Lee, YounglangWessel, Alex W.Xu, JiazhiReinke, Julia G.Lee, EriesKim, Somin M.Hsu, Amy P.Zilberman-Rudenko, JevgeniaCao, ShaEnos, ClintonBrooks, Stephen R.Deng, ZuomingLin, Binde Jesus, Adriana A.Hupalo, Daniel N.Piotto, Daniela G.P.Terreri, Maria T.Dimitriades, Victoria R.Dalgard, Clifton L.Holland, Steven M.Goldbach-Mansky, RaphaelaSiegel, Richard M.Hanson, Eric P.2023-05-182023-05-182022Lee Y, Wessel AW, Xu J, et al. Genetically programmed alternative splicing of NEMO mediates an autoinflammatory disease phenotype. J Clin Invest. 2022;132(6):e128808. doi:10.1172/JCI128808https://hdl.handle.net/1805/33091Host 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.en-USAttribution 4.0 InternationalGeneticsImmunologyInflammationGenetic diseasesInnate immunitySignal transductionArticle