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Identification of eight novel proteasome variants in five unrelated cases of proteasome-associated autoinflammatory syndromes (PRAAS)

Authors :
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
Source :
Frontiers in Immunology, Vol 14 (2023)
Publication Year :
2023
Publisher :
Frontiers Media S.A., 2023.

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.

Details

Language :
English
ISSN :
16643224
Volume :
14
Database :
Directory of Open Access Journals
Journal :
Frontiers in Immunology
Publication Type :
Academic Journal
Accession number :
edsdoj.797414f038e44fa0bb0b536c59ac957d
Document Type :
article
Full Text :
https://doi.org/10.3389/fimmu.2023.1190104