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The Genetic and Molecular Basis of Severe Combined Immunodeficiency

  • Immunology (HB Gaspar, Section Editor)
  • Published:
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Abstract

Severe combined immunodeficiency (SCID) is a life-threatening disease caused by a heterogeneous group of genetic defects. It is characterized by profound defects of T-cell development, also affecting B and NK cells in some cases. Since the first molecular identification of a causal gene for SCID in 1985, 14 more molecular causes have been identified in patients with a classical SCID phenotype, with no T cells. Some genetic defects specifically block lymphocyte ontogeny, whereas others affect T-cell function and a few cause extra-hematopoietic alterations with a rare complex phenotype. Over the last 15 years, several new causal genes have been identified in patients with low T-cell counts and impaired T-cell function. Patients with a clinical SCID phenotype with normal numbers of dysfunctional T cells have also recently been reported. This last condition is described immunologically as combined immunodeficiency. These discoveries have expanded the complexity and difficulties of molecular characterization in patients with a clinical SCID phenotype. Studies of these disorders have increased our understanding of the role of single-gene products in the development, differentiation, and function of the immune system in humans.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Chapel H, Geha R, Rosen F. Primary immunodeficiency diseases: an update. Clin Exp Immunol. 2003;132:9–15.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. •• Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, Cunningham-Rundles C, Etzioni A, Franco JL, Gaspar HB, Holland SM, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2014;5:162. A comprehensive review on classification of the different molecular defects responsible of primary immunodeficiency.

  3. Buckley RH. Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Annu Rev Immunol. 2004;22:625–55.

    Article  CAS  PubMed  Google Scholar 

  4. Glanzmann E, Riniker P. Essential lymphocytophthisis; new clinical aspect of infant pathology. Ann Paediatr. 1950;175:1–32.

    CAS  PubMed  Google Scholar 

  5. Hitzig WH, Biro Z, Bosch H, Huser HJ. Agammaglobulinemia & alymphocytosis with atrophy of lymphatic tissue. Helvet Paediatr Acta. 1958;13:551–85.

    CAS  Google Scholar 

  6. Fischer A. Severe combined immunodeficiencies (SCID). Clin Exp Immunol. 2000;122:143–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. • Puck JM. The case for newborn screening for severe combined immunodeficiency and related disorders. Ann N Y Acad Sci. 2011;1246:108–17. A comprehensive review about newborn screening for detecting children with severe combined immunodeficiency.

  8. Giblett ER, Anderson JE, Cohen F, Pollara B, Meuwissen HJ. Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity. Lancet. 1972;2:1067–9.

    Article  CAS  PubMed  Google Scholar 

  9. Valerio D, McIvor RS, Williams SR, Duyvesteyn MG, van Ormondt H, van der Eb AJ, Martin DW Jr. Cloning of human adenosine deaminase cDNA and expression in mouse cells. Gene. 1984;31:147–53.

    Article  CAS  PubMed  Google Scholar 

  10. Ochs HD, Smith CIE, Puck J. Primary immunodeficiencies: a molecular and genetic approach. 3rd ed. New York: Oxford University Press; 2013.

    Book  Google Scholar 

  11. Bonthron DT, Markham AF, Ginsburg D, Orkin SH. Identification of a point mutation in the adenosine deaminase gene responsible for immunodeficiency. J Clin Invest. 1985;76:894–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Valerio D, Dekker BM, Duyvesteyn MG, van der Voorn L, Berkvens TM, van Ormondt H, van der Eb AJ. One adenosine deaminase allele in a patient with severe combined immunodeficiency contains a point mutation abolishing enzyme activity. EMBO J. 1986;5:113–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  13. Shovlin CL, Simmonds HA, Fairbanks LD, Deacock SJ, Hughes JM, Lechler RI, Webster AD, Sun XM, Webb JC, Soutar AK. Adult onset immunodeficiency caused by inherited adenosine deaminase deficiency. J Immunol. 1994;153:2331–9.

