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

• DOI: 10.1084/jem.20240843
• Publication Date: 2025-01-15T14:45:17Z
• Authors: Quentin Riller; Boris Sorin; Charline Courteille; Duong Ho-Nhat; Tom Le Voyer; Jean-Christophe D...; Marie-Claude Stol...; Muriel Schmutz; Olivier Pellé; Thomas Becquard; María Rodrigo Rie...; 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-Fe...; Nicolas Cagnard; Aurélien Corneau; Isabelle Meyts; Véronique Baud; Jean-Laurent Casa...; Alain Fischer; Emmanuel Dejardin; Anne Puel; Cécile Boulanger; Bénédicte Neven; Frédéric Rieux-La...
• Keywords: Immune Dysregulation; Protein kinase domain; IκB kinase

IKKα, encoded by CHUK, is crucial in the non-canonical NF-κB pathway and part of IKK complex activating canonical alongside IKKβ. The absence IKKα causes fetal encasement syndrome humans, fatal utero, while an impaired IKKα-NIK interaction was reported a single patient combined immunodeficiency. Here, we describe compound heterozygous variants kinase domain female with hypogammaglobulinemia, recurrent lung infections, Hay–Wells syndrome-like features. We showed that both were loss-of-function. Non-canonical activation profoundly diminished stromal immune cells unexpectedly partially impaired. Reintroducing wt CHUK restored activation. had neutralizing autoantibodies against type I IFN, akin to deficiencies. Thus, this first case biallelic mutations disrupting function, broadening defect understanding, suggesting IKKα’s role target gene expression humans.