---
title: "TBK1 Mutation Impairing IRF3 Activation Linked to Familial Recurrent Myopericarditis"
id: "frontiers-in-immunology-18-a-tbk1-mutation-disrupting-irf3-activation-is-associated-with-familial"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-18-a-tbk1-mutation-disrupting-irf3-activation-is-associated-with-familial"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1906965"
published_at: "2026-08-05T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# TBK1 Mutation Impairing IRF3 Activation Linked to Familial Recurrent Myopericarditis
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-18-a-tbk1-mutation-disrupting-irf3-activation-is-associated-with-familial
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1906965)
- **Published At:** 2026-08-05T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The source article title reports an association between a **TBK1 mutation** that disrupts **IRF3 activation** and **familial recurrent myopericarditis**. - The item is indexed in Frontiers in Immunology. - The publicly provided source content accessible here contains only site navigation and journal metadata; the full article text, methods, results, case details, and conclusions were not included in the supplied source. - No patient-level data, genetic variant details (e.g., nucleotide or protein change), functional assay results, inheritance pattern, clinical course, diagnostic testing, management, or outcomes were available in the provided material. - The title implies a mechanistic link between a kinase mutation (TBK1) and impaired activation of the transcription factor IRF3 in the context of recurrent myopericarditis affecting members of a family, but specific evidence and experimental or clinical details were not reported in the provided source. - The URL and journal (Frontiers in Immunology) were provided, but the main article body and figures were not present in the source data supplied for this rewrite. - Because the full manuscript content was not available in the source, readers should consult the original Frontiers in Immunology article for complete methods, results, variant annotation, and clinical recommendations.
## Clinical Analysis & Structured Key Points
Frontiers | A TBK1 mutation disrupting IRF3 activation is associated with familial recurrent myopericarditis ORIGINAL RESEARCH article Front. Immunol. , 05 August 2026 Sec. Autoimmune and Autoinflammatory Disorders: Autoinflammatory Disorders Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1906965 Published in Frontiers in Immunology Autoimmune and Autoinflammatory Disorders: Autoinflammatory Disorders 7 impact factor 11.3 citescore Part of a Research Topic From Idiopathic to Autoinflammatory Pericarditis: Clinical characteristics, Inflammasome Pathways, Biomarkers and Therapeutic Advances Submission open 1931 views 1 articles Editor & Reviewers Edited by A M Angela Mauro Reviewed by J C Juan Carlos Fernandez Cadena B J Brendan James Floyd Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Figure 5 View in article ORIGINAL RESEARCH article Front. Immunol. , 05 August 2026 Sec. Autoimmune and Autoinflammatory Disorders: Autoinflammatory Disorders Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1906965 A TBK1 mutation disrupting IRF3 activation is associated with familial recurrent myopericarditis C J Claire J. Peet 1,2 † T O Thomas Orchard 1 † C H Carlos H. B. Cruz 3 A H Ariana Hernandez-Cordero 1 E O Ebun Omoyinmi 2 S K Satveer K. Mahil 4 H J Helen J. Lachmann 2 F F Franca Fraternali 3,5 * F C Francesca Capon 1,6,7 * 1. Department of Medical and Molecular Genetics, King’s College London, London, United Kingdom 2. National Amyloidosis Centre, Royal Free London NHS Foundation Trust, London & Division of Medicine, University College London, London, United Kingdom 3. Research Department of Structural and Molecular Biology, Division of Biosciences, University College London, London, United Kingdom 4. St John’s Institute of Dermatology, King’s College London, London, United Kingdom 5. Department of Biological Sciences, Birkbeck, University of London, London, United Kingdom 6. BC Children’s Hospital Research Institute, Vancouver, BC, Canada 7. Department of Medical Genetics and Centre for Molecular Medicine and Therapeutics, The University of British Columbia, Vancouver, BC, Canada See more Article metrics View details Abstract