Missense variant in XYZ results in hyperactivation of mTOR signaling pathway and increased T-cell senescence

Abstract

Abstract Phosphatidylinositol-4-phosphate 5-kinase I (XYZ) is a member of the class I PIP5K family that is responsible for the phosphorylation of phosphatidylinositol 4-phosphate (PIP) to produce phosphatidylinositol 4,5-biphosphate (PIP2). PIP2 is an important intermediate in the PI3K signaling pathway and is phosphorylated by PI3K to create phosphatidylinositol 3, 4, 5-triphosphate (PIP3), which is an important signaling molecule in TCR activation. Through whole exome sequencing, we have recently identified a 14-year old female Turkish patient with a homozygous missense variant in the activation loop of XYZ. The patient presents with lymphadenopathy, hemolytic anemia, low IgA, no IgE, positive antinuclear antibodies, and reactive airway disease. She has low naïve T-cells, increased CD45RA+ T-effector memory (TEMRA) cells, and increased CD57, a marker of T-cell senescence, on CD8+ T-cells. Patient T-cell blasts show increased phosphorylation of S6 levels upon TCR stimulation. Further, overexpression of mutant XYZ in T-cells resulted in increased phosphorylation of S6 at baseline compared to overexpression of wild type XYZ. Overall, these results suggest that the XYZ variant leads to hyperactivation of the mTOR signaling pathway, which may contribute to T-cell senescence and disease. This research was supported [in part] by the Intramural Research Program of the NIH, NIAID