Identification and Functional Analysis of a de novo IKZF3 Mutation in a Pediatric Patient with Combined Immunodeficiency.
IKZF3
AIOLOS
Combined Immunodeficiency
Inborn Errors of Immunity
Journal
Journal of clinical immunology
ISSN: 1573-2592
Titre abrégé: J Clin Immunol
Pays: Netherlands
ID NLM: 8102137
Informations de publication
Date de publication:
17 May 2024
17 May 2024
Historique:
received:
25
09
2023
accepted:
03
04
2024
medline:
17
5
2024
pubmed:
17
5
2024
entrez:
17
5
2024
Statut:
epublish
Résumé
AIOLOS, a vital member of the IKAROS protein family, plays a significant role in lymphocyte development and function through DNA binding and protein-protein interactions. Mutations in the IKZF3 gene, which encodes AIOLOS, lead to a rare combined immunodeficiency often linked with infections and malignancy. In this study, we evaluated a 1-year-4-month-old female patient presenting with recurrent infections, diarrhea, and failure to thrive. Laboratory investigations revealed decreased T lymphocyte and immunoglobulin levels. Through whole-exome and Sanger sequencing, we discovered a de novo mutation in IKZF3 (NM_012481; exon 5 c.571G > C, p.Gly191Arg), corresponding to the third DNA-binding zinc finger region of the encoded protein AIOLOS. Notably, the patient with the AIOLOS G191R mutation showed reduced recent thymic emigrants in naïve CD4
Identifiants
pubmed: 38758229
doi: 10.1007/s10875-024-01706-9
pii: 10.1007/s10875-024-01706-9
doi:
Substances chimiques
IKZF3 protein, human
0
Types de publication
Journal Article
Case Reports
Langues
eng
Sous-ensembles de citation
IM
Pagination
117Subventions
Organisme : National Natural Science Foundation of China
ID : 32360184
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
Staels F, Collignon T, Betrains A, Gerbaux M, Willemsen M, Humblet-Baron S, et al. Monogenic adult-onset inborn errors of immunity. Front Immunol. 2021;12: 753978.
doi: 10.3389/fimmu.2021.753978
pubmed: 34867986
pmcid: 8635491
Fischer A. Gene therapy for inborn errors of immunity: past, present and future. Nat Rev Immunol. 2023;23(6):397–408.
doi: 10.1038/s41577-022-00800-6
pubmed: 36434109
Elsink K, Huibers MM, Hollink IH, Simons A, Zonneveld-Huijssoon E, van der Veken LT, et al. Implementation of early next-generation sequencing for inborn errors of immunity: a prospective observational cohort study of diagnostic yield and clinical implications in Dutch genome diagnostic centers. Front Immunol. 2021;12: 780134.
doi: 10.3389/fimmu.2021.780134
pubmed: 34992599
pmcid: 8724043
Suspitsin EN, Guseva MN, Kostik MM, Sokolenko AP, Skripchenko NV, Levina AS, et al. Next generation sequencing analysis of consecutive Russian patients with clinical suspicion of inborn errors of immunity. Clin Genet. 2020;98(3):231–9.
doi: 10.1111/cge.13789
pubmed: 32441320
John LB, Ward AC. The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity. Mol Immunol. 2011;48(9–10):1272–8.
doi: 10.1016/j.molimm.2011.03.006
pubmed: 21477865
Heizmann B, Kastner P, Chan S. The Ikaros family in lymphocyte development. Curr Opin Immunol. 2018;51:14–23.
doi: 10.1016/j.coi.2017.11.005
pubmed: 29278858
Yamashita M, Morio T. Inborn errors of IKAROS and AIOLOS. Curr Opin Immunol. 2021;72:239–48.
doi: 10.1016/j.coi.2021.06.010
pubmed: 34265590
Marke R, van Leeuwen FN, Scheijen B. The many faces of IKZF1 in B-cell precursor acute lymphoblastic leukemia. Haematologica. 2018;103(4):565.
doi: 10.3324/haematol.2017.185603
pubmed: 29519871
pmcid: 5865415
Zhang X, Zhang X, Li X, Lv Y, Zhu Y, Wang J, et al. The specific distribution pattern of IKZF1 mutation in acute myeloid leukemia. J Hematol Oncol. 2020;13:1–5.
doi: 10.1186/s13045-020-00972-5
Hetemäki I, Kaustio M, Kinnunen M, Heikkilä N, Keskitalo S, Nowlan K, et al. Loss-of-function mutation in IKZF2 leads to immunodeficiency with dysregulated germinal center reactions and reduction of MAIT cells. Science Immunol. 2021;6(65):eabe3454.
doi: 10.1126/sciimmunol.abe3454
Shahin T, Mayr D, Shoeb MR, Kuehn HS, Hoeger B, Giuliani S, et al. Identification of germline monoallelic mutations in IKZF2 in patients with immune dysregulation. Blood Adv. 2022;6(7):2444–51.
