III型钠磷转运蛋白2（PiT2）功能与IBGC发生分子机制

特发性脑基底节钙化（IBGC）是以基底节和大脑其它部位发生对称性钙化为特征，表现神经系统锥体外系临床症状（癫痫、慢性头痛、痴呆和精神病等）的一种遗传病，其发病分子机制不清楚。本课题组前期工作克隆了首个IBGC致病基因SLC20A2，SLC20A2编码一种III型钠磷共转蛋白2（PiT2）。PiT2功能如何？其突变如何导致IBGC发生呢？本研究拟收集更多IBGC患者对该基因进行突变分析，进一步确定突变类型；从体外（分子水平研究该基因的相互作用蛋白及其在Pi感应的信号通路作用；细胞水平研究基因突变导致Pi转运功能变化和膜电位改变）和体内（模式动物水平研究该基因在个体发育中的作用及其突变导致人类IBGC发生机制）对SLC20A2进行系统功能分析，阐明PiT2在Pi转运和信号转导中的作用机制，揭示IBGC致病精细分子机制，为开发相关治疗药物奠定基础。

Idiopathic basal ganglia calcification (IBGC) is a genetic condition characterized by symmetric calcification in the basal ganglia and other brain regions, a wide spectrum of neuropsychiatric symptoms, including seizures, chronic headache, dementia, and psychosis etc. Its causative genes and the underlying pathophysiology have remained elusive. Here, we identified some mutations in SLC20A2 in IBGC-affected families of varied ancestry. To our knowledge, this is the first gene linked to the IBGC disease and that mutations in this gene are distributed worldwide. The SLC20A2 gene encoded type III sodium-dependent phosphate transporter 2 (PiT2) that belongs to the inorganic phosphate (Pi) transporter family. It is not fully aware of the PiT2's functions. How is the IBGC disease resulted in by PiT2 mutations? In this study, we will further identify the PiT2 mutational category by mutation analysis of SLC20A2 gene in many patients with IBGC. We will analyze the system function of PiT2, firstly, from interaction protein and signal transduction in Pi sensing, and the changes of Pi transport and membrane potential by the SLC20A2 gene mutations in molecular and cellular level in vitro. Secondly, from the effects in individual development by knock out and knock in SLC20A2 homologous genes of fruit flies and mice in vivo. We will find the mechanism of action in Pi transport and signal transduction from PiT2 and reveal fine molecular pathogenic mechanism of IBGC. It is very important significance for searching drug targets and developing drugs for cure IBGC disease.