Abstract
NF-κB signaling, acting through NFKB1 dependent canonical and NFKB2 dependent non-canonical pathways plays a critical role in inflammatory and immune responses. Recent studies have associated mutations in these two genes with a common variable immunodeficiency (CVID). While evaluating a female patient seeking a diagnosis explaining her recurrent infections, we found a novel heterozygous c.1831C > T (p.Arg611∗) nonsense mutation in the NFKB2 gene which introduces a Stop codon in the ankyrin repeat domain of p100. Whole exome sequencing (WES) analysis, followed by Sanger sequencing, identified this previously unknown mutation in two other family members. Penetrance of the c.1831C > T variant was assessed by flow-cytometry and protein expression in peripheral blood mononuclear cells (PBMC); whereas, activation of the NF-κB2 signaling pathway was examined through immunoblotting and real-time PCR. Heterozygous c.1831C > T variant led to the expansion of lymphocyte B subpopulations with concomitant reduction of plasmablasts, low IgG levels, and accumulation of p52 in PBMC. On the other hand, tested subjects had normal levels of IgM, IgA, IgE and no impairment in lymphocytes proliferation. Although evaluated patients did not fulfill all clinical features of CVID, their health should be monitored in the future for possible late manifestation of the disease. In conclusion, we showed that NFKB2 haplodeficiency caused by c.1831C > T nonsense mutation is asymptomatic, possibly due to the compensatory mechanisms and allele redundancy.
Highlights
IntroductionThe human NFKB2 gene locus (chromosome 10q24) encodes a p100/p52 transcription factor that belongs to the NF-κB signal transduction pathway
The human NFKB2 gene locus encodes a p100/p52 transcription factor that belongs to the NF-κB signal transduction pathway
Our approach led to the prioritization of a novel nonsense mutation in the coding exon (17th exon consisting of 169 nucleotides) of the NFKB2 gene, namely chr10:104160444, C > T NM_001077494.3:p.Arg611∗/c.1831C > T
Summary
The human NFKB2 gene locus (chromosome 10q24) encodes a p100/p52 transcription factor that belongs to the NF-κB signal transduction pathway. In mammals, this family consists of five members: p65 (RelA), RelB, c-Rel, NF-κB1 (p105/p50), and NF-κB2 (p100/p52). Full-length NF-κB1 (p105) and NF-κB2 (p100) proteins act as their own inhibitors (Figure 1C) For these proteins, proteasomal processing is required before translocation to the nucleus, where NF-κB1 (p50) and NF-κB2 (p52) bind to their target genes. NIK triggers a kinase leading to phosphorylation of p100 at two conserved C-terminal serines (Ser866, Ser870) by IKKα kinase This is followed by ubiquitination of lysine 855 and subsequent proteasomal processing, removing C-terminus from p100 to generate p52. Heterodimer of p52 and RelB is translocated into the nucleus where this active complex acts as a transcription factor (Oeckinghaus et al, 2011)
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