IKZF1 Gene

The IKZF1 gene (IKZF1 stands for "IKAROS Family Zinc Finger 1") is a protein-coding gene located on chromosome 7p12.2. Several alternatively spliced transcript variants have been described for the IKZF1 gene, encoding different isoforms. Most isoforms share a common C-terminal domain that contains two zinc finger motifs required for hetero- or homo-dimerization and for interactions with other proteins. However, isoforms differ in the number of N-terminal zinc finger motifs that bind DNA and in the presence of nuclear localization signals, so there are members with and without DNA-binding properties. Only a few isoforms contain the required three or more N-terminal zinc motifs that confer high affinity for binding to a specific nuclear DNA sequence element in the promoters of target genes. The non-DNA-binding isoforms are largely located in the cytoplasm and likely function as dominant-negative factors.

The IKZF1 gene encodes a transcription factor belonging to the family of zinc finger DNA-binding proteins associated with chromatin remodeling. Expression of the "IKAROS Family Zinc Finger 1" protein is restricted to the fetal and adult hemo-lymphopoietic system. The protein functions as a regulator of lymphocyte differentiation.

Overexpression of some dominant-negative isoforms has been associated with B-cell malignancies such as acute lymphoblastic leukemia (ALL).

Diseases associated with IKZF1 include:

• Immunodeficiency 13 and IKZF1 defect (CVID13) (OMIM:616873; Goldman FD et al. 2021; Kuehn HS et al. 2016)

and

• Diamond-Blackfan Anemia-Like (OMIM: 617911; Brodie SA et al. 2021).

1. Brodie SA et al (2021) Pathogenic germline IKZF1 variant alters hematopoietic gene expression profiles. Cold Spring Harb Mol Case Stud 7:a006015.
2. Georgopoulos K et al (1994) The Ikaros gene is required for the development of all lymphoid lineages. Cell 79: 143-156.
3. Goldman FD et al (2021) Congenital pancytopenia and absence of B lymphocytes in a neonate with a mutation in the Ikaros gene. Pediat Blood Cancer 58: 591-597.
4. Kuehn HS et al (2016) Loss of B cells in patients with heterozygous mutations in IKAROS. New Eng J Med 374: 1032-1043.