ArticleThe Journal of clinical investigation2022
Genetically programmed alternative splicing of NEMO mediates an autoinflammatory disease phenotype.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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30 citing papers in PubMed, 39 citations in OpenAlex.
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- Monogenic disorders of the TNF signalling pathway.Nature reviews. Rheumatology · 2026Review
- Recent variant discoveries and emerging genetic mechanisms in autoinflammatory diseases.Frontiers in immunology · 2026Review
- Pediatric ectodermal dysplasia with immunodeficiency caused by a hemizygousFrontiers in immunology · 2026Review
- First 2-year experience of nationwide newborn screening for severe forms of T and B cell immunodeficiency: 2.3 million newborns analyzed using TREC and KREC in Russia.Frontiers in immunology · 2026Article
- Mendelian susceptibility to mycobacterial disease: IFN-γ-driven immunity collapse underlies heterogeneous infections.Frontiers in immunology · 2026Review
- Rheumatologic and Autoimmune Features of Inborn Errors of Immunity: Implications for Diagnosis and Management.Journal of human immunity · 2025Article
- Clinical relevance of loss-of-function mutations ofGenes & diseases · 2025Article
- Single-Cell RNA Sequencing in Incontinentia Pigmenti With Neonatal Encephalopathy Reveals Broad Immune Activation Moderated by Steroids.Neurology(R) neuroimmunology & neuroinflammation · 2025Article
- Splice site and de novo variants can cause PLCG2-associated immune dysregulation with cold urticaria.The Journal of allergy and clinical immunology · 2025Article
- The protective role of kakkalide in sepsis-induced intestinal barrier dysfunction via inhibition of NF-κB pathway activation.Journal of clinical biochemistry and nutrition · 2025Article
- Mechanistic Insights into Alternative Gene Splicing in Oxidative Stress and Tissue Injury.Antioxidants & redox signaling · 2024Review
- Nucleotide metabolism, leukodystrophies, and CNS pathology.Journal of inherited metabolic disease · 2024Review
- Principles of clinical genetics for rheumatologists: clinical indications and interpretation of broad-based genetic testing.Advances in rheumatology (London, England) · 2024Review
- Get Spliced: Uniting Alternative Splicing and Arthritis.International journal of molecular sciences · 2024Review
- Altered X-chromosome inactivation predisposes to autoimmunity.Science advances · 2024Article
- AZD1390, an ataxia telangiectasia mutated inhibitor, attenuates microglia-mediated neuroinflammation and ischemic brain injury.CNS neuroscience & therapeutics · 2024Article
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Authors and funding
23 authors at 8 institutions in 3 countries.
Funding
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.
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