{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T21:35:33Z","timestamp":1792445733049,"version":"4.5.0"},"reference-count":90,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,11,16]],"date-time":"2024-11-16T00:00:00Z","timestamp":1731715200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2024,11,16]],"date-time":"2024-11-16T00:00:00Z","timestamp":1731715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100004410","name":"T\u00fcrkiye Bilimsel ve Teknolojik Ara\u015ftirma Kurumu","doi-asserted-by":"publisher","award":["121S667"],"award-info":[{"award-number":["121S667"]}],"id":[{"id":"10.13039\/501100004410","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009727","name":"Hospital Research Foundation","doi-asserted-by":"publisher","award":["2023-S-DTFA-003-QA25325"],"award-info":[{"award-number":["2023-S-DTFA-003-QA25325"]}],"id":[{"id":"10.13039\/100009727","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009727","name":"Hospital Research Foundation","doi-asserted-by":"publisher","award":["2023-S-DTFA-003-QA25325"],"award-info":[{"award-number":["2023-S-DTFA-003-QA25325"]}],"id":[{"id":"10.13039\/100009727","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"Department of Health | National Health and Medical Research Council","doi-asserted-by":"publisher","award":["2027602"],"award-info":[{"award-number":["2027602"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"DOI":"10.1038\/s41467-024-54345-4","type":"journal-article","created":{"date-parts":[[2024,11,16]],"date-time":"2024-11-16T07:51:44Z","timestamp":1731743504000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Defective kinase activity of IKK\u03b1 leads to combined immunodeficiency and disruption of immune tolerance in humans"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7457-9164","authenticated-orcid":false,"given":"G\u00f6khan","family":"Cildir","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9458-3953","authenticated-orcid":false,"given":"Umran","family":"Aba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damla","family":"Pehlivan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis","family":"Tvorogov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3422-3184","authenticated-orcid":false,"given":"Nicholas I.","family":"Warnock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0726-5004","authenticated-orcid":false,"given":"Canberk","family":"Ipsir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elif","family":"Arik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung Hoow","family":"Kok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ceren","family":"Bozkurt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidem","family":"Tekeoglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaye","family":"Inal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmut","family":"Cesur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ercan","family":"Kucukosmanoglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim","family":"Karahan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berna","family":"Savas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deniz","family":"Balci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayhan","family":"Yaman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazli Deveci","family":"Demirba\u015f","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilhan","family":"Tezcan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sule","family":"Haskologlu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Figen","family":"Dogu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1145-0843","authenticated-orcid":false,"given":"Aydan","family":"Ikinciogullar\u0131","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ozlem","family":"Keskin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5709-857X","authenticated-orcid":false,"given":"Damon J.","family":"Tumes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9398-8465","authenticated-orcid":false,"given":"Baran","family":"Erman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,16]]},"reference":[{"key":"54345_CR1","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1016\/j.molmed.2016.03.002","volume":"22","author":"G Cildir","year":"2016","unstructured":"Cildir, G., Low, K. C. & Tergaonkar, V. Noncanonical NF-kappaB Signaling in Health and Disease. Trends Mol. Med. 22, 414\u2013429 (2016).","journal-title":"Trends Mol. Med."