{"doi":"10.1172/jci128808","title":"Genetically programmed alternative splicing of NEMO mediates an autoinflammatory disease phenotype","abstract":"Host defense and inflammation are regulated by the NF-κB essential modulator (NEMO), a scaffolding protein with a broad immune cell and tissue expression profile. Hypomorphic mutations in inhibitor of NF-κB kinase regulatory subunit gamma (IKBKG) encoding NEMO typically present with immunodeficiency. Here, we characterized a pediatric autoinflammatory syndrome in 3 unrelated male patients with distinct X-linked IKBKG germline mutations that led to overexpression of a NEMO protein isoform lacking the domain encoded by exon 5 (NEMO-Δex5). This isoform failed to associate with TANK binding kinase 1 (TBK1), and dermal fibroblasts from affected patients activated NF-κB in response to TNF but not TLR3 or RIG-I-like receptor (RLR) stimulation when isoform levels were high. By contrast, T cells, monocytes, and macrophages that expressed NEMO-Δex5 exhibited increased NF-κB activation and IFN production, and blood cells from these patients expressed a strong IFN and NF-κB transcriptional signature. Immune cells and TNF-stimulated dermal fibroblasts upregulated the inducible IKK protein (IKKi) that was stabilized by NEMO-Δex5, promoting type I IFN induction and antiviral responses. These data revealed how IKBKG mutations that lead to alternative splicing of skipping exon 5 cause a clinical phenotype we have named NEMO deleted exon 5 autoinflammatory syndrome (NDAS), distinct from the immune deficiency syndrome resulting from loss-of-function IKBKG mutations.","journal":"Journal of Clinical Investigation","year":2022,"id":241169,"datarank":1.880831602905518,"base_score":3.784189633918261,"endowment":3.784189633918261,"self_citation_contribution":0.5676284450877392,"citation_network_contribution":1.3132031578177787,"self_endowment_contribution":0.5676284450877392,"citer_contribution":1.3132031578177787,"corpus_percentile":null,"corpus_rank":null,"citation_count":43,"citer_count":43,"citers_with_citation_signal":31,"citers_with_endowment":31,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9537,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT00001788","NCT00001372","NCT02974595"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":249781,"name":"Alex W. Wessel","orcid":"0000-0002-0438-7842","position":1,"is_corresponding":false},{"id":870548,"name":"Jiazhi Xu","orcid":null,"position":2,"is_corresponding":false},{"id":870549,"name":"Julia G. Reinke","orcid":null,"position":3,"is_corresponding":false},{"id":869854,"name":"Eries Lee","orcid":"0000-0002-8977-4998","position":4,"is_corresponding":false},{"id":869855,"name":"Somin M. Kim","orcid":"0000-0002-0361-1048","position":5,"is_corresponding":false},{"id":362027,"name":"Amy P. Hsu","orcid":"0000-0001-6841-2122","position":6,"is_corresponding":false},{"id":870550,"name":"Jevgenia Zilberman-Rudenko","orcid":null,"position":7,"is_corresponding":false},{"id":703161,"name":"Sha Cao","orcid":"0000-0003-3033-9219","position":8,"is_corresponding":false},{"id":869856,"name":"Clinton Enos","orcid":"0000-0002-6783-1904","position":9,"is_corresponding":false},{"id":218255,"name":"Stephen R. Brooks","orcid":"0000-0001-5592-5332","position":10,"is_corresponding":false},{"id":4101,"name":"Zuoming Deng","orcid":null,"position":11,"is_corresponding":false},{"id":297406,"name":"Bin Lin","orcid":"0000-0002-8032-937X","position":12,"is_corresponding":false},{"id":104156,"name":"Adriana A. de Jesus","orcid":"0000-0001-8966-8362","position":13,"is_corresponding":false},{"id":870551,"name":"Daniel N. Hupalo","orcid":null,"position":14,"is_corresponding":false},{"id":869857,"name":"Daniela G.P. Piotto","orcid":"0000-0003-2829-842X","position":15,"is_corresponding":false},{"id":870552,"name":"Maria T. Terreri","orcid":null,"position":16,"is_corresponding":false},{"id":796431,"name":"Victoria R. Dimitriades","orcid":"0000-0002-6802-1612","position":17,"is_corresponding":false},{"id":241309,"name":"Clifton L. Dalgard","orcid":"0000-0003-2025-8239","position":18,"is_corresponding":false},{"id":104227,"name":"Steven M. 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