2017年1月10日，国际知名遗传学杂志《human molecular genetics》上正式发表东南大学生命科学研究院“发育与疾病相关基因”教育部重点实验室韩俊海课题组题为Mutations of PQBP1 in Renpenning syndrome promote ubiquitin-mediated degradation of FMRP and cause synaptic over-growth的研究论文。博士研究生张晓艳为论文的第一作者，通讯作者为张子超副研究员。

 

Renpenning 综合征是一类x染色体连锁的精神发育迟滞疾病，主要由多聚谷氨酰胺结合蛋白1(Polyglutamine binding protein 1，简称PQBP1)基因突变引起，但分子功能和致病机理目前还不完全清楚。本项研究中检测了在病人中高发的几例PQBP1不同位点突变(c.461_462delAG,c.459_462delAGAG,c.463_464dupAG)的分子以及突触功能，解析其致病机制。结果表明，与PQBP1正常形式相比，c.459_462delAGAG和c.463_464dupAG突变会产生一段全新的C末端序列，与非磷酸化形式的FMRP有强亲和力，促进FMRP通过泛素化途径降解，进而导致FMRP下游靶标MAP1B的上调以及神经元突触可塑性变化。此外，研究中选取果蝇神经肌肉接头(NMJ)作为在体模型，同样证实PQBP1 c.463_464dupAG转基因果蝇呈现出明显的内源dFMRP下调以及突触过度生长的缺陷。此项研究发现了Renpenning 综合征的全新分子致病机理，即PQBP1 c.459_462delAGAG和c.463_464dupAG突变后下调FMRP，为治疗Renpenning 综合征提供新的治疗策略。

 

 

原文摘要：Renpenning syndrome is a group of X-linked intellectual disability (XLID) syndromes caused by mutations in human polyglutamine-binding protein 1 (PQBP1) gene. Little is known about the molecular pathogenesis of the various mutations that cause the notable variability in patients. In this study, we examine the cellular and synaptic functions of the most common mutations found in the patients: c.461_462delAG, c.459_462delAGAG, and c.463_464dupAG in an AG hexamer in PQBP1 exon 4. We discovered that PQBP1c.459_462delAGAG and c.463_464dupAG mutations encode a new C-terminal epitope that preferentially binds non-phosphorylatedfragile X mental retardation protein (FMRP) and promotes its ubiquitin-mediated degradation. Impairment of FMRP function up-regulates its targets such as MAP1B, and disrupts FMRP-dependent synaptic scaling in primary cultured neurons. In Drosophila neuromuscular junction (NMJ) model, PQBP1 c.463_464dupAG transgenic flies showed remarkable defects of synaptic over-growth, which can be rescued by exogenously expressing dFMRP. Our data strongly support a gain-of-function pathogenic mechanism ofPQBP1 c.459_462delAGAG and c.463_464dupAG mutations, and suggest that therapeutic strategies to restore FMRP function may be beneficial for those patients.