Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes

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Kaustio , M , Haapaniemi , E , Göös , H , Hautala , T , Park , G , Syrjänen , J , Einarsdottir , E , Sahu , B , Kilpinen , S , Rounioja , S , Fogarty , C L , Glumoff , V , Kulmala , P , Katayama , S , Tamene , F , Trotta , L , Morgunova , E , Krjutskov , K , Nurmi , K , Eklund , K , Lagerstedt , A , Helminen , M , Martelius , T , Mustjoki , S , Taipale , J , Saarela , J , Kere , J , Varjosalo , M & Seppanen , M 2017 , ' Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes ' , Journal of Allergy and Clinical Immunology , vol. 140 , no. 3 , pp. 782-796 . https://doi.org/10.1016/j.jaci.2016.10.054

Title: Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes
Author: Kaustio, Meri; Haapaniemi, Emma; Göös, Helka; Hautala, Timo; Park, Giljun; Syrjänen, Jaana; Einarsdottir, Elisabet; Sahu, Biswajyoti; Kilpinen, Sanna; Rounioja, Samuli; Fogarty, Christopher L.; Glumoff, Virpi; Kulmala, Petri; Katayama, Shintaro; Tamene, Fitsum; Trotta, Luca; Morgunova, Ekaterina; Krjutskov, Kaarel; Nurmi, Katariina; Eklund, Kari; Lagerstedt, Anssi; Helminen, Merja; Martelius, Timi; Mustjoki, Satu; Taipale, Jussi; Saarela, Janna; Kere, Juha; Varjosalo, Markku; Seppanen, Mikko
Contributor: University of Helsinki, University of Helsinki
University of Helsinki, Folkhalsan Inst Genet
University of Helsinki, Institute of Biotechnology
University of Helsinki, Medicum
University of Helsinki, Research Programs Unit
University of Helsinki, Research Programs Unit
University of Helsinki, Clinicum
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Clinicum
University of Helsinki, Infektiosairauksien yksikkö
University of Helsinki, University of Helsinki
University of Helsinki, Karolinska Institutet
University of Helsinki, University of Helsinki
University of Helsinki, Research Programs Unit
University of Helsinki, Institute of Biotechnology
University of Helsinki, Clinicum
Date: 2017-09
Language: eng
Number of pages: 15
Belongs to series: Journal of Allergy and Clinical Immunology
ISSN: 0091-6749
URI: http://hdl.handle.net/10138/297945
Abstract: Background: The nuclear factor kappa light-chain enhancer of activated B cells (NF-kappa B) signaling pathway is a key regulator of immune responses. Accordingly, mutations in several NF-kappa B 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 Behc, et 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 Behcet disease, can be caused by rare monogenic variants in genes of the NF-kappa B pathway.
Subject: Nuclear factor k light-chain enhancer of activated B cells
hypogammaglobulinemia
autoinflammation
Behcet disease
NFKB1
p50
p105
B cell
NF-KAPPA-B
COMMON VARIABLE IMMUNODEFICIENCY
ANHIDROTIC ECTODERMAL DYSPLASIA
T-CELLS
BEHCETS-DISEASE
AUTOINFLAMMATORY DISEASE
INTESTINAL HOMEOSTASIS
BACTERIAL-INFECTIONS
DENDRITIC CELLS
P50 SUBUNIT
3111 Biomedicine
3121 General medicine, internal medicine and other clinical medicine
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