Defective kinase activity of IKKα leads to combined immunodeficiency and disruption of immune tolerance in humans

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dc.contributor.authorCildir, G.
dc.contributor.authorAba, U.
dc.contributor.authorPehlivan, D.
dc.contributor.authorTvorogov, D.
dc.contributor.authorWarnock, N.I.
dc.contributor.authorIpsir, C.
dc.contributor.authorArik, E.
dc.contributor.authorKok, C.H.
dc.contributor.authorBozkurt, C.
dc.contributor.authorTekeoglu, S.
dc.contributor.authorInal, G.
dc.contributor.authorCesur, M.
dc.contributor.authorKucukosmanoglu, E.
dc.contributor.authorKarahan, I.
dc.contributor.authorSavas, B.
dc.contributor.authorBalci, D.
dc.contributor.authorYaman, A.
dc.contributor.authorDemirbaş, N.D.
dc.contributor.authorTezcan, I.
dc.contributor.authorHaskologlu, S.
dc.contributor.authoret al.
dc.date.issued2024
dc.descriptionPublished online: 16 November 2024
dc.description.abstractIKKα 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.
dc.description.statementofresponsibilityGökhan Cildir, Umran Aba, Damla Pehlivan, Denis Tvorogov, Nicholas I. Warnock, Canberk Ipsir, Elif Arik, Chung Hoow Kok, Ceren Bozkurt, SidemTekeoglu, Gaye Inal, Mahmut Cesur, Ercan Kucukosmanoglu, IbrahimKarahan, Berna Savas, Deniz Balci, Ayhan Yaman, Nazli Deveci Demirbaş, Ilhan Tezcan, Sule Haskologlu, Figen Dogu, Aydan Ikinciogulları, OzlemKeskin, Damon J. Tumes and Baran Erman
dc.identifier.citationNature Communications, 2024; 15(1):9944-1-9944-18
dc.identifier.doi10.1038/s41467-024-54345-4
dc.identifier.issn2041-1723
dc.identifier.issn2041-1723
dc.identifier.orcidKok, C.H. [0000-0002-3181-7852]
dc.identifier.orcidTumes, D.J. [0000-0001-5709-857X]
dc.identifier.urihttps://hdl.handle.net/2440/143998
dc.language.isoen
dc.publisherSpringer Nature
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/2027602
dc.rights© 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/.
dc.source.urihttps://doi.org/10.1038/s41467-024-54345-4
dc.subjectImmune Tolerance
dc.subject.meshHumans
dc.subject.meshImmunologic Deficiency Syndromes
dc.subject.meshNF-kappa B
dc.subject.meshPedigree
dc.subject.meshSignal Transduction
dc.subject.meshImmune Tolerance
dc.subject.meshHomozygote
dc.subject.meshGerm-Line Mutation
dc.subject.meshMutation, Missense
dc.subject.meshChild
dc.subject.meshChild, Preschool
dc.subject.meshFemale
dc.subject.meshMale
dc.subject.meshI-kappa B Kinase
dc.subject.meshHEK293 Cells
dc.titleDefective kinase activity of IKKα leads to combined immunodeficiency and disruption of immune tolerance in humans
dc.title.alternativeDefective kinase activity of IKKalpha leads to combined immunodeficiency and disruption of immune tolerance in humans
dc.typeJournal article
pubs.publication-statusPublished

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