Meri Kaustio1, Emma Haapaniemi2, Helka Göös3, Timo Hautala4, Giljun Park5, Jaana Syrjänen6, Elisabet Einarsdottir7, Biswajyoti Sahu8, Sanna Kilpinen9, Samuli Rounioja10, Christopher L Fogarty11, Virpi Glumoff12, Petri Kulmala13, Shintaro Katayama14, Fitsum Tamene3, Luca Trotta1, Ekaterina Morgunova14, Kaarel Krjutškov15, Katariina Nurmi16, Kari Eklund16, Anssi Lagerstedt17, Merja Helminen18, Timi Martelius19, Satu Mustjoki20, Jussi Taipale14, Janna Saarela1, Juha Kere21, Markku Varjosalo3, Mikko Seppänen22. 1. Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland. 2. Folkhälsan Institute of Genetics, Helsinki, Finland; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden. 3. Institute of Biotechnology, University of Helsinki, Helsinki, Finland. 4. Department of Internal Medicine, Oulu University Hospital, Oulu, Finland. 5. Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland. 6. Department of Internal Medicine, Tampere University Hospital, Tampere, Finland. 7. 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. 8. Research Programs Unit, Genome-scale Biology Program, University of Helsinki, Helsinki, Finland. 9. Department of Internal Medicine, Jyväskylä Central Hospital, Jyväskylä, Finland. 10. Fimlab Laboratories, Tampere University Hospital, Tampere, Finland; Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland. 11. 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. 12. Research Unit of Biomedicine, University of Oulu, Oulu, Finland. 13. 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. 14. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden. 15. Folkhälsan Institute of Genetics, Helsinki, Finland; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; Competence Centre on Health Technologies, Tartu, Estonia. 16. Department of Rheumatology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 17. Fimlab Laboratories, Tampere University Hospital, Tampere, Finland. 18. Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland. 19. Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 20. Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland; Comprehensive Cancer Center, Helsinki University Central Hospital, Helsinki, Finland. 21. 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. 22. 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.
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.
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.
Authors: Manfred Fliegauf; Renate Krüger; Sophie Steiner; Leif Gunnar Hanitsch; Sarah Büchel; Volker Wahn; Horst von Bernuth; Bodo Grimbacher Journal: Front Immunol Date: 2021-04-27 Impact factor: 7.561
Authors: Charlotte A Slade; Catriona McLean; Thomas Scerri; Tran Binh Giang; Steven Megaloudis; Alexander Strathmore; Jessica C Tempany; Katherine Nicholls; Colleen D'Arcy; Melanie Bahlo; Philip D Hodgkin; Jo A Douglass; Vanessa L Bryant Journal: J Clin Immunol Date: 2019-03-29 Impact factor: 8.542