Journal Articles Journal of Experimental Medicine Year : 2025

Mutations disrupting the kinase domain of IKKα lead to immunodeficiency and immune dysregulation in humans

1 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
2 AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP)
3 AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris]
4 Hôpital Necker - Enfants Malades [AP-HP]
5 St. Giles Laboratory of Human Genetics of Infectious Diseases
6 AP-HP - Hopital Saint-Louis [AP-HP]
7 SMS - Sciences et Méthodes Séparatives
8 Equipe Inserm U1163 - Immunogenetics of pediatric autoimmune diseases
9 ERN - RARE - LIVER - European Reference Network on Hepatological Diseases [Hamburg, Germany]
10 Université Paris-Saclay
11 Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
12 UAR 3633 / US24 - Structure Fédérative de Recherche Necker
13 OncokappaB (URP_7324) - NF-kappaB, Différenciation et Cancer
14 Institut Curie [Paris]
15 U932 - Immunité et cancer
16 UPCité - Université Paris Cité
17 Evo-Eco-Paléo (EEP) - Évolution, Écologie et Paléontologie (Evo-Eco-Paleo) - UMR 8198
18 BIP-D - Plate Forme Paris Descartes de Bioinformatique
19 PASS - Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé
20 PASS-CYPS - Cytométrie Pitié-Salpêtrière
21 UZ Leuven - Universitair Ziekenhuis Leuven = University Hospital of Leuven = Hopital universitaire de Louvain
22 Rockefeller University [New York]
23 Equipe Inserm U1163 - Human genetics of infectious diseases : Mendelian predisposition
24 HHMI - Howard Hughes Medical Institute
25 RAISE - Centre de Référence pour les Maladies Rhumatologiques Auto-Immunes et Systémiques [CHU Necker]
26 CdF (institution) - Collège de France
27 ULiège - Université de Liège = University of Liège = Universiteit van Luik = Universität Lüttich
28 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
29 CNRS - Centre National de la Recherche Scientifique
30 INSERM - Institut National de la Santé et de la Recherche Médicale
31 CIML - Centre d'Immunologie de Marseille - Luminy
32 AMU - Aix Marseille Université
Charline Courteille
Duong Ho-Nhat
Charles Bretot
Véronique Baud

Abstract

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.

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Quentin Riller, Boris Sorin, Charline Courteille, Duong Ho-Nhat, Tom Le Voyer, et al.. Mutations disrupting the kinase domain of IKKα lead to immunodeficiency and immune dysregulation in humans. Journal of Experimental Medicine, 2025, 222 (2), ⟨10.1084/jem.20240843⟩. ⟨hal-05080410⟩
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