Zinngrebe, Julia, Moepps, Barbara, Monecke, Thomas, Gierschik, Peter, Schlichtig, Ferdinand, Barth, Thomas F. E., Strauss, Gudrun, Boldrin, Elena ORCID: 0000-0001-6815-3060, Posovszky, Carsten ORCID: 0000-0002-9487-8812, Schulz, Ansgar, Beringer, Ortraud, Rieser, Eva, Jacobsen, Eva-Maria, Lorenz, Myriam Ricarda, Schwarz, Klaus, Pannicke, Ulrich, Walczak, Henning, Niessing, Dierk ORCID: 0000-0002-5589-369X, Schuetz, Catharina, Fischer-Posovszky, Pamela and Debatin, Klaus-Michael ORCID: 0000-0002-8397-1886 (2022). Compound heterozygous variants in OTULIN are associated with fulminant atypical late-onset ORAS. EMBO Mol. Med., 14 (3). HOBOKEN: WILEY. ISSN 1757-4684

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Abstract

Autoinflammatory diseases are a heterogenous group of disorders defined by fever and systemic inflammation suggesting involvement of genes regulating innate immune responses. Patients with homozygous loss-of-function variants in the OTU-deubiquitinase OTULIN suffer from neonatal-onset OTULIN-related autoinflammatory syndrome (ORAS) characterized by fever, panniculitis, diarrhea, and arthritis. Here, we describe an atypical form of ORAS with distinct clinical manifestation of the disease caused by two new compound heterozygous variants (c.258G>A (p.M86I)/c.500G>C (p.W167S)) in the OTULIN gene in a 7-year-old affected by a life-threatening autoinflammatory episode with sterile abscess formation. On the molecular level, we find binding of OTULIN to linear ubiquitin to be compromised by both variants; however, protein stability and catalytic activity is most affected by OTULIN variant p.W167S. These molecular changes together lead to increased levels of linear ubiquitin linkages in patient-derived cells triggering the disease. Our data indicate that the spectrum of ORAS patients is more diverse than previously thought and, thus, supposedly asymptomatic individuals might also be affected. Based on our results, we propose to subdivide the ORAS into classical and atypical entities.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Zinngrebe, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moepps, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Monecke, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gierschik, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schlichtig, FerdinandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barth, Thomas F. E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Strauss, GudrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boldrin, ElenaUNSPECIFIEDorcid.org/0000-0001-6815-3060UNSPECIFIED
Posovszky, CarstenUNSPECIFIEDorcid.org/0000-0002-9487-8812UNSPECIFIED
Schulz, AnsgarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beringer, OrtraudUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rieser, EvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jacobsen, Eva-MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lorenz, Myriam RicardaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwarz, KlausUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pannicke, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walczak, HenningUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niessing, DierkUNSPECIFIEDorcid.org/0000-0002-5589-369XUNSPECIFIED
Schuetz, CatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer-Posovszky, PamelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Debatin, Klaus-MichaelUNSPECIFIEDorcid.org/0000-0002-8397-1886UNSPECIFIED
URN: urn:nbn:de:hbz:38-685521
DOI: 10.15252/emmm.202114901
Journal or Publication Title: EMBO Mol. Med.
Volume: 14
Number: 3
Date: 2022
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1757-4684
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NECROSIS-FACTOR-ALPHA; SPATA2 LINKS CYLD; LINEAR UBIQUITIN; SIGNALING COMPLEX; TUMOR-SUPPRESSOR; CELL-DEATH; LUBAC; INFLAMMATION; IMMUNODEFICIENCY; AUTOINFLAMMATIONMultiple languages
Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/68552

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