AUTHOR=Papendorf Jonas Johannes , Ebstein Frédéric , Alehashemi Sara , Piotto Daniela Gerent Petry , Kozlova Anna , Terreri Maria Teresa , Shcherbina Anna , Rastegar Andre , Rodrigues Marta , Pereira Renan , Park Sophia , Lin Bin , Uss Kat , Möller Sophie , da Silva Pina Ana Flávia , Sztajnbok Flavio , Torreggiani Sofia , Niemela Julie , Stoddard Jennifer , Rosenzweig Sergio D. , Oler Andrew J. , McNinch Colton , de Guzman Marietta M. , Fonseca Adriana , Micheloni Nicole , Fraga Melissa Mariti , Perazzio Sandro Félix , Goldbach-Mansky Raphaela , de Jesus Adriana A. , Krüger Elke TITLE=Identification of eight novel proteasome variants in five unrelated cases of proteasome-associated autoinflammatory syndromes (PRAAS) JOURNAL=Frontiers in Immunology VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1190104 DOI=10.3389/fimmu.2023.1190104 ISSN=1664-3224 ABSTRACT=

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.