A novel genetic mutation reveals the molecular and cellular mechanisms of severe recurrent skin inflammation

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PROJECT ABSTRACT Inborn errors of immunity (IEI) are genetic disorders caused by monogenic germline mutations and have broad clinical manifestations. Here, we present two patients affected by pyoderma gangrenosum (PG), an extremely rare and severe neutrophilic necrotic skin disorder, without severe systemic autoinflammatory symptoms. Whole exome sequencing (WES) revealed a homozygous R57C OTULIN missense mutation in each patient. OTULIN encodes a deubiquitinase that is the only known enzyme that specifically cleaves linear ubiquitin chains that have been added to target proteins by the linear ubiquitin chain assembly complex (LUBAC). The balance between removal and addition of ubiquitin is crucial for immune homeostasis and responses to infection. Previously reported germline OTULIN mutations affect this protein’s catalytic domain and cause a severe systemic autoinflammatory largely driven by overactivation of NF-B signaling called OTULIN-related autoinflammatory syndrome (ORAS). Here, we define a new monogenic disease caused by mutations in a different domain of OTULIN and causing a distinct clinical phenotype. We have demonstrated that the R57C mutation prevents OTULIN from binding to the LUBAC component HOIP but the ability to downregulate NF-B activity remains intact suggesting a context-specific function of OTULIN. These patients’ unique phenotype suggests that a previously unrecognized function for OTULIN in the skin. The overall hypothesis of this proposal is that OTULIN’s function in keratinocytes differs from that in other cellular contexts, and this novel mutation leads to development of pyoderma gangrenosum in patients. We will use computational method and cutting-edge in vitro and ex vivo approaches to identify the roles of post-translational modification in regulating OTULIN-dependent immune signaling. 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 for maintaining immune homeostasis.