    CAS  PubMed  Google Scholar 

  14. Neven B, Leroy S, Decaluwe H, Le Deist F, Picard C, Moshous D, Mahlaoui N, Debre M, Casanova JL, Dal Cortivo L, et al. Long-term outcome after hematopoietic stem cell transplantation of a single-center cohort of 90 patients with severe combined immunodeficiency. Blood. 2009;113:4114–24.

    Article  CAS  PubMed  Google Scholar 

  15. de VO, Seynhaeve V. Reticular dysgenesia. Lancet. 1959;2:1123–5.

    Google Scholar 

  16. Ownby DR, Pizzo S, Blackmon L, Gall SA, Buckley RH. Severe combined immunodeficiency with leukopenia (reticular dysgenesis) in siblings: immunologic and histopathologic findings. J Pediatr. 1976;89:382–7.

    Article  CAS  PubMed  Google Scholar 

  17. Haas RJ, Niethammer D, Goldmann SF, Heit W, Bienzle U, Kleihauer E. Congenital immunodeficiency and agranulocytosis (reticular dysgenesia). Acta Paediatr Scand. 1977;66:279–83.

    Article  CAS  PubMed  Google Scholar 

  18. Pannicke U, Honig M, Hess I, Friesen C, Holzmann K, Rump EM, Barth TF, Rojewski MT, Schulz A, Boehm T, et al. Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2. Nat Genet. 2009;41:101–5.

    Article  CAS  PubMed  Google Scholar 

  19. Lagresle-Peyrou C, Six EM, Picard C, Rieux-Laucat F, Michel V, Ditadi A, de Demerens Chappedelaine C, Morillon E, Valensi F, Simon-Stoos KL, et al. Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness. Nat Genet. 2009;41:106–11.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. de Saint Basile G, Arveiler B, Oberle I, Malcolm S, Levinsky RJ, Lau YL, Hofker M, Debre M, Fischer A, Griscelli C, et al. Close linkage of the locus for X chromosome-linked severe combined immunodeficiency to polymorphic DNA markers in Xq11-q13. Proc Natl Acad Sci USA. 1987;84:7576–9.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Puck JM, Deschenes SM, Porter JC, Dutra AS, Brown CJ, Willard HF, Henthorn PS. The interleukin-2 receptor gamma chain maps to Xq13.1 and is mutated in X-linked severe combined immunodeficiency, SCIDX1. Hum Mol Genet. 1993;2:1099–104.

    Article  CAS  PubMed  Google Scholar 

  22. Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S, Modi WS, McBride OW, Leonard WJ. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993;73:147–57.

    Article  CAS  PubMed  Google Scholar 

  23. Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D, Sugamura K. Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex. J Immunol. 2001;167:1–5.

    Article  CAS  PubMed  Google Scholar 

  24. Puck JM. IL2RGbase: a database of gamma c-chain defects causing human X-SCID. Immunol Today. 1996;17:507–11.

    Article  CAS  PubMed  Google Scholar 

  25. Niemela JE, Puck JM, Fischer RE, Fleisher TA, Hsu AP. Efficient detection of thirty-seven new IL2RG mutations in human X-linked severe combined immunodeficiency. Clin Immunol. 2000;95:33–8.

    Article  CAS  PubMed  Google Scholar 

  26. Stephan JL, Vlekova V, Le Deist F, Blanche S, Donadieu J, De Saint-Basile G, Durandy A, Griscelli C, Fischer A. Severe combined immunodeficiency: a retrospective single-center study of clinical presentation and outcome in 117 patients. J Pediatr. 1993;123:564–72.

    Article  CAS  PubMed  Google Scholar 

  27. Buckley RH, Schiff RI, Schiff SE, Markert ML, Williams LW, Harville TO, Roberts JL, Puck JM. Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants. J Pediatr. 1997;130:378–87.