},{"key":"54345_CR2","doi-asserted-by":"publisher","first-page":"a000158","DOI":"10.1101\/cshperspect.a000158","volume":"2","author":"A Israel","year":"2010","unstructured":"Israel, A. The IKK complex, a central regulator of NF-kappaB activation. Cold Spring Harb. Perspect. Biol. 2, a000158 (2010).","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"54345_CR3","doi-asserted-by":"publisher","first-page":"3995","DOI":"10.4049\/jimmunol.176.7.3995","volume":"176","author":"D Kinoshita","year":"2006","unstructured":"Kinoshita, D. et al. Essential role of IkappaB kinase alpha in thymic organogenesis required for the establishment of self-tolerance. J. Immunol. 176, 3995\u20134002 (2006).","journal-title":"J. Immunol."},{"key":"54345_CR4","doi-asserted-by":"publisher","first-page":"2218","DOI":"10.1002\/eji.201545677","volume":"45","author":"L Onder","year":"2015","unstructured":"Onder, L. et al. Alternative NF-kappaB signaling regulates mTEC differentiation from podoplanin-expressing precursors in the cortico-medullary junction. Eur. J. Immunol. 45, 2218\u20132231 (2015).","journal-title":"Eur. J. Immunol."},{"key":"54345_CR5","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1002\/eji.201546253","volume":"46","author":"S Baik","year":"2016","unstructured":"Baik, S., Sekai, M., Hamazaki, Y., Jenkinson, W. E. & Anderson, G. Relb acts downstream of medullary thymic epithelial stem cells and is essential for the emergence of RANK(+) medullary epithelial progenitors. Eur. J. Immunol. 46, 857\u2013862 (2016).","journal-title":"Eur. J. Immunol."},{"key":"54345_CR6","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1016\/j.chom.2017.03.006","volume":"21","author":"F Zhu","year":"2017","unstructured":"Zhu, F. et al. Autoreactive T Cells and Chronic Fungal Infection Drive Esophageal Carcinogenesis. Cell Host Microbe 21, 478\u2013493 e477 (2017).","journal-title":"Cell Host Microbe"},{"key":"54345_CR7","doi-asserted-by":"publisher","first-page":"2964","DOI":"10.1172\/JCI28326","volume":"116","author":"M Zhu","year":"2006","unstructured":"Zhu, M. et al. NF-kappaB2 is required for the establishment of central tolerance through an Aire-dependent pathway. J. Clin. Invest 116, 2964\u20132971 (2006).","journal-title":"J. Clin. Invest"},{"key":"54345_CR8","doi-asserted-by":"publisher","first-page":"509","DOI":"10.3389\/fimmu.2013.00509","volume":"4","author":"S Gardam","year":"2014","unstructured":"Gardam, S. & Brink, R. Non-Canonical NF-kappaB Signaling Initiated by BAFF Influences B Cell Biology at Multiple Junctures. Front Immunol. 4, 509 (2014).","journal-title":"Front Immunol."},{"key":"54345_CR9","doi-asserted-by":"publisher","first-page":"5467","DOI":"10.1182\/blood-2012-01-401547","volume":"119","author":"MY Balkhi","year":"2012","unstructured":"Balkhi, M. Y. et al. IKKalpha-mediated signaling circuitry regulates early B lymphopoiesis during hematopoiesis. Blood 119, 5467\u20135477 (2012).","journal-title":"Blood"},{"key":"54345_CR10","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1038\/s41435-018-0025-0","volume":"20","author":"MY Balkhi","year":"2019","unstructured":"Balkhi, M. Y., Willette-Brown, J., Wittmann, G. & Hu, Y. IKKalpha deficiency disrupts the development of marginal zone and follicular B cells. Genes Immun. 20, 224\u2013233 (2019).","journal-title":"Genes Immun."},{"key":"54345_CR11","doi-asserted-by":"publisher","first-page":"12827","DOI":"10.1073\/pnas.1105774108","volume":"108","author":"H Hu","year":"2011","unstructured":"Hu, H. et al. Noncanonical NF-kappaB regulates inducible costimulator (ICOS) ligand expression and T follicular helper cell development. Proc. Natl Acad. Sci. USA 108, 12827\u201312832 (2011).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"54345_CR12","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1038\/nri.2017.52","volume":"17","author":"SC Sun","year":"2017","unstructured":"Sun, S. C. The non-canonical NF-kappaB pathway in immunity and inflammation. Nat. Rev. Immunol. 17, 545\u2013558 (2017).","journal-title":"Nat. Rev. Immunol."},{"key":"54345_CR13","doi-asserted-by":"publisher","first-page":"1371","DOI":"10.1038\/ni.1676","volume":"9","author":"BJ Zarnegar","year":"2008","unstructured":"Zarnegar, B. J. et al. Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat. Immunol. 9, 1371\u20131378 (2008).","journal-title":"Nat. Immunol."},{"key":"54345_CR14","doi-asserted-by":"publisher","first-page":"1364","DOI":"10.1038\/ni.1678","volume":"9","author":"S Vallabhapurapu","year":"2008","unstructured":"Vallabhapurapu, S. et al. Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling. Nat. Immunol. 9, 1364\u20131370 (2008).","journal-title":"Nat. Immunol."},{"key":"54345_CR15","doi-asserted-by":"publisher","first-page":"1907","DOI":"10.1016\/j.celrep.2016.10.067","volume":"17","author":"S Polley","year":"2016","unstructured":"Polley, S. et al. Structural Basis for the Activation of IKK1\/alpha. Cell Rep. 17, 1907\u20131914 (2016).","journal-title":"Cell Rep."},{"key":"54345_CR16","doi-asserted-by":"publisher","first-page":"1309","DOI":"10.1016\/j.cellsig.2005.10.011","volume":"18","author":"C Liang","year":"2006","unstructured":"Liang, C., Zhang, M. & Sun, S. C. beta-TrCP binding and processing of NF-kappaB2\/p100 involve its phosphorylation at serines 866 and 870. Cell Signal 18, 1309\u20131317 (2006).","journal-title":"Cell Signal"},{"key":"54345_CR17","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.764164","volume":"9","author":"G Ghosh","year":"2021","unstructured":"Ghosh, G. & Wang, V. Y. Origin of the Functional Distinctiveness of NF-kappaB\/p52. Front Cell Dev. Biol. 9, 764164 (2021).","journal-title":"Front Cell Dev. Biol."},{"key":"54345_CR18","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1038\/ni.2066","volume":"12","author":"N Shembade","year":"2011","unstructured":"Shembade, N., Pujari, R., Harhaj, N. S., Abbott, D. W. & Harhaj, E. W. The kinase IKKalpha inhibits activation of the transcription factor NF-kappaB by phosphorylating the regulatory molecule TAX1BP1. Nat. Immunol. 12, 834\u2013843 (2011).","journal-title":"Nat. Immunol."},{"key":"54345_CR19","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1016\/j.cell.2007.03.056","volume":"129","author":"B Liu","year":"2007","unstructured":"Liu, B. et al. Proinflammatory stimuli induce IKKalpha-mediated phosphorylation of PIAS1 to restrict inflammation and immunity. Cell 129, 903\u2013914 (2007).","journal-title":"Cell"},{"key":"54345_CR20","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.molcel.2007.02.019","volume":"26","author":"WC Huang","year":"2007","unstructured":"Huang, W. C., Ju, T. K., Hung, M. C. & Chen, C. C. Phosphorylation of CBP by IKKalpha promotes cell growth by switching the binding preference of CBP from p53 to NF-kappaB. Mol. Cell 26, 75\u201387 (2007).","journal-title":"Mol. Cell"},{"key":"54345_CR21","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05722-3","volume":"9","author":"A Di Rita","year":"2018","unstructured":"Di Rita, A. et al. HUWE1 E3 ligase promotes PINK1\/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKalpha. Nat. Commun. 9, 3755 (2018).","journal-title":"Nat. Commun."},{"key":"54345_CR22","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1084\/jem.20161867","volume":"214","author":"MA Diamanti","year":"2017","unstructured":"Diamanti, M. A. et al. IKKalpha controls ATG16L1 degradation to prevent ER stress during inflammation. J. Exp. Med 214, 423\u2013437 (2017).","journal-title":"J. Exp. Med"},{"key":"54345_CR23","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.molcel.2011.11.018","volume":"45","author":"M Liu","year":"2012","unstructured":"Liu, M. et al. IKKalpha activation of NOTCH links tumorigenesis via FOXA2 suppression. Mol. Cell 45, 171\u2013184 (2012).","journal-title":"Mol. Cell"},{"key":"54345_CR24","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1016\/j.celrep.2013.10.046","volume":"5","author":"X Xia","year":"2013","unstructured":"Xia, X. et al. An IKKalpha-nucleophosmin axis utilizes inflammatory signaling to promote genome integrity. Cell Rep. 5, 1243\u20131255 (2013).","journal-title":"Cell Rep."},{"key":"54345_CR25","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2023114719","volume":"42","author":"I Pecharroman","year":"2023","unstructured":"Pecharroman, I. et al. IkappaB kinase-alpha coordinates BRD4 and JAK\/STAT signaling to subvert DNA damage-based anticancer therapy. EMBO J. 42, e114719 (2023).","journal-title":"EMBO J."},{"key":"54345_CR26","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1038\/s41586-020-2533-0","volume":"583","author":"A Armache","year":"2020","unstructured":"Armache, A. et al. Histone H3.3 phosphorylation amplifies stimulation-induced transcription. Nature 583, 852\u2013857 (2020).","journal-title":"Nature"},{"key":"54345_CR27","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1084\/jem.20091346","volume":"208","author":"L Li","year":"2011","unstructured":"Li, L. et al. Transcriptional regulation of the Th17 immune response by IKK(alpha). J. Exp. Med. 208, 787\u2013796 (2011).","journal-title":"J. Exp. Med."