. 427-432.
  18. Brooks E.G., Filipivich A.H., Padgett J.W. et al. T-cell receptor analysis in Omenn’s syndrome: evidence for defects in gene rearrangement and assembly. Blood. 1999, v. 93, p. 242-250.
  19. Loechelt B.J., Shapiro R.S., Jyonouchi H., Filipovich A.H. Mismatched bone marrow transplantation for Omenn syndrome: A variant of severe combined immunodeficiency. Bone Marrow Transplant. 1995, v. 16, p. 381-385.
  20. Gomez L., Le Deist F., Blanche S. et al. Treatment of Omenn syndrome by bone marrow transplantation. J. Pediatr. 1995, v. 127, p. 76-81.
  21. Ochs H.D., Davis S.D., Mickelson E. et al. Combined immunodeficiency and reticuloendotheliosis with eosinophilia. J. Pediatr. 1974, v. 35, p. 463-466.
  22. Noordzij J.G., De Burin-Versteeg., Verkaik N.S. 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, v. 100, p. 2145-2152.
  23. De Saint Basile G., Le Deist F., De Villartay J.P. et al. Restricted heterogeneity of T lymphocytes in combined immunodeficiency with hypereosinophilia (Omenn’s syndrome). J. Clin. Invest. 1991, v. 87, p. 1352-1359.
  24. Melamed I., Cohen A., Roifman C.M. Expansion of CD3+CD4-CD8- T-cell population expressing high levels of IL-5 in Omenn’s syndrome. Clin. Exp. Immunol. 1994, v. 95, p. 14-21.
  25. 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, v. 102, p. 312-321.
  26. Chilosi M., Facchetti F., Notarangelo L.D. 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. 1996, v. 26, p. 329-334.
  27. Ehl S., Schwarz K., Enders A. et al. A variant of SCID with specific immune responses and predominance of gammadelta T-cells. J. Clin. Invest. 2005, v. 115 (11), p. 3140-3148.

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