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

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

Journal: Journal of clinical immunology 2022;41(1):1-10

PMID: 33392855

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.

DOI: 10.1007/s10875-020-00936-x

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MeSH Terms: Alleles, Diagnosis, Differential, Genetic Association Studies, Genetic Diseases, Inborn, Genetic Predisposition to Disease, Genetic Variation, Genotype, Germ-Line Mutation, Haploinsufficiency, Humans, Ikaros Transcription Factor, Mutation, Penetrance, Phenotype, Primary Immunodeficiency Diseases, Prognosis, Protein Binding, Protein Interaction Domains and Motifs, Protein Multimerization