},{"key":"54345_CR28","doi-asserted-by":"publisher","first-page":"955","DOI":"10.4049\/jimmunol.1700457","volume":"199","author":"Z He","year":"2017","unstructured":"He, Z. et al. Regulation of Th17 Differentiation by IKKalpha-Dependent and -Independent Phosphorylation of RORgammat. J. Immunol. 199, 955\u2013964 (2017).","journal-title":"J. Immunol."},{"key":"54345_CR29","doi-asserted-by":"publisher","first-page":"2639","DOI":"10.1038\/emboj.2008.196","volume":"27","author":"P Descargues","year":"2008","unstructured":"Descargues, P., Sil, A. K. & Karin, M. IKKalpha, a critical regulator of epidermal differentiation and a suppressor of skin cancer. EMBO J. 27, 2639\u20132647 (2008).","journal-title":"EMBO J."},{"key":"54345_CR30","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1038\/35070605","volume":"410","author":"Y Hu","year":"2001","unstructured":"Hu, Y. et al. IKKalpha controls formation of the epidermis independently of NF-kappaB. Nature 410, 710\u2013714 (2001).","journal-title":"Nature"},{"key":"54345_CR31","doi-asserted-by":"publisher","first-page":"2487","DOI":"10.1073\/pnas.0712044105","volume":"105","author":"P Descargues","year":"2008","unstructured":"Descargues, P. et al. IKKalpha is a critical coregulator of a Smad4-independent TGFbeta-Smad2\/3 signaling pathway that controls keratinocyte differentiation. Proc. Natl Acad. Sci. USA 105, 2487\u20132492 (2008).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"54345_CR32","doi-asserted-by":"publisher","first-page":"1631","DOI":"10.1056\/NEJMoa0911698","volume":"363","author":"J Lahtela","year":"2010","unstructured":"Lahtela, J. et al. Mutant CHUK and severe fetal encasement malformation. N. Engl. J. Med. 363, 1631\u20131637 (2010).","journal-title":"N. Engl. J. Med."},{"key":"54345_CR33","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1002\/ajmg.a.36896","volume":"167A","author":"EJ Leslie","year":"2015","unstructured":"Leslie, E. J. et al. Expanding the genetic and phenotypic spectrum of popliteal pterygium disorders. Am. J. Med Genet. A 167A, 545\u2013552 (2015).","journal-title":"Am. J. Med Genet. A"},{"key":"54345_CR34","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abf6723","volume":"6","author":"W Bainter","year":"2021","unstructured":"Bainter, W. et al. Combined immunodeficiency with autoimmunity caused by a homozygous missense mutation in inhibitor of nuclear factor \u03baB kinase alpha (IKKalpha). Sci. Immunol. 6, eabf6723 (2021).","journal-title":"Sci. Immunol."},{"key":"54345_CR35","doi-asserted-by":"publisher","first-page":"E812","DOI":"10.1073\/pnas.1717520115","volume":"115","author":"NY Song","year":"2018","unstructured":"Song, N. Y. et al. IKKalpha inactivation promotes Kras-initiated lung adenocarcinoma development through disrupting major redox regulatory pathways. Proc. Natl Acad. Sci. USA 115, E812\u2013E821 (2018).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"54345_CR36","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1038\/s41525-021-00226-4","volume":"6","author":"D Chang","year":"2021","unstructured":"Chang, D. & Shain, A. H. The landscape of driver mutations in cutaneous squamous cell carcinoma. NPJ Genom. Med. 6, 61 (2021).","journal-title":"NPJ Genom. Med"},{"key":"54345_CR37","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-19744-w","volume":"8","author":"KT Chang","year":"2018","unstructured":"Chang, K. T., Guo, J., di Ronza, A. & Sardiello, M. Aminode: Identification of Evolutionary Constraints in the Human Proteome. Sci. Rep. 8, 1357 (2018).","journal-title":"Sci. Rep."},{"key":"54345_CR38","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1038\/s41586-021-03205-y","volume":"590","author":"D Taliun","year":"2021","unstructured":"Taliun, D. et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature 590, 290\u2013299 (2021).","journal-title":"Nature"},{"key":"54345_CR39","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","volume":"581","author":"KJ Karczewski","year":"2020","unstructured":"Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434\u2013443 (2020).","journal-title":"Nature"},{"key":"54345_CR40","doi-asserted-by":"publisher","first-page":"D941","DOI":"10.1093\/nar\/gky1015","volume":"47","author":"JG Tate","year":"2019","unstructured":"Tate, J. G. et al. COSMIC: the Catalogue Of Somatic Mutations In Cancer. Nucleic Acids Res. 47, D941\u2013D947 (2019).","journal-title":"Nucleic Acids Res."