ArticleThe Journal of experimental medicine2024
A de novo dominant-negative variant is associated with OTULIN-related autoinflammatory syndrome.
Article in The Journal of experimental medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 17 citations in OpenAlex.
- Pyoderma gangrenosum caused by the molecular uncoupling of OTULIN catalytic activity and LUBAC binding.Nature immunology · 2026Article
- Decoding variants of uncertain significance in systemic autoinflammatory diseases.Nature reviews. Rheumatology · 2026Review
- Monogenic disorders of the TNF signalling pathway.Nature reviews. Rheumatology · 2026Review
- OTULIN: a master regulator of linear ubiquitin homeostasis in immune signaling, inflammation, and disease.Frontiers in immunology · 2026Review
- Recent variant discoveries and emerging genetic mechanisms in autoinflammatory diseases.Frontiers in immunology · 2026Review
- Association of peripheral blood LUBAC and OTULIN expression with severity and outcome in acute ischemic stroke: a prospective cohort study.Frontiers in immunology · 2026Article
- Novel genotypes, phenotypes, and triggers in humans with OTULIN haploinsufficiency.Journal of human immunity · 2025Article
- Update on new autoinflammatory disorders from the 2024 Pediatric Rheumatology European Society Congress.Pediatric rheumatology online journal · 2025Review
- Type I interferon-mediated autoinflammation in two unrelated patients due to a proximal intronic splice site variant inResearch square · 2025Article
- Primary disorders of polyubiquitination: Dual roles in autoinflammation and immunodeficiency.The Journal of experimental medicine · 2025Review
- Deciphering Key Regulatory Roles of Linear Ubiquitination in Cell Fate Determination and Disease.Research (Washington, D.C.) · 2025Review
- Contribution of next generation sequencing to the diagnosis of inborn errors of immunity in a pediatric cohort.Frontiers in immunology · 2025Article
- NEMO-NDAS: Case Report and Review of the Literature.Pediatric dermatologyReview
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Authors and funding
22 authors at 6 institutions in 1 country.
Funding
Abstract
OTULIN-related autoinflammatory syndrome (ORAS), a severe autoinflammatory disease, is caused by biallelic pathogenic variants of OTULIN, a linear ubiquitin-specific deubiquitinating enzyme. Loss of OTULIN attenuates linear ubiquitination by inhibiting the linear ubiquitin chain assembly complex (LUBAC). Here, we report a patient who harbors two rare heterozygous variants of OTULIN (p.P152L and p.R306Q). We demonstrated accumulation of linear ubiquitin chains upon TNF stimulation and augmented TNF-induced cell death in mesenchymal stem cells differentiated from patient-derived iPS cells, which confirms that the patient has ORAS. However, although the de novo p.R306Q variant exhibits attenuated deubiquitination activity without reducing the amount of OTULIN, the deubiquitination activity of the p.P152L variant inherited from the mother was equivalent to that of the wild-type. Patient-derived MSCs in which the p.P152L variant was replaced with wild-type also exhibited augmented TNF-induced cell death and accumulation of linear chains. The finding that ORAS can be caused by a dominant-negative p.R306Q variant of OTULIN furthers our understanding of disease pathogenesis.
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Registered trials
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