TPI缺乏症斑马鱼模型的构建及分析

Generation and analysis of TPI deficiency zebrafish model

磷酸丙糖异构酶缺乏症(triosephosphate isomerase deficiency,TPI DF)是一种严重的多系统退行性疾病,通常表现为溶血性贫血、神经肌肉功能障碍和易感染,患者多于起病5年内死亡。目前尚不清楚TPI DF的具体发病机制,缺乏有效的临床治疗方法。本研究选取TPI DF患者中最常见的突变位点TPI1^(E105D),构建了表达人源性TPI1^(E105D)(hTPI1^(E105D))的转基因斑马鱼(Danio rerio)模型[Tg(Ubi:TPI1^(E105D)-eGFP)]。功能分析表明,过表达TPI1^(E105D)影响红系及髓系细胞发育、导致神经以及肌肉发育异常。综上所述,本研究构建了磷酸丙糖异构酶缺乏症的斑马鱼疾病模型,并能够复现TPI DF患者的大部分临床表型,该模型为后续研究TPI DF的发病机制及药物筛选提供了新的实验动物模型。

Triosephosphate isomerase deficiency(TPI DF)is a severe multisystem degenerative disease,manifested clinically as hemolytic anemia,neuromuscular abnormalities,and susceptibility to infection,frequently leading to death within 5 years of onset.There is a lack of effective clinical treatment as the pathogenesis underlying TPI DF remains largely unknown.In this study,we generate a transgenic zebrafish line[Tg(Ubi:TPI1^(E105D)-eGFP)]with the human TPI1^(E105D)(hTPI1^(E105D))mutation,which is the most recurrent mutation in TPI DF patients.Overexpression of hTPI1^(E105D)affects the development of erythroid and myeloid cells and leads to impaired neural and muscular development.In conclusion,we create a TPI DF zebrafish model to recapitulate the majority clinical features of TPI DF patients,providing a new animal model for pathogenesis study and drug screening of TPI DF.