Genetically programmed alternative splicing of NEMO mediates an autoinflammatory disease phenotype
Younglang Lee, Alex W Wessel, Jiazhi Xu, Julia G Reinke, Eries Lee, Somin M Kim, Amy P Hsu, Jevgenia Zilberman-Rudenko, Sha Cao, Clinton Enos, Stephen R Brooks, Zuoming Deng, Bin Lin, Adriana A de Jesus, Daniel N Hupalo, Daniela Gp Piotto, Maria T Terreri, Victoria R Dimitriades, Clifton L Dalgard, Steven M Holland, Raphaela Goldbach-Mansky, Richard M Siegel, Eric P Hanson, Younglang Lee, Alex W Wessel, Jiazhi Xu, Julia G Reinke, Eries Lee, Somin M Kim, Amy P Hsu, Jevgenia Zilberman-Rudenko, Sha Cao, Clinton Enos, Stephen R Brooks, Zuoming Deng, Bin Lin, Adriana A de Jesus, Daniel N Hupalo, Daniela Gp Piotto, Maria T Terreri, Victoria R Dimitriades, Clifton L Dalgard, Steven M Holland, Raphaela Goldbach-Mansky, Richard M Siegel, Eric P Hanson
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.
Trial registration: ClinicalTrials.gov NCT00001788 NCT00001372 NCT02974595.
Keywords: Genetic diseases; Genetics; Immunology; Inflammation; Innate immunity; Signal transduction.
Conflict of interest statement
Conflict of interest: CE has served on an advisory board for Union Chimique Belge. RGM has received study support under government cooperative research and development agreements (CRADAs) from Swedish Orphan Biovitrum AB, Regeneron, Eli Lilly, and Novartis. RMS has been an employee of Novartis since 2018 and currently owns Novartis stock, though he worked for the NIH at the time he worked on this manuscript. EPH’s spouse receives income from Eli Lilly and holds unvested restricted stock options.
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