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Published on: December 16, 2021
Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation
Neil Romberg1, Khatoun Al Moussawi2, Carol Nelson-Williams3,4
1Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.
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.
Insights
A novel mutation in NLRC4 causes a severe autoinflammatory disease in newborns, leading to enterocolitis and fever. This discovery highlights the critical role of the NLRC4 inflammasome in immune regulation and disease.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Innate immune receptors, such as NOD-like receptors (NLRs), initiate inflammatory responses upon detecting pathogen-associated molecular patterns.
- Activation of NLRs leads to inflammasome assembly, caspase-1 activation, and the production of interleukin-1 family cytokines (IL1FCs), resulting in pyroptosis and fever.
- Constitutive activation of these pathways is linked to various autoinflammatory diseases.
Observation:
- A family presented with a previously undocumented syndrome characterized by neonatal-onset enterocolitis, periodic fever, and severe autoinflammation.
- The condition was linked to a de novo gain-of-function mutation (p.Val341Ala) in the NLRC4 gene, affecting the HD1 domain.
- This mutation cosegregated with the disease within the family.
Findings:
- Mutant NLRC4 results in constitutive IL1FC production and macrophage cell death.
- Macrophages from affected individuals show a propensity towards pyroptosis upon infection.
- Abnormal inflammasome component staining was observed in infected macrophages from patients.
Implications:
- Identifies a novel, life-threatening autoinflammatory disease caused by NLRC4 gain-of-function mutation.
- Underscores the critical and diverse roles of the NLRC4 inflammasome in innate immunity and disease pathogenesis.
- Suggests potential therapeutic targets for this treatable autoinflammatory condition.
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