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

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dc.authorscopusidAyhan Yaman / 55697653700
dc.authorwosidAyhan Yaman / AAO-2530-2020
dc.contributor.authorÇıldır, Gökhan
dc.contributor.authorAba, Ümran
dc.contributor.authorPehlivan, Damla
dc.contributor.authorTvorogov, Denis
dc.contributor.authorWarnock, Nicholas I.
dc.contributor.authorİpşir, Canberk
dc.contributor.authorArık, Elif
dc.contributor.authorKok, Chung Hoow
dc.contributor.authorBozkurt, Ceren
dc.contributor.authorTekeoğlu, Sidem
dc.contributor.authorİnal, Gaye
dc.contributor.authorCesur, Mahmut
dc.contributor.authorKüçükosmanoğlu, Ercan
dc.contributor.authorKarahan, İbrahim
dc.contributor.authorSavaş, Berna
dc.contributor.authorBalcı, Deniz
dc.contributor.authorYaman, Ayhan
dc.contributor.authorDemirbaş, Nazlı Deveci
dc.contributor.authorTezcan, İlhan
dc.contributor.authorHaskoloğlu, Şule
dc.contributor.authorDoğu, Figen
dc.contributor.authorİkincioğulları, Aydan
dc.contributor.authorKeskin, Özlem
dc.contributor.authorTümes, Damon J.
dc.contributor.authorErman, Baran
dc.date.accessioned2025-05-09T13:03:38Z
dc.date.available2025-05-09T13:03:38Z
dc.date.issued2024
dc.departmentİstinye Üniversitesi, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü
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. © The Author(s) 2024.
dc.description.sponsorshipWe would like to thank \u201CCan Sucak Candan Biseyler\u201D Foundation (CSCBF) for their support and contributions during the study. CSCBF was founded in 2018 to honour Can Sucak who lost his life due to complications of primary immunodeficiency. CSCBF supports research in the field of primary immunodeficiency and promotes awareness. G.C. and D.J.T. are supported by grants from the Hospital Research Foundation (THRF) (Grant 2023-S-DTFA-003-QA25325) and NHMRC of Australia (Grant 2027602). B.E was supported for immune repertoire study by the Scientific and Technological Research Council of T\u00FCrkiye (121S667).
dc.identifier.citationCildir, G., Aba, U., Pehlivan, D., Tvorogov, D., Warnock, N. I., Ipsir, C., ... & Erman, B. (2024). Defective kinase activity of IKKα leads to combined immunodeficiency and disruption of immune tolerance in humans. Nature communications, 15(1), 9944.
dc.identifier.doi10.1038/s41467-024-54345-4
dc.identifier.issn20411723
dc.identifier.pmid39550372
dc.identifier.scopusqualityQ1
dc.identifier.urihttp://dx.doi.org/10.1038/s41467-024-54345-4
dc.identifier.urihttps://hdl.handle.net/20.500.12713/7252
dc.identifier.wosWOS:001355664400001
dc.indekslendigikaynakScopus
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakPubMed
dc.institutionauthorYaman, Ayhan
dc.institutionauthoridAyhan Yaman / 0000-0002-5651-1286
dc.language.isoen
dc.publisherNature Research
dc.relation.ispartofNature Communications
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.relation.tubitak121S667
dc.rightsinfo:eu-repo/semantics/openAccess
dc.titleDefective kinase activity of IKKα leads to combined immunodeficiency and disruption of immune tolerance in humans
dc.typeArticle

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