Introduction: Idiopathic recurrent pericarditis (IRP) is an immune-mediated disease characterized by episodes of pericardial inflammation. While IRP is increasingly considered an autoinflammatory condition, pathogenic pathways remain poorly understood. In this context, gene discovery can reveal new disease mechanisms. Methods: We carried out whole-exome sequencing in a pedigree where three individuals suffered from IRP presenting with myocardial involvement (myopericarditis). We first investigated mutation effects computationally, by estimating free-energy changes and undertaking molecular dynamic simulations of wild type and mutant proteins. Next, we overexpressed wild-type and mutagenized cDNAs in HEK293 cells, characterizing protein expression and phosphorylation by western blotting. Finally, we measured gene expression in primary pericardial fibroblasts, using real-time PCR. Results: We identified a Y105C mutation in TBK1, a kinase that regulates antiviral responses driven by the IRF3 transcription factor. The Y105C substitution maps at the interface between the kinase and scaffold domain of TBK1. Accordingly, molecular modeling predicted a destabilizing effect of the variant, which was experimentally validated in over-expression studies. The Y105C mutation also affected kinase activity, causing a significant reduction in IRF3 phosphorylation. While TBK1 was required for TLR3-IRF3 signaling in primary human pericardial fibroblasts, TLR3 was weakly expressed in these cells. Conclusions: A TBK1 Y105C mutation that reduces IRF3 phosporylation is associated with familial recurrent myopericarditis. Given TLR3 is lowly expressed in pericardial fibroblasts, these cells may be especially vulnerable to mutations that disrupt TLR3-IRF3 signaling. Thus, our findings suggest that inherited susceptibility to viral infections may be an important factor in the pathogenesis of IRP. 1 Introduction Idiopathic recurrent pericarditis (IRP) is a rare immune-mediated condition, characterized by acute episodes of pericardial inflammation ( 1 ). Disease flares present with severe chest pain, which can be accompanied by a pericardial friction rub, electrocardiographic changes, and/or pericardial effusion. In approximately 15% of cases, IRP is complicated by myocardial involvement, giving rise to myopericarditis ( 2 ). While pericarditis recurrence has a profound effect on quality of life ( 3 ), the underlying risk factors and pathogenic pathways are not well understood. As IRP responds to drugs blocking inflammasome-dependent IL-1 activation (colchicine) or IL-1 signaling (anakinra, rilonacept) ( 4 – 6 ), an autoinflammatory pathogenesis has been proposed ( 7 , 8 ). This is supported by several lines of evidence. First, pericarditis is a feature of autoinflammatory syndromes such as familial mediterranean fever and mevalonate kinase deficiency ( 9 ). Second, common IL1B variants have been associated with the disease in a genome-wide association study ( 10 ). Finally damaging changes in inflammasome genes ( NLRP3 , MEFV ) have been detected among affected individuals ( 11 ). Nonetheless, the mechanisms underlying abnormal IL-1 production in IRP are unclear. Studies of patient serum and pericardial effusions have suggested an involvement of viral infections, most notably those caused by enteroviruses (e.g. coxsackie B3 virus), influenza A virus and more recently, coronaviruses ( 12 – 15 ). In this context, disease flares might occur because of repeated infection, viral latency or priming of a subsequent autoinflammatory response. An alternative hypothesis is that non-infectious events (e.g. pericardial injury) might trigger the release of damage associated molecular patterns, leading to inflammasome activation, recruitment of innate immune cells and self-perpetuating inflammation ( 16 , 17 ). While various animal models of pericarditis have been established, they are of limited utility, as they cannot recapitulate the recurrent nature of IRP ( 18 – 20 ). Conversely, gene discovery in monogenic forms of the disease has unique potential to uncover pathogenic pathways. Here, we investigated a recurrent myopericarditis kindred and uncovered a damaging mutation of the TBK1 gene. We then showed that the disease allele disrupts the stability of the TBK1 protein and its ability to activate the IRF3 transcription factor. As IRF3 plays a critical role in innate antiviral responses, our findings implicate genetic susceptibility to viral infections in the pathogenesis of IRP. 2 Methods 2.1 Study participants This study was conducted in accordance with the principles of the declaration of Helsinki. Ethical approval for the genetic analysis of IRP cases and their relatives was obtained from the Royal Free Hospital and University College Medical School Research Ethics Committee (ref 06/Q0501/42), while the use of discarded skin was approved by the London – Chelsea Ethics Committee (14/LO/2169). All participants granted their written informed consent. 