By studying a case of hyperinflammatory syndrome with a homozygous nonsense mutation in Roquin-1, scientists discovered the mechanism of human immune dysregulation triggered by mutations in Roquin-1 protein.
Recently, researchers from Ghent University Hospital in Belgium published an article entitled "A human immune dysfunction syndrome characterized by severe hyperinflammation with a homozygous nonsense roquin-1 mutation" in Nature Communications. By studying a case of hyperinflammatory syndrome with a homozygous nonsense mutation in Roquin-1, they discovered the mechanism of human immune dysregulation triggered by mutations in Roquin-1 protein, which may provide a new approach for the diagnosis and treatment of human immune dysregulation syndrome.
Hyperinflammation is a life-threatening condition caused by severe and uncontrolled immune cell activation and hypercytokinemia, usually resulting from defects in negative feedback mechanisms. In the typical hyperinflammatory syndrome, familial hemolymphohistiocytosis (HLH) results in excessive activation of immune cells due to innate or acquired causes, secretion of a large number of cytokines to form a cytokine storm, leading to multiple organ function injury or even death. In this study, researchers studied a case of recurrent HLH harboring a homozygous nonsense R688 * RC3H1 mutation. Roquin-1 protein, encoded by RC3H1, is a post-transcriptional repressor of immunomodulatory proteins such as ICOS (inducible costimulatory molecule) and TNF (tumor necrosis factor). Comparison of the R688* mutant case with the mouse M199R mutant revealed that both were phenotypically similar with respect to immune cell activation, hypercytokinemia, and disease progression. The R688* mutation in RC3H1 is located within the proline-rich domain and generates a truncated mutant of Roquin-1 that impedes mRNA decay, leading to dysregulation of the cytokine. The results of this study suggest that impaired function of Roquin-1 triggers inflammation due to failure to suppress immune activation and may provide a new approach for the diagnosis and treatment of hyperinflammatory syndromes.