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Mechanisms of PiT2-loop7 Missense Mutations Induced Pi Dyshomeostasis

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Abstract

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 membrane localization by affecting adenosine monophosphate-activated protein kinase (AMPK)- or protein kinase B (AKT)-mediated PiT2 phosphorylation. In contrast, the p.S121C and p.S601W mutations in the PD domains did not affect PiT2 phosphorylation but rather impaired its substrate-binding abilities. These results suggested that missense mutations in PiT2-loop7 can cause Pi dyshomeostasis by affecting the phosphorylation-regulated cell-surface localization of PiT2. This study helps understand the pathogenesis of PFBC caused by PiT2-loop7 missense mutations and indicates that increasing the phosphorylation levels of PiT2-loop7 could be a promising strategy for developing PFBC therapies.

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Acknowledgments

This study was mainly supported by the National Natural Science Foundation of China (31871262) and a Shanghai Municipal Science and Technology Major Project (2018SHZDZX05).

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  1. Hao Sun and Xuan Xu contributed equally to this work.

Authors and Affiliations

  1. College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan, 430074, China

    Hao Sun, Junyu Luo & Mugen Liu

  2. Institute of Neuroscience, State Key Laboratory of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China

    Xuan Xu, Tingbin Ma, Jiaming Cui, Shujia Zhu & Jing-Yu Liu

  3. Department of Forensic Medicine, Tongji Medical College, HUST, Wuhan, 430030, China

    Bo Xiong

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  1. Hao Sun
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Sun, H., Xu, X., Luo, J. et al. Mechanisms of PiT2-loop7 Missense Mutations Induced Pi Dyshomeostasis. Neurosci. Bull. 39, 57–68 (2023). https://doi.org/10.1007/s12264-022-00893-y

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  • DOI: https://doi.org/10.1007/s12264-022-00893-y

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