{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T21:06:18Z","timestamp":1789506378585,"version":"build-2803163510"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T00:00:00Z","timestamp":1749513600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union\u2019s","doi-asserted-by":"publisher","award":["779295"],"award-info":[{"award-number":["779295"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Chronic urticarial lesions, a common condition of mostly unknown cause, can occur in immune dysregulation disorders such as hypocomplementaemic urticarial vasculitis syndrome (HUVS), neutrophilic urticarial dermatosis (NUD) and systemic autoinflammatory diseases (SAIDs), including Schnitzler syndrome.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To identify the molecular basis of nonpruritic chronic urticarial eruptions in four unrelated patients initially diagnosed with neonatal NUD, Schnitzler syndrome, HUVS or giant-cell arteritis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Conventional next-generation sequencing (NGS) of leucocyte DNA was supplemented with high-depth NGS (&amp;gt; 1500\u00d7) to improve the detection of low-level mosaicism in SAID-related genes. Functional assays were performed on recombinant NLRP3 proteins to assess the impact of the identified variations on the nuclear factor-\u03baB (NF-\u03baB) pathway.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>One patient presented with persistent isolated urticarial lesions since birth, while the other three experienced late-onset skin lesions. In contrast to the initially suspected diagnoses, conventional NGS revealed NLRP3 mosaicism in two patients, with variant allele fractions (VAFs) of 5% and 11%, respectively. In the other two patients, high-depth NGS uncovered NLRP3 mosaicism with VAFs as low as 2\u20133%. All identified variations activated the NF-\u03baB pathway, demonstrating a gain-of-function effect. Subsequent anti-interleukin-1 therapy led to symptom improvement for all patients.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This study highlights the importance of considering NLRP3 mosaicism as an underlying pathological mechanism in chronic urticarial lesions, whether of early or late onset, and whether isolated or mimicking other conditions. As blood contains key target cells for NLRP3 inflammasome activation, even extremely low-level leucocyte mosaicism can be pathogenic. High-depth NGS-based diagnosis of NLRP3-related disorders enables timely initiation of anti-IL-1 therapy, which is crucial to preventing complications such as systemic amyloidosis.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bjd\/ljaf220","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T14:16:06Z","timestamp":1749564966000},"page":"914-923","source":"Crossref","is-referenced-by-count":3,"title":["Low-level <i>NLRP3<\/i> mosaicism in chronic urticarial lesions: extending the phenotypic spectrum of <i>NLRP3<\/i>-related disorders and therapeutic implications"],"prefix":"10.1093","volume":"193","author":[{"given":"Aphrodite","family":"Daskalopoulou","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM UMR_S933, Maladies G\u00e9n\u00e9tiques d\u2019Expression P\u00e9diatrique, H\u00f4pital Trousseau , Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman","family":"Assrawi","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM UMR_S933, Maladies G\u00e9n\u00e9tiques d\u2019Expression P\u00e9diatrique, H\u00f4pital Trousseau , Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farah","family":"Diab","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM UMR_S933, Maladies G\u00e9n\u00e9tiques d\u2019Expression P\u00e9diatrique, H\u00f4pital Trousseau , Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Louvrier","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM UMR_S933, Maladies G\u00e9n\u00e9tiques d\u2019Expression P\u00e9diatrique, H\u00f4pital Trousseau , Paris ,","place":["France"]},{"name":"UF de G\u00e9n\u00e9tique Mol\u00e9culaire, Assistance Publique-Hopitaux de Paris, H\u00f4pital Trousseau , Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxime","family":"Samson","sequence":"additional","affiliation":[{"name":"Service de M\u00e9decine Interne et Immunologie Clinique, H\u00f4pital du Bocage, CHU-Dijon , Dijon ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Piterboth","sequence":"additional","affiliation":[{"name":"UF