Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency

Abstract

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency. Patients with CVID are prone to recurrent bacterial infection due to the failure of adequate immunoglobulin production. Monogenetic defects have been identified in ~25% of CVID patients. Recently, mutations in IKZF1 , encoding the zinc-finger transcription factor IKAROS which is broadly expressed in hematopoietic cells, have been associated with a CVID-like phenotype. Herein we describe 11 patients with heterozygous IKZF1 variants from eight different families with autosomal dominant CVID and two siblings with an IKZF1 variant presenting with inflammatory bowel disease (IBD). This study shows that mutations affecting the DNA binding domain of IKAROS can impair the interaction with the target DNA sequence thereby preventing heterochromatin and pericentromeric localization (HC-PC) of the protein. Our results also indicate an impairment of pericentromeric localization of IKAROS by overexpression of a truncated variant, caused by an immature stop codon in IKZF1 . We also describe an additional variant in TNFSF10 , encoding Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL), additionally presented in individuals of Family A. Our results indicate that this variant may impair the TRAIL-induced apoptosis in target cell lines and prohibit the NFκB activation by TRAIL and may act as a modifier in Family A.

Update on Infections in Primary Antibody Deficiencies

“…Heterozygous AD mutations in IKZF1 , encoding the zinc-finger transcription factor IKAROS were recently reported in patients with CVID phenotype ( 54 , 55 , 110 ). These patients have progressive loss of serum immunoglobulins and B cells.…”

Germline IKAROS dimerization haploinsufficiency causes hematologic cytopenias and malignancies

“…Our work not only reinforces the genetic and clinical relationship between IKAROS and Evans syndrome as recently reported, but also provides biologic validation of this genotype-phenotype correlation describing a novel dimerization defective mechanism for IKAROS-associated diseases. Other germline heterozygous mutations predicted to negatively affect IKAROS' dimerization domain (K286*, D186fs, M306*, and C394*) have been recently published 12,21 . Although the intrinsic dimerization defect and mechanism of action were not part of the scope of those manuscripts, these mutants appeared to exhibit incomplete clinical penetrance and were mainly associated with hematologic manifestations (i.e., B-ALL and different degrees of B-cell deficiency); recurrent infections likely occurred in only one of those cases 12,21 .…”

“…Other germline heterozygous mutations predicted to negatively affect IKAROS' dimerization domain (K286*, D186fs, M306*, and C394*) have been recently published 12,21 . Although the intrinsic dimerization defect and mechanism of action were not part of the scope of those manuscripts, these mutants appeared to exhibit incomplete clinical penetrance and were mainly associated with hematologic manifestations (i.e., B-ALL and different degrees of B-cell deficiency); recurrent infections likely occurred in only one of those cases 12,21 .…”

“…Recently, we and others reported germline heterozygous IKZF1 allelic variants associated with specific immunological phenotypes. The phenotypes consisted of a common variable immunodeficiency (CVID)-like presentation with progressive B-cell loss, hypogammaglobulinemia and antibody dysfunction, along with recurrent and severe bacterial infections; B-ALL susceptibility and autoimmune manifestations were also observed 12, [16][17][18][19][20][21][22] .…”

Pathogenic germline IKZF1 variant alters hematopoietic gene expression profiles

“…The autoimmune GI manifestations in the twins reported here are consistent with those of autoimmune disease associated with both rare and common IKZF1 variants. Several studies have reported associations between heterozygous pathogenic IKZF1 variants and immune deficiency, impaired B-cell development, and/or autoimmune diseases, including immune thrombocytopenic purpura, IgA vasculitis, and systemic lupus erythematosus (SLE), CVID, anti-phospholipid syndrome, and immune thrombocytopenia ( Wojcik et al 2007 ; Hoshino et al 2017 ; Van Nieuwenhove et al 2018 ; Dieudonne et al 2019 ; Eskandarian et al 2019 ). Common variants in IKZF1 have also been associated with risk of SLE and inflammatory bowel disease ( He et al 2010 ; Wang et al 2013 ; Tajuddin et al 2016 ).…”