Camille Louvrier1, Eman Assrawi2, Elma El Khouri2, Isabelle Melki3, Bruno Copin4, Emmanuelle Bourrat3, Noémie Lachaume3, Bérengère Cador-Rousseau5, Philippe Duquesnoy2, William Piterboth4, Fawaz Awad2, Claire Jumeau2, Marie Legendre1, Gilles Grateau6, Sophie Georgin-Lavialle6, Sonia A Karabina2, Serge Amselem7, Irina Giurgea8. 1. Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), "Childhood genetic disorders", Paris, France; Département de Génétique Médicale, Hôpital Armand Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France. 2. Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), "Childhood genetic disorders", Paris, France. 3. Service de Pédiatrie Générale, Maladies Infectieuses et Médecine Interne Pédiatrique, Centre de Référence Rhumatismes et Auto-Immunité Systémique de l'Enfant, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, Paris, France. 4. Département de Génétique Médicale, Hôpital Armand Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France. 5. Service de Médecine Interne, Centre Hospitalier Universitaire Pontchaillou, Rennes, France. 6. Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), "Childhood genetic disorders", Paris, France; Service de Médecine Interne, et Centre de Référence des Maladies Autoinflammatoires et des Amyloses Inflammatoires, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France. 7. Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), "Childhood genetic disorders", Paris, France; Département de Génétique Médicale, Hôpital Armand Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address: serge.amselem@inserm.fr. 8. Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), "Childhood genetic disorders", Paris, France; Département de Génétique Médicale, Hôpital Armand Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address: irina.giurgea@inserm.fr.
Abstract
BACKGROUND: NLRP3-associated autoinflammatory diseases (NLRP3-AIDs) include conditions of various severities, due to germline or somatic mosaic NLRP3 mutations. OBJECTIVE: To identify mosaic- versus germline-specific NLRP3 mutations' characteristics, we reinterpreted all the mutations reported in NLRP3-AIDs and performed an in-depth study of 3 novel patients. METHODS: The pathogenicity of all reported mosaic/germline mutations was reassessed according to international recommendations and their location on the NLRP3 3-dimensional structure. Deep-targeted sequencing and NLRP3-inflammasome-activation assays were used to identify the disease-causing mutation in 3 patients. RESULTS: We identified, in 3 patients, mosaic mutations affecting the same NLRP3 amino acid (Glu569). This residue belongs to 1 of the 2 mosaic mutational hot spots that face each other in the core of the NLRP3 ATPase domain. The review of the 90 NLRP3 mutations identified in 277 patients revealed that those hot spots account for 68.5% of patients (37 of 54) with mosaic mutations. Glu569 is affected in 22% of the patients (12 of 54) with mosaic mutations and in 0.4% of patients (1 of 223) with germline mutations. Only 8 of 90 mutations were found in mosaic and germinal states. All of the germline mutations were associated with a severe phenotype. These data suggest that mutations found only in mosaic state could be incompatible with life if present in germinal state. None of the 5 most frequent germline mutations was identified in mosaic state. Mutations found only in germinal state could, therefore, be asymptomatic in mosaic state. CONCLUSIONS: The phenotypic spectrum of NLRP3-AIDs appears to be related to the germinal/mosaic status and localization of the underlying mutations.
BACKGROUND:NLRP3-associated autoinflammatory diseases (NLRP3-AIDs) include conditions of various severities, due to germline or somatic mosaic NLRP3 mutations. OBJECTIVE: To identify mosaic- versus germline-specific NLRP3 mutations' characteristics, we reinterpreted all the mutations reported in NLRP3-AIDs and performed an in-depth study of 3 novel patients. METHODS: The pathogenicity of all reported mosaic/germline mutations was reassessed according to international recommendations and their location on the NLRP3 3-dimensional structure. Deep-targeted sequencing and NLRP3-inflammasome-activation assays were used to identify the disease-causing mutation in 3 patients. RESULTS: We identified, in 3 patients, mosaic mutations affecting the same NLRP3 amino acid (Glu569). This residue belongs to 1 of the 2 mosaic mutational hot spots that face each other in the core of the NLRP3 ATPase domain. The review of the 90 NLRP3 mutations identified in 277 patients revealed that those hot spots account for 68.5% of patients (37 of 54) with mosaic mutations. Glu569 is affected in 22% of the patients (12 of 54) with mosaic mutations and in 0.4% of patients (1 of 223) with germline mutations. Only 8 of 90 mutations were found in mosaic and germinal states. All of the germline mutations were associated with a severe phenotype. These data suggest that mutations found only in mosaic state could be incompatible with life if present in germinal state. None of the 5 most frequent germline mutations was identified in mosaic state. Mutations found only in germinal state could, therefore, be asymptomatic in mosaic state. CONCLUSIONS: The phenotypic spectrum of NLRP3-AIDs appears to be related to the germinal/mosaic status and localization of the underlying mutations.
Authors: Keith A Sikora; Kristina V Wells; Ertugrul Cagri Bolek; Adrianna I Jones; Peter C Grayson Journal: Rheumatology (Oxford) Date: 2022-08-03 Impact factor: 7.046
Authors: Julien Stackowicz; Nicolas Gaudenzio; Nadine Serhan; Eva Conde; Ophélie Godon; Thomas Marichal; Philipp Starkl; Bianca Balbino; Axel Roers; Pierre Bruhns; Friederike Jönsson; Philippe Moguelet; Sophie Georgin-Lavialle; Lori Broderick; Hal M Hoffman; Stephen J Galli; Laurent L Reber Journal: J Exp Med Date: 2021-09-03 Impact factor: 14.307