Objectives Inflammasomes are multiprotein complexes that sense pathogens and trigger biological mechanisms to control infection. Nucleotide-binding oligomerisation domain-like receptor (NLR) containing a PYRIN domain 1 (NLRP1), NLRP3 and NLRC4 plays a key role in this innate immune system by directly assembling in inflammasomes and regulating inflammation. Mutations in NLRP3 and NLRC4 are linked to hereditary autoinflammatory diseases, whereas polymorphisms in NLRP1 are associated with autoimmune disorders such as vitiligo and rheumatoid arthritis. Whether human NLRP1 mutation is associated with autoinflammation remains to be determined.
Methods To search for novel genes involved in systemic juvenile idiopathic arthritis, we performed homozygosity mapping and exome sequencing to identify causative genes. Immunoassays were performed with blood samples from patients.
Results We identified a novel disease in three patients from two unrelated families presenting diffuse skin dyskeratosis, autoinflammation, autoimmunity, arthritis and high transitional B-cell level. Molecular screening revealed a non-synonymous homozygous mutation in NLRP1 (c.2176C>T; p.Arg726Trp) in two cousins born of related parents originating from Algeria and a de novo heterozygous mutation (c.3641C>G, p.Pro1214Arg) in a girl of Dutch origin. The three patients showed elevated systemic levels of caspase-1 and interleukin 18, which suggested involvement of NLRP1 inflammasome.
Conclusions We demonstrate the responsibility of human NLRP1 in a novel autoinflammatory disorder that we propose to call NAIAD for NLRP1-associated autoinflammation with arthritis and dyskeratosis. This disease could be a novel autoimmuno-inflammatory disease combining autoinflammatory and autoimmune features. Our data, combined with that in the literature, highlight the pleomorphic role of NLRP1 in inflammation and immunity.
Trial registration number NCT02067962; Results.
- Fever Syndromes
- Juvenile Idiopathic Arthritis
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Handling editor Tore K Kvien
SG and ES contributed equally.
Contributors DG, ES, SG, and FTM-T analysed exome data and performed molecular analyses. PP and PL-P performed and analysed immunophenotyping. MG and JP performed the linkage analysis. DB, CC, MS, MM, EH, MR, EJ and AC provided clinical information from the patients. EF and VC performed the histology. GS designed the NGS panel and analysed the results. CJ and FA helped conduct the study. DG and IT conducted the study. SG, PL-P, FA, DG and IT wrote the manuscript.
Funding Part of this work was funded by the Arthritis Foundation http://www.fondation-arthritis.org/ and the Direction Générale de l'Organisation des Soins of the inter-regional Programme Hospitalier de Recherche Clinique, named GENEinJIA, ClinicalTrials.gov Identifier: NCT02067962.
Competing interests None.
Patient consent Obtained.
Ethics approval Comité de Protection des Personnes sud méditerranée I (committee number 13 88—reference approval: 1262, ID number of the study 2013-A01516-39) and Etablissement du sang français (EFS; EFS-PM no21PLER2015-0013).
Provenance and peer review Not commissioned; externally peer reviewed.