Current Pediatrics Reports

, Volume 3, Issue 1, pp 22–33 | Cite as

The Genetic and Molecular Basis of Severe Combined Immunodeficiency

  • Capucine PicardEmail author
  • Despina Moshous
  • Alain Fischer
Immunology (HB Gaspar, Section Editor)
Part of the following topical collections:
  1. Immunology


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.


Severe combined immunodeficiency Primary immunodeficiencies T-cell lymphopenia Genetic defect 



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.


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.


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

  1. 1.
    Chapel H, Geha R, Rosen F. Primary immunodeficiency diseases: an update. Clin Exp Immunol. 2003;132:9–15.CrossRefPubMedCentralPubMedGoogle Scholar
  2. 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.Google Scholar
  3. 3.
    Buckley RH. Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Annu Rev Immunol. 2004;22:625–55.CrossRefPubMedGoogle Scholar
  4. 4.
    Glanzmann E, Riniker P. Essential lymphocytophthisis; new clinical aspect of infant pathology. Ann Paediatr. 1950;175:1–32.PubMedGoogle Scholar
  5. 5.
    Hitzig WH, Biro Z, Bosch H, Huser HJ. Agammaglobulinemia & alymphocytosis with atrophy of lymphatic tissue. Helvet Paediatr Acta. 1958;13:551–85.Google Scholar
  6. 6.
    Fischer A. Severe combined immunodeficiencies (SCID). Clin Exp Immunol. 2000;122:143–9.CrossRefPubMedCentralPubMedGoogle Scholar
  7. 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.Google Scholar
  8. 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.CrossRefPubMedGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 10.
    Ochs HD, Smith CIE, Puck J. Primary immunodeficiencies: a molecular and genetic approach. 3rd ed. New York: Oxford University Press; 2013.CrossRefGoogle Scholar
  11. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  12. 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.PubMedCentralPubMedGoogle Scholar
  13. 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.PubMedGoogle Scholar
  14. 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.CrossRefPubMedGoogle Scholar
  15. 15.
    de VO, Seynhaeve V. Reticular dysgenesia. Lancet. 1959;2:1123–5.Google Scholar
  16. 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.CrossRefPubMedGoogle Scholar
  17. 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.CrossRefPubMedGoogle Scholar
  18. 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.CrossRefPubMedGoogle Scholar
  19. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  20. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  21. 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.CrossRefPubMedGoogle Scholar
  22. 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.CrossRefPubMedGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 24.
    Puck JM. IL2RGbase: a database of gamma c-chain defects causing human X-SCID. Immunol Today. 1996;17:507–11.CrossRefPubMedGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. 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.CrossRefPubMedGoogle Scholar
  28. 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.CrossRefPubMedGoogle Scholar
  29. 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.CrossRefPubMedGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. 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.PubMedGoogle Scholar
  32. 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.CrossRefPubMedGoogle Scholar
  33. 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.CrossRefPubMedGoogle Scholar
  34. 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.CrossRefPubMedGoogle Scholar
  35. 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.CrossRefPubMedGoogle Scholar
  36. 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.CrossRefPubMedGoogle Scholar
  37. 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.CrossRefPubMedGoogle Scholar
  38. 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.CrossRefPubMedGoogle Scholar
  39. 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.CrossRefPubMedGoogle Scholar
  40. 40.
    Schatz DG, Oettinger MA, Baltimore D. The V(D)J recombination activating gene, RAG-1. Cell. 1989;59:1035–48.CrossRefPubMedGoogle Scholar
  41. 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.CrossRefPubMedGoogle Scholar
  42. 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.CrossRefPubMedGoogle Scholar
  43. 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.CrossRefPubMedGoogle Scholar
  44. 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.Google Scholar
  45. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  46. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  47. 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.Google Scholar
  48. 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.CrossRefPubMedGoogle Scholar
  49. 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.CrossRefPubMedGoogle Scholar
  50. 50.
    Dvorak CC, Cowan MJ. Radiosensitive severe combined immunodeficiency disease. Immunol Allergy Clin N Am. 2010;30:125–42.CrossRefGoogle Scholar
  51. 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.CrossRefPubMedGoogle Scholar
  52. 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.Google Scholar
  53. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  54. 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.PubMedCentralPubMedGoogle Scholar
