Sylvie Grandemange1,2, Elodie Sanchez2,3, Pascale Louis-Plence2,4, Frédéric Tran Mau-Them2,3, Didier Bessis4,5, Christine Coubes3, Eric Frouin6, Marieke Seyger7, Manon Girard3, Jacques Puechberty3, Valérie Costes4,6, Michel Rodière8, Aurélia Carbasse8, Eric Jeziorski4,8, Pierre Portales9, Guillaume Sarrabay1,2,4, Michel Mondain4,10, Christian Jorgensen2,4,11, Florence Apparailly2,4,11, Esther Hoppenreijs12, Isabelle Touitou1,2,4, David Geneviève2,3,4. 1. Centre de référence des maladies autoinflammatoires, CeRéMAI, CHRU de Montpellier, Montpellier, France. 2. INSERM, U1183, IRMB, Hôpital Saint Eloi, CHU Montpellier, Montpellier, France. 3. 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. 4. Université de Montpellier, Montpellier, France. 5. Service de dermatologie, Hôpital Saint Eloi, CHRU Montpellier, Montpellier, France. 6. Laboratoire d'Anatomie et Cytologie Pathologiques, Hôpital Gui de Chauliac, CHRU Montpellier, Montpellier, France. 7. Dermatology Department, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 8. Pédiatrie, Hôpital Arnaud de Villeneuve, CHRU Montpellier, Montpellier, France. 9. Laboratoire d'Immunologie, CHRU Montpellier, Montpellier, France. 10. Service d'Oto-Rhino-Laryngologie, CHRU Montpellier, Montpellier, France. 11. Department for Osteoarticular Diseases, University Hospital Lapeyronie, Montpellier, France. 12. Department of Pediatrics, Pediatric Rheumatology, Radboud University Nijmegen Medical Centre and Sint Maartenskliniek, Nijmegen, The Netherlands.
Abstract
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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 humanNLRP1 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 humanNLRP1 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Authors: Scott B Drutman; Filomeen Haerynck; Franklin L Zhong; David Hum; Nicholas J Hernandez; Serkan Belkaya; Franck Rapaport; Sarah Jill de Jong; David Creytens; Simon J Tavernier; Katrien Bonte; Sofie De Schepper; Jutte van der Werff Ten Bosch; Lazaro Lorenzo-Diaz; Andy Wullaert; Xavier Bossuyt; Gérard Orth; Vincent R Bonagura; Vivien Béziat; Laurent Abel; Emmanuelle Jouanguy; Bruno Reversade; Jean-Laurent Casanova Journal: Proc Natl Acad Sci U S A Date: 2019-09-04 Impact factor: 11.205