NLRP3-associated autoinflammatory diseases: Phenotypic and molecular characteristics of germline versus somatic mutations.
Camille Louvrier,Eman Assrawi,Elma El Khouri,Isabelle Melki,Bruno Copin,Emmanuelle Bourrat,Noémie Lachaume,Bérengère Cador-Rousseau,Philippe Duquesnoy,William Piterboth,Fawaz Awad,Claire Jumeau,Marie Legendre,G. Grateau,S. Georgin-Lavialle,Sonia Karabina,Serge Amselem,Irina Giurgea +17 more
TLDR
The phenotypic spectrum of NLRP3-AIDs appears to be related to the germinal/mosaic status and localization of the underlying mutations, which suggests that mutations found only in mosaic state could be incompatible with life if present in Germinal state.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.read more
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Adult-onset autoinflammation caused by somatic mutations in UBA1: A Dutch case series of patients with VEXAS
Caspar I van der Made,Judith Potjewijd,Annemiek Hoogstins,Huub P.J. Willems,Arjan J. Kwakernaak,Ruud G. L. de Sévaux,Paul L A van Daele,Annet Simons,Marloes W Heijstek,David B. Beck,Mihai G. Netea,Pieter van Paassen,A. Elizabeth Hak,Lars T. van der Veken,Marielle E. van Gijn,Alexander Hoischen,Frank L. van de Veerdonk,Helen L. Leavis,Abraham Rutgers +18 more
TL;DR: In this article, a reanalysis of whole-exome sequencing data from a cohort of undiagnosed patients with autoinflammation from academic hospitals in The Netherlands was performed.
Journal ArticleDOI
Adult-onset autoinflammation caused by somatic mutations in UBA1: A Dutch case series of patients with VEXAS
TL;DR: In this article , a reanalysis of whole-exome sequencing data from a cohort of undiagnosed patients with autoinflammation from academic hospitals in The Netherlands was performed, and targeted Sanger sequencing was applied in cases with high clinical suspicion of VEXAS.
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Diagnosis and Management of the Cryopyrin-Associated Periodic Syndromes (CAPS): What Do We Know Today?
TL;DR: In this article, a review summarizes the current evidence in diagnosis and management of patients with cryopyrin-associated periodic syndromes (CAPS) and a targeted anti-IL-1 therapy should be started as soon as possible.
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Systemic autoinflammatory diseases: Clinical state of the art.
Sophie Georgin-Lavialle,Stéphanie Ducharme-Bénard,Guillaume Sarrabay,Léa Savey,Gilles Grateau,Véronique Hentgen +5 more
TL;DR: This review is a guide for the clinician in suspecting and establishing a diagnosis of systemic autoinflammatory diseases, and more than 50 new monogenic SAIDs have been discovered thanks to advances in genetics.
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Neutrophil-specific gain-of-function mutations in Nlrp3 promote development of cryopyrin-associated periodic syndrome.
Julien Stackowicz,Julien Stackowicz,Nicolas Gaudenzio,Nadine Serhan,Eva Conde,Ophélie Godon,Thomas Marichal,Philipp Starkl,Philipp Starkl,Bianca Balbino,Bianca Balbino,Axel Roers,Pierre Bruhns,Friederike Jönsson,Philippe Moguelet,Sophie Georgin-Lavialle,Lori Broderick,Hal M. Hoffman,Stephen J. Galli,Laurent L. Reber +19 more
TL;DR: In this paper, gain-of-function mutations in Nlrp3 restricted to neutrophils, and to a lesser extent macrophages/dendritic cells, but not MCs, are sufficient to trigger severe CAPS.
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TL;DR: A gene, called CIAS1, is expressed in peripheral blood leukocytes and encodes a protein with a pyrin domain, a nucleotide-binding site (NBS, NACHT subfamily) domain and a leucine-rich repeat (LRR) motif region, suggesting a role in the regulation of inflammation and apoptosis.
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Chronic Infantile Neurological Cutaneous and Articular Syndrome Is Caused by Mutations in CIAS1, a Gene Highly Expressed in Polymorphonuclear Cells and Chondrocytes
Jérôme Feldmann,Anne-Marie Prieur,Pierre Quartier,Patrick Berquin,Stéphanie Certain,Elisabetta Cortis,D. Teillac-Hamel,Alain Fischer,Geneviève de Saint Basile +8 more
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Ivona Aksentijevich,Miroslawa Nowak,Mustapha Mallah,Jae Jin Chae,Wendy T. Watford,Sigrun R. Hofmann,Leonard D. Stein,Ricardo Russo,Donald P. Goldsmith,Peter B. Dent,Helene F. Rosenberg,Frances Austin,Elaine F. Remmers,James E. Balow,Sergio D. Rosenzweig,Hirsh D. Komarow,Nitza G. Shoham,Geryl Wood,Janet Jones,Nadira Mangra,Hector Carrero,Barbara S. Adams,Terry L. Moore,Kenneth N. Schikler,Hal M. Hoffman,Daniel J. Lovell,Robert N. Lipnick,Karyl S. Barron,John J. O'Shea,Daniel L. Kastner,Raphaela Goldbach-Mansky +30 more
TL;DR: IL-1 regulation byCIAS1 suggests that IL-1 receptor blockade may constitute a rational approach to the treatment of NOMID/CINCA syndrome, and the total number of known germline mutations in CIAS1 is increased to 20, causing a spectrum of diseases ranging from familial cold autoinflammatory syndrome to Muckle-Wells syndrome.
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