A de novo dominant-negative PSMB8 mutation causes severe CANDLE/PRAAS due to arrested proteasome biogenesis
The DN-PSMB8 p.G209R variant broadens the clinical and mechanistic PRAAS spectrum by causing 20S proteasome maturation arrest and uncovering a convergence between mitochondrial dysfunction and the ISR. Our findings implicate cytopenia in a pattern of vascular pathology, including PSVD of the liver. We further identify PKR and GCN2 as key mediators of maladaptive IFN-I responses and potential therapeutic targets.
Authors
- Frédéric Ebstein (ORCID: https://orcid.org/0000-0002-3729-7878)
- Iren Horkayne‐Szakaly
- Gijs W.E. Santen (ORCID: https://orcid.org/0000-0003-1959-3267)
- Bénédicte Neven (ORCID: https://orcid.org/0000-0001-8941-0935)
- Jason M. Brenchley (ORCID: https://orcid.org/0000-0001-8357-2984)
- Olaf Neth (ORCID: https://orcid.org/0000-0001-5018-0466)
- Paul Bastard (ORCID: https://orcid.org/0000-0002-5926-8437)
- Peter Mustillo (ORCID: https://orcid.org/0000-0002-8420-8655)
- David E. Kleiner (ORCID: https://orcid.org/0000-0003-3442-4453)
- Franziska G. Thiel (ORCID: https://orcid.org/0000-0001-6322-9222)
- Sara Alehashemi (ORCID: https://orcid.org/0000-0002-6531-6108)
- Hannes Wolfgramm (ORCID: https://orcid.org/0000-0002-6028-0046)
- Leif Steil (ORCID: https://orcid.org/0000-0002-0733-8421)
- Martin Wendlandt
- Pilar Blanco-Lobo (ORCID: https://orcid.org/0000-0003-1893-8198)
- Christian Hentschker
- Robbert G. M. Bredius (ORCID: https://orcid.org/0000-0001-8151-1539)
- Simone Venz
- Kátia Tomie Kozu (ORCID: https://orcid.org/0000-0001-8743-7827)
- Anne Pagnier (ORCID: https://orcid.org/0000-0002-3981-8331)
- Roshini S. Abraham (ORCID: https://orcid.org/0000-0001-8109-8502)
- AnnaCarin Horne (ORCID: https://orcid.org/0000-0002-2878-4463)
- Katherine R. Calvo (ORCID: https://orcid.org/0000-0002-0771-4191)
- Raphaela Goldbach‐Mansky
- Shoghik Akoghlanian (ORCID: https://orcid.org/0000-0002-8264-316X)
- T. Huizinga (ORCID: https://orcid.org/0000-0001-7033-7520)
- Charlotte Friend (ORCID: https://orcid.org/0009-0004-7866-4760)
- E. Alvarez (ORCID: https://orcid.org/0000-0002-7566-5678)
- Ruba Al‐Abdulla (ORCID: https://orcid.org/0000-0002-5194-9801)
- G. Boursier
- Mayra Dorna
- Farzana Bhuyan (ORCID: https://orcid.org/0000-0003-2316-1221)
- Kat Uss
- Jonas Johannes Papendorf
- Petter Brodin (ORCID: https://orcid.org/0000-0002-8103-0046)
- Karin Palmblad (ORCID: https://orcid.org/0000-0003-1197-5201)
- Y K Onno Teng (ORCID: https://orcid.org/0000-0001-9920-2195)
- Anvitha Metpally
- José Bernabéu‐Wittel (ORCID: https://orcid.org/0000-0002-3639-8482)
- Fabiola Castello Casta
- Adriana A. de Jesus (ORCID: https://orcid.org/0000-0003-2352-909X)
- Benjamin Fournier (ORCID: https://orcid.org/0000-0002-4189-996X)
- Thais Costa Lima de Moura
- Maud Tusseau
- Uwe Völker (ORCID: https://orcid.org/0000-0002-5689-3448)
- Léa Poirier (ORCID: https://orcid.org/0009-0003-7400-8363)
- Elke Krüger (ORCID: https://orcid.org/0000-0002-2551-242X)
- Jesper Kers
- Laura Fernandez-Silveira
- Emely Borngräber
- Sophie Wolfgramm
Institutions
- Université Claude Bernard Lyon 1 (FR)
- École Normale Supérieure de Lyon (FR)
- Centre National de la Recherche Scientifique (FR)
- Nationwide Children's Hospital (US)
- Karolinska University Hospital (SE)
- Inserm (FR)
- Lyon College (US)
- Université de Montpellier (FR)
- Université Paris Cité (FR)
- Universitätsmedizin Greifswald (DE)
- Leiden University Medical Center (NL)
- Erasmus MC (NL)
- Assistance Publique – Hôpitaux de Paris (FR)
- Centre de Référence des Maladies Autoinflammatoires et des Amyloses (FR)
- Hospices Civils de Lyon (FR)
- Instituto de Biomedicina de Sevilla (ES)
- National Institute of Allergy and Infectious Diseases (US)
- National Cancer Institute (US)
- Hospital Universitário da Universidade de São Paulo (BR)
- Institut du Thorax (FR)
- Hospital Universitario Virgen del Rocío (ES)
- National Institutes of Health Clinical Center (US)
- Institut des Maladies Génétiques Imagine (FR)
- Université Grenoble Alpes (FR)
Publication Details
- Journal
- Annals of the Rheumatic Diseases
- Published
- 2025-11-01
- DOI
- https://doi.org/10.1016/j.ard.2025.10.021
- Citations
- 3
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- U.S. Department of Health and Human Services
- Institut des maladies génétiques Imagine
- Deutsche Forschungsgemeinschaft
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- National Institutes of Health