ArticleNature genetics2014
Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation.
Article in Nature genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 265 papers.
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Who cites it
265 citing papers in PubMed, 506 citations in OpenAlex.
- Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases.The Journal of clinical investigation · 2020Trial
- Advancements in Diagnosis and Care for Immune Dysregulation and Inborn Errors of Immunity in Pediatric Rheumatology: Our 50-Year Journey.Arthritis care & research · 2026Review
- Innate immune sensors of inflammasomes and PANoptosomes: structural-mechanistic insights and therapeutic implications.Cell research · 2026Review
- Beyond NLRP3: expanding the spectrum of NLR-associated autoinflammatory diseases.Rheumatology (Oxford, England) · 2026Article
- Decoding variants of uncertain significance in systemic autoinflammatory diseases.Nature reviews. Rheumatology · 2026Review
- Free IL-18 in NLRC4-associated autoinflammatory disease without macrophage activation syndrome.Rheumatology (Oxford, England) · 2026Article
- Early management of hemophagocytic lymphohistiocytosis/macrophage activation syndrome: a systematic literature review.EULAR rheumatology open · 2026Review
- Current understanding of the NLRC4 Inflammasome in autoinflammation and enterocolitis.Communications biology · 2026Review
- Article
- Autoinflammation with infantile enterocolitis associated with a novel CARD domain mutation inFrontiers in pediatrics · 2026Article
- Autoinflammation with infantile enterocolitis induced by a heterozygous variant (c.1357C > T) in the NLRC4 gene: a case report.Frontiers in pediatrics · 2026Article
- Cold-Induced Urticarias with Familial Background: Clinical Spectrum, Pathogenesis, and Diagnostic Challenges.Diagnostics (Basel, Switzerland) · 2025Review
- Gastrointestinal microbiota and inflammasomes interplay in health and disease: a gut feeling.Gut · 2025Review
- An animal model of NLRC4-associated autoinflammation and infantile enterocolitis reveals novel therapeutic strategies.Cellular & molecular immunology · 2025Article
- Molecular mechanisms and regulation of inflammasome activation and signaling: sensing of pathogens and damage molecular patterns.Cellular & molecular immunology · 2025Review
- IL-1 family cytokines in inflammation and immunity.Cellular & molecular immunology · 2025Review
- The Role of Inflammasomes in LPS and Gram-Negative Bacterial Sepsis.Journal of clinical medicine · 2025Review
- Pyroptosis in gastric mucosal injury‑related diseases (Review).International journal of molecular medicine · 2025Review
- Inflammasomes and autophagy in cancer: unlocking targeted therapies.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Rheumatologic and Autoimmune Features of Inborn Errors of Immunity: Implications for Diagnosis and Management.Journal of human immunity · 2025Article
205 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 2 institutions in 1 country.
Funding
Abstract
Upon detection of pathogen-associated molecular patterns, innate immune receptors initiate inflammatory responses. These receptors include cytoplasmic NOD-like receptors (NLRs) whose stimulation recruits and proteolytically activates caspase-1 within the inflammasome, a multiprotein complex. Caspase-1 mediates the production of interleukin-1 family cytokines (IL1FCs), leading to fever and inflammatory cell death (pyroptosis). Mutations that constitutively activate these pathways underlie several autoinflammatory diseases with diverse clinical features. We describe a family with a previously unreported syndrome featuring neonatal-onset enterocolitis, periodic fever, and fatal or near-fatal episodes of autoinflammation. We show that the disease is caused by a de novo gain-of-function mutation in NLRC4 encoding a p.Val341Ala substitution in the HD1 domain of the protein that cosegregates with disease. Mutant NLRC4 causes constitutive IL1FC production and macrophage cell death. Infected macrophages from affected individuals are polarized toward pyroptosis and exhibit abnormal staining for inflammasome components. These findings identify and describe the cause of a life-threatening but treatable autoinflammatory disease that underscores the divergent roles of the NLRC4 inflammasome.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.