Cildir, G.Aba, U.Pehlivan, D.Tvorogov, D.Warnock, N.I.Ipsir, C.Arik, E.Kok, C.H.Bozkurt, C.Tekeoglu, S.Inal, G.Cesur, M.Kucukosmanoglu, E.Karahan, I.Savas, B.Balci, D.Yaman, A.Demirbaş, N.D.Tezcan, I.Haskologlu, S.et al.2025-03-242025-03-242024Nature Communications, 2024; 15(1):9944-1-9944-182041-17232041-1723https://hdl.handle.net/2440/143998Published online: 16 November 2024IKKα is a multifunctional serine/threonine kinase that controls various biological processes, either dependent on or independent of its kinase activity. However, the importance of the kinase function of IKKα in human physiology remains unknown since no biallelic variants disrupting its kinase activity have been reported. In this study, we present a homozygous germline missense variant in the kinase domain of IKKα, which is present in three children from two Turkish families. This variant, referred to as IKKαG167R, is in the activation segment of the kinase domain and affects the conserved (DF/LG) motif responsible for coordinating magnesium atoms for ATP binding. As a result, IKKαG167R abolishes the kinase activity of IKKα, leading to impaired activation of the non-canonical NF-κB pathway. Patients carrying IKKαG167R exhibit a range of immune system abnormalities, including the absence of secondary lymphoid organs, hypogammaglobulinemia and limited diversity of T and B cell receptors with evidence of autoreactivity. Overall, our findings indicate that, unlike a nonsense IKKα variant that results in early embryonic lethality in humans, the deficiency of IKKα's kinase activity is compatible with human life. However, it significantly disrupts the homeostasis of the immune system, underscoring the essential and non-redundant kinase function of IKKα in humans.en© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived fromthis article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creativecommons.org/licenses/by-nc-nd/4.0/.Immune ToleranceHumansImmunologic Deficiency SyndromesNF-kappa BPedigreeSignal TransductionImmune ToleranceHomozygoteGerm-Line MutationMutation, MissenseChildChild, PreschoolFemaleMaleI-kappa B KinaseHEK293 CellsJournal article10.1038/s41467-024-54345-4717928Kok, C.H. [0000-0002-3181-7852]Tumes, D.J. [0000-0001-5709-857X]