Journal Article

Vulnerability to Meningococcal Disease in Immunodeficiency Due to a Novel Pathogenic Missense Variant in NFKB1

Atschekzei, Faranaz, Anim, Manfred, Schmidt, Reinhold Ernst, Schmidt, Gunnar, Dubrowinskaja, Natalia, Witte, Torsten, Sogkas, Georgios

2021

Overview

NF-κB1 deficiency is suggested to be the most common cause of common variable immunodeficiency (CVID). NFKB1 encodes for the p105 precursor protein of NF-κB1, which is converted into the active transcriptional subunit p50 through proteasomal processing of its C-terminal half upon stimulation and is implicated in the canonical NF-kB pathway. Rare monoallelic NFKB1 variants have been shown to cause (haplo) insufficiency. Our report describes a novel NFKB1 missense variant (c.691C>T, p.R230C; allele frequency 0.00004953) in a family vulnerable to meningitis, sepsis, and late-onset hypogammaglobulinemia. We investigated the pathogenic relevance of this variant by lymphocyte stimulation, immunophenotyping, overexpression study and immunoblotting. The ectopic expression of p50 for c.691 C>T restricted transcriptionally active p50 in the cytoplasm, and immunoblotting revealed reduced p105/50 expression. This study shows that the deleterious missense variant in NFKB1 adversely affects the transcriptional and translational activity of NFκB1, impairing its function. Patients immunological parameters show a progressive course of hypogammaglobulinemia, which may partially account for the incomplete disease penetrance and suggest the need for closer immunological monitoring of those mutation carriers.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Active Transport, Cell Nucleus - genetics / Antibodies / Cell Nucleus - metabolism / Cells, Cultured / common variable immune deficiency (CVID) / Common variable immunodeficiency / Common Variable Immunodeficiency - genetics / Common Variable Immunodeficiency - metabolism / Cytoplasm / Ectopic expression / Family Health / Female / Gene frequency / Genes / Genetic Predisposition to Disease - genetics / Genetic testing / Genomics / HEK293 Cells / Humans / Hypogammaglobulinemia / Immune system / Immunoblotting / Immunology / Lymphocytes / Male / Meningitis / Meningococcal disease / Meningococcal Infections - genetics / Meningococcal Infections - metabolism / Middle Aged / Mutation / Mutation, Missense / NF-kappa B p50 Subunit - genetics / NF-kappa B p50 Subunit - metabolism / NF-κB protein / NFKB1 / Nfkb1 (p50) / Pedigree / Plasmids / primary antibody deficiency (PAD) / Proteasomes / Proteins / Reagents / Sepsis / Sequence Analysis, DNA - methods / T cell receptors / Transcription / Variance analysis / Young Adult