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Logo of jcinvestThe Journal of Clinical Investigation
J Clin Invest. 1995 February; 95(2): 895–899.
PMCID: PMC295580

Female germ line mosaicism as the origin of a unique IL-2 receptor gamma-chain mutation causing X-linked severe combined immunodeficiency.


The IL2RG gene encoding the gamma chain of the lymphocyte receptor for IL-2 lies in human Xq13.1 and is mutated in males with X-linked severe combined immunodeficiency (SCID). In a large Canadian pedigree genetic linkage studies demonstrated that the proband's grandmother was the source of an X-linked SCID mutation. However, her T cells did not show the expected skewed X chromosome inactivation pattern of female carriers of SCID, despite her having one affected son and two carrier daughters with skewed X inactivation. Single strand conformation polymorphism analysis of IL2RG in the affected proband was abnormal in exon 5; sequencing revealed a nine nucleotide in-frame duplication insertion. The three duplicated amino acids included the first tryptophan of the "WSXWS" motif found in all members of the cytokine receptor gene superfamily. Mutation detection in the pedigree confirmed that the founder grandmother's somatic cells had only normal IL2RG, and further showed that the SCID-associated X chromosome haplotype was inherited by three daughters, one with a wild type IL2RG gene and two others with the insertional mutation. Female germ line mosaicism is unusual, but its presence in this X-linked SCID family emphasizes the limitations of genetic diagnosis by linkage as compared with direct mutation analysis.

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Selected References

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  • 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 Apr 9;73(1):147–157. [PubMed]
  • Puck JM, Deschênes 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 Aug;2(8):1099–1104. [PubMed]
  • Puck JM. X-linked immunodeficiencies. Adv Hum Genet. 1993;21:107–144. [PubMed]
  • Puck JM, Nussbaum RL, Conley ME. Carrier detection in X-linked severe combined immunodeficiency based on patterns of X chromosome inactivation. J Clin Invest. 1987 May;79(5):1395–1400. [PMC free article] [PubMed]
  • Puck JM, Krauss CM, Puck SM, Buckley RH, Conley ME. Prenatal test for X-linked severe combined immunodeficiency by analysis of maternal X-chromosome inactivation and linkage analysis. N Engl J Med. 1990 Apr 12;322(15):1063–1066. [PubMed]
  • de Saint Basile G, Arveiler B, Oberlé 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 U S A. 1987 Nov;84(21):7576–7579. [PubMed]
  • Puck JM, Conley ME, Bailey LC. Refinement of linkage of human severe combined immunodeficiency (SCIDX1) to polymorphic markers in Xq13. Am J Hum Genet. 1993 Jul;53(1):176–184. [PubMed]
  • Markiewicz S, DiSanto JP, Chelly J, Fairweather N, Le Marec B, Griscelli C, Graeber MB, Müller U, Fischer A, Monaco AP, et al. Fine mapping of the human SCIDX1 locus at Xq12-13.1. Hum Mol Genet. 1993 Jun;2(6):651–654. [PubMed]
  • Puck JM. Molecular basis for three X-linked immune disorders. Hum Mol Genet. 1994;3(Spec No):1457–1461. [PubMed]
  • Puck JM, Stewart CC, Nussbaum RL. Maximum-likelihood analysis of human T-cell X chromosome inactivation patterns: normal women versus carriers of X-linked severe combined immunodeficiency. Am J Hum Genet. 1992 Apr;50(4):742–748. [PubMed]
  • Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet. 1992 Dec;51(6):1229–1239. [PubMed]
  • Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2766–2770. [PubMed]
  • Hall JG. Review and hypotheses: somatic mosaicism: observations related to clinical genetics. Am J Hum Genet. 1988 Oct;43(4):355–363. [PubMed]
  • Darras BT, Blattner P, Harper JF, Spiro AJ, Alter S, Francke U. Intragenic deletions in 21 Duchenne muscular dystrophy (DMD)/Becker muscular dystrophy (BMD) families studied with the dystrophin cDNA: location of breakpoints on HindIII and BglII exon-containing fragment maps, meiotic and mitotic origin of the mutations. Am J Hum Genet. 1988 Nov;43(5):620–629. [PubMed]
  • Bakker E, Veenema H, Den Dunnen JT, van Broeckhoven C, Grootscholten PM, Bonten EJ, van Ommen GJ, Pearson PL. Germinal mosaicism increases the recurrence risk for 'new' Duchenne muscular dystrophy mutations. J Med Genet. 1989 Sep;26(9):553–559. [PMC free article] [PubMed]
  • Bröcker-Vriends AH, Briët E, Dreesen JC, Bakker B, Reitsma P, Pannekoek H, van de Kamp JJ, Pearson PL. Somatic origin of inherited haemophilia A. Hum Genet. 1990 Aug;85(3):288–292. [PubMed]
  • Gitschier J. Maternal duplication associated with gene deletion in sporadic hemophilia. Am J Hum Genet. 1988 Sep;43(3):274–279. [PubMed]
  • Hendriks RW, Mensink EJ, Kraakman ME, Thompson A, Schuurman RK. Evidence for male X chromosomal mosaicism in X-linked agammaglobulinemia. Hum Genet. 1989 Oct;83(3):267–270. [PubMed]
  • DiSanto JP, Dautry-Varsat A, Certain S, Fischer A, de Saint Basile G. Interleukin-2 (IL-2) receptor gamma chain mutations in X-linked severe combined immunodeficiency disease result in the loss of high-affinity IL-2 receptor binding. Eur J Immunol. 1994 Feb;24(2):475–479. [PubMed]
  • Duriez B, Sobrier ML, Duquesnoy P, Tixier-Boichard M, Decuypere E, Coquerelle G, Zeman M, Goossens M, Amselem S. A naturally occurring growth hormone receptor mutation: in vivo and in vitro evidence for the functional importance of the WS motif common to all members of the cytokine receptor superfamily. Mol Endocrinol. 1993 Jun;7(6):806–814. [PubMed]
  • Miyazaki T, Maruyama M, Yamada G, Hatakeyama M, Taniguchi T. The integrity of the conserved 'WS motif' common to IL-2 and other cytokine receptors is essential for ligand binding and signal transduction. EMBO J. 1991 Nov;10(11):3191–3197. [PubMed]
  • Ihle JN, Quelle FW, Miura O. Signal transduction through the receptor for erythropoietin. Semin Immunol. 1993 Oct;5(5):375–389. [PubMed]
  • Nakagawa Y, Kosugi H, Miyajima A, Arai K, Yokota T. Structure of the gene encoding the alpha subunit of the human granulocyte-macrophage colony stimulating factor receptor. Implications for the evolution of the cytokine receptor superfamily. J Biol Chem. 1994 Apr 8;269(14):10905–10912. [PubMed]
  • Russell SM, Keegan AD, Harada N, Nakamura Y, Noguchi M, Leland P, Friedmann MC, Miyajima A, Puri RK, Paul WE, et al. Interleukin-2 receptor gamma chain: a functional component of the interleukin-4 receptor. Science. 1993 Dec 17;262(5141):1880–1883. [PubMed]
  • Noguchi M, Nakamura Y, Russell SM, Ziegler SF, Tsang M, Cao X, Leonard WJ. Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor. Science. 1993 Dec 17;262(5141):1877–1880. [PubMed]
  • Kondo M, Takeshita T, Ishii N, Nakamura M, Watanabe S, Arai K, Sugamura K. Sharing of the interleukin-2 (IL-2) receptor gamma chain between receptors for IL-2 and IL-4. Science. 1993 Dec 17;262(5141):1874–1877. [PubMed]

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