  55. 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.CrossRefPubMedGoogle Scholar
  56. 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.CrossRefPubMedGoogle Scholar
  57. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  58. 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.CrossRefPubMedGoogle Scholar
  59. 59.
    Kasparek TR, Humphrey TC. DNA double-strand break repair pathways, chromosomal rearrangements and cancer. Semin Cell Dev Biol. 2011;22:886–97.CrossRefPubMedGoogle Scholar
  60. 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.CrossRefPubMedGoogle Scholar
  61. 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.PubMedGoogle Scholar
  62. 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.CrossRefPubMedGoogle Scholar
  63. 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.CrossRefPubMedGoogle Scholar
  64. 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.CrossRefPubMedGoogle Scholar
  65. 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.CrossRefPubMedGoogle Scholar
  66. 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.CrossRefPubMedGoogle Scholar
  67. 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.CrossRefPubMedGoogle Scholar
  68. 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.CrossRefPubMedGoogle Scholar
  69. 69.
    Fischer A, de Saint Basile G, Le Deist F. CD3 deficiencies. Curr Opin Allergy Clin Immunol. 2005;5:491–5.CrossRefPubMedGoogle Scholar
  70. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  71. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  72. 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.CrossRefPubMedGoogle Scholar
  73. 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.CrossRefPubMedGoogle Scholar
  74. 74.
    Hermiston ML, Xu Z, Weiss A. CD45: a critical regulator of signaling thresholds in immune cells. Annu Rev Immunol. 2003;21:107–37.CrossRefPubMedGoogle Scholar
  75. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  76. 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.CrossRefPubMedGoogle Scholar
  77. 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.CrossRefGoogle Scholar
  78. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  79. 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.PubMedGoogle Scholar
  80. 80.
    Markert ML. Purine nucleoside phosphorylase deficiency. Immunodefic Rev. 1991;3:45–81.PubMedGoogle Scholar
  81. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  82. 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.CrossRefPubMedGoogle Scholar
  83. 83.
    Flanagan SP. ‘Nude’, a new hairless gene with pleiotropic effects in the mouse. Genet Res. 1966;8:295–309.CrossRefPubMedGoogle Scholar
  84. 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.CrossRefPubMedGoogle Scholar
  85. 85.
    Schorpp M, Hofmann M, Dear TN, Boehm T. Characterization of mouse and human nude genes. Immunogenetics. 1997;46:509–15.CrossRefPubMedGoogle Scholar
  86. 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.CrossRefPubMedGoogle Scholar
  87. 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.Google Scholar
  88. 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.CrossRefPubMedGoogle Scholar
  89. 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.CrossRefPubMedGoogle Scholar
  90. 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.CrossRefPubMedGoogle Scholar
  91. 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.CrossRefPubMedGoogle Scholar
  92. 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.CrossRefPubMedGoogle Scholar
  93. 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.CrossRefPubMedGoogle Scholar
  94. 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.PubMedGoogle Scholar
  95. 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.CrossRefPubMedGoogle Scholar
  96. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  97. 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.CrossRefPubMedGoogle Scholar
  98. 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.CrossRefPubMedGoogle Scholar
  99. 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.CrossRefPubMedGoogle Scholar
  100. 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. 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.CrossRefPubMedGoogle Scholar
  102. 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. 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.Google Scholar
  104. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  105. 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.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media New York 2014

Authors and Affiliations

  • Capucine Picard
    • 1
    • 2
    • 3
    Email author
  • Despina Moshous
    • 3
    • 4
    • 5
  • Alain Fischer
    • 3
    • 4
    • 5
    • 6
  1. 1.Study Center for Primary ImmunodeficienciesNecker-Enfant Malades Hospital, Assistance Publique - Hôpitaux de Paris (AP-HP)ParisFrance
  2. 2.Laboratory of Human Genetics of Infectious Diseases, Necker BranchINSERM UMR 1163ParisFrance
  3. 3.Sorbonne Paris Cité, Imagine InstitutParis Descartes UniversityParisFrance
  4. 4.INSERM UMR 1163ParisFrance
  5. 5.Pediatric Hematology-Immunology UnitNecker Enfant Malades Hospital, AP-HPParisFrance
  6. 6.College de FranceParisFrance

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