Send to

Choose Destination
Front Immunol. 2019 Apr 16;10:568. doi: 10.3389/fimmu.2019.00568. eCollection 2019.

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

Author information

Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
Centre for Integrative Biological Signalling Studies, Albert-Ludwigs University of Freiburg, Freiburg, Germany.
Royal Hospital for Children, Glasgow, United Kingdom.
Department of Medical Physics, Centro Atómico Bariloche, CONICET, San Carlos de Bariloche, Argentina.
Clinic for Rheumatology and Clinical Immunology, Faculty of Medicine, CCI, Medical Center, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
Satellite Center Freiburg, RESIST-Cluster of Excellence 2155, Hanover Medical School, Freiburg, Germany.
Satellite Center Freiburg, German Center for Infection Research, Freiburg, Germany.


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.


CVID; IKAROS; TRAIL DNA binding; monogenic defects; nuclear localization

Supplemental Content

Full text links

Icon for Frontiers Media SA Icon for PubMed Central
Loading ...
Support Center