},{"key":"54345_CR41","doi-asserted-by":"publisher","first-page":"pl1","DOI":"10.1126\/scisignal.2004088","volume":"6","author":"J Gao","year":"2013","unstructured":"Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal 6, pl1 (2013).","journal-title":"Sci. Signal"},{"key":"54345_CR42","doi-asserted-by":"publisher","first-page":"D886","DOI":"10.1093\/nar\/gky1016","volume":"47","author":"P Rentzsch","year":"2019","unstructured":"Rentzsch, P., Witten, D., Cooper, G. M., Shendure, J. & Kircher, M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res 47, D886\u2013D894 (2019).","journal-title":"Nucleic Acids Res"},{"key":"54345_CR43","first-page":"20","volume":"7","author":"I Adzhubei","year":"2013","unstructured":"Adzhubei, I., Jordan, D. M. & Sunyaev, S. R. Predicting functional effect of human missense mutations using PolyPhen-2. Curr. Protoc. Hum. Genet 7, 20 (2013).","journal-title":"Curr. Protoc. Hum. Genet"},{"key":"54345_CR44","doi-asserted-by":"publisher","first-page":"W201","DOI":"10.1093\/nar\/gkx390","volume":"45","author":"D Raimondi","year":"2017","unstructured":"Raimondi, D. et al. DEOGEN2: prediction and interactive visualization of single amino acid variant deleteriousness in human proteins. Nucleic Acids Res. 45, W201\u2013W206 (2017).","journal-title":"Nucleic Acids Res."},{"key":"54345_CR45","doi-asserted-by":"publisher","first-page":"W446","DOI":"10.1093\/nar\/gkab266","volume":"49","author":"R Steinhaus","year":"2021","unstructured":"Steinhaus, R. et al. MutationTaster2021. Nucleic Acids Res. 49, W446\u2013W451 (2021).","journal-title":"Nucleic Acids Res."},{"key":"54345_CR46","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19669-x","volume":"11","author":"V Pejaver","year":"2020","unstructured":"Pejaver, V. et al. Inferring the molecular and phenotypic impact of amino acid variants with MutPred2. Nat. Commun. 11, 5918 (2020).","journal-title":"Nat. Commun."},{"key":"54345_CR47","doi-asserted-by":"publisher","first-page":"2197","DOI":"10.1016\/j.jmb.2019.04.009","volume":"431","author":"S Ittisoponpisan","year":"2019","unstructured":"Ittisoponpisan, S. et al. Can Predicted Protein 3D Structures Provide Reliable Insights into whether Missense Variants Are Disease Associated? J. Mol. Biol. 431, 2197\u20132212 (2019).","journal-title":"J. Mol. Biol."},{"key":"54345_CR48","doi-asserted-by":"publisher","first-page":"W239","DOI":"10.1093\/nar\/gkl190","volume":"34","author":"V Parthiban","year":"2006","unstructured":"Parthiban, V., Gromiha, M. M. & Schomburg, D. CUPSAT: prediction of protein stability upon point mutations. Nucleic Acids Res 34, W239\u2013W242 (2006).","journal-title":"Nucleic Acids Res"},{"key":"54345_CR49","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1093\/bioinformatics\/btz502","volume":"36","author":"J Wang","year":"2020","unstructured":"Wang, J. et al. iCn3D, a web-based 3D viewer for sharing 1D\/2D\/3D representations of biomolecular structures. Bioinformatics 36, 131\u2013135 (2020).","journal-title":"Bioinformatics"},{"key":"54345_CR50","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1016\/j.ccr.2013.03.009","volume":"23","author":"Z Xiao","year":"2013","unstructured":"Xiao, Z. et al. The pivotal role of IKKalpha in the development of spontaneous lung squamous cell carcinomas. Cancer Cell 23, 527\u2013540 (2013).","journal-title":"Cancer Cell"},{"key":"54345_CR51","doi-asserted-by":"publisher","first-page":"2964","DOI":"10.1182\/blood-2014-06-578542","volume":"124","author":"CE Lee","year":"2014","unstructured":"Lee, C. E. et al. Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100. Blood 124, 2964\u20132972 (2014).","journal-title":"Blood"},{"key":"54345_CR52","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1038\/s41586-023-06717-x","volume":"623","author":"T Le Voyer","year":"2023","unstructured":"Le Voyer, T. et al. Autoantibodies against type I IFNs in humans with alternative NF-kappaB pathway deficiency. Nature 623, 803\u2013813 (2023).","journal-title":"Nature"},{"key":"54345_CR53","doi-asserted-by":"publisher","first-page":"20798","DOI":"10.1073\/pnas.0806491106","volume":"105","author":"LT Lam","year":"2008","unstructured":"Lam, L. T. et al. Compensatory IKKalpha activation of classical NF-kappaB signaling during IKKbeta inhibition identified by an RNA interference sensitization screen. Proc. Natl Acad. Sci. USA 105, 20798\u201320803 (2008).