Mutations of PQBP1 in Renpenning syndrome promote ubiquitin-mediated degradation of FMRP and cause synaptic dysfunction
Mutations of PQBP1 in Renpenning syndrome promote ubiquitin-mediated degradation of FMRP and cause synaptic dysfunction
复制标题
Renpenning 综合征中 PQBP1 突变促进泛素介导的 FMRP 降解并导致突触功能障碍
DOI：
10.1093/hmg/ddx010
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发表时间：
2017-03-01
影响因子：
3.5
通讯作者：
Zhang, Zi Chao
中科院分区：
文献类型：
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作者：
Zhang, Xiao-Yan;Qi, Junxia;Zhang, Zi Chao
Renpenning综合征是一组由人多谷氨酰胺结合蛋白1 （PQBP1）基因突变引起的x连锁智力残疾综合征。引起患者显著变异的各种突变的分子发病机制尚不清楚。在这项研究中，我们研究了在PQBP1外显子4的AG六聚体中发现的最常见突变的细胞和突触功能：c. 461_462delAG, c. 459_462delAGAG和c. 463_464dupAG。我们发现PQBP1 c. 459_462delAGAG和c. 463_464dupAG突变编码了一个新的c末端表位，该表位优先结合非磷酸化的脆性X智力迟钝蛋白（FMRP）并促进其泛素介导的降解。FMRP功能受损可上调其靶蛋白如MAP1B，并破坏原代培养神经元中依赖FMRP的突触尺度。在果蝇神经肌肉连接模型中，PQBP1 c. 463_464dupAG转基因果蝇表现出明显的突触过度生长缺陷，外源表达dFMRP可以挽救这种缺陷。我们的数据有力地支持PQBP1 c. 459_462delAGAG和c. 463_464dupAG突变的功能获得致病机制，并提示恢复FMRP功能的治疗策略可能对这些患者有益。
Renpenning syndrome is a group of X-linked intellectual disability 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 PQBP1 c. 459_462delAGAG and c. 463_464dupAG mutations encode a new C-terminal epitope that preferentially binds non-phosphorylated fragile 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 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 of PQBP1 c. 459_462delAGAG and c. 463_464dupAG mutations, and suggest that therapeutic strategies to restore FMRP function may be beneficial for those patients.