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.
Mutations disrupting the kinase domain of IKKα lead to immunodeficiency and immune dysregulation in humans
B. Sorin, C. Courteille, D. Ho-Nhat, T. Le Voyer, J.-C. Debray, M.-C. Stolzenberg, M. Schmutz, and O. Pellé contributed equally to this paper.
A. Puel and C. Boulanger share senior authorship.
B. Neven and F. Rieux-Laucat share senior authorship.
Disclosures: L. Delage reported personal fees from Sanofi outside the submitted work. I. Meyts reported grants from CSL Behring, other from Takeda, and other from Boehringer-Ingelheim outside the submitted work. No other disclosures were reported.
- Award Id(s): ANR-10-IAHU-01,ANR-18-RHUS-0010,ANR-18-CE17-0001,ANR-22-CE15-0047-02,ANR-10-LABX-62-IBEID,ANR-20-CE93-003,ANR-21-LIBA-0002,ANR-22-CE15-0046,ANR-21-RHUS-08-COVIFERON
- Award Id(s): EQU202103012670
- Award Id(s): ECTZ275762
- Award Id(s): R01AI127564
- Award Id(s): 101057100
- Award Id(s): G0B5120N
- Award Id(s): 40007512
Quentin Riller, Boris Sorin, Charline Courteille, Duong Ho-Nhat, Tom Le Voyer, Jean-Christophe Debray, Marie-Claude Stolzenberg, Muriel Schmutz, Olivier Pellé, Thomas Becquard, María Rodrigo Riestra, Laureline Berteloot, Mélanie Migaud, Laure Delage, Marie Jeanpierre, Charlotte Boussard, Camille Brunaud, Aude Magérus, Charles Bretot, Victor Michel, Camille Roux, Capucine Picard, Cécile Masson, Christine Bole-Feysot, Nicolas Cagnard, Aurélien Corneau, Isabelle Meyts, Véronique Baud, Jean-Laurent Casanova, Alain Fischer, Emmanuel Dejardin, Anne Puel, Cécile Boulanger, Bénédicte Neven, Frédéric Rieux-Laucat; Mutations disrupting the kinase domain of IKKα lead to immunodeficiency and immune dysregulation in humans. J Exp Med 3 February 2025; 222 (2): e20240843. doi: https://doi.org/10.1084/jem.20240843
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