Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1995 Sep;57(3):564–571.

Two mutational hotspots in the interleukin-2 receptor gamma chain gene causing human X-linked severe combined immunodeficiency.

A E Pepper 1, R H Buckley 1, T N Small 1, J M Puck 1
PMCID: PMC1801277  PMID: 7668284

Abstract

Human severe combined immunodeficiency (SCID), a syndrome of profoundly impaired cellular and humoral immunity, is most commonly caused by mutations in the X-linked gene for interleukin-2 (IL-2) receptor gamma chain (IL2RG). For mutational analysis of IL2RG in males with SCID, SSCP screening was followed by DNA sequencing. Of 40 IL2RG mutations found in unrelated SCID patients, 6 were point mutations at the CpG dinucleotide at cDNA 690-691, encoding amino acid R226. This residue lies in the extracellular domain of the protein in a region not previously recognized to be significantly conserved in the cytokine receptor gene family, 11 amino acids upstream from the highly conserved WSXWS motif. Three additional instances of mutation at another CpG dinucleotide at cDNA 879 produced a premature termination signal in the intracellular domain of IL2RG, resulting in loss of the SH2-homologous intracellular domain known to be essential for signaling from the IL-2 receptor complex. Mutations at these two hotspots constitute > 20% of the X-linked SCID mutations found by our group and a similar proportion of all reported IL2RG mutations.

Full text

PDF
565

Images in this article

566Figure 1
on p.566
567Figure 2
on p.567
567Figure 3
on p.567
567Figure 4
on p.567

