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Functional and biochemical characterization of novel genetic variants in IRAK4 and IRF4 causing human inborn errors of immunity Jia, Alicia

Abstract

Human inborn errors of immunity (IEIs) are a group of genetic disorders in which specific components of the human immune system are missing, dysfunctional, or poorly regulated. IEIs negatively impact the protective functions of the immune system, increasing susceptibility to infections, autoimmunity, inflammation, and malignancy. The investigation of monogenic IEIs enables the diagnosis and treatment of the affected individuals and provides unique opportunities to understand the role of the immune system and the functional roles of its constituents. Toll-like receptor (TLR) signaling is a key aspect of the innate immune response, and interleukin-1 receptor-associated kinase 4 (IRAK4) plays a vital role in the TLR signaling cascade which enables the production of protective inflammatory cytokines. Human IRAK4-deficiency is an autosomal recessive IEI which presents with a blunted inflammatory response to infection and susceptibility to certain bacteria. We demonstrate that the novel IRAK4 (c.1049delG, p.(Gly350Glufs*15)) variant abrogates IRAK4 protein expression and abolishes TLR signaling, expanding the knowledge of pathogenic variants causing human IRAK4-deficiency. We have also identified 3 unrelated individuals with a phenotype of combined immunodeficiency (agammaglobulinemia and infectious susceptibility) who carry a novel heterozygous de novo missense variant in Interferon Regulatory Factor 4 (IRF4) gene (c.284C>G, p.T95R). IRF4 is a transcription factor expressed in immune cells which plays a critical role in the differentiation of various immune cells. We demonstrate adaptive immune cell differentiation defects in proband primary cells, as well as decreased effector cytokine production in T cells. We also demonstrate that the IRF4 T95R variant is able to bind the canonical GAAA binding site as well as a novel GATA binding site. Therefore, we propose that the IRF4 T95R variant is defined as a neomorphic variant, as it has gained novel DNA-binding functions. This increase in DNA-binding sequence promiscuity may result in a dominant negative redistribution of the wild-type IRF4 and the combined immunodeficiency phenotype in the proband. We have characterized a novel neomorphic variant in the IRF4 gene and defined a novel human IEI which highlights the potential of IRF4 as an immunomodulatory therapeutic target.

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