A Novel Mendelian Disease of Autoimmunity caused by Mutations in a small GTPase

Abstract

In this study, we harness Whole Exome Sequencing (WES) to interrogate the underlying genetic cause in a patient cohort suffering from a Mendelian disease of immune dysregulation characterized by severe lymphopenia, splenomegaly, anemia, thrombocytopenia and liver failure. Bioinformatic analysis revealed novel mutations in a small GTPase that led to a near complete loss of mature protein in patient cells. Animal models lacking these genes develop a disease remarkably similar to that observed in the human patients, however, the molecular role of this GTPase in the immune system remains a fundamental gap in our knowledge. Due to a remarkable similarity in phenotypes between mice deficient for this small GTPase and T cell specific deletions of regulators of mTORC1, we hypothesized that this gene may be involved in the mTORC1 signaling pathway. We observe a robust association between this GTPase and members of the ragulator complex which is required for recruitment of mTORC1 to the lysosome and subsequent signalling. Furthermore, in human T cells deficient for this GTPase we observe increased phosphorylation of targets downstream of mTORC1. Overall, our data suggest that this GTPase is a novel T cell specific negative regulator of mTORC1 signalling. This research was supported by the Intramural Research Program of NIAID, NIH.