doi: 10.1182/bloodadvances.2021006367
pubmed: 34920454
pmcid: 9006292
Gokhale AS, Gangaplara A, Lopez-Occasio M, Thornton AM, Shevach EM. Selective deletion of Eos (Ikzf4) in T-regulatory cells leads to loss of suppressive function and development of systemic autoimmunity. J Autoimmun. 2019;105: 102300.
doi: 10.1016/j.jaut.2019.06.011
pubmed: 31296356
pmcid: 11046398
Lentaigne C, Greene D, Sivapalaratnam S, Favier R, Seyres D, Thys C, et al. Germline mutations in the transcription factor IKZF5 cause thrombocytopenia. Blood. 2019;134(23):2070–81.
doi: 10.1182/blood.2019000782
pubmed: 31217188
Lazarian G, Yin S, Ten Hacken E, Sewastianik T, Uduman M, Font-Tello A, et al. A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation. Cancer Cell. 2021;39(3):380-93.e8.
doi: 10.1016/j.ccell.2021.02.003
pubmed: 33689703
pmcid: 8034546
Ma S, Pathak S, Mandal M, Trinh L, Clark MR, Lu R. Ikaros and Aiolos inhibit pre-B-cell proliferation by directly suppressing c-Myc expression. Mol Cell Biol. 2010;30(17):4149–58.
doi: 10.1128/MCB.00224-10
pubmed: 20566697
pmcid: 2937562
Yamashita M, Kuehn HS, Okuyama K, Okada S, Inoue Y, Mitsuiki N, et al. A variant in human AIOLOS impairs adaptive immunity by interfering with IKAROS. Nat Immunol. 2021;22(7):893–903.
doi: 10.1038/s41590-021-00951-z
pubmed: 34155405
pmcid: 8958960
Kuehn HS, Chang J, Yamashita M, Niemela JE, Zou C, Okuyama K, et al. T and B cell abnormalities, pneumocystis pneumonia, and chronic lymphocytic leukemia associated with an AIOLOS defect in patients. J Exp Med. 2021;218(12): e20211118.
doi: 10.1084/jem.20211118
pubmed: 34694366
pmcid: 8548914
Kuehn HS, Sakovich IS, Niemela JE, Silva AAG, Stoddard JL, Polyakova EA, et al. Disease-associated AIOLOS variants lead to immune deficiency/dysregulation by haploinsufficiency and redefine AIOLOS functional domains. J Clin Investig. 2024;134(3): e172573.
doi: 10.1172/JCI172573
pubmed: 38015619
pmcid: 10836806
Ding Y, Zhou L, Xia Y, Wang W, Wang Y, Li L, et al. Reference values for peripheral blood lymphocyte subsets of healthy children in China. J Allergy Clin Immunol. 2018;142(3):970-3.e8.
doi: 10.1016/j.jaci.2018.04.022
pubmed: 29746882
Zhao Q, Dai R, Li Y, Wang Y, Chen X, Shu Z, et al. Trends in TREC values according to age and gender in Chinese children and their clinical applications. Eur J Pediatr. 2022;181(2):529–38.
doi: 10.1007/s00431-021-04223-8
pubmed: 34405301
Cobb BS, Morales-Alcelay S, Kleiger G, Brown KE, Fisher AG, Smale ST. Targeting of Ikaros to pericentromeric heterochromatin by direct DNA binding. Genes Dev. 2000;14(17):2146–60.
doi: 10.1101/gad.816400
pubmed: 10970879
pmcid: 316893
Caballero R, Setien F, Lopez-Serra L, Boix-Chornet M, Fraga MF, Ropero S, et al. Combinatorial effects of splice variants modulate function of Aiolos. J Cell Sci. 2007;120(Pt 15):2619–30.
doi: 10.1242/jcs.007344
pubmed: 17646674
Morgan B, Sun L, Avitahl N, Andrikopoulos K, Ikeda T, Gonzales E, et al. Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation. EMBO J. 1997;16(8):2004–13.
doi: 10.1093/emboj/16.8.2004
pubmed: 9155026
pmcid: 1169803
Kohler S, Keil T, Alexander T, Thiel A, Swierzy M, Ismail M, et al. Altered naive CD4(+) T cell homeostasis in myasthenia gravis and thymoma patients. J Neuroimmunol. 2019;327:10–4.
doi: 10.1016/j.jneuroim.2019.01.005
pubmed: 30686546
Yamashita M, Morio T. AIOLOS variants causing immunodeficiency in human and mice. Front Immunol. 2022;13: 866582.
doi: 10.3389/fimmu.2022.866582
pubmed: 35444653
pmcid: 9014263
Apostolov A. Studying the posttranslational modifications of tran- scription factor Ikaros and their role in its function: Strasbourg. 2012
Kuehn HS, Chang J, Yamashita M, Niemela JE, Zou C, Okuy- ama K, et al. T and B cell abnormalities, pneumocystis pneumo- nia, and chronic lymphocytic leukemia associated with an AIO- LOS defect in patients. J Exp Med. 2021;218(12):e20211118. 27.