ArticleThe Journal of experimental medicine2021
Biochemically deleterious human NFKB1 variants underlie an autosomal dominant form of common variable immunodeficiency.
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Article in The Journal of experimental medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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35 citing papers in PubMed, 53 citations in OpenAlex.
- From Undifferentiated Connective Tissue Disease to Common Variable Immunodeficiency: A Novel NFKB1 Mutation in a Pediatric Case.Clinical case reports · 2026Article
- A Detrimental NFKB2 Missense Variant is Associated with Hypogammaglobulinemia.Journal of clinical immunology · 2026Article
- Heterozygous NFKB1 variant causes inflammatory dysregulation shaped by broader genetic context in common variable immunodeficiency.JCI insight · 2026Article
- Clinical and immunological characterization ofFrontiers in immunology · 2026Article
- The Presentation, Diagnosis, and Management of Autosomal Dominant Common Variable Immunodeficiency Type XII with NFKB1 Mutation and Autoimmune Neutropenia Treated with Allogenic Stem Cell Transplantation.Hematology reports · 2025Article
- Inborn errors of immunity reveal molecular requirements for generation and maintenance of human CD4The Journal of allergy and clinical immunology · 2025Article
- Common Variable Immunodeficiency Clinical Manifestations Are Shaped by Presence and Type of Heterozygous NFKB1 Variants.The journal of allergy and clinical immunology. In practice · 2025Article
- The monogenic landscape of human infectious diseases.The Journal of allergy and clinical immunology · 2025Review
- Incontinentia pigmenti underlies thymic dysplasia, autoantibodies to type I IFNs, and viral diseases.The Journal of experimental medicine · 2024Article
- Maintenance of X chromosome inactivation after T cell activation requires NF-κB signaling.Science immunology · 2024Article
- Truncating NFKB1 variants cause combined NLRP3 inflammasome activation and type I interferon signaling and predispose to necrotizing fasciitis.Cell reports. Medicine · 2024Article
- In search of a function for human type III interferons: insights from inherited and acquired deficits.Current opinion in immunology · 2024Review
- ExploringPharmaceuticals (Basel, Switzerland) · 2024Article
- Recurrent opportunistic infections in a HIV-negative patient with combined C6 andOpen medicine (Warsaw, Poland) · 2024Article
- Monogenic Inborn Errors of Immunity with impaired IgG response to polysaccharide antigens but normal IgG levels and normal IgG response to protein antigens.Frontiers in pediatrics · 2024Review
- Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency.Nature · 2023Article
- Article
- Human RELA dominant-negative mutations underlie type I interferonopathy with autoinflammation and autoimmunity.The Journal of experimental medicine · 2023Article
- Human Genomics of COVID-19 Pneumonia: Contributions of Rare and Common Variants.Annual review of biomedical data science · 2023Review
- Inborn errors of human B cell development, differentiation, and function.The Journal of experimental medicine · 2023Review
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Authors and funding
41 authors at 12 institutions in 4 countries.
Juan LiSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0003-4376-7781
Wei-Te LeiSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0003-1677-8901
Peng ZhangSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0002-6129-567X
Franck RapaportSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0001-6553-2110
Yoann SeeleuthnerLaboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, Necker Hospital for Sick Children, Paris, France.ORCID 0000-0002-1878-8567
Bingnan LyuSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0003-2133-9479
Takaki AsanoSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0003-1424-2433
Jérémie RosainLaboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, Necker Hospital for Sick Children, Paris, France.ORCID 0000-0002-2822-161X
Boualem HammadiGeneral Chemistry Laboratory, Department of Clinical Chemistry, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris, Paris, France.ORCID 0000-0003-0182-1700
Yu ZhangLaboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.ORCID 0000-0002-6904-0372
Simon J PelhamSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0002-3119-662X
András N SpaanSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0001-5981-7259
Mélanie MigaudLaboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, Necker Hospital for Sick Children, Paris, France.ORCID 0000-0003-3062-1214
David HumSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0001-5374-321X
Benedetta BigioSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0001-7291-5638
Maya ChrabiehLaboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, Necker Hospital for Sick Children, Paris, France.ORCID 0000-0003-0772-4805
Vivien BéziatSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0002-4020-824X