    Article  CAS  PubMed  Google Scholar 

  28. Laffort C, Le Deist F, Favre M, Caillat-Zucman S, Radford-Weiss I, Debre M, Fraitag S, Blanche S, Cavazzana-Calvo M, de Saint Basile G, et al. Severe cutaneous papillomavirus disease after haemopoietic stem-cell transplantation in patients with severe combined immune deficiency caused by common gammac cytokine receptor subunit or JAK-3 deficiency. Lancet. 2004;363:2051–4.

    Article  CAS  PubMed  Google Scholar 

  29. Russell SM, Tayebi N, Nakajima H, Riedy MC, Roberts JL, Aman MJ, Migone TS, Noguchi M, Markert ML, Buckley RH, et al. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science. 1995;270:797–800.

    Article  CAS  PubMed  Google Scholar 

  30. Macchi P, Villa A, Giliani S, Sacco MG, Frattini A, Porta F, Ugazio AG, Johnston JA, Candotti F, O’Shea JJ, et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature. 1995;377:65–8.

    Article  CAS  PubMed  Google Scholar 

  31. Candotti F, Oakes SA, Johnston JA, Giliani S, Schumacher RF, Mella P, Fiorini M, Ugazio AG, Badolato R, Notarangelo LD, et al. Structural and functional basis for JAK3-deficient severe combined immunodeficiency. Blood. 1997;90:3996–4003.

    CAS  PubMed  Google Scholar 

  32. Schumacher RF, Mella P, Lalatta F, Fiorini M, Giliani S, Villa A, Candotti F, Notarangelo LD. Prenatal diagnosis of JAK3 deficient SCID. Prenat Diagn. 1999;19:653–6.

    Article  CAS  PubMed  Google Scholar 

  33. Buckley RH, Schiff SE, Schiff RI, Markert L, Williams LW, Roberts JL, Myers LA, Ward FE. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med. 1999;340:508–16.

    Article  CAS  PubMed  Google Scholar 

  34. Vihinen M, Villa A, Mella P, Schumacher RF, Savoldi G, O’Shea JJ, Candotti F, Notarangelo LD. Molecular modeling of the Jak3 kinase domains and structural basis for severe combined immunodeficiency. Clin Immunol. 2000;96:108–18.

    Article  CAS  PubMed  Google Scholar 

  35. Frucht DM, Gadina M, Jagadeesh GJ, Aksentijevich I, Takada K, Bleesing JJ, Nelson J, Muul LM, Perham G, Morgan G, et al. Unexpected and variable phenotypes in a family with JAK3 deficiency. Genes Immun. 2001;2:422–32.

    Article  CAS  PubMed  Google Scholar 

  36. Notarangelo LD, Mella P, Jones A, de Saint Basile G, Savoldi G, Cranston T, Vihinen M, Schumacher RF. Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency. Hum Mutat. 2001;18:255–63.

    Article  CAS  PubMed  Google Scholar 

  37. Roberts JL, Lengi A, Brown SM, Chen M, Zhou YJ, O’Shea JJ, Buckley RH. Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation. Blood. 2004;103:2009–18.

    Article  CAS  PubMed  Google Scholar 

  38. Ichihara Y, Matsuoka H, Tsuge I, Okada J, Torii S, Yasui H, Kurosawa Y. Abnormalities in DNA rearrangements of immunoglobulin gene loci in precursor B cells derived from X-linked agammaglobulinemia patient and a severe combined immunodeficiency patient. Immunogenetics. 1988;27:330–7.

    Article  CAS  PubMed  Google Scholar 

  39. Schwarz K, Hansen-Hagge TE, Knobloch C, Friedrich W, Kleihauer E, Bartram CR. Severe combined immunodeficiency (SCID) in man: B cell-negative (B-) SCID patients exhibit an irregular recombination pattern at the JH locus. J Exp Med. 1991;174:1039–48.

    Article  CAS  PubMed  Google Scholar 

  40. Schatz DG, Oettinger MA, Baltimore D. The V(D)J recombination activating gene, RAG-1. Cell. 1989;59:1035–48.

    Article  CAS  PubMed  Google Scholar 

  41. van Gent DC, Ramsden DA, Gellert M. The RAG1 and RAG2 proteins establish the 12/23 rule in V(D)J recombination. Cell. 1996;85:107–13.

