Genetically programmed alternative splicing of NEMO mediates an autoinflammatory disease phenotype.

Host defense and inflammation are regulated by the NF-?B essential modulator (NEMO), a scaffolding protein with a broad immune cell and tissue expression profile. Hypomorphic mutations in inhibitor of NF-?B 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-?ex5). This isoform failed to associate with TANK binding kinase 1 (TBK1), and dermal fibroblasts from affected patients activated NF-?B 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-?ex5 exhibited increased NF-?B activation and IFN production, and blood cells from these patients expressed a strong IFN and NF-?B transcriptional signature. Immune cells and TNF-stimulated dermal fibroblasts upregulated the inducible IKK protein (IKKi) that was stabilized by NEMO-?ex5, 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.
Mesh Terms:
Alternative Splicing, Child, Hereditary Autoinflammatory Diseases, Humans, I-kappa B Kinase, Immunologic Deficiency Syndromes, Male, NF-kappa B, Phenotype
J Clin Invest
Date: Dec. 15, 2021
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