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ashworth A., Kraft A. Cloning of a potentially soluble receptor for human GM-CSF. Nucleic Acids Res. 1990 Dec 11;18(23):7178–7178. doi: 10.1093/nar/18.23.7178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barrett M. J., Buckley R. H., Schiff S. E., Kidd P. C., Ward F. E. Accelerated development of immunity following transplantation of maternal marrow stem cells into infants with severe combined immunodeficiency and transplacentally acquired lymphoid chimerism. Clin Exp Immunol. 1988 Apr;72(1):118–123. [PMC free article] [PubMed] [Google Scholar]
  3. Bortin M. M., Rimm A. A. Severe combined immunodeficiency disease. Characterization of the disease and results of transplantation. JAMA. 1977 Aug 15;238(7):591–600. [PubMed] [Google Scholar]
  4. Boutin J. M., Edery M., Shirota M., Jolicoeur C., Lesueur L., Ali S., Gould D., Djiane J., Kelly P. A. Identification of a cDNA encoding a long form of prolactin receptor in human hepatoma and breast cancer cells. Mol Endocrinol. 1989 Sep;3(9):1455–1461. doi: 10.1210/mend-3-9-1455. [DOI] [PubMed] [Google Scholar]
  5. Chua A. O., Chizzonite R., Desai B. B., Truitt T. P., Nunes P., Minetti L. J., Warrier R. R., Presky D. H., Levine J. F., Gately M. K. Expression cloning of a human IL-12 receptor component. A new member of the cytokine receptor superfamily with strong homology to gp130. J Immunol. 1994 Jul 1;153(1):128–136. [PubMed] [Google Scholar]
  6. Conley M. E., Buckley R. H., Hong R., Guerra-Hanson C., Roifman C. M., Brochstein J. A., Pahwa S., Puck J. M. X-linked severe combined immunodeficiency. Diagnosis in males with sporadic severe combined immunodeficiency and clarification of clinical findings. J Clin Invest. 1990 May;85(5):1548–1554. doi: 10.1172/JCI114603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Conley M. E., Nowell P. C., Henle G., Douglas S. D. XX T cells and XY B cells in two patients with severe combined immune deficiency. Clin Immunol Immunopathol. 1984 Apr;31(1):87–95. doi: 10.1016/0090-1229(84)90192-2. [DOI] [PubMed] [Google Scholar]
  8. DiSanto J. P., 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. doi: 10.1002/eji.1830240232. [DOI] [PubMed] [Google Scholar]
  9. DiSanto J. P., Rieux-Laucat F., Dautry-Varsat A., Fischer A., de Saint Basile G. Defective human interleukin 2 receptor gamma chain in an atypical X chromosome-linked severe combined immunodeficiency with peripheral T cells. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9466–9470. doi: 10.1073/pnas.91.20.9466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Emini E. A., Hughes J. V., Perlow D. S., Boger J. Induction of hepatitis A virus-neutralizing antibody by a virus-specific synthetic peptide. J Virol. 1985 Sep;55(3):836–839. doi: 10.1128/jvi.55.3.836-839.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Giri J. G., Ahdieh M., Eisenman J., Shanebeck K., Grabstein K., Kumaki S., Namen A., Park L. S., Cosman D., Anderson D. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 1994 Jun 15;13(12):2822–2830. doi: 10.1002/j.1460-2075.1994.tb06576.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hayashi K., Yandell D. W. How sensitive is PCR-SSCP? Hum Mutat. 1993;2(5):338–346. doi: 10.1002/humu.1380020503. [DOI] [PubMed] [Google Scholar]
  13. Henthorn P. S., Somberg R. L., Fimiani V. M., Puck J. M., Patterson D. F., Felsburg P. J. IL-2R gamma gene microdeletion demonstrates that canine X-linked severe combined immunodeficiency is a homologue of the human disease. Genomics. 1994 Sep 1;23(1):69–74. doi: 10.1006/geno.1994.1460. [DOI] [PubMed] [Google Scholar]
  14. Hirschhorn R. Overview of biochemical abnormalities and molecular genetics of adenosine deaminase deficiency. Pediatr Res. 1993 Jan;33(1 Suppl):S35–S41. doi: 10.1203/00006450-199305001-00194. [DOI] [PubMed] [Google Scholar]
  15. Ishii N., Asao H., Kimura Y., Takeshita T., Nakamura M., Tsuchiya S., Konno T., Maeda M., Uchiyama T., Sugamura K. Impairment of ligand binding and growth signaling of mutant IL-2 receptor gamma-chains in patients with X-linked severe combined immunodeficiency. J Immunol. 1994 Aug 1;153(3):1310–1317. [PubMed] [Google Scholar]
  16. Jameson B. A., Wolf H. The antigenic index: a novel algorithm for predicting antigenic determinants. Comput Appl Biosci. 1988 Mar;4(1):181–186. doi: 10.1093/bioinformatics/4.1.181. [DOI] [PubMed] [Google Scholar]
  17. 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. doi: 10.1126/science.8266076. [DOI] [PubMed] [Google Scholar]
  18. Leonard W. J., Depper J. M., Crabtree G. R., Rudikoff S., Pumphrey J., Robb R. J., Krönke M., Svetlik P. B., Peffer N. J., Waldmann T. A. Molecular cloning and expression of cDNAs for the human interleukin-2 receptor. Nature. 1984 Oct 18;311(5987):626–631. doi: 10.1038/311626a0. [DOI] [PubMed] [Google Scholar]
  19. Markiewicz S., Subtil A., Dautry-Varsat A., Fischer A., de Saint Basile G. Detection of three nonsense mutations and one missense mutation in the interleukin-2 receptor gamma chain gene in SCIDX1 that differently affect the mRNA processing. Genomics. 1994 May 1;21(1):291–293. doi: 10.1006/geno.1994.1265. [DOI] [PubMed] [Google Scholar]
  20. Miyazaki T., Kawahara A., Fujii H., Nakagawa Y., Minami Y., Liu Z. J., Oishi I., Silvennoinen O., Witthuhn B. A., Ihle J. N. Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science. 1994 Nov 11;266(5187):1045–1047. doi: 10.1126/science.7973659. [DOI] [PubMed] [Google Scholar]
  21. Noguchi M., Nakamura Y., Russell S. M., Ziegler S. F., Tsang M., Cao X., Leonard W. J. Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor. Science. 1993 Dec 17;262(5141):1877–1880. doi: 10.1126/science.8266077. [DOI] [PubMed] [Google Scholar]
  22. Noguchi M., Yi H., Rosenblatt H. M., Filipovich A. H., Adelstein S., Modi W. S., McBride O. W., Leonard W. J. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993 Apr 9;73(1):147–157. doi: 10.1016/0092-8674(93)90167-o. [DOI] [PubMed] [Google Scholar]
  23. Penny L. A., Forget B. G. Genomic organization of the human erythropoietin receptor gene. Genomics. 1991 Dec;11(4):974–980. doi: 10.1016/0888-7543(91)90022-7. [DOI] [PubMed] [Google Scholar]
  24. Puck J. M., Conley M. E., Bailey L. C. Refinement of linkage of human severe combined immunodeficiency (SCIDX1) to polymorphic markers in Xq13. Am J Hum Genet. 1993 Jul;53(1):176–184. [PMC free article] [PubMed] [Google Scholar]
  25. Puck J. M., Deschênes S. M., Porter J. C., Dutra A. S., Brown C. J., Willard H. F., Henthorn P. S. 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. doi: 10.1093/hmg/2.8.1099. [DOI] [PubMed] [Google Scholar]
  26. Puck J. M., Stewart C. C., Nussbaum R. L. 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. [PMC free article] [PubMed] [Google Scholar]
  27. Ram K. T., Barker D. F., Puck J. M. Dinucleotide repeat polymorphism at the DXS441 locus. Nucleic Acids Res. 1992 Mar 25;20(6):1428–1428. doi: 10.1093/nar/20.6.1428. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Russell S. M., Johnston J. A., Noguchi M., Kawamura M., Bacon C. M., Friedmann M., Berg M., McVicar D. W., Witthuhn B. A., Silvennoinen O. Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID. Science. 1994 Nov 11;266(5187):1042–1045. doi: 10.1126/science.7973658. [DOI] [PubMed] [Google Scholar]
  29. Russell S. M., Keegan A. D., Harada N., Nakamura Y., Noguchi M., Leland P., Friedmann M. C., Miyajima A., Puri R. K., Paul W. E. Interleukin-2 receptor gamma chain: a functional component of the interleukin-4 receptor. Science. 1993 Dec 17;262(5141):1880–1883. doi: 10.1126/science.8266078. [DOI] [PubMed] [Google Scholar]
  30. Stephan J. L., 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 Oct;123(4):564–572. doi: 10.1016/s0022-3476(05)80951-5. [DOI] [PubMed] [Google Scholar]
  31. Willard H. F., Cremers F., Mandel J. L., Monaco A. P., Nelson D. L., Schlessinger D. Report and abstracts of the Fifth International Workshop on Human X Chromosome Mapping 1994. Heidelberg, Germany, April 24-27, 1994. Cytogenet Cell Genet. 1994;67(4):295–358. doi: 10.1159/000133870. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES