Hyperinflammatory diseases are rare but often severely debilitating and life-threatening diseases. Although inborn errors of the immune system are at the basis of hyperinflammatory diseases, our knowledge of the underlying genetic defects remains incomplete. This strongly impedes early diagnosis and restricts patients from obtaining optimal healthcare. Furthermore, failure to
understand the molecular mechanisms driving these disorders inhibits the development of novel targeted medicines and limits the therapeutic options available to physicians and their patients. Recently, we discovered a novel mutation in the C3H1 zinc finger protein Roquin1 in a patient diagnosed with hemophagocytic lymphohistiocytosis (HLH), a disease characterised by the
uncontrolled activation of the immune system resulting in multi-organ damage and death if untreated. Roquin1 is part of a larger family of proteins that control RNA metabolism and that are crucial for many aspects of immune regulation. In this project we try to obtain mechanistic insights how this pathogenic Roquin1 variant results in hyperinflammation. Furthermore, combining both mouse models and genomic approaches we aim to identify more pathogenic Roquin1 variants contributing to hyperinflammatory disease. Finally, we want to test whether Roquin1 could serve as a promising therapeutic target in hyperinflammatory syndromes.
The results of this project will impact basic immunological insights and provide additional clinical tools.