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

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. Introduction Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency with an estimated incidence of 1:50,000–1:25,000. The disease is characterized by recurrent infections, due to a marked decrease in serum IgG commonly in association with reduced IgM and/or IgA. Most CVID-affected individuals have reduced numbers of isotype-switched memory B cells but relative preservation of pre-germinal center B cells (1–3). As a clinically and genetically heterogeneous disorder, CVID has a variable age of onset. In a recent study, an early disease onset (<10 years) was reported in 33.7% of the individuals in a cohort of 2,212 European CVID patients, however, the median diagnos...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research