A de novo IKZF4 Variant Underlies Hypogammaglobulinemia and Increased Infection Susceptibility through Downregulating the NF-κB Pathway.
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PURPOSE: Inborn errors of immunity (IEI) are a group of complex diseases characterized by reduced immunity and increased susceptibility to external pathogens, autoinflammation, autoimmune conditions, and/or malignancy. The IKAROS zinc-finger (IKZF) family is a group of C2H2 zinc-finger transcription factors that includes IKAROS (IKZF1), HELIOS (IKZF2), AIOLOS (IKZF3), EOS (IKZF4), and PEGASUS (IKZF5). Variants in IKZF have been reported to cause human IEI except IKZF4. This research aimed to identify the pathogenicity and underlying mechanisms of IKZF4 as a novel candidate gene for IEI. METHODS: Here, we used whole-exome sequencing to identify candidate variants of IEI. Western blotting, quantitative polymerase chain reaction, immune staining, co-immunoprecipitation, flow cytometry, Luminex assays, and single-cell RNA sequencing were used to explore the phenotypes and functional effects in cell and mouse models. RESULTS: An 11-month-old patient presented with repeated fever and convulsions accompanied by persistently reduced immunoglobulin levels and abnormal immune indices, which supported the diagnosis of IEI. A de novo c.1472delG variant (GRCh37/hg19, NM_022465.3) in IKZF4 was selected as the candidate variant for IEI. The c.1472delG variant caused reduced EOS expression and truncated protein (predicted molecular weight ~ 57 kDa), defective pericentromeric heterochromatin targeting, and impaired protein interactions of EOS. A mouse model harboring the corresponding variant in Ikzf4 (Ikzf4+/c.1475delG) showed a proinflammatory switch in regulatory T cells, accompanied by reduced levels of immunoglobulins and a decreased ratio of marginal zone B cells after lipopolysaccharide stimulation, which were potentially caused by the down-regulated transcriptional regulation of EOS on the nuclear factor kappa-B pathway. CONCLUSION: This research identified IKZF4 as a novel candidate gene for IEI, advancing our knowledge of the IKZF family and the complexity of human IEI.