Jacinta BustamanteSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0002-3439-2482
Shen-Ying ZhangSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0002-9449-3672
Emmanuelle JouanguySt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0002-7358-9157
Stephanie Boisson-DupuisSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0002-7115-116X
Jamila El BaghdadiGenetics Unit, Military Hospital Mohamed V, Rabat, Morocco.ORCID 0000-0002-1920-2310
Vishukumar AimaniandaMolecular Mycology Unit, Pasteur Institute, Centre National de la Recherche Scientifique UMR 2000, Paris, France.ORCID 0000-0001-5813-7497
Katharina ThomaInstitute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwigs University of Freiburg, Freiburg, Germany.ORCID 0000-0002-9477-2735
Manfred FliegaufInstitute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwigs University of Freiburg, Freiburg, Germany.ORCID 0000-0001-5860-6177
Bodo GrimbacherInstitute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwigs University of Freiburg, Freiburg, Germany.ORCID 0000-0002-6897-6806
Anne-Sophie KorganowDepartment of Clinical Immunology and Internal Medicine, National Reference Center for Autoimmune Diseases, University Hospitals of Strasbourg, Strasbourg, France.ORCID 0000-0002-1664-6311
Carol SaundersCenter for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO.ORCID 0000-0002-7407-7735
V Koneti RaoLaboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.ORCID 0000-0002-7881-6902
Gulbu UzelLaboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.ORCID 0000-0002-3942-1086
Alexandra F FreemanLaboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.ORCID 0000-0001-7005-8345
Steven M HollandLaboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.ORCID 0000-0003-3207-5464
Helen C SuLaboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.ORCID 0000-0002-5582-9110
Charlotte Cunningham-RundlesDivision of Clinical Immunology, Icahn School of Medicine at Mount Sinai, New York, NY.ORCID 0000-0003-0725-0320
Claire FieschiDepartment of Clinical Immunology, Saint-Louis Hospital, Paris, France.ORCID 0000-0003-2136-6178
Laurent AbelSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0001-7016-6493
Anne PuelSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0003-2603-0323
Aurélie CobatSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0001-7209-6257
Jean-Laurent Casanova *St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0002-7782-4169
Qian Zhang *St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0002-9040-3289
Bertrand Boisson *St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.ORCID 0000-0001-5240-3555
Inserm · FRRockefeller University · USNational Institutes of Health · USUniversity of Freiburg · DEAssistance Publique – Hôpitaux de Paris · FRCentre National de la Recherche Scientifique · FRChang Gung University · TWChildren's Mercy Hospital · USHôpital Saint-Louis · FRHoward Hughes Medical Institute · USIcahn School of Medicine at Mount Sinai · USUniversité de Strasbourg · FR
Funding
Developing, Demonstrating, and Disseminating Innovative Programs to Achieve Translational SuccessUL1TR001866 · NCATS · ROCKEFELLER UNIVERSITY · PI COLLER, BARRY, KRUEGER, JAMES G · 2016 to 2025
$40.6MRegulation of IgA class switching in the intestinal mucosaP01AI061093 · NIAID · MOUNT SINAI SCHOOL OF MEDICINE OF NYU · PI CASANOVA, JEAN-LAURENT · 2004 to 2021
$29.8MMarie Curie 789645NCATS NIH HHS UL1 TR001866NCRR NIH HHSNIAID NIH HHSNIAID NIH HHS P01 AI061093NIH HHS P01AI061093NIH HHS UL1TR001866
Abstract
Autosomal dominant (AD) NFKB1 deficiency is thought to be the most common genetic etiology of common variable immunodeficiency (CVID). However, the causal link between NFKB1 variants and CVID has not been demonstrated experimentally and genetically, and there has been insufficient biochemical characterization and enrichment analysis. We show that the cotransfection of NFKB1-deficient HEK293T cells (lacking both p105 and its cleaved form p50) with a κB reporter, NFKB1/p105, and a homodimerization-defective RELA/p65 mutant results in p50:p65 heterodimer-dependent and p65:p65 homodimer-independent transcriptional activation. We found that 59 of the 90 variants in patients with CVID or related conditions were loss of function or hypomorphic. By contrast, 258 of 260 variants in the general population or patients with unrelated conditions were neutral. None of the deleterious variants displayed negative dominance. The enrichment in deleterious NFKB1 variants of patients with CVID was selective and highly significant (P = 2.78 × 10-15). NFKB1 variants disrupting NFKB1/p50 transcriptional activity thus underlie AD CVID by haploinsufficiency, whereas neutral variants in this assay should not be considered causal.
Indexed as
AnimalsCell LineChlorocebus aethiopsCommon Variable ImmunodeficiencyCOS CellsHaploinsufficiencyHEK293 CellsHumansNF-kappa BNF-kappa B p50 SubunitPhenotypeTranscriptional ActivationNF-kappa BNF-kappa B p50 SubunitNFKB1 protein, human
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