Author:
Zhou Qing,Yu Xiaomin,Demirkaya Erkan,Deuitch Natalie,Stone Deborah,Tsai Wanxia Li,Kuehn Hye Sun,Wang Hongying,Yang Dan,Park Yong Hwan,Ombrello Amanda K.,Blake Mary,Romeo Tina,Remmers Elaine F.,Chae Jae Jin,Mullikin James C.,Güzel Ferhat,Milner Joshua D.,Boehm Manfred,Rosenzweig Sergio D.,Gadina Massimo,Welch Steven B.,Özen Seza,Topaloglu Rezan,Abinun Mario,Kastner Daniel L.,Aksentijevich Ivona
Abstract
Systemic autoinflammatory diseases are caused by mutations in genes that function in innate immunity. Here, we report an autoinflammatory disease caused by loss-of-function mutations in OTULIN (FAM105B), encoding a deubiquitinase with linear linkage specificity. We identified two missense and one frameshift mutations in one Pakistani and two Turkish families with four affected patients. Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency. HEK293 cells transfected with mutated OTULIN had decreased enzyme activity relative to cells transfected with WT OTULIN, and showed a substantial defect in the linear deubiquitination of target molecules. Stimulated patients’ fibroblasts and peripheral blood mononuclear cells showed evidence for increased signaling in the canonical NF-κB pathway and accumulated linear ubiquitin aggregates. Levels of proinflammatory cytokines were significantly increased in the supernatants of stimulated primary cells and serum samples. This discovery adds to the emerging spectrum of human diseases caused by defects in the ubiquitin pathway and suggests a role for targeted cytokine therapies.
Publisher
Proceedings of the National Academy of Sciences
Cited by
199 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献