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Compound heterozygous variants in OTULIN are associated with fulminant atypical late-onset ORAS

Zinngrebe, Julia; Moepps, Barbara; Monecke, Thomas; Gierschik, Peter; Schlichtig, Ferdinand; Barth, Thomas FE; Strauß, Gudrun; ... Debatin, Klaus-Michael; + view all (2022) Compound heterozygous variants in OTULIN are associated with fulminant atypical late-onset ORAS. EMBO Molecular Medicine , 14 (3) , Article e14901. 10.15252/emmm.202114901. Green open access

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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.

Type: Article
Title: Compound heterozygous variants in OTULIN are associated with fulminant atypical late-onset ORAS
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/emmm.202114901
Publisher version: https://doi.org/10.15252/emmm.202114901
Language: English
Additional information: © 2022 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: LUBAC, ORAS, OTULIN, autoinflammation, linear ubiquitin
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10144272
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