First description of late-onset autoinflammatory disease due to somatic NLRC4 mosaicism

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  • dc.contributor.author Ionescu, Daniela
  • dc.contributor.author Peñín Franch, Alejandro
  • dc.contributor.author Mensa Vilaró, Anna
  • dc.contributor.author Castillo, Paola
  • dc.contributor.author Hurtado Navarro, Laura
  • dc.contributor.author Molina-López, Cristina
  • dc.contributor.author Romero-Chala, Silvia
  • dc.contributor.author Plaza, Susana
  • dc.contributor.author Fabregat, Virginia
  • dc.contributor.author Buján, Segundo
  • dc.contributor.author Marques, Joana
  • dc.contributor.author Casals López, Ferran
  • dc.contributor.author Yagüe, Jordi L.
  • dc.contributor.author Oliva Miguel, Baldomero
  • dc.contributor.author Fernández-Pereira, Luis Miguel
  • dc.contributor.author Pelegrín, Pablo
  • dc.contributor.author Aróstegui Gorospe, Juan Ignacio
  • dc.date.accessioned 2022-03-03T06:49:03Z
  • dc.date.available 2022-03-03T06:49:03Z
  • dc.date.issued 2022
  • dc.description.abstract Objective: Autoinflammatory diseases are inherited disorders of innate immunity that usually start during childhood. However, several recent reports have described an increasing number of patients with autoinflammatory disease starting in adulthood. This study was undertaken to investigate the underlying cause of a case of late-onset uncharacterized autoinflammatory disease. Methods: Genetics studies were performed using Sanger sequencing and next-generation sequencing (NGS) methods. In silico, in vitro, and ex vivo analyses were performed to determine the functional consequences of the detected variant. Results: We studied a 57-year-old woman who at the age of 47 years began to have recurrent episodes of fever, myalgias, arthralgias, diffuse abdominal pain, diarrhea, adenopathies, and systemic inflammation, which were relatively well controlled with anti-interleukin-1 (anti-IL-1) drugs. NGS analyses did not detect germline variants in any of the known autoinflammatory disease-associated genes, but they identified the p.Ser171Phe NLRC4 variant in unfractionated blood, with an allele fraction (2-4%) compatible with gene mosaicism. Structural modeling analyses suggested that this missense variant might favor the open, active conformation of the NLRC4 protein, and in vitro and ex vivo analyses confirmed its propensity to oligomerize and activate the NLRC4 inflammasome, with subsequent overproduction of IL-18. Conclusion: Our findings indicate that the postzygotic p.Ser171Phe NLRC4 variant is a plausible cause of the disease in the enrolled patient. Functional and structural studies clearly support, for the first time, its gain-of-function behavior, consistent with previously reported NLRC4 pathogenic variants. These novel findings should be considered in the diagnostic evaluation of patients with adult-onset uncharacterized autoinflammatory disease.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Ionescu D, Peñín-Franch A, Mensa-Vilaró A, Castillo P, Hurtado-Navarro L, Molina-López C, Romero-Chala S, Plaza S, Fabregat V, Buján S, Marques J, Casals F, Yagüe J, Oliva B, Fernández-Pereira LM, Pelegrín P, Aróstegui JI. First description of late-onset autoinflammatory disease due to somatic NLRC4 mosaicism. Arthritis Rheumatol. 2022 Apr;74(4):692-9. DOI: 10.1002/art.41999
  • dc.identifier.doi http://dx.doi.org/10.1002/art.41999
  • dc.identifier.issn 2326-5191
  • dc.identifier.uri http://hdl.handle.net/10230/52609
  • dc.language.iso eng
  • dc.publisher Wiley
  • dc.relation.ispartof Arthritis Rheumatol. 2022 Apr;74(4):692-9
  • dc.rights © 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
  • dc.title First description of late-onset autoinflammatory disease due to somatic NLRC4 mosaicism
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion