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=Volume 14 - 2023

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 consequence of increased proteotoxic stress by mechanisms that are not fully understood.Here, we report on five unrelated CANDLE/PRAAS patients carrying novel inherited proteasome missense and/or nonsense variants. Four patients were compound heterozygous for novel pathogenic variants in the known CANDLE/PRAAS disease genes, PSMB8 and PSMB10, while one patient showed additive loss-of-function mutations in PSMB8, and in 2 previously not associated disease genes, PSMA5 and PSMC5. Our in vitro investigations provide evidence on the pathogenicity of these variants. 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-causing genetic variants and improve a molecular diagnosis and genetic counseling of patients with sterile autoinflammation.