    Article  PubMed  Google Scholar 

  42. Schwarz K, Gauss GH, Ludwig L, Pannicke U, Li Z, Lindner D, Friedrich W, Seger RA, Hansen-Hagge TE, Desiderio S, et al. RAG mutations in human B cell-negative SCID. Science. 1996;274:97–9.

    Article  CAS  PubMed  Google Scholar 

  43. Schuetz C, Huck K, Gudowius S, Megahed M, Feyen O, Hubner B, Schneider DT, Manfras B, Pannicke U, Willemze R, et al. An immunodeficiency disease with RAG mutations and granulomas. N Engl J Med. 2008;358:2030–8.

    Article  CAS  PubMed  Google Scholar 

  44. •• van der Burg M, Gennery AR. Educational paper. The expanding clinical and immunological spectrum of severe combined immunodeficiency. Eur J Pediatr. 2011;170:561–71. An excellent review about human severe combined immunodeficiency. This manuscript describes the clinical and immunological features of each molecular defect.

  45. Cavazzana-Calvo M, Le Deist F, De Saint Basile G, Papadopoulo D, De Villartay JP, Fischer A. Increased radiosensitivity of granulocyte macrophage colony-forming units and skin fibroblasts in human autosomal recessive severe combined immunodeficiency. J Clin Invest. 1993;91:1214–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Nicolas N, Moshous D, Cavazzana-Calvo M, Papadopoulo D, de Chasseval R, Le Deist F, Fischer A, de Villartay JP. 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. 1998;188:627–34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. •• Schatz DG, Swanson PC. V(D)J recombination: mechanisms of initiation. Annu Rev Genet. 2011;45:167–202. An excellent and comprehensive review on VDJ recombination genetic defects.

  48. Moshous D, Li L, Chasseval R, Philippe N, Jabado N, Cowan MJ, Fischer A, de Villartay JP. A new gene involved in DNA double-strand break repair and V(D)J recombination is located on human chromosome 10p. Hum Mol Genet. 2000;9:583–8.

    Article  CAS  PubMed  Google Scholar 

  49. Moshous D, Callebaut I, de Chasseval R, Corneo B, Cavazzana-Calvo M, Le Deist F, Tezcan I, Sanal O, Bertrand Y, Philippe N, 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 

  50. Dvorak CC, Cowan MJ. Radiosensitive severe combined immunodeficiency disease. Immunol Allergy Clin N Am. 2010;30:125–42.

    Article  Google Scholar 

  51. Li L, Moshous D, Zhou Y, Wang J, Xie G, Salido E, Hu D, de Villartay JP, Cowan MJ. A founder mutation in Artemis, an SNM1-like protein, causes SCID in Athabascan-speaking Native Americans. J Immunol. 2002;168:6323–9.

    Article  CAS  PubMed  Google Scholar 

  52. •• Schuetz C, Neven B, Dvorak CC, Leroy S, Ege MJ, Pannicke U, Schwarz K, Schulz AS, Hoenig M, Sparber-Sauer M, et al. SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID. Blood 2014;123:281–9. An excellent manuscript on patients with T-B-NK+SCID disorders. This manuscript describes the clinical and immunological features of each molecular defect, and discusses the therapeutic approaches.

  53. Lieber MR. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem. 2010;79:181–211.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. van der Burg M, Ijspeert H, Verkaik NS, Turul T, Wiegant WW, Morotomi-Yano K, Mari PO, Tezcan I, Chen DJ, Zdzienicka MZ, et al. A DNA-PKcs mutation in a radiosensitive T-B-SCID patient inhibits Artemis activation and nonhomologous end-joining. J Clin Invest. 2009;119:91–8.

