智障相关基因PQBP1-Y65C错义突变导致小颅畸形的分子机制研究

Renpenning综合征是一类X连锁的智力障碍，由多聚谷氨酰胺结合蛋白PQBP1基因外显子区域的多种不同突变导致，患者典型的表型包括小颅畸形，但因为缺少合适的动物模型研究，我们对其致病机理还不清楚。小颅畸形是由胚胎神经发生过程中产生的神经元数目减少所导致，申请人前期的工作发现了PQBP1可能直接参与纺锤体形成从而影响细胞有丝分裂。本项目中申请人将在前期研究基础上，利用PqbpY65C点突变小鼠模型进一步通过蛋白质谱、流式细胞术、免疫荧光和免疫印迹等技术手段从分子、细胞和动物多个层次探索PQBP1-Y65C突变对其互作蛋白网络的影响，以及对细胞增殖和神经发生过程的影响，从而阐释其导致小颅畸形的病理机制。这将扩展我们对于PQBP1的分子功能和胚胎早期神经发生调控机制的认识，成为未来我们进一步开展相关疾病诊断治疗研究的重要依据。

Renpenning syndrome is a type of X-linked intellectual disability caused by many mutations in the exons of polyglutamine binding protein 1 (PQBP1) gene. Its typical phenotype is microcephaly but the underlying molecular pathogenesis is unclear due to the lack of proper animal models. In our previous studies, we found that PQBP1 might participate in spindle formation and affect mitosis. In this proposal, to understand the pathogenesis of microcephaly in Renpenning syndrome, we have developed a new Pqbp1-Y65C mouse model and will explore how this mutation affect the protein interaction and neurogenesis using a combination of different techniques including protein mass spectrometry, flow cytometry, immunofluorescence and immunoblotting and so on. It will expand our understandings of the molecular functions of PQBP1 and the regulation of early embryonic neurogenesis.