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Article (Scientific journals)
Mutations disrupting the kinase domain of IKKα lead to immunodeficiency and immune dysregulation in humans.
Riller, Quentin; Sorin, Boris; Courteille, Charline et al.
2025 • In Journal of Experimental Medicine, 222 (2)
Peer Reviewed verified by ORBi
Permalink
https://hdl.handle.net/2268/327168
DOI
10.1084/jem.20240843
PubMed
39812688
 

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Keywords :
I-kappa B Kinase; NF-kappa B; CHUK protein, human; Humans; Female; Mutation; Agammaglobulinemia/genetics; Agammaglobulinemia/immunology; Protein Domains; Signal Transduction; HEK293 Cells; I-kappa B Kinase/genetics; I-kappa B Kinase/metabolism; NF-kappa B/metabolism; Immunologic Deficiency Syndromes/genetics; Immunologic Deficiency Syndromes/immunology
Abstract :
[en] IKKα, encoded by CHUK, is crucial in the non-canonical NF-κB pathway and part of the IKK complex activating the canonical pathway alongside IKKβ. The absence of IKKα causes fetal encasement syndrome in humans, fatal in utero, while an impaired IKKα-NIK interaction was reported in a single patient and causes combined immunodeficiency. Here, we describe compound heterozygous variants in the kinase domain of IKKα in a female patient with hypogammaglobulinemia, recurrent lung infections, and Hay-Wells syndrome-like features. We showed that both variants were loss-of-function. Non-canonical NF-κB activation was profoundly diminished in stromal and immune cells while the canonical pathway was unexpectedly partially impaired. Reintroducing wt CHUK restored non-canonical NF-κB activation. The patient had neutralizing autoantibodies against type I IFN, akin to non-canonical NF-κB pathway deficiencies. Thus, this is the first case of biallelic CHUK mutations disrupting IKKα kinase function, broadening non-canonical NF-κB defect understanding, and suggesting IKKα's role in canonical NF-κB target gene expression in humans.
Disciplines :
Genetics & genetic processes
Author, co-author :
Riller, Quentin ;  Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France
Sorin, Boris ;  Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France
Courteille, Charline ;  Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France
Ho-Nhat, Duong ;  Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France
Le Voyer, Tom ;  Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France ; Clinical Immunology Department, Assistance Publique Hôpitaux de Paris (AP-HP), Saint-Louis Hospital, Paris, France
Debray, Jean-Christophe  ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Stolzenberg, Marie-Claude ;  Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France
Schmutz, Muriel ;  Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France
Pellé, Olivier ;  Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France
Becquard, Thomas ;  NF-κB, Differentiation and Cancer, URP7324, University Paris Cité, Paris, France
Rodrigo Riestra, María ;  Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France
Berteloot, Laureline ;  Pediatric Radiology Department, AP-HP, Hôpital Universitaire Necker-Enfants Malades, Paris, France ; INSERM UMRS 1163, Institut Imagine , Paris, France
Migaud, Mélanie ;  Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France
Delage, Laure ;  Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France
Jeanpierre, Marie ;  Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France
Boussard, Charlotte ;  Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France
Brunaud, Camille ;  Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France
Magérus, Aude ;  Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France
Bretot, Charles ;  NF-κB, Differentiation and Cancer, URP7324, University Paris Cité, Paris, France
Michel, Victor ;  Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France
Roux, Camille ;  Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France
Picard, Capucine ;  Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique-Hopitaux de Paris (AP-HP), University Paris Cité , Paris, France
Masson, Cécile ;  Bioinformatic Platform, INSERM UMR 1163, Imagine Institute, University Paris Cité , Paris, France
Bole-Feysot, Christine ;  Genomic Platform, INSERM UMR 1163, Imagine Institute, University Paris Cité , Paris, France
Cagnard, Nicolas ;  Bioinformatic Platform, INSERM UMR 1163, Imagine Institute, University Paris Cité , Paris, France
Corneau, Aurélien ;  UMS037, PASS, Plateforme de Cytométrie de la Pitié-Salpêtrière CyPS, Sorbonne Université , Paris, France
Meyts, Isabelle ;  Laboratory for Inborn Errors of Immunity, Department of Microbiology, Immunology and Transplantation, Department of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium ; Department of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
Baud, Véronique ;  NF-κB, Differentiation and Cancer, URP7324, University Paris Cité, Paris, France
Casanova, Jean-Laurent ;  Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France ; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA ; Howard Hughes Medical Institute , New York, NY, USA ; Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, Paris, France
Fischer, Alain ;  INSERM UMRS 1163, Institut Imagine , Paris, France ; Collège de France , Paris, France ; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Dejardin, Emmanuel  ;  Université de Liège - ULiège > GIGA > GIGA Immunobiology - Molecular Immunology and Signal Transduction
Puel, Anne ;  Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France ; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
Boulanger, Cécile ;  Genetics of Autoimmune Diseases and Cancer, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium ; Department of Pediatric Hematology and Oncology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
Neven, Bénédicte ;  Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France ; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Rieux-Laucat, Frédéric ;  Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Imagine Institute, University Paris Cité, Paris, France
More authors (25 more) Less
Language :
English
Title :
Mutations disrupting the kinase domain of IKKα lead to immunodeficiency and immune dysregulation in humans.
Publication date :
03 February 2025
Journal title :
Journal of Experimental Medicine
ISSN :
0022-1007
eISSN :
1540-9538
Publisher :
Rockefeller University Press, United States
Volume :
222
Issue :
2
Peer reviewed :
Peer Reviewed verified by ORBi
Additional URL :
https://rupress.org/jem/article-pdf/doi/10.1084/jem.20240843/1937723/jem_20240843.pdf
Available on ORBi :
since 20 January 2025

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