    PubMed Central  PubMed  Google Scholar 

  55. O’Driscoll M, Cerosaletti KM, Girard PM, Dai Y, Stumm M, Kysela B, Hirsch B, Gennery A, Palmer SE, Seidel J, et al. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell. 2001;8:1175–85.

    Article  PubMed  Google Scholar 

  56. Buck D, Malivert L, de Chasseval R, Barraud A, Fondaneche MC, Sanal O, Plebani A, Stephan JL, Hufnagel M, le Deist F, et al. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell. 2006;124:287–99.

    Article  CAS  PubMed  Google Scholar 

  57. van der Burg M, van Veelen LR, Verkaik NS, Wiegant WW, Hartwig NG, Barendregt BH, Brugmans L, Raams A, Jaspers NG, Zdzienicka MZ, et al. A new type of radiosensitive T-B-NK+ severe combined immunodeficiency caused by a LIG4 mutation. J Clin Invest. 2006;116:137–45.

    Article  PubMed Central  PubMed  Google Scholar 

  58. Buck D, Moshous D, de Chasseval R, Ma Y, le Deist F, Cavazzana-Calvo M, Fischer A, Casanova JL, Lieber MR, de Villartay JP. Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV. Eur J Immunol. 2006;36:224–35.

    Article  CAS  PubMed  Google Scholar 

  59. Kasparek TR, Humphrey TC. DNA double-strand break repair pathways, chromosomal rearrangements and cancer. Semin Cell Dev Biol. 2011;22:886–97.

    Article  CAS  PubMed  Google Scholar 

  60. Puel A, Ziegler SF, Buckley RH, Leonard WJ. Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency. Nat Genet. 1998;20:394–7.

    Article  CAS  PubMed  Google Scholar 

  61. Roifman CM, Zhang J, Chitayat D, Sharfe N. A partial deficiency of interleukin-7R alpha is sufficient to abrogate T-cell development and cause severe combined immunodeficiency. Blood. 2000;96:2803–7.

    CAS  PubMed  Google Scholar 

  62. Regueiro JR, Arnaiz-Villena A, de Ortiz Landazuri M, Martin Villa JM, Vicario JL, Pascual-Ruiz V, Guerra-Garcia F, Alcami J, Lopez-Botet M, Manzanares J. Familial defect of CD3 (T3) expression by T cells associated with rare gut epithelial cell autoantibodies. Lancet. 1986;1:1274–5.

    Article  CAS  PubMed  Google Scholar 

  63. Alarcon B, Regueiro JR, Arnaiz-Villena A, Terhorst C. Familial defect in the surface expression of the T-cell receptor-CD3 complex. N Engl J Med. 1988;319:1203–8.

    Article  CAS  PubMed  Google Scholar 

  64. Arnaiz-Villena A, Timon M, Corell A, Perez-Aciego P, Martin-Villa JM, Regueiro JR. Brief report: primary immunodeficiency caused by mutations in the gene encoding the CD3-gamma subunit of the T-lymphocyte receptor. N Engl J Med. 1992;327:529–33.

    Article  CAS  PubMed  Google Scholar 

  65. Dadi HK, Simon AJ, Roifman CM. Effect of CD3delta deficiency on maturation of alpha/beta and gamma/delta T-cell lineages in severe combined immunodeficiency. N Engl J Med. 2003;349:1821–8.

    Article  CAS  PubMed  Google Scholar 

  66. Soudais C, de Villartay JP, Le Deist F, Fischer A, Lisowska-Grospierre B. Independent mutations of the human CD3-epsilon gene resulting in a T cell receptor/CD3 complex immunodeficiency. Nat Genet. 1993;3:77–81.

    Article  CAS  PubMed  Google Scholar 

  67. de Saint Basile G, Geissmann F, Flori E, Uring-Lambert B, Soudais C, Cavazzana-Calvo M, Durandy A, Jabado N, Fischer A, Le Deist F. Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3. J Clin Invest. 2004;114:1512–7.

