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

Frontiers in Immunology

Immunology

Gunnar Schmidt¹  Natalia Dubrowinskaja²  Torsten Witte²  Manfred Anim³  Reinhold Ernst Schmidt⁴  Faranaz Atschekzei⁴  Georgios Sogkas⁴ 

[1] Department of Human Genetics, Hannover Medical School, Hannover, Germany;Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany;Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany;Hannover Biomedical Research School (HBRS), Hannover Medical School, Hanover, Germany;Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany;RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Hanover, Germany;

关键词: common variable immune deficiency (CVID);    NFKB1;    Nfkb1 (p50);    hypogammaglobulinemia;    primary antibody deficiency (PAD);   

DOI  :  10.3389/fimmu.2021.767188

 received in 2021-08-30, accepted in 2021-12-02,  发布年份 2021

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

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Copyright © 2021 Anim, Sogkas, Schmidt, Dubrowinskaja, Witte, Schmidt and Atschekzei