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"54345_CR54","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5977","volume":"5","author":"BN Martin","year":"2014","unstructured":"Martin, B. N. et al. IKKalpha negatively regulates ASC-dependent inflammasome activation. Nat. Commun. 5, 4977 (2014).","journal-title":"Nat. Commun."},{"key":"54345_CR55","doi-asserted-by":"publisher","first-page":"W199","DOI":"10.1093\/nar\/gkz401","volume":"47","author":"Y Liao","year":"2019","unstructured":"Liao, Y., Wang, J., Jaehnig, E. J., Shi, Z. & Zhang, B. WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs. Nucleic Acids Res. 47, W199\u2013W205 (2019).","journal-title":"Nucleic Acids Res."},{"key":"54345_CR56","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2005","unstructured":"Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545\u201315550 (2005).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"54345_CR57","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1016\/j.jaci.2023.06.024","volume":"152","author":"HI Navarro","year":"2023","unstructured":"Navarro, H. I. et al. RelB-deficient autoinflammatory pathology presents as interferonopathy, but in mice is interferon-independent. J. Allergy Clin. Immunol. 152, 1261\u20131272 (2023).","journal-title":"J. Allergy Clin. Immunol."},{"key":"54345_CR58","doi-asserted-by":"publisher","first-page":"1627","DOI":"10.1016\/j.celrep.2019.01.041","volume":"26","author":"G Monaco","year":"2019","unstructured":"Monaco, G. et al. RNA-Seq Signatures Normalized by mRNA Abundance Allow Absolute Deconvolution of Human Immune Cell Types. Cell Rep. 26, 1627\u20131640 e1627 (2019).","journal-title":"Cell Rep."},{"key":"54345_CR59","doi-asserted-by":"publisher","first-page":"1595","DOI":"10.1016\/j.celrep.2014.07.037","volume":"8","author":"B Zhao","year":"2014","unstructured":"Zhao, B. et al. The NF-kappaB genomic landscape in lymphoblastoid B cells. Cell Rep. 8, 1595\u20131606 (2014).","journal-title":"Cell Rep."},{"key":"54345_CR60","doi-asserted-by":"publisher","first-page":"eade7953","DOI":"10.1126\/sciimmunol.ade7953","volume":"8","author":"IRFI Consortium","year":"2023","unstructured":"Consortium, I. R. F. I. et al. A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency. Sci. Immunol. 8, eade7953 (2023).","journal-title":"Sci. Immunol."},{"key":"54345_CR61","doi-asserted-by":"crossref","unstructured":"Kaiser, F. M. P. et al. Biallelic PAX5 mutations cause hypogammaglobulinemia, sensorimotor deficits, and autism spectrum disorder. J. Exp. Med. 219, e20220498 (2022).","DOI":"10.1084\/jem.20220498"},{"key":"54345_CR62","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1093\/cei\/uxac109","volume":"212","author":"HS Kuehn","year":"2023","unstructured":"Kuehn, H. S., Boast, B. & Rosenzweig, S. D. Inborn errors of human IKAROS: LOF and GOF variants associated with primary immunodeficiency. Clin. Exp. Immunol. 212, 129\u2013136 (2023).","journal-title":"Clin. Exp. Immunol."},{"key":"54345_CR63","doi-asserted-by":"publisher","first-page":"3151","DOI":"10.1084\/jem.20180668","volume":"215","author":"L Roussel","year":"2018","unstructured":"Roussel, L. et al. Loss of human ICOSL results in combined immunodeficiency. J. Exp. Med. 215, 3151\u20133164 (2018).","journal-title":"J. Exp. Med."},{"key":"54345_CR64","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1038\/s41586-019-1595-3","volume":"574","author":"RJM Bashford-Rogers","year":"2019","unstructured":"Bashford-Rogers, R. J. M. et al. Analysis of the B cell receptor repertoire in six immune-mediated diseases. Nature 574, 122\u2013126 (2019).","journal-title":"Nature"},{"key":"54345_CR65","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6360","volume":"5","author":"KL Willmann","year":"2014","unstructured":"Willmann, K. L. et al. Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity. Nat. Commun. 5, 5360 (2014).","journal-title":"Nat. Commun."},{"key":"54345_CR66","doi-asserted-by":"publisher","first-page":"1641","DOI":"10.1016\/j.jaci.2014.11.038","volume":"135","author":"V Lougaris","year":"2015","unstructured":"Lougaris, V. et al. Defective natural killer-cell cytotoxic activity in NFKB2-mutated CVID-like disease. J. Allergy Clin. Immunol. 135, 1641\u20131643 (2015).","journal-title":"J. Allergy Clin. Immunol."