title: Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Meri
authors.initials: M
authors.lastname: Kaustio
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Haapaniemi
authors.affiliation: Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors.forename: Helka
authors.initials: H
authors.lastname: Göös
authors.affiliation: Department of Internal Medicine, Oulu University Hospital, Oulu, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Hautala
authors.affiliation: Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland.
authors.forename: Giljun
authors.initials: G
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Tampere University Hospital, Tampere, Finland.
authors.forename: Jaana
authors.initials: J
authors.lastname: Syrjänen
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Einarsdottir
authors.affiliation: Research Programs Unit, Genome-scale Biology Program, University of Helsinki, Helsinki, Finland.
authors.forename: Biswajyoti
authors.initials: B
authors.lastname: Sahu
authors.affiliation: Department of Internal Medicine, Jyväskylä Central Hospital, Jyväskylä, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Kilpinen
authors.affiliation: Fimlab Laboratories, Tampere University Hospital, Tampere, Finland; Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland.
authors.forename: Samuli
authors.initials: S
authors.lastname: Rounioja
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland; Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Fogarty
authors.affiliation: Research Unit of Biomedicine, University of Oulu, Oulu, Finland.
authors.forename: Virpi
authors.initials: V
authors.lastname: Glumoff
authors.affiliation: Research Unit of Biomedicine, University of Oulu, Oulu, Finland; Research Unit for Pediatrics, Pediatric Neurology, Pediatric Surgery, Child Psychiatry, Dermatology, Clinical Genetics, Obstetrics and Gynecology, Otorhinolaryngology and Ophthalmology (PEDEGO) and MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Petri
authors.initials: P
authors.lastname: Kulmala
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Katayama
authors.affiliation: Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors.forename: Fitsum
authors.initials: F
authors.lastname: Tamene
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Luca
authors.initials: L
authors.lastname: Trotta
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Morgunova
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; Competence Centre on Health Technologies, Tartu, Estonia.
authors.forename: Kaarel
authors.initials: K
authors.lastname: Krjutškov
authors.affiliation: Department of Rheumatology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Katariina
authors.initials: K
authors.lastname: Nurmi
authors.affiliation: Department of Rheumatology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Kari
authors.initials: K
authors.lastname: Eklund
authors.affiliation: Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
authors.forename: Anssi
authors.initials: A
authors.lastname: Lagerstedt
authors.affiliation: Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland.
authors.forename: Merja
authors.initials: M
authors.lastname: Helminen
authors.affiliation: Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Timi
authors.initials: T
authors.lastname: Martelius
authors.affiliation: Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland; Comprehensive Cancer Center, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Satu
authors.initials: S
authors.lastname: Mustjoki
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jussi
authors.initials: J
authors.lastname: Taipale
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Janna
authors.initials: J
authors.lastname: Saarela
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland. Electronic address: juha.kere@ki.se.
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.affiliation: Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Varjosalo
authors.affiliation: Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Rare Diseases Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Seppänen
mesh_terms: D000328:Adult; D000368:Aged; D001327:Autoimmune Diseases / Q000235:genetics*; D002460:Cell Line; D002648:Child; D005260:Female; D006579:Heterozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D007249:Inflammation / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics*; D010641:Phenotype
chemical_list: D016328:NF-kappa B
keywords: B cell; Behçet disease; NFKB1; Nuclear factor κ light-chain enhancer of activated B cells; autoinflammation; hypogammaglobulinemia; p105; p50