2.2 Whole-exome sequencing Whole-exome sequencing was undertaken on DNA samples obtained from three affected individuals and two unaffected family members. Paired-end reads were aligned to the hg19 reference genome using Novoalign (Novocraft Technologies) and Genome Analysis Toolkit (GATK; the Broad Institute). Variants calling was implemented with VCFtools and SAMtools ( 21 ). Sequence changes were then annotated using ANNOVAR ( 22 ). After removing synonymous substitutions, variants were filtered to only keep those showing a minor allele frequency (MAF) 3.0 were retained and assessed for biological relevance. In a parallel analysis, Exomiser ( 29 ) was used to examine all variants that had a MAF Y105C TBK1 variant in a myopericarditis pedigree. (A) Left: recurrent myopericarditis pedigree and segregation of the Y105C variant. Right: Workflow for the stepwise filtering of the whole exome sequence data. (B) Sanger sequencing chromatogram demonstrating heterozygosity for the c.A314G allele in the proband. (C) Schematic showing the location of the Y105C allele within the domain architecture of the TBK1 protein. The position of representative alleles associated with susceptibility to viral infection (G159A) and autoinflammation (Y212D) is also shown. KD, kinase domain; MAF, minor allele frequency; SDD, scaffold/dimerization domain; ULD, ubiquitin-like domain; WT, wildtype. While the father reported a diarrheal illness prior to the onset of chest pain, there were no prodromal symptoms suggestive of viral infection in the other two cases. All myopericarditis episodes were managed with non-steroidal anti-inflammatory drugs (alone or with colchicine). Affected individuals were well between recurrences and had no other disease history. The proband’s mother and sister were both unaffected ( Figure 1A ). 3.2 Identification of a TBK1 mutation by whole-exome sequencing Whole-exome sequencing was undertaken in the three affected family members as well as the unaffected mother and sister. An average of 25,822 variants were detected in each study participant, with >90% of the target exome covered at a depth of 20X. Filtering was then implemented to only retain variants that were very rare (MAF R1080C in SOGA1 , c.C2312T>P767L in DNM2 and c.A314G>Y105C in TBK1 . While DNM2 and SOGA1 encode proteins that contribute to microtubule assembly ( 47 , 48 ), TBK1 is a mediator of antiviral immunity and inflammation ( 49 ). The Y105C TBK1 variant was therefore considered the most likely disease-causing mutation ( Figure 1A ). As the above result could have been influenced by the choice of filtering criteria and by our assumptions on disease pathogenesis, a parallel unbiased analysis was also undertaken. The allele frequency threshold was relaxed (MAF Y105C substitution as the top-ranked variant in the dataset. Conversely, neither the SOGA1 nor the DNM2 changes were among the top 10 variants. The presence of the c.A314G>Y105C mutation was confirmed by Sanger sequencing of the three affected family members ( Figure 1B ). Of note, the change was also detected in the unaffected sister, suggesting reduced penetrance or delayed disease onset in this individual. Taken together, these findings identify the TBK1 Y105C substitution as a disease allele associated with familial recurrent myopericarditis. 3.3 Computational analysis of TBK1 variants TBK1 encodes a highly conserved serine threonine kinase which consists of an N-terminal kinase domain (KD), a ubiquitin-like domain and a C-terminal scaffold/dimerization domain (SDD) ( Figure 1C ). Interestingly, mutations mapping to the TBK1 KD have been associated with susceptibility to severe viral infection or autoinflammation ( 50 – 5
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