    Article  PubMed  Google Scholar 

  68. Rieux-Laucat F, Hivroz C, Lim A, Mateo V, Pellier I, Selz F, Fischer A, Le Deist F. Inherited and somatic CD3zeta mutations in a patient with T-cell deficiency. N Engl J Med. 2006;354:1913–21.

    Article  CAS  PubMed  Google Scholar 

  69. Fischer A, de Saint Basile G, Le Deist F. CD3 deficiencies. Curr Opin Allergy Clin Immunol. 2005;5:491–5.

    Article  CAS  PubMed  Google Scholar 

  70. Roberts JL, Lauritsen JP, Cooney M, Parrott RE, Sajaroff EO, Win CM, Keller MD, Carpenter JH, Carabana J, Krangel MS, et al. T-B+NK+ severe combined immunodeficiency caused by complete deficiency of the CD3zeta subunit of the T-cell antigen receptor complex. Blood. 2007;109:3198–206.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Cale CM, Klein NJ, Novelli V, Veys P, Jones AM, Morgan G. Severe combined immunodeficiency with abnormalities in expression of the common leucocyte antigen, CD45. Arch Dis Child. 1997;76:163–4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Kung C, Pingel JT, Heikinheimo M, Klemola T, Varkila K, Yoo LI, Vuopala K, Poyhonen M, Uhari M, Rogers M, et al. Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease. Nat Med. 2000;6:343–5.

    Article  CAS  PubMed  Google Scholar 

  73. Tchilian EZ, Wallace DL, Wells RS, Flower DR, Morgan G, Beverley PC. A deletion in the gene encoding the CD45 antigen in a patient with SCID. J Immunol. 2001;166:1308–13.

    Article  CAS  PubMed  Google Scholar 

  74. Hermiston ML, Xu Z, Weiss A. CD45: a critical regulator of signaling thresholds in immune cells. Annu Rev Immunol. 2003;21:107–37.

    Article  CAS  PubMed  Google Scholar 

  75. Morgan NV, Goddard S, Cardno TS, McDonald D, Rahman F, Barge D, Ciupek A, Straatman-Iwanowska A, Pasha S, Guckian M, et al. Mutation in the TCRalpha subunit constant gene (TRAC) leads to a human immunodeficiency disorder characterized by a lack of TCRalphabeta+T cells. J Clin Invest. 2011;121:695–702.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Giblett ER, Ammann AJ, Wara DW, Sandman R, Diamond LK. Nucleoside-phosphorylase deficiency in a child with severely defective T-cell immunity and normal B-cell immunity. Lancet. 1975;1:1010–3.

    Article  CAS  PubMed  Google Scholar 

  77. Ricciuti F, Ruddle FH. Assignment of nucleoside phosphorylase to D-14 and localization of X-linked loci in man by somatic cell genetics. Nature. 1973;241:180–2.

    Article  CAS  Google Scholar 

  78. Williams SR, Goddard JM, Martin DW Jr. Human purine nucleoside phosphorylase cDNA sequence and genomic clone characterization. Nucleic Acids Res. 1984;12:5779–87.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Williams SR, Gekeler V, McIvor RS, Martin DW Jr. A human purine nucleoside phosphorylase deficiency caused by a single base change. J Biol Chem. 1987;262:2332–8.

    CAS  PubMed  Google Scholar 

  80. Markert ML. Purine nucleoside phosphorylase deficiency. Immunodefic Rev. 1991;3:45–81.

    CAS  PubMed  Google Scholar 

  81. Simmonds HA, Fairbanks LD, Morris GS, Morgan G, Watson AR, Timms P, Singh B. Central nervous system dysfunction and erythrocyte guanosine triphosphate depletion in purine nucleoside phosphorylase deficiency. Arch Dis Child. 1987;62:385–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Pignata C, Fiore M, Guzzetta V, Castaldo A, Sebastio G, Porta F, Guarino A. Congenital alopecia and nail dystrophy associated with severe functional T-cell immunodeficiency in two sibs. Am J Med Genet. 1996;65:167–70.