},{"key":"54345_CR67","doi-asserted-by":"publisher","first-page":"303","DOI":"10.3389\/fped.2019.00303","volume":"7","author":"A Aird","year":"2019","unstructured":"Aird, A. et al. Novel Heterozygous Mutation in NFKB2 Is Associated With Early Onset CVID and a Functional Defect in NK Cells Complicated by Disseminated CMV Infection and Severe Nephrotic Syndrome. Front Pediatr. 7, 303 (2019).","journal-title":"Front Pediatr."},{"key":"54345_CR68","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1107609","volume":"13","author":"LJ Howson","year":"2022","unstructured":"Howson, L. J. & Bryant, V. L. Insights into mucosal associated invariant T cell biology from human inborn errors of immunity. Front Immunol. 13, 1107609 (2022).","journal-title":"Front Immunol."},{"key":"54345_CR69","doi-asserted-by":"publisher","first-page":"1701","DOI":"10.1016\/j.cell.2018.10.022","volume":"175","author":"BJ Schmiedel","year":"2018","unstructured":"Schmiedel, B. J. et al. Impact of Genetic Polymorphisms on Human Immune Cell Gene Expression. Cell 175, 1701\u20131715 e1716 (2018).","journal-title":"Cell"},{"key":"54345_CR70","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2023.e22911","volume":"9","author":"Y Sato","year":"2023","unstructured":"Sato, Y., Osada, E. & Manome, Y. Non-canonical NFKB signaling endows suppressive function through FOXP3-dependent regulatory T cell program. Heliyon 9, e22911 (2023).","journal-title":"Heliyon"},{"key":"54345_CR71","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1038\/ni.3491","volume":"17","author":"BD Stadinski","year":"2016","unstructured":"Stadinski, B. D. et al. Hydrophobic CDR3 residues promote the development of self-reactive T cells. Nat. Immunol. 17, 946\u2013955 (2016).","journal-title":"Nat. Immunol."},{"key":"54345_CR72","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/j.jaci.2019.03.022","volume":"144","author":"SR Daley","year":"2019","unstructured":"Daley, S. R. et al. Cysteine and hydrophobic residues in CDR3 serve as distinct T-cell self-reactivity indices. J. Allergy Clin. Immunol. 144, 333\u2013336 (2019).","journal-title":"J. Allergy Clin. Immunol."},{"key":"54345_CR73","doi-asserted-by":"crossref","unstructured":"Tangye, S. G., Nguyen, T., Deenick, E. K., Bryant, V. L., Ma, C. S. Inborn errors of human B cell development, differentiation, and function. J. Exp. Med. 220, (2023).","DOI":"10.1084\/jem.20221105"},{"key":"54345_CR74","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.cell.2016.12.012","volume":"168","author":"Q Zhang","year":"2017","unstructured":"Zhang, Q., Lenardo, M. J. & Baltimore, D. 30 Years of NF-kappaB: A Blossoming of Relevance to Human Pathobiology. Cell 168, 37\u201357 (2017).","journal-title":"Cell"},{"key":"54345_CR75","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1126\/science.284.5412.321","volume":"284","author":"Q Li","year":"1999","unstructured":"Li, Q., Antwerp, Van, Mercurio, D., Lee, F. & Verma, K. F. IM. Severe liver degeneration in mice lacking the IkappaB kinase 2 gene. Science 284, 321\u2013325 (1999).","journal-title":"Science"},{"key":"54345_CR76","doi-asserted-by":"publisher","first-page":"2046","DOI":"10.1182\/blood-2014-04-571265","volume":"124","author":"T Mousallem","year":"2014","unstructured":"Mousallem, T. et al. A nonsense mutation in IKBKB causes combined immunodeficiency. Blood 124, 2046\u20132050 (2014).","journal-title":"Blood"},{"key":"54345_CR77","doi-asserted-by":"publisher","first-page":"2504","DOI":"10.1056\/NEJMoa1309199","volume":"369","author":"U Pannicke","year":"2013","unstructured":"Pannicke, U. et al. Deficiency of innate and acquired immunity caused by an IKBKB mutation. N. Engl. J. Med. 369, 2504\u20132514 (2013).","journal-title":"N. Engl. J. Med."},{"key":"54345_CR78","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.517544","volume":"11","author":"T Qin","year":"2020","unstructured":"Qin, T. et al. A Novel Homozygous Mutation Destabilizes IKKbeta and Leads to Human Combined Immunodeficiency. Front Immunol. 11, 517544 (2020).","journal-title":"Front Immunol."},{"key":"54345_CR79","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.clim.2018.10.019","volume":"205","author":"GDE Cuvelier","year":"2019","unstructured":"Cuvelier, G. D. E. et al. Clinical presentation, immunologic features, and hematopoietic stem cell transplant outcomes for IKBKB immune deficiency. Clin. Immunol. 205, 138\u2013147 (2019).","journal-title":"Clin. Immunol."