{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T14:35:13Z","timestamp":1793284513903,"version":"4.5.0"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"2","funder":[{"name":"Intramural Research Program"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,25]]},"abstract":"<jats:title>Summary<\/jats:title>\n               <jats:p>IKAROS\/IKZF1 plays a pivotal role in lymphocyte differentiation and development. Germline mutations in IKZF1, which have been shown to be associated with primary immunodeficiency, can be classified through four different mechanisms of action depending on the protein expression and its functional defects: haploinsufficiency, dimerization defective, dominant negative, and gain of function. These different mechanisms are associated with variable degrees of susceptibility to infectious diseases, autoimmune disorders, allergic diseases, and malignancies. To date, more than 30 heterozygous IKZF1 germline variants have been reported in patients with primary immunodeficiency. Here we review recent discoveries and clinical\/immunological characterization of IKAROS-associated diseases that are linked to different mechanisms of action in IKAROS function.<\/jats:p>","DOI":"10.1093\/cei\/uxac109","type":"journal-article","created":{"date-parts":[[2022,11,26]],"date-time":"2022-11-26T11:49:25Z","timestamp":1669463365000},"page":"129-136","source":"Crossref","is-referenced-by-count":61,"title":["Inborn errors of human IKAROS: LOF and GOF variants associated with primary immunodeficiency"],"prefix":"10.1093","volume":"212","author":[{"given":"Hye Sun","family":"Kuehn","sequence":"first","affiliation":[{"name":"Immunology Service, Department of Laboratory Medicine, National Institutes of Health Clinical Center , Bethesda, MD , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigette","family":"Boast","sequence":"additional","affiliation":[{"name":"Immunology Service, Department of Laboratory Medicine, National Institutes of Health Clinical Center , Bethesda, MD , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5550-9678","authenticated-orcid":false,"given":"Sergio D","family":"Rosenzweig","sequence":"additional","affiliation":[{"name":"Immunology Service, Department of Laboratory Medicine, National Institutes of Health Clinical Center , Bethesda, MD , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,11,26]]},"reference":[{"key":"2023042515451421600_CIT0001","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1126\/science.1439790","article-title":"IKAROS, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment","volume":"258","author":"Georgopoulos","year":"1992","journal-title":"Science"},{"key":"2023042515451421600_CIT0002","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1093\/emboj\/16.8.2004","article-title":"Aiolos, a lymphoid restricted transcription factor that interacts with IKAROS to regulate lymphocyte differentiation","volume":"16","author":"Morgan","year":"1997","journal-title":"EMBO J"},{"key":"2023042515451421600_CIT0003","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1101\/gad.12.6.782","article-title":"Helios, a T cell-restricted IKAROS family member that quantitatively associates with IKAROS at centromeric heterochromatin","volume":"12","author":"Hahm","year":"1998","journal-title":"Genes Dev"},{"key":"2023042515451421600_CIT0004","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/S0960-9822(98)70202-7","article-title":"Helios, a novel dimerization partner of IKAROS expressed in the earliest hematopoietic progenitors","volume":"8","author":"Kelley","year":"1998","journal-title":"Curr Biol"},{"key":"2023042515451421600_CIT0005","doi-asserted-by":"crossref","first-page":"38347","DOI":"10.1074\/jbc.M005457200","article-title":"Eos and pegasus, two members of the IKAROS family of proteins with distinct DNA binding activities","volume":"275","author":"Perdomo","year":"2000","journal-title":"J Biol Chem"},{"key":"2023042515451421600_CIT0006","first-page":"8292","article-title":"The IKAROS gene encodes a family of functionally diverse zinc finger DNA-binding proteins","volume":"14","author":"Molnar","year":"1994","journal-title":"Mol Cell Biol"},{"key":"2023042515451421600_CIT0007","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.3389\/fimmu.2019.01299","article-title":"IKAROS zinc finger transcription factors: regulators of cytokine signaling pathways and CD4(+) T helper cell differentiation","volume":"10","author":"Powell","year":"2019","journal-title":"Front Immunol"},{"key":"2023042515451421600_CIT0008","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.ccell.2018.03.021","article-title":"Germline genetic IKZF1 variation and predisposition to childhood acute lymphoblastic leukemia","volume":"33","author":"Churchman","year":"2018","journal-title":"Cancer Cell"},{"key":"2023042515451421600_CIT0009","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1056\/NEJMoa0808253","article-title":"Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia","volume":"360","author":"Mullighan","year":"2009","journal-title":"N Engl J Med"},{"key":"2023042515451421600_CIT0010","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/nature06866","article-title":"BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of IKAROS","volume":"453","author":"Mullighan","year":"2008","journal-title":"Nature"},{"key":"2023042515451421600_CIT0011","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1080\/1744666X.2021.1901582","article-title":"Germline