de G\u00e9n\u00e9tique Mol\u00e9culaire, Assistance Publique-Hopitaux de Paris, H\u00f4pital Trousseau , Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berengere","family":"Cador-Rousseau","sequence":"additional","affiliation":[{"name":"Service de M\u00e9decine Interne, H\u00f4pital Sud, CHU de Rennes , Rennes ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Henno","sequence":"additional","affiliation":[{"name":"Service d\u2019Anatomie et Cytologie Pathologiques, H\u00f4pital Pontchaillou, CHU de Rennes , Rennes ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Legendre","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM UMR_S933, Maladies G\u00e9n\u00e9tiques d\u2019Expression P\u00e9diatrique, H\u00f4pital Trousseau , Paris ,","place":["France"]},{"name":"UF de G\u00e9n\u00e9tique Mol\u00e9culaire, Assistance Publique-Hopitaux de Paris, H\u00f4pital Trousseau , Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Lipsker","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Strasbourg et Clinique Dermatologique, H\u00f4pitaux Universitaires de Strasbourg , Strasbourg ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serge","family":"Amselem","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM UMR_S933, Maladies G\u00e9n\u00e9tiques d\u2019Expression P\u00e9diatrique, H\u00f4pital Trousseau , Paris ,","place":["France"]},{"name":"UF de G\u00e9n\u00e9tique Mol\u00e9culaire, Assistance Publique-Hopitaux de Paris, H\u00f4pital Trousseau , Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia A","family":"Karabina","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM UMR_S933, Maladies G\u00e9n\u00e9tiques d\u2019Expression P\u00e9diatrique, H\u00f4pital Trousseau , Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5035-2958","authenticated-orcid":false,"given":"Irina","family":"Giurgea","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM UMR_S933, Maladies G\u00e9n\u00e9tiques d\u2019Expression P\u00e9diatrique, H\u00f4pital Trousseau , Paris ,","place":["France"]},{"name":"UF de G\u00e9n\u00e9tique Mol\u00e9culaire, Assistance Publique-Hopitaux de Paris, H\u00f4pital Trousseau , Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,6,10]]},"reference":[{"key":"2025101708275786900_ljaf220-B1","doi-asserted-by":"crossref","first-page":"808543","DOI":"10.3389\/falgy.2022.808543","article-title":"Differential diagnosis of urticarial lesions","volume":"3","author":"Matos","year":"2022","journal-title":"Front Allergy"},{"key":"2025101708275786900_ljaf220-B2","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1016\/j.jaci.2022.02.007","article-title":"Urticarial vasculitis: clinical and laboratory findings with a particular emphasis on differential diagnosis","volume":"149","author":"Marzano","year":"2022","journal-title":"J Allergy Clin Immunol"},{"key":"2025101708275786900_ljaf220-B3","first-page":"36","article-title":"Hypocomplementemic urticarial vasculitis syndrome: a case report and literature review","volume":"5","author":"Buck","year":"2012","journal-title":"J Clin Aesthet Dermatol"},{"key":"2025101708275786900_ljaf220-B4","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1111\/j.1365-4632.2006.02847.x","article-title":"Hypocomplementemic urticarial vasculitis: a rare presentation of systemic lupus erythematosus","volume":"45","author":"Aydogan","year":"2006","journal-title":"Int J Dermatol"},{"key":"2025101708275786900_ljaf220-B5","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/j.annder.2018.06.010","article-title":"Neutrophilic urticarial dermatosis: a review","volume":"145","author":"Gusdorf","year":"2018","journal-title":"Ann Dermatol Venereol"},{"key":"2025101708275786900_ljaf220-B6","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1111\/jdv.15984","article-title":"Neutrophilic urticarial dermatosis: an entity bridging monogenic and polygenic autoinflammatory disorders, and beyond","volume":"34","author":"Gusdorf","year":"2020","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"2025101708275786900_ljaf220-B7","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/ng756","article-title":"Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle\u2013Wells syndrome","volume":"29","author":"Hoffman","year":"2001","journal-title":"Nat Genet"},{"key":"2025101708275786900_ljaf220-B8","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1146\/annurev.immunol.021908.132715","article-title":"The