title: A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis).
abstract: OBJECTIVE
  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 inNLRP3andNLRC4are linked to hereditary autoinflammatory diseases, whereas polymorphisms inNLRP1are associated with autoimmune disorders such as vitiligo and rheumatoid arthritis. Whether humanNLRP1mutation 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 inNLRP1(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 humanNLRP1in a novel autoinflammatory disorder that we propose to call NAIAD forNLRP1-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 ofNLRP1in inflammation and immunity.
  
  
  BACKGROUND
  NCT02067962; Results.
authors.affiliation: Centre de référence des maladies autoinflammatoires, CeRéMAI, CHRU de Montpellier, Montpellier, France.|INSERM, U1183, IRMB, Hôpital Saint Eloi, CHU Montpellier, Montpellier, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Grandemange
authors.affiliation: INSERM, U1183, IRMB, Hôpital Saint Eloi, CHU Montpellier, Montpellier, France.|Département de Génétique Médicale, maladies rares et médecine personnalisée, centre de référence anomalies du développement et syndromes malformatifs, plateforme recherche de remaniements chromosomiques par puces à ADN, Hôpital Arnaud de Villeneuve, CHRU Montpellier, Montpellier, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Sanchez
authors.affiliation: INSERM, U1183, IRMB, Hôpital Saint Eloi, CHU Montpellier, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Louis-Plence
authors.affiliation: INSERM, U1183, IRMB, Hôpital Saint Eloi, CHU Montpellier, Montpellier, France.|Département de Génétique Médicale, maladies rares et médecine personnalisée, centre de référence anomalies du développement et syndromes malformatifs, plateforme recherche de remaniements chromosomiques par puces à ADN, Hôpital Arnaud de Villeneuve, CHRU Montpellier, Montpellier, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Tran Mau-Them
authors.affiliation: Université de Montpellier, Montpellier, France.|Service de dermatologie, Hôpital Saint Eloi, CHRU Montpellier, Montpellier, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Bessis
authors.affiliation: Département de Génétique Médicale, maladies rares et médecine personnalisée, centre de référence anomalies du développement et syndromes malformatifs, plateforme recherche de remaniements chromosomiques par puces à ADN, Hôpital Arnaud de Villeneuve, CHRU Montpellier, Montpellier, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Coubes
authors.affiliation: Laboratoire d'Anatomie et Cytologie Pathologiques, Hôpital Gui de Chauliac, CHRU Montpellier, Montpellier, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Frouin
authors.affiliation: Dermatology Department, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Seyger
authors.affiliation: Département de Génétique Médicale, maladies rares et médecine personnalisée, centre de référence anomalies du développement et syndromes malformatifs, plateforme recherche de remaniements chromosomiques par puces à ADN, Hôpital Arnaud de Villeneuve, CHRU Montpellier, Montpellier, France.
authors.forename: Manon
authors.initials: M
authors.lastname: Girard
authors.affiliation: Département de Génétique Médicale, maladies rares et médecine personnalisée, centre de référence anomalies du développement et syndromes malformatifs, plateforme recherche de remaniements chromosomiques par puces à ADN, Hôpital Arnaud de Villeneuve, CHRU Montpellier, Montpellier, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Puechberty
authors.affiliation: Université de Montpellier, Montpellier, France.|Laboratoire d'Anatomie et Cytologie Pathologiques, Hôpital Gui de Chauliac, CHRU Montpellier, Montpellier, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Costes
authors.affiliation: Pédiatrie, Hôpital Arnaud de Villeneuve, CHRU Montpellier, Montpellier, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Rodière
authors.affiliation: Pédiatrie, Hôpital Arnaud de Villeneuve, CHRU Montpellier, Montpellier, France.
authors.forename: Aurélia
authors.initials: A
authors.lastname: Carbasse
authors.affiliation: Université de Montpellier, Montpellier, France.|Pédiatrie, Hôpital Arnaud de Villeneuve, CHRU Montpellier, Montpellier, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Jeziorski
authors.affiliation: Laboratoire d'Immunologie, CHRU Montpellier, Montpellier, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Portales
authors.affiliation: Centre de référence des maladies autoinflammatoires, CeRéMAI, CHRU de Montpellier, Montpellier, France.|INSERM, U1183, IRMB, Hôpital Saint Eloi, CHU Montpellier, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Sarrabay
authors.affiliation: Université de Montpellier, Montpellier, France.|Service d'Oto-Rhino-Laryngologie, CHRU Montpellier, Montpellier, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Mondain
authors.affiliation: INSERM, U1183, IRMB, Hôpital Saint Eloi, CHU Montpellier, Montpellier, France.|Université de Montpellier, Montpellier, France.|Department for Osteoarticular Diseases, University Hospital Lapeyronie, Montpellier, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Jorgensen
authors.affiliation: INSERM, U1183, IRMB, Hôpital Saint Eloi, CHU Montpellier, Montpellier, France.|Université de Montpellier, Montpellier, France.|Department for Osteoarticular Diseases, University Hospital Lapeyronie, Montpellier, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Apparailly
authors.affiliation: Department of Pediatrics, Pediatric Rheumatology, Radboud University Nijmegen Medical Centre and Sint Maartenskliniek, Nijmegen, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Hoppenreijs
authors.affiliation: Centre de référence des maladies autoinflammatoires, CeRéMAI, CHRU de Montpellier, Montpellier, France.|INSERM, U1183, IRMB, Hôpital Saint Eloi, CHU Montpellier, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Touitou
authors.affiliation: INSERM, U1183, IRMB, Hôpital Saint Eloi, CHU Montpellier, Montpellier, France.|Département de Génétique Médicale, maladies rares et médecine personnalisée, centre de référence anomalies du développement et syndromes malformatifs, plateforme recherche de remaniements chromosomiques par puces à ADN, Hôpital Arnaud de Villeneuve, CHRU Montpellier, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: David
authors.initials: D
authors.lastname: Geneviève
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000462:Algeria; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001171:Arthritis, Juvenile / Q000150:complications / Q000235:genetics* / Q000276:immunology; D001327:Autoimmune Diseases / Q000150:complications / Q000235:genetics* / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D044383:Black People; D020170:Caspase 1 / Q000276:immunology; D002648:Child; D003241:Consanguinity; D005260:Female; D056660:Hereditary Autoinflammatory Diseases / Q000150:complications / Q000235:genetics* / Q000276:immunology; D006720:Homozygote; D006801:Humans; D020382:Interleukin-18 / Q000276:immunology; D008297:Male; D009154:Mutation; D000070576:NLR Proteins; D009426:Netherlands; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology; D012871:Skin Diseases / Q000150:complications / Q000235:genetics* / Q000276:immunology; D013577:Syndrome; D044465:White People
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C000589760:IL18 protein, human; D020382:Interleukin-18; D000070576:NLR Proteins; C427903:NLRP1 protein, human; D020170:Caspase 1
keywords: Arthritis; Fever Syndromes; Inflammation; Juvenile Idiopathic Arthritis