Open Access

Jonas Johannes Papendorf, Frédéric Ebstein, Sara Alehashemi, Daniela Gerent Petry Piotto, Anna Kozlova, Maria Teresa Terreri, Anna Shcherbina, Andre Rastegar, Marta Rodrigues, Renan Pereira, Sophia Park, Bin Lin, Kat Uss, Sophie Möller, Ana Flávia da Silva Pina, Flavio Sztajnbok, Sofia Torreggiani, Julie Niemela, Jennifer Stoddard, Sergio D. Rosenzweig, Andrew J. Oler, Colton McNinch, Marietta M. de Guzman, Adriana Fonseca, Nicole Micheloni, Melissa Mariti Fraga, Sandro Félix Perazzio, Raphaela Goldbach-Mansky, Adriana A. de Jesus, Elke Krüger

• Mutations in genes coding for proteasome subunits and/or proteasome assembly helpers typically cause recurring autoinflammation referred to as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE) or proteasome-associated autoinflammatory syndrome (PRAAS). Patients with CANDLE/PRAAS present with mostly chronically elevated type I interferon scores that emerge as a consequence of increased proteotoxic stress by mechanisms that are not fully understood. Here, we report on five unrelated patients with CANDLE/PRAAS carrying novel inherited proteasome missense and/or nonsense variants. Four patients were compound heterozygous for novel pathogenic variants in the known CANDLE/PRAAS associated genes, PSMB8 and PSMB10, whereas one patient showed additive loss-of-function mutations in PSMB8. Variants in two previously not associated proteasome genes, PSMA5 and PSMC5, were found in a patient who also carried the PSMB8 founder mutation, p.T75M. All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes. Our observations expand the spectrum of PRAAS-associated genetic variants and improve a molecular diagnosis and genetic counseling of patients with sterile autoinflammation.