Alt. symbols: ZNFN1A1 | hIk-1 | LyF-1 | Hs.54452 | IKAROS | PPP1R92

Approved name: IKAROS family zinc finger 1
Alt. names: zinc finger protein, subfamily 1A, 1 (Ikaros), IKAROS family zinc finger 1 (Ikaros) | protein phosphatase 1, regulatory subunit 92

Location: 7p12.2: 50304068 - 50405101 (+)
Gene type: protein_coding, 22 transcripts.

Scores: LoFtool: | pLI: 0.98575132 | LOEUF: 0.156

HGNC: 13176

NCBI: 10320, RefSeq: NG_034231.1

Ensembl: ENSG00000185811.21

LRG_1121 | Status: public

OMIM: 603023

Expression | ProteinAtlas

IKZF1 (IKAROS Family Zinc Finger 1) encodes a transcription factor that belongs to the family of zinc-finger DNA-binding proteins associated with chromatin remodeling. The expression of this protein is restricted to the fetal and adult hemo-lymphopoietic system, and has crucial functions as a regulator of lymphocyte differentiation. In particular, it has been found in recent years to be a major tumor suppressor involved in human B-cell acute lymphoblastic leukemia and that it also has a part in the differentiation and function of individual T helper cells. Moreover, Ikaros also plays a role during the later stages of B cell development during VDJ recombination for class switching of the antibody isotypes and expression of the B cell receptor. Most isoforms share a common C-terminal domain, which contains two zinc finger motifs that are required for hetero- or homo-dimerization, and for interactions with other proteins. The isoforms, however, differ in the number of N-terminal zinc finger motifs that bind DNA and in nuclear localization signal presence, resulting in members with and without DNA-binding properties. Only a few isoforms contain three or more N-terminal zinc motifs that confer high affinity binding to a specific core DNA sequence element in the promoters of target genes. The non-DNA-binding isoforms are largely found in the cytoplasm, and are thought to function as dominant-negative factors. Overexpression of some dominant-negative isoforms have been associated with B-cell malignancies, such as acute lymphoblastic leukemia (ALL).

Heterozygous germline mutations in this gene were first reported in a neonate with profound B lymphopenia, near absent NK cells, and normal T cell number, he additionally presented with severe polyhydramnios, hydrops, and ascites at birth. This newborn was found to carry a de novo heterozygous p.Y210C mutation (Goldman et al. 2012). In 2016, Kuehn et al. reported 6 additional mutations in 29 individuals with CVID from 6 unrelated families, including 4 missense mutations: p.R162L/Q, p.H167R, p.R1 84Q, a 16.8-kb intragenic deletion and a 4.7-Mb multigenic deletion. This novel autosomal dominant form of common variable immunodeficiency, type 13 [MIM:616873], is caused by IKAROS haploinsufficiency and it is characterized by recurrent infections and markedly reduced number of B cells. Some of these mutations showed incomplete penetrance as one adult and few children were unaffected carriers at the moment of study. Similar clinical phenotypes and incomplete penetrance was observed in the families reported by Eskandarian et al. (2019). The authors concluded that at least p.R143W, p.C150R, p.K286X, and possibly pM494V, are loss-of-function mutations. Kuehn et al. also reported the development of (B-cell) acute lymphoblastic leukemia (ALL) in 2 of the 29 patients. The association of IKZF1 mutations with ALL was confirmed by succeeding studies: Yoshida et al. (2017) reported a patient with primary immunodeficiency carrying the p.N159S mutation who progressed to T-cell ALL; whereas Churchman et al. (2018) reported 28 mutations in 45 cases with familial or sporadic B-cell ALL. The latter study showed that the majority of these variants have deleterious effects on IKAROS function, despite the fact that many of them are not predicted to be damaging in silico. Churchman et al. (2018) conclude that these mutations, regardless of their localization along the different regions or functional domains of the protein, result in impaired DNA binding and regulation of transcriptional targets, induction of aberrant leukemic cell adhesion, and impaired drug responsiveness. Somatic mutations also result in B-cell ALL. Boutboul, D. et al. (2018) reported 7 unrelated patients with early-onset combined immunodeficiency, who carried a de novo germline IKZF1 mutation, either the previously reported p.N159S (6 of 7) or the novel p.N159T (1 case) mutation. [Load More]