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Somatic Mosaic NLRP3 Mutations and Inflammasome Activation in Late-Onset Chronic Urticaria. | LitMetric

Somatic Mosaic NLRP3 Mutations and Inflammasome Activation in Late-Onset Chronic Urticaria.

J Invest Dermatol

Sorbonne Université, INSERM, Hôpital Trousseau, Maladies génétiques d'expression pédiatrique, Paris, France; Unité Fonctionnelle de génétique moléculaire, Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau, Paris, France. Electronic address:

Published: April 2020

AI Article Synopsis

  • - Chronic urticaria, a persistent skin condition often without clear triggers, was studied in two unrelated patients over 60 who experienced it for decades and did not respond to standard treatment.
  • - Researchers identified somatic mosaic mutations in the NLRP3 gene, linked to inflammation, through targeted sequencing, suggesting these mutations occurred early in embryonic development.
  • - Both patients achieved complete remission from their symptoms after treatment with anti-IL-1 receptor antagonists, highlighting the potential importance of NLRP3 mutations in diagnosing and treating late-onset chronic urticaria.

Article Abstract

Chronic urticaria is a common skin disorder with heterogeneous causes. In the absence of physical triggers, chronic urticarial rash is called idiopathic or spontaneous. The objective of this study was to identify the molecular and cellular bases of a disease condition displayed by two unrelated patients aged over 60 years who presented for two decades with a chronic urticaria resistant to standard therapy that occurred in the context of systemic inflammation not triggered by cold. In both patients, a targeted sequencing approach using a next generation technology identified somatic mosaic mutations in NLRP3, a gene encoding a key inflammasome component. The study of several of both patients' cell types showed that, despite the late onset of the disease, NLRP3 mutations were not found to be restricted to myelomonocytic cells. Rather, the data obtained strongly suggested that the mutational event occurred very early, during embryonic development. As shown by functional studies, the identified mutations-an in-frame deletion and a recurrent NLRP3 missense mutation-have a gain-of-function effect on NLRP3-inflammasome activation. Consistently, a complete remission was obtained in both patients with anti-IL-1 receptor antagonists. This study unveils that in late-onset chronic urticaria, the search for autoinflammatory markers and somatic mosaic NLRP3 mutations may have important diagnostic and therapeutic consequences.

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Source
http://dx.doi.org/10.1016/j.jid.2019.06.153DOI Listing

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