2. Academic Validation
  3. Genetically programmed alternative splicing of NEMO mediates an autoinflammatory disease phenotype

Genetically programmed alternative splicing of NEMO mediates an autoinflammatory disease phenotype

  • J Clin Invest. 2022 Mar 15;132(6):e128808. doi: 10.1172/JCI128808.
Younglang Lee 1 2,  Alex W Wessel 1 2,  Jiazhi Xu 3,  Julia G Reinke 3,  Eries Lee 1 2,  Somin M Kim 1 2,  Amy P Hsu 4,  Jevgenia Zilberman-Rudenko 1 2,  Sha Cao 5,  Clinton Enos 1 2,  Stephen R Brooks 6,  Zuoming Deng 6,  Bin Lin 7,  Adriana A de Jesus 7,  Daniel N Hupalo 8,  Daniela Gp Piotto 9,  Maria T Terreri 9,  Victoria R Dimitriades 10,  Clifton L Dalgard 8 11,  Steven M Holland 4,  Raphaela Goldbach-Mansky 7,  Richard M Siegel 2 12,  Eric P Hanson 3
Affiliations

Affiliations

  • 1 Immunodeficiency and Inflammatory Disease Unit and.
  • 2 Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, Maryland, USA.
  • 3 Indiana University School of Medicine, Wells Center for Pediatric Research, Indianapolis, Indiana, USA.
  • 4 Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
  • 5 Department of Biostatistics, Indiana University, School of Medicine, Indianapolis, Indiana, USA.
  • 6 Biodata Mining and Discovery Section, Office of Science and Technology, NIAMS and.
  • 7 Translational Autoinflammatory Diseases Section (TADS), LCIM, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
  • 8 The American Genome Center, Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
  • 9 Escola Paulista de Medicina/Universidade Federal de São Paulo, São Paulo, Brazil.
  • 10 Division of Infectious Diseases, Immunology & Allergy University of California Davis Health, Sacramento, California, USA.
  • 11 Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
  • 12 Novartis Institutes for BioMedical Research WSJ, Basel, Switzerland.
PMID: 35289316 DOI: 10.1172/JCI128808
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.

Keywords

Genetic diseases; Genetics; Immunology; Inflammation; Innate immunity; Signal transduction.

Figures