},{"key":"54345_CR80","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.655354","volume":"12","author":"AY Kreins","year":"2021","unstructured":"Kreins, A. Y., Bonfanti, P. & Davies, E. G. Current and Future Therapeutic Approaches for Thymic Stromal Cell Defects. Front Immunol. 12, 655354 (2021).","journal-title":"Front Immunol."},{"key":"54345_CR81","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1084\/jem.20111316","volume":"209","author":"M Herman","year":"2012","unstructured":"Herman, M. et al. Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood. J. Exp. Med. 209, 1567\u20131582 (2012).","journal-title":"J. Exp. Med."},{"key":"54345_CR82","doi-asserted-by":"publisher","first-page":"1634","DOI":"10.1016\/j.bbamcr.2009.09.001","volume":"1793","author":"S Moretti","year":"2009","unstructured":"Moretti, S. et al. Insights into the molecular function of the inactivating mutations of B-Raf involving the DFG motif. Biochim Biophys. Acta 1793, 1634\u20131645 (2009).","journal-title":"Biochim Biophys. Acta"},{"key":"54345_CR83","doi-asserted-by":"publisher","first-page":"297","DOI":"10.3389\/fimmu.2019.00297","volume":"10","author":"C Klemann","year":"2019","unstructured":"Klemann, C. et al. Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2. Front Immunol. 10, 297 (2019).","journal-title":"Front Immunol."},{"key":"54345_CR84","doi-asserted-by":"publisher","first-page":"1624","DOI":"10.3389\/fimmu.2017.01624","volume":"8","author":"N Schlechter","year":"2017","unstructured":"Schlechter, N. et al. Exome Sequencing Identifies a Novel MAP3K14 Mutation in Recessive Atypical Combined Immunodeficiency. Front Immunol. 8, 1624 (2017).","journal-title":"Front Immunol."},{"key":"54345_CR85","doi-asserted-by":"publisher","first-page":"7043","DOI":"10.1021\/acs.jmedchem.7b00484","volume":"60","author":"NG Anthony","year":"2017","unstructured":"Anthony, N. G. et al. Inhibitory Kappa B Kinase alpha (IKKalpha) Inhibitors That Recapitulate Their Selectivity in Cells against Isoform-Related Biomarkers. J. Med Chem. 60, 7043\u20137066 (2017).","journal-title":"J. Med Chem."},{"key":"54345_CR86","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1007\/s10875-024-01658-0","volume":"44","author":"U Aba","year":"2024","unstructured":"Aba, U. et al. A Novel Homozygous Germline Mutation in Transferrin Receptor 1 (TfR1) Leads to Combined Immunodeficiency and Provides New Insights into Iron-Immunity Axis. J. Clin. Immunol. 44, 55 (2024).","journal-title":"J. Clin. Immunol."},{"key":"54345_CR87","unstructured":"Bastard, P. et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science 370, eabd4585 (2020)."},{"key":"54345_CR88","doi-asserted-by":"publisher","first-page":"1814","DOI":"10.3906\/sag-2010-176","volume":"51","author":"O Besci","year":"2021","unstructured":"Besci, O. et al. Reference values for T and B lymphocyte subpopulations in Turkish children and adults. Turk. J. Med Sci. 51, 1814\u20131824 (2021).","journal-title":"Turk. J. Med Sci."},{"key":"54345_CR89","first-page":"125","volume":"46","author":"A Ikinciogullari","year":"2004","unstructured":"Ikinciogullari, A. et al. Peripheral blood lymphocyte subsets in healthy Turkish children. Turk. J. Pediatr. 46, 125\u2013130 (2004).","journal-title":"Turk. J. Pediatr."},{"key":"54345_CR90","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","volume":"26","author":"MD Robinson","year":"2010","unstructured":"Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139\u2013140 (2010).","journal-title":"Bioinformatics"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-54345-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-54345-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-54345-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,16]],"date-time":"2024-11-16T09:02:30Z","timestamp":1731747750000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-54345-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,16]]},"references-count":90,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["54345"],"URL":"https:\/\/doi.org\/10.1038\/s41467-024-54345-4","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-4023537\/v1","asserted-by":"object"}]},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,16]]},"assertion":[{"value":"23 April 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 November 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 November 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"9944"}}