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IKAROS-Associated Diseases in 2020: Genotypes, Phenotypes, and Outcomes in Primary Immune Deficiency/Inborn Errors of Immunity

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Abstract

IKAROS, encoded by IKZF1, is a zinc finger transcription factor and a critical regulator of hematopoiesis. Mutations in IKZF1 have been implicated in immune deficiency, autoimmunity, and malignancy in humans. Somatic IKZF1 loss-of-function mutations and deletions have been shown to increase predisposition to the development of B cell acute lymphoblastic leukemia (B-ALL) and associated with poor prognosis. In the last 4 years, germline heterozygous IKZF1 mutations have been reported in primary immune deficiency/inborn errors of immunity. These allelic variants, acting by either haploinsufficiency or dominant negative mechanisms affecting particular functions of IKAROS, are associated with common variable immunodeficiency, combined immunodeficiency, or primarily hematologic phenotypes in affected patients. In this review, we provide an overview of genetic, clinical, and immunological manifestations in patients with IKZF1 mutations, and the molecular and cellular mechanisms that contribute to their disease as a consequence of IKAROS dysfunction.

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Acknowledgments

These studies were supported by the Intramural Research Program, NIH Clinical Center, US National Institutes of Health (NIH). The content of this article does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.

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This work was supported by the Intramural Research Program, NIH Clinical Center, US National Institutes of Health (NIH).

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  1. Immunology Service, Department of Laboratory Medicine, National Institutes of Health (NIH) Clinical Center, 10 Center Dr., Bldg 10, Rm. 2C410F, Bethesda, MD, 20892, USA

    Hye Sun Kuehn, Cristiane J. Nunes-Santos & Sergio D. Rosenzweig

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HSK, CJNS, and SDR collected the data, analyzed the data, and wrote the manuscript.

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Correspondence to Sergio D. Rosenzweig.

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Kuehn, H.S., Nunes-Santos, C.J. & Rosenzweig, S.D. IKAROS-Associated Diseases in 2020: Genotypes, Phenotypes, and Outcomes in Primary Immune Deficiency/Inborn Errors of Immunity. J Clin Immunol 41, 1–10 (2021). https://doi.org/10.1007/s10875-020-00936-x

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