ADAR1 loss-of-function variants altering RNA editing define a new interferon-dependent psoriasis subtype.

Authors

Florence Assan, Margot Tragin, Sahiti Marella, Joanna Lipecka, Kévin Roger, Mohammed Zarhrate, Vincent Bondet, Vincent Nguyen, Fadela Akroun, Patrick Nitschké, Ida Chiara Guerrera, Christine Bole, Araksya Izmiryan, Maria Emilia Puig-Lombardi, Jennifer Fox, Joseph Kirma, Haihan Zhang, Yiqian Gu, Rachael Bogle, Katia Boniface, Julien Seneschal, Luis Seabra, Alice Lepelley, Marie-Louise Frémond, Nadège Bondurand, Emmauelle Jouanguy, Robert L Modlin, Jean-Laurent Casanova, Jeremy Di Domizio, Michel Gilliet, Emilie Sbidian, Maxime Battistella, Emmanuel Mahé, Sarah Guégan, Lam C Tsoi, Pascal Richette, Pascal Claudepierre, Arnaud Rigolet, Claire Giannesini, Antonio Costanzo, Darragh Duffy, Brad R Rosenberg, Dharshini Sathishkumar, Emmanuelle Bourrat, Chung Hsing Chang, Alain Hovnanian, Johann E Gudjonsson, Yanick J Crow, Hervé Bachelez

Published in

The Journal of experimental medicine. Volume 223. Issue 9. Sep 07, 2026. Epub Jul 09, 2026.

Abstract

Recent evidence implicates altered RNA editing and dysregulated type I IFN signaling in immune-mediated diseases, including psoriasis, although the underlying genetic mechanisms remain poorly defined. We investigated four unrelated multiplex families with early-onset plaque psoriasis, with or without psoriatic arthritis, segregating as a monogenic trait and characterized by a strong IFN signature in skin and blood. Whole-exome sequencing identified four rare heterozygous loss-of-function mutations in ADAR1 cosegregating with disease and elevated IFN-stimulated gene expression. Six additional rare variants were detected in an independent cohort of 125 psoriasis patients. Single-cell transcriptomics identified keratinocytes and melanocytes as major IFN sources. Functional studies showed that ADAR1 knockdown or expression of ADAR1G1119R and ADAR1P3A alleles pathogenic variants reduced adenosine-to-inosine RNA editing and increased IFN-stimulated genes and inflammatory cytokines, effects reversed by upadacitinib and deucravacitinib. These findings define a novel IFN-dependent psoriasis subtype caused by inborn defects of ADAR1-mediated RNA editing, with direct implications for precision medicine in psoriatic disease.

PMID:
42424135
Bibliographic data and abstract were imported from PubMed on 10 Jul 2026.

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