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
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.
Funder
Deutsche Forschungsgemeinschaft
Subject
Immunology,Immunology and Allergy
Cited by
1 articles.
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