IKZF1 mutations and their impact on immunity: IKAROS-associated diseases and pathophysiology","volume":"17","author":"Kuehn","year":"2021","journal-title":"Expert Rev Clin Immunol"},{"key":"2023042515451421600_CIT0012","doi-asserted-by":"crossref","first-page":"3071","DOI":"10.1172\/JCI98164","article-title":"Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency","volume":"128","author":"Boutboul","year":"2018","journal-title":"J Clin Invest"},{"key":"2023042515451421600_CIT0013","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1056\/NEJMoa1512234","article-title":"Loss of B cells in patients with heterozygous mutations in IKAROS","volume":"374","author":"Kuehn","year":"2016","journal-title":"N Engl J Med"},{"key":"2023042515451421600_CIT0014","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.jaci.2017.08.019","article-title":"A novel IKAROS haploinsufficiency kindred with unexpectedly late and variable B-cell maturation defects","volume":"141","author":"Bogaert","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"2023042515451421600_CIT0015","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.jaci.2016.09.029","article-title":"Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations","volume":"140","author":"Hoshino","year":"2017","journal-title":"J Allergy Clin Immunol"},{"key":"2023042515451421600_CIT0016","doi-asserted-by":"crossref","first-page":"568","DOI":"10.3389\/fimmu.2019.00568","article-title":"Assessing the functional relevance of variants in the IKAROS family zinc finger protein 1 (IKZF1) in a cohort of patients with primary immunodeficiency","volume":"10","author":"Eskandarian","year":"2019","journal-title":"Front Immunol"},{"key":"2023042515451421600_CIT0017","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1007\/s10875-020-00781-y","article-title":"Management of chronic immune thrombocytopenia and presumed autoimmune hepatitis in a child with IKAROS haploinsufficiency","volume":"40","author":"Groth","year":"2020","journal-title":"J Clin Immunol"},{"key":"2023042515451421600_CIT0018","doi-asserted-by":"crossref","first-page":"e101","DOI":"10.1093\/rheumatology\/keaa492","article-title":"Cutaneous IgA vasculitis-presenting manifestation of a novel mutation in the IKZF1 gene","volume":"60","author":"Banday","year":"2021","journal-title":"Rheumatology (Oxford)"},{"key":"2023042515451421600_CIT0019","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s10875-019-00643-2","article-title":"IKZF1 loss-of-function variant causes autoimmunity and severe familial antiphospholipid syndrome","volume":"39","author":"Dieudonne","year":"2019","journal-title":"J Clin Immunol"},{"key":"2023042515451421600_CIT0020","doi-asserted-by":"crossref","first-page":"53","DOI":"10.18176\/jiaci.0207","article-title":"B-cell deficiency: a de novo IKZF1 patient and review of the 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myeloma cells","volume":"343","author":"Kronke","year":"2014","journal-title":"Science"},{"key":"2023042515451421600_CIT0039","doi-asserted-by":"crossref","first-page":"705497","DOI":"10.3389\/fped.2021.705497","article-title":"IKAROS-associated diseases: from mice to humans and back again","volume":"9","author":"Boast","year":"2021","journal-title":"Front Pediatr"},{"key":"2023042515451421600_CIT0040","doi-asserted-by":"crossref","first-page":"E6","DOI":"10.1016\/S2665-9913(19)30142-0","article-title":"Contribution of rare and predicted pathogenic gene variants to childhood-onset lupus: a large, genetic panel analysis of British and French cohorts (vol 2, pg e99, 2020)","volume":"2","author":"Belot","year":"2020","journal-title":"Lancet Rheumatol"},{"key":"2023042515451421600_CIT0041","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1038\/s41590-021-00951-z","article-title":"A variant in human AIOLOS impairs adaptive immunity by interfering with IKAROS","volume":"22","author":"Yamashita","year":"2021","journal-title":"Nat Immunol"},{"key":"2023042515451421600_CIT0042","doi-asserted-by":"crossref","first-page":"e20211118","DOI":"10.1084\/jem.20211118","article-title":"T and B cell abnormalities, pneumocystis pneumonia, and chronic lymphocytic leukemia associated with an AIOLOS defect in patients","volume":"218","author":"Kuehn","year":"2021","journal-title":"J Exp Med"},{"key":"2023042515451421600_CIT0043","doi-asserted-by":"crossref","first-page":"eabe3454","DOI":"10.1126\/sciimmunol.abe3454","article-title":"Loss-of-function mutation in IKZF2 leads to immunodeficiency with dysregulated germinal center reactions and reduction of MAIT cells","volume":"6","author":"Hetemaki","year":"2021","journal-title":"Sci Immunol"},{"key":"2023042515451421600_CIT0044","doi-asserted-by":"crossref","first-page":"eabe3981","DOI":"10.1126\/sciimmunol.abe3981","article-title":"Germline biallelic mutation affecting the transcription factor Helios causes pleiotropic defects of immunity","volume":"6","author":"Shahin","year":"2021","journal-title":"Sci Immunol"},{"key":"2023042515451421600_CIT0045","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.1182\/bloodadvances.2021006367","article-title":"Identification of germline monoallelic mutations in IKZF2 in patients with immune dysregulation","volume":"6","author":"Shahin","year":"2022","journal-title":"Blood Adv"}],"container-title":["Clinical and Experimental 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