Autoinflammatory & rare systemic diseases
A de novo dominant-negative PSMB8 mutation causes severe CANDLE/proteasome-associated autoinflammatory syndromes (PRAAS) due to arrested proteasome biogenesis
Authors' conclusion
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.
Study context
- Population
- Patients with the de novo DN-PSMB8 p.G209R variant (PRAAS/CANDLE)
Main finding
As reported in the abstract
- Clinical presentation: early-onset systemic inflammation, panniculitis, cytopenias, infections and porto-sinusoidal vascular liver disease (PSVD)
- Partial response to JAK inhibition and/or interferon-α/β receptor blockade (anifrolumab)
- PSMB8 p.G209R caused steric hindrance impairing β5i propeptide processing and final 20S proteasome formation
- Intracellular protein aggregation, impaired mitochondrial metabolism and altered neutral lipid processing
- IFN-I signature of patients' T cells reduced by blockade of integrated stress response (ISR) kinases protein kinase R (PKR) and GCN2, and by JAK signalling
Original publication
A de novo dominant-negative PSMB8 mutation causes severe CANDLE/PRAAS due to arrested proteasome biogenesis. Ann Rheum Dis. Published 17 November 2025. doi:10.
Composed by AI from the published abstract and checked against it. How Briefs are made →