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.

中文翻译：

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OTULIN 复合杂合变异与暴发性非典型迟发型 ORAS 相关


自身炎症性疾病是一组由发烧和全身炎症定义的异质性疾病，表明调节先天免疫反应的基因参与其中。 OTU-去泛素酶OTULIN纯合功能丧失变异的患者患有新生儿发病的 OTULIN 相关自身炎症综合征 (ORAS)，其特征为发烧、脂膜炎、腹泻和关节炎。在这里，我们描述了一种非典型形式的 ORAS，具有由OTULIN基因中两个新的复合杂合变异体 (c.258G>A (p.M86I)/c.500G>C (p.W167S)) 引起的疾病的独特临床表现一名 7 岁儿童患有危及生命的自身炎症，并形成无菌脓肿。在分子水平上，我们发现 OTULIN 与线性泛素的结合受到两种变体的影响；然而，蛋白质稳定性和催化活性受 OTULIN 变体 p.W167S 的影响最大。这些分子变化共同导致患者来源的细胞中线性泛素连接水平增加，从而引发疾病。我们的数据表明，ORAS 患者的范围​​比之前想象的更加多样化，因此，所谓的无症状个体也可能受到影响。根据我们的结果，我们建议将 ORAS 细分为经典实体和非典型实体。