    Article  CAS  PubMed  Google Scholar 

  83. Flanagan SP. ‘Nude’, a new hairless gene with pleiotropic effects in the mouse. Genet Res. 1966;8:295–309.

    Article  CAS  PubMed  Google Scholar 

  84. Nehls M, Pfeifer D, Schorpp M, Hedrich H, Boehm T. New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature. 1994;372:103–7.

    Article  CAS  PubMed  Google Scholar 

  85. Schorpp M, Hofmann M, Dear TN, Boehm T. Characterization of mouse and human nude genes. Immunogenetics. 1997;46:509–15.

    Article  CAS  PubMed  Google Scholar 

  86. Frank J, Pignata C, Panteleyev AA, Prowse DM, Baden H, Weiner L, Gaetaniello L, Ahmad W, Pozzi N, Cserhalmi-Friedman PB, et al. Exposing the human nude phenotype. Nature. 1999;398:473–4.

    Article  CAS  PubMed  Google Scholar 

  87. • Markert ML, Marques JG, Neven B, Devlin BH, McCarthy EA, Chinn IK, Albuquerque AS, Silva SL, Pignata C, de Saint Basile G, et al. First use of thymus transplantation therapy for FOXN1 deficiency (nude/SCID): a report of 2 cases. Blood. 2011;117:688–96. This paper reports the first thymic engraftment in patients with FOXN1 deficiency.

  88. Pignata C. A lesson for unraveling complex aspects of novel immunodeficiencies from the human equivalent of the nude/SCID phenotype. J Hematother Stem Cell Res. 2002;11:409–14.

    Article  PubMed  Google Scholar 

  89. Palamaro L, Romano R, Fusco A, Giardino G, Gallo V, Pignata C. FOXN1 in organ development and human diseases. Int Rev Immunol. 2014;33:83–93.

    Article  CAS  PubMed  Google Scholar 

  90. Kirkpatrick JA Jr, DiGeorge AM. Congenital absence of the thymus. The American journal of roentgenology, radium therapy, and nuclear medicine. 1968;103:32–7.

    Article  PubMed  Google Scholar 

  91. de la Chapelle A, Herva R, Koivisto M, Aula P. A deletion in chromosome 22 can cause DiGeorge syndrome. Hum Genet. 1981;57:253–6.

    Article  PubMed  Google Scholar 

  92. Kelley RI, Zackai EH, Emanuel BS, Kistenmacher M, Greenberg F, Punnett HH. The association of the DiGeorge anomalad with partial monosomy of chromosome 22. J Pediatr. 1982;101:197–200.

    Article  CAS  PubMed  Google Scholar 

  93. Hollander G, Gill J, Zuklys S, Iwanami N, Liu C, Takahama Y. Cellular and molecular events during early thymus development. Immunol Rev. 2006;209:28–46.

    Article  CAS  PubMed  Google Scholar 

  94. Le Deist F, Hivroz C, Partiseti M, Thomas C, Buc HA, Oleastro M, Belohradsky B, Choquet D, Fischer A. A primary T-cell immunodeficiency associated with defective transmembrane calcium influx. Blood. 1995;85:1053–62.

    PubMed  Google Scholar 

  95. Feske S, Gwack Y, Prakriya M, Srikanth S, Puppel SH, Tanasa B, Hogan PG, Lewis RS, Daly M, Rao A. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature. 2006;441:179–85.

    Article  CAS  PubMed  Google Scholar 

  96. Picard C, McCarl CA, Papolos A, Khalil S, Luthy K, Hivroz C, LeDeist F, Rieux-Laucat F, Rechavi G, Rao A, et al. STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity. N Engl J Med. 2009;360:1971–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  97. Feske S. ORAI1 and STIM1 deficiency in human and mice: roles of store-operated Ca2+ entry in the immune system and beyond. Immunol Rev. 2009;231:189–209.

