Damaging heterozygous mutations in NFKB1 lead to diverse immunological phenotypes

Publication date: Available online 21 January 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Meri Kaustio, Emma Haapaniemi, Helka Göös, Timo Hautala, Giljun Park, Jaana Syrjänen, Elisabet Einarsdottir, Biswajyoti Sahu, Sanna Kilpinen, Samuli Rounioja, Christopher L. Fogarty, Virpi Glumoff, Petri Kulmala, Shintaro Katayama, Fitsum Tamene, Luca Trotta, Ekaterina Morgunova, Kaarel Krjutškov, Katariina Nurmi, Kari Eklund, Anssi Lagerstedt, Merja Helminen, Timi Martelius, Satu Mustjoki, Jussi Taipale, Janna Saarela, Juha Kere, Markku Varjosalo, Mikko Seppänen
BackgroundThe NF-κB signaling pathway is a key regulator of immune responses. Accordingly, mutations in several NF-κB pathway genes cause immunodeficiency.ObjectiveWe sought to identify the cause of disease in three unrelated Finnish kindreds with variable symptoms of immunodeficiency and autoinflammation.MethodsWe applied genetic linkage analysis and next generation sequencing, and functional analyses of NFKB1 and its mutated alleles.ResultsIn all affected individuals, 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 multi-organ autoimmunity. Patients with a p.H67R substitution developed antibody deficiency and suffered from autoinflammatory episodes including aphthae, gastrointestinal disease, febrile attacks, and small vessel vasculitis characteristic of Behcet's 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.ConclusionOur findings broaden the scope of phenotypes caused by mutations in NFKB1, and suggest that a subset of autoinflammatory diseases such as Behcet's disease may be caused by rare monogenic variants in genes of the NF-κB pathway.

Teaser

In addition to antibody deficiency, mutations in NFKB1 may lead to excessive inflammatory response and manifest as Behcet's disease, inflammatory gastrointestinal disease, or severe autoinflammatory postoperative complications.


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