Abstract
Interleukin 2 receptor alpha chain (IL-2Rα or CD25) deficiency (OMIM #606367) is an immune dysregulation disorder segregating in autosomal recessive form. The disease is caused by biallelic variants in the IL-2Rα gene encoding IL-2Rα also known as CD25 protein. IL-2Rα combines with γ and β chains of interleukin 2 receptor to form a functional interleukin 2 receptor (IL-2R). In the present study, we identified a Pakistani family presenting a unique presentation of IL-2Rα deficiency. Clinical whole exome sequencing revealed a novel splice donor site variant (NM_001378789.1 (NP_001365718); c.64 + 1G > A) in the IL-2Rα gene. American College of Medical Genetics (ACMG) guidelines interpreted the identified variant as likely pathogenic. The IL-2Rα gene mutation usually presents with autoimmunity and immunodeficiency but in our patient, it presents with congenital diarrhea, metabolic crisis, and strong family history of death in infancy due to the similar complications. Her congenital diarrhea is attributed to autoimmunity in the form of autoimmune enteropathy and eczema. The laboratory findings revealed severe metabolic acidosis hypokalemia and elevated lactate and ammonia levels. This is a new presentation of IL-2Rα gene mutation. The present study highlights the importance of clinical whole exome sequencing in the correct diagnosis of congenital disorders. The study will also help clinical geneticists for genetic counseling and prevention of the disease in the affected family.
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References
Bennett RL, French KS, Resta RG, Doyle DL (2008) Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. J Genet Couns 17(5):424–433. https://doi.org/10.1007/s10897-008-9169-9
Bezrodnik L, Caldirola MS, Seminario AG, Moreira I, Gaillard MI (2014) Follicular bronchiolitis as phenotype associated with CD25 deficiency. Clin Exp Immunol 175(2):227–234. https://doi.org/10.1111/cei.12214
Butter F, Davison L, Viturawong T, Scheibe M, Vermeulen M, Todd JA, Mann M (2012) Proteome-wide analysis of disease-associated SNPs that show allele-specific transcription factor binding. PLoS Genet 8:e1002982. https://doi.org/10.1371/journal.pgen.1002982
Caudy AA, Reddy ST, Chatila T, Atkinson JP, Verbsky JW (2007) CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J Allergy Clin Immunol 119(2):482–487. https://doi.org/10.1016/j.jaci.2006.10.007
Charbonnier LM, Janssen E, Chou J, Ohsumi TK, Keles S, Hsu JT, Massaad MJ, Garcia-Lloret M, Hanna-Wakim R, Dbaibo G, Alangari AA, Alsultan A, Al-Zahrani D, Geha RS, Chatila TA (2015) Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA. J Allergy Clin Immunol 135(1):217–227. https://doi.org/10.1016/j.jaci.2014.10.019
Goncalves DG, Prando Cau L,Salles PD, Anagusko CLY, Mendonca LO, Barros MT et al (2017) Another case of interleukin-2 receptor alpha chain (IL2RA) deficiency. J Allergy Immun 139(2). https://doi.org/10.1016/j.jaci.2016.12.011
Goudy K, Aydin D, Barzaghi F, Gambineri E, Vignoli M, Ciullini Mannurita S et al (2013) Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin Immunol 46(3):248–261. https://doi.org/10.1016/j.clim.2013.01.004
Haeberle S, Wei X, Bieber K, Goletz S, Ludwig RJ, Schmidt E, Enk AH, Hadaschik EN (2018) Regulatory T-cell deficiency leads to pathogenic bullous pemphigoid antigen 230 autoantibody and autoimmune bullous disease. J Allergy Clin Immunol 142(6):1831–1842. https://doi.org/10.1016/j.jaci.2018.04.006
Knevel R, de Rooy DP, Zhernakova A et al (2013) Association of variants in IL2RA with progression of joint destruction in rheumatoid arthritis. Arthritis Rheum 65:1684–1693. https://doi.org/10.1002/art.37938
Li H, Zhou H, Zhang Q et al (2013) Functional polymorphism rs7072793 C>T affect individual susceptibility to breast cancer by modulating CD25 transcription activity. Mol Carcinog 52:370–376. https://doi.org/10.1002/mc.21865
Lisyova J, Chandoga J, Jungova P et al (2018) An unusually high frequency of SCAD deficiency caused by two pathogenic variants in the ACADS gene and its relationship to the ethnic structure in Slovakia. BMC Med Genet 19:64. https://doi.org/10.1186/s12881-018-0566-0
Lowe CE, Cooper JD, Brusko T, Walker NM, Smyth DJ, Bailey R, Bourget K, Plagnol V, Field S, Atkinson M, Clayton DG, Wicker LS, Todd JA (2007) Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat Genet 39(9):1074–1082. https://doi.org/10.1038/ng2102
Monostori P, Klinke G, Hauke J, Richter S, Bierau J, Garbade SF et al (2019) Extended diagnosis of purine and pyrimidine disorders from urine: LC MS/MS assay development and clinical validation. PLoS ONE 2019:e0212458. https://doi.org/10.1371/journal.pone.0212458
Muramatsu K, Ujiie H, Kobayashi I, Nishie W, Izumi K, Ito T, Yoshimoto N, Natsuga K, Iwata H, Shimizu H (2018) Regulatory T-cell dysfunction induces autoantibodies to bullous pemphigoid antigens in mice and human subjects. J Allergy Clin Immunol 142(6):1818-1830.e6. https://doi.org/10.1016/j.jaci.2018.03.014
Rickert M, Wang X, Boulanger MJ, Goriatcheva N, Garcia KC (2005) The structure of interleukin-2 complexed with its alpha receptor. Science 3;308(5727):1477–1480
Schwartz AM, Demin DE, Vorontsov IE, Kasyanov AS, Putlyaeva LV, Tatosyan KA, Kulakovskiy IV, Kuprash DV (2017) Multiple single nucleotide polymorphisms in the first intron of the IL2RA gene affect transcription factor binding and enhancer activity. Gene 602:50–56. https://doi.org/10.1016/j.gene.2016.11.032
Sharfe N, Dadi HK, Shahar M, Roifman CM (1997) Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. Proc Natl Acad Sci USA 94(7):3168–3171. https://doi.org/10.1073/pnas.94.7.3168
Vignoli M, Ciullini Mannurita S, Fioravanti A, Tumino M, Grassi A, Guariso G, Favre C, D’Elios MM, Gambineri E (2019) CD25 deficiency: a new conformational mutation prevents the receptor expression on cell surface. Clin Immunol 201:15–19. https://doi.org/10.1016/j.clim.2019.02.003
Wang LM, Zhang DM, Xu YM, Sun SL (2011) Interleukin 2 receptor α gene polymorphism and risk of multiple sclerosis: a meta-analysis. J Int Med Res 39:1625–1635. https://doi.org/10.1177/147323001103900505
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We would like to thank the patient and her family for their cooperation in this study.
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Waheed, N., Naseer, M., Haider, N. et al. Whole exome sequencing identified a novel splice donor site variant in interleukin 2 receptor alpha chain. Immunogenetics 75, 71–79 (2023). https://doi.org/10.1007/s00251-022-01278-1
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DOI: https://doi.org/10.1007/s00251-022-01278-1