inflammasomes: guardians of the body","volume":"27","author":"Martinon","year":"2009","journal-title":"Annu Rev Immunol"},{"key":"2025101708275786900_ljaf220-B9","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1146\/annurev.immunol.25.022106.141627","article-title":"Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease","volume":"27","author":"Masters","year":"2009","journal-title":"Annu Rev Immunol"},{"key":"2025101708275786900_ljaf220-B10","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.cell.2010.01.040","article-title":"The inflammasomes","volume":"140","author":"Schroder","year":"2010","journal-title":"Cell"},{"key":"2025101708275786900_ljaf220-B11","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/s41586-019-1295-z","article-title":"Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome","volume":"570","author":"Sharif","year":"2019","journal-title":"Nature"},{"key":"2025101708275786900_ljaf220-B12","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/s41586-022-05570-8","article-title":"Cryo-EM structures of the active NLRP3 inflammasome disc","volume":"613","author":"Xiao","year":"2023","journal-title":"Nature"},{"key":"2025101708275786900_ljaf220-B13","doi-asserted-by":"crossref","first-page":"787","DOI":"10.4049\/jimmunol.0901363","article-title":"Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression","volume":"183","author":"Bauernfeind","year":"2009","journal-title":"J Immunol"},{"key":"2025101708275786900_ljaf220-B14","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/s41590-025-02088-9","article-title":"Mechanisms of NLRP3 activation and inhibition elucidated by functional analysis of disease-associated variants","volume":"26","author":"Feng","year":"2025","journal-title":"Nat Immunol"},{"key":"2025101708275786900_ljaf220-B15","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S1074-7613(04)00046-9","article-title":"NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle\u2013Wells autoinflammatory disorder","volume":"20","author":"Agostini","year":"2004","journal-title":"Immunity"},{"key":"2025101708275786900_ljaf220-B16","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1111\/j.1365-2249.2011.04533.x","article-title":"Immunology in clinic review series; focus on autoinflammatory diseases: update on monogenic autoinflammatory diseases: the role of interleukin (IL)-1 and an emerging role for cytokines beyond IL-1","volume":"167","author":"Goldbach-Mansky","year":"2012","journal-title":"Clin Exp Immunol"},{"key":"2025101708275786900_ljaf220-B17","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1007\/s11926-024-01147-8","article-title":"AA amyloidosis: a contemporary view","volume":"26","author":"Mirioglu","year":"2024","journal-title":"Curr Rheumatol Rep"},{"key":"2025101708275786900_ljaf220-B18","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1002\/art.21618","article-title":"PYPAF1 nonsense mutation in a patient with an unusual autoinflammatory syndrome: role of PYPAF1 in inflammation","volume":"54","author":"J\u00e9ru","year":"2006","journal-title":"Arthritis Rheum"},{"key":"2025101708275786900_ljaf220-B19","doi-asserted-by":"crossref","first-page":"4827","DOI":"10.1093\/rheumatology\/keac145","article-title":"AA amyloidosis complicating cryopyrin-associated periodic syndrome: a study of 86 cases including 23 French patients and systematic review","volume":"61","author":"Rodrigues","year":"2022","journal-title":"Rheumatology (Oxford)"},{"key":"2025101708275786900_ljaf220-B20","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.1182\/blood-2003-07-2531","article-title":"Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders CINCA\/NOMID, MWS, and FCU","volume":"103","author":"Neven","year":"2004","journal-title":"Blood"},{"key":"2025101708275786900_ljaf220-B21","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1002\/j.1460-2075.1982.tb01276.x","article-title":"Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold","volume":"1","author":"Walker","year":"1982","journal-title":"EMBO J"},{"key":"2025101708275786900_ljaf220-B22","doi-asserted-by":"crossref","first-page":"4572","DOI":"10.3390\/molecules25194572","article-title":"ATP-binding and hydrolysis in inflammasome activation","volume":"25","author":"Sandall","year":"2020","journal-title":"Molecules"},{"key":"2025101708275786900_ljaf220-B23","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1038\/s42003-022-04120-2","article-title":"ATP-binding