Female Germ Line Mosaicism As the Origin of a Unique IL-2 Receptor Gamma-chain Mutation Causing X-linked Severe Combined Immunodeficiency

Overview

Journal J Clin Invest

Specialty General Medicine

Date 1995 Feb 1

PMID 7860773

Citations 11

Authors

J M Puck

A E Pepper

P M Bedard

R Laframboise

Affiliations

Soon will be listed here.

Abstract

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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References

Brocker-Vriends A, Briet E, Dreesen J, Bakker B, Reitsma P, Pannekoek H . Somatic origin of inherited haemophilia A. Hum Genet. 1990; 85(3):288-92. DOI: 10.1007/BF00206748. View

Puck J, Krauss C, Puck S, Buckley R, Conley M . Prenatal test for X-linked severe combined immunodeficiency by analysis of maternal X-chromosome inactivation and linkage analysis. N Engl J Med. 1990; 322(15):1063-6. DOI: 10.1056/NEJM199004123221508. View

Puck J, Stewart C, Nussbaum R . 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; 50(4):742-8. PMC: 1682632. View

Allen R, Zoghbi H, Moseley A, Rosenblatt H, Belmont J . 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; 51(6):1229-39. PMC: 1682906. View

Noguchi M, Yi H, Rosenblatt H, Filipovich A, Adelstein S, Modi W . Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993; 73(1):147-57. DOI: 10.1016/0092-8674(93)90167-o. View

Puck J . X-linked immunodeficiencies. Adv Hum Genet. 1993; 21:107-44. DOI: 10.1007/978-1-4615-3010-7_2. View

Puck J, Conley M, Bailey L . Refinement of linkage of human severe combined immunodeficiency (SCIDX1) to polymorphic markers in Xq13. Am J Hum Genet. 1993; 53(1):176-84. PMC: 1682225. View

Markiewicz S, DiSanto J, Chelly J, Fairweather N, Le Marec B, Griscelli C . Fine mapping of the human SCIDX1 locus at Xq12-13.1. Hum Mol Genet. 1993; 2(6):651-4. DOI: 10.1093/hmg/2.6.651. View

Duriez B, Sobrier M, Duquesnoy P, Tixier-Boichard M, Decuypere E, Coquerelle G . 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; 7(6):806-14. DOI: 10.1210/mend.7.6.8361502. View

10.

Puck J, Deschenes S, Porter J, Dutra A, Brown C, Willard H . 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(8):1099-104. DOI: 10.1093/hmg/2.8.1099. View

11.

Ihle J, Quelle F, Miura O . Signal transduction through the receptor for erythropoietin. Semin Immunol. 1993; 5(5):375-89. DOI: 10.1006/smim.1993.1043. View

12.

Kondo M, Takeshita T, Ishii N, Nakamura M, Watanabe S, Arai K . Sharing of the interleukin-2 (IL-2) receptor gamma chain between receptors for IL-2 and IL-4. Science. 1993; 262(5141):1874-7. DOI: 10.1126/science.8266076. View

13.

Noguchi M, Nakamura Y, Russell S, Ziegler S, Tsang M, Cao X . Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor. Science. 1993; 262(5141):1877-80. DOI: 10.1126/science.8266077. View

14.

Russell S, Keegan A, Harada N, Nakamura Y, Noguchi M, Leland P . Interleukin-2 receptor gamma chain: a functional component of the interleukin-4 receptor. Science. 1993; 262(5141):1880-3. DOI: 10.1126/science.8266078. View

15.

DiSanto J, 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; 24(2):475-9. DOI: 10.1002/eji.1830240232. View

16.

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; 269(14):10905-12. View

17.

Puck J . Molecular basis for three X-linked immune disorders. Hum Mol Genet. 1994; 3 Spec No:1457-61. DOI: 10.1093/hmg/3.suppl_1.1457. View

18.

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; 10(11):3191-7. PMC: 453042. DOI: 10.1002/j.1460-2075.1991.tb04881.x. View

19.

Puck J, Nussbaum R, Conley M . Carrier detection in X-linked severe combined immunodeficiency based on patterns of X chromosome inactivation. J Clin Invest. 1987; 79(5):1395-400. PMC: 424401. DOI: 10.1172/JCI112967. View

20.

de Saint Basile G, Arveiler B, Oberle I, Malcolm S, Levinsky R, Lau Y . 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; 84(21):7576-9. PMC: 299342. DOI: 10.1073/pnas.84.21.7576. View