biostudies-literatureUnknown39(1)Sun HPiT2 is an inorganic phosphate (Pi) transporter whose mutations are linked to primary familial brain calcification (PFBC). PiT2 mainly consists of two ProDom (PD) domains and a large intracellular loop region (loop7). The PD domains are crucial for the Pi transport, but the role of PiT2-loop7 remains unclear. In PFBC patients, mutations in PiT2-loop7 are mainly nonsense or frameshift mutations that probably cause PFBC due to C-PD1131 deletion. To date, six missense mutations have been identified in PiT2-loop7; however, the mechanisms by which these mutations cause PFBC are poorly understood. Here, we found that the p.T390A and p.S434W mutations in PiT2-loop7 decreased the Pi transport activity and cell surface levels of PiT2. Furthermore, we showed that these two mutations attenuated its mNeuroscience bulletin57-68https://www.ebi.ac.uk/biostudies/studies/S-EPMC9849530biostudies-literatureMechanisms of PiT2-loop7 Missense Mutations Induced Pi Dyshomeostasis.PMC9849530Luo JLiu MCui JXiong BLiu JYSun HXu XMa TZhu SfalseMechanisms of PiT2-loop7 Missense Mutations Induced Pi Dyshomeostasis.PiT2 is an inorganic phosphate (Pi) transporter whose mutations are linked to primary familial brain calcification (PFBC). PiT2 mainly consists of two ProDom (PD) domains and a large intracellular loop region (loop7). The PD domains are crucial for the Pi transport, but the role of PiT2-loop7 remains unclear. In PFBC patients, mutations in PiT2-loop7 are mainly nonsense or frameshift mutations that probably cause PFBC due to C-PD1131 deletion. To date, six missense mutations have been identified in PiT2-loop7; however, the mechanisms by which these mutations cause PFBC are poorly understood. Here, we found that the p.T390A and p.S434W mutations in PiT2-loop7 decreased the Pi transport activity and cell surface levels of PiT2. Furthermore, we showed that these two mutations attenuated its m2023-01-01T00:00:00Z2023 Jan2026-05-29T02:13:24.733Z2025-04-04T10:30:04.839ZS-EPMC98495303571384410.1007/s12264-022-00893-y