and hydrolysis of human NLRP3","volume":"5","author":"Brinkschulte","year":"2022","journal-title":"Commun Biol"},{"key":"2025101708275786900_ljaf220-B24","doi-asserted-by":"crossref","first-page":"5862","DOI":"10.1038\/s41467-021-26142-w","article-title":"NLRP3 phosphorylation in its LRR domain critically regulates inflammasome assembly","volume":"12","author":"Niu","year":"2021","journal-title":"Nat Commun"},{"key":"2025101708275786900_ljaf220-B25","doi-asserted-by":"crossref","first-page":"102717","DOI":"10.1016\/j.jbc.2022.102717","article-title":"The leucine-rich repeat (LRR) domain of NLRP3 is required for NLRP3 inflammasome activation in macrophages","volume":"298","author":"Duan","year":"2022","journal-title":"J Biol Chem"},{"key":"2025101708275786900_ljaf220-B26","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.3390\/cells13161365","article-title":"Implication of the LRR domain in the regulation and activation of the NLRP3 inflammasome","volume":"13","author":"Cescato","year":"2024","journal-title":"Cells"},{"key":"2025101708275786900_ljaf220-B27","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1056\/NEJMoa2026834","article-title":"Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease","volume":"383","author":"Beck","year":"2020","journal-title":"N Engl J Med"},{"key":"2025101708275786900_ljaf220-B28","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1056\/NEJMc2212928","article-title":"TET2-driver and NLRC4-passenger variants in adult-onset autoinflammation","volume":"388","author":"De Langhe","year":"2023","journal-title":"N Engl J Med"},{"key":"2025101708275786900_ljaf220-B29","doi-asserted-by":"crossref","first-page":"3625","DOI":"10.1002\/art.30512","article-title":"High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study","volume":"63","author":"Tanaka","year":"2011","journal-title":"Arthritis Rheum"},{"key":"2025101708275786900_ljaf220-B30","first-page":"S115","article-title":"Genetic and clinical features of cryopyrin-associated periodic syndromes in Turkish children","volume":"34","author":"Eroglu","year":"2016","journal-title":"Clin Exp Rheumatol"},{"key":"2025101708275786900_ljaf220-B31","doi-asserted-by":"crossref","first-page":"17023","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-\u03baB signaling in inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal Transduct Target Ther"},{"key":"2025101708275786900_ljaf220-B32","doi-asserted-by":"crossref","first-page":"e420","DOI":"10.1111\/pde.13660","article-title":"Neonatal urticaria: Could it be CAPS?","volume":"35","author":"Cutts","year":"2018","journal-title":"Pediatr Dermatol"},{"key":"2025101708275786900_ljaf220-B33","doi-asserted-by":"crossref","first-page":"3435","DOI":"10.1111\/all.15411","article-title":"Absence of NLRP3 somatic mutations and VEXAS-related UBA1 mutations in a large cohort of patients with Schnitzler syndrome","volume":"77","author":"Louvrier","year":"2022","journal-title":"Allergy"},{"key":"2025101708275786900_ljaf220-B34","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1016\/j.jaip.2024.04.049","article-title":"Low-level NLRP3 somatic mosaicism in adult-onset cryopyrin-associated periodic syndrome misdiagnosed as chronic urticaria","volume":"12","author":"Pesqu\u00e9","year":"2024","journal-title":"J Allergy Clin Immunol Pract"}],"container-title":["British Journal of Dermatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bjd\/advance-article-pdf\/doi\/10.1093\/bjd\/ljaf220\/63464386\/ljaf220.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bjd\/article-pdf\/193\/5\/914\/63464386\/ljaf220.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bjd\/article-pdf\/193\/5\/914\/63464386\/ljaf220.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T12:28:05Z","timestamp":1760704085000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bjd\/article\/193\/5\/914\/8159931"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,10]]},"references-count":34,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,6,10]]},"published-print":{"date-parts":[[2025,10,17]]}},"URL":"https:\/\/doi.org\/10.1093\/bjd\/ljaf220","relation":{},"ISSN":["0007-0963","1365-2133"],"issn-type":[{"value":"0007-0963","type":"print"},{"value":"1365-2133","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,11]]},"published":{"date-parts":[[2025,6,10]]}}}