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. 2017 Sep;140(3):782-796.
doi: 10.1016/j.jaci.2016.10.054. Epub 2017 Jan 21.

Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes

Meri Kaustio  1 , Emma Haapaniemi  2 , Helka Göös  3 , Timo Hautala  4 , Giljun Park  5 , Jaana Syrjänen  6 , Elisabet Einarsdottir  7 , Biswajyoti Sahu  8 , Sanna Kilpinen  9 , Samuli Rounioja  10 , Christopher L Fogarty  11 , Virpi Glumoff  12 , Petri Kulmala  13 , Shintaro Katayama  14 , Fitsum Tamene  3 , Luca Trotta  1 , Ekaterina Morgunova  14 , Kaarel Krjutškov  15 , Katariina Nurmi  16 , Kari Eklund  16 , Anssi Lagerstedt  17 , Merja Helminen  18 , Timi Martelius  19 , Satu Mustjoki  20 , Jussi Taipale  14 , Janna Saarela  1 , Juha Kere  21 , Markku Varjosalo  3 , Mikko Seppänen  22
Affiliations

Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes

Meri Kaustio et al. J Allergy Clin Immunol. 2017 Sep.

Erratum in

  • Corrigenda.
    [No authors listed] [No authors listed] J Allergy Clin Immunol. 2021 Dec;148(6):1603. doi: 10.1016/j.jaci.2021.09.012. J Allergy Clin Immunol. 2021. PMID: 34872652 No abstract available.

Abstract

Background: The nuclear factor κ light-chain enhancer of activated B cells (NF-κB) signaling pathway is a key regulator of immune responses. Accordingly, mutations in several NF-κB pathway genes cause immunodeficiency.

Objective: We sought to identify the cause of disease in 3 unrelated Finnish kindreds with variable symptoms of immunodeficiency and autoinflammation.

Methods: We applied genetic linkage analysis and next-generation sequencing and functional analyses of NFKB1 and its mutated alleles.

Results: In all affected subjects we detected novel heterozygous variants in NFKB1, encoding for p50/p105. Symptoms in variant carriers differed depending on the mutation. Patients harboring a p.I553M variant presented with antibody deficiency, infection susceptibility, and multiorgan autoimmunity. Patients with a p.H67R substitution had antibody deficiency and experienced autoinflammatory episodes, including aphthae, gastrointestinal disease, febrile attacks, and small-vessel vasculitis characteristic of Behçet disease. Patients with a p.R157X stop-gain experienced hyperinflammatory responses to surgery and showed enhanced inflammasome activation. In functional analyses the p.R157X variant caused proteasome-dependent degradation of both the truncated and wild-type proteins, leading to a dramatic loss of p50/p105. The p.H67R variant reduced nuclear entry of p50 and showed decreased transcriptional activity in luciferase reporter assays. The p.I553M mutation in turn showed no change in p50 function but exhibited reduced p105 phosphorylation and stability. Affinity purification mass spectrometry also demonstrated that both missense variants led to altered protein-protein interactions.

Conclusion: Our findings broaden the scope of phenotypes caused by mutations in NFKB1 and suggest that a subset of autoinflammatory diseases, such as Behçet disease, can be caused by rare monogenic variants in genes of the NF-κB pathway.

Keywords: B cell; Behçet disease; NFKB1; Nuclear factor κ light-chain enhancer of activated B cells; autoinflammation; hypogammaglobulinemia; p105; p50.

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