    Article  CAS  PubMed  Google Scholar 

  98. Chan AC, Kadlecek TA, Elder ME, Filipovich AH, Kuo WL, Iwashima M, Parslow TG, Weiss A. ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency. Science. 1994;264:1599–601.

    Article  CAS  PubMed  Google Scholar 

  99. Elder ME, Lin D, Clever J, Chan AC, Hope TJ, Weiss A, Parslow TG. Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. Science. 1994;264:1596–9.

    Article  CAS  PubMed  Google Scholar 

  100. Hauck F, Randriamampita C, Martin E, Gerart S, Lambert N, Lim A, Soulier J, Maciorowski Z, Touzot F, Moshous D, et al. Primary T-cell immunodeficiency with immunodysregulation caused by autosomal recessive LCK deficiency. J Allergy Clin Immunol. 2012;130(1144–1152):e1111.

    Google Scholar 

  101. Stepensky P, Keller B, Buchta M, Kienzler AK, Elpeleg O, Somech R, Cohen S, Shachar I, Miosge LA, Schlesier M, et al. Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects. J Allergy Clin Immunol. 2013;131:477–85.

    Article  CAS  PubMed  Google Scholar 

  102. Greil J, Rausch T, Giese T, Bandapalli OR, Daniel V, Bekeredjian-Ding I, Stutz AM, Drees C, Roth S, Ruland J, et al. Whole-exome sequencing links caspase recruitment domain 11 (CARD11) inactivation to severe combined immunodeficiency. J Allergy Clin Immunol. 2013;131(1376–1383):e1373.

    Google Scholar 

  103. •• Pannicke U, Baumann B, Fuchs S, Henneke P, Rensing-Ehl A, Rizzi M, Janda A, Hese K, Schlesier M, Holzmann K, et al. Deficiency of innate and acquired immunity caused by an IKBKB mutation. N Engl J Med. 2013;369:2504–14. This paper reports the first identification of mutation in the IKBKB gene in patients.

  104. Jabara HH, Ohsumi T, Chou J, Massaad MJ, Benson H, Megarbane A, Chouery E, Mikhael R, Gorka O, Gewies A, et al. A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency. J Allergy Clin Immunol. 2013;132:151–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  105. Turvey SE, Durandy A, Fischer A, Fung SY, Geha RS, Gewies A, Giese T, Greil J, Keller B, McKinnon ML, et al. The CARD11-BCL10-MALT1 (CBM) signalosome complex: stepping into the limelight of human primary immunodeficiency. J Allergy Clin Immunol. 2014;134:276–84.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We would like to thank all the members of our laboratory and unit for helpful discussions, and critical reading of the text, and our collaborators worldwide for their trust and patience.

Disclosure

Capucine Picard, Despina Moshous, and Alain Fischer declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. Study Center for Primary Immunodeficiencies, Necker-Enfant Malades Hospital, Assistance Publique - Hôpitaux de Paris (AP-HP), 149 Rue de Sevres, 75015, Paris, France

    Capucine Picard

  2. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France

    Capucine Picard

  3. Sorbonne Paris Cité, Imagine Institut, Paris Descartes University, Paris, France

    Capucine Picard, Despina Moshous & Alain Fischer

  4. INSERM UMR 1163, Paris, France

    Despina Moshous & Alain Fischer

  5. Pediatric Hematology-Immunology Unit, Necker Enfant Malades Hospital, AP-HP, Paris, France

    Despina Moshous & Alain Fischer

  6. College de France, Paris, France

    Alain Fischer

Authors
  1. Capucine Picard
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  2. Despina Moshous
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  3. Alain Fischer
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Correspondence to Capucine Picard.

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This article is part of the Topical Collection on Immunology.

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Picard, C., Moshous, D. & Fischer, A. The Genetic and Molecular Basis of Severe Combined Immunodeficiency. Curr Pediatr Rep 3, 22–33 (2015). https://doi.org/10.1007/s40124-014-0070-8

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  • DOI: https://doi.org/10.1007/s40124-014-0070-8

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