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.
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, treatment with inhibitors of mTORC1 led to remarkable clinical improvements in our mouse model and also one of our human patients. Overall, we have described a novel, T cell specific member of the ragulator complex and it’s role in maintaining immune homeostasis in humans. This research was supported by the Intramural Research Program of NIAID, NIH.
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