TPI缺乏症斑马鱼模型的构建及分析

doi:10.16288/j.yczz.23-316

遗传 ›› 2024, Vol. 46 ›› Issue (3): 232-241.doi: 10.16288/j.yczz.23-316

TPI缺乏症斑马鱼模型的构建及分析

孙飘¹(), 李颖¹(), 刘帆¹, 王璐¹^,²()

1.中国医学科学院血液病医院(中国医学科学院血液学研究所)，实验血液学国家重点实验室，国家血液系统疾病临床医学研究中心，细胞生态海河实验室，天津 300020
2.天津医学健康研究院，天津 301600

收稿日期:2023-12-22 修回日期:2024-02-05 出版日期:2024-03-20 发布日期:2024-02-22
通讯作者: 王璐 E-mail:sunpiao@ihcams.ac.cn;liying3@ihcams.ac.cn;wanglu1@ihcams.ac.cn
作者简介:孙飘，硕士研究生，专业方向：干细胞与再生医学。E-mail: sunpiao@ihcams.ac.cn;
李颖，博士，研究方向：干细胞与再生医学。E-mail: liying3@ihcams.ac.cn;
孙飘和李颖同为第一作者。
基金资助:
国家自然科学基金项目(32222027);国家自然科学基金项目(32170838);天津市杰出青年项目(21JCJQJC00120)

Generation and analysis of TPI deficiency zebrafish model

Piao Sun¹(), Ying Li¹(), Fan Liu¹, Lu Wang¹^,²()

1. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
2. Tianjin Institutes of Health Science, Tianjin 301600, China

Received:2023-12-22 Revised:2024-02-05 Published:2024-03-20 Online:2024-02-22
Contact: Lu Wang E-mail:sunpiao@ihcams.ac.cn;liying3@ihcams.ac.cn;wanglu1@ihcams.ac.cn
Supported by:
National Natural Science Foundation of China(32222027);National Natural Science Foundation of China(32170838);Science Fund for Distinguished Young Scholars of Tianjin Municipality(21JCJQJC00120)

摘要/Abstract

摘要：

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。

关键词: 磷酸丙糖异构酶缺乏症, TPI1^E105D, 斑马鱼, 疾病模型

Abstract:

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.

Key words: triosephosphate isomerase deficiency (TPI DF), TPI1^E105D, zebrafish, disease model

孙飘, 李颖, 刘帆, 王璐. TPI缺乏症斑马鱼模型的构建及分析[J]. 遗传, 2024, 46(3): 232-241.

Piao Sun, Ying Li, Fan Liu, Lu Wang. Generation and analysis of TPI deficiency zebrafish model[J]. Hereditas(Beijing), 2024, 46(3): 232-241.

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参考文献 23

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突变位点	与功能域的关系	功能
M1K	二聚化位点	影响催化活性
C42Y	靠近底物结合位点和二聚化位点	影响催化活性和分子稳定性
A63D	靠近二聚化位点	影响分子稳定性
G73A	底物结合位点，靠近二聚化位点	影响催化活性和分子稳定性
E105D	靠近二聚化位点	影响分子稳定性
G123R	不影响功能域	无异常
G146*	TPI翻译提前终止	不明
V155M	不影响功能域	无异常
I171V	位于底物结合位点和柔性环内	影响催化活性和分子稳定性
R190*	TPI翻译提前终止	不明
V232M	底物结合位点，靠近二聚化位点	影响催化活性和分子稳定性
F241L	底物结合位点	影响催化活性
F241S	底物结合位点	影响催化活性

TPI缺乏症斑马鱼模型的构建及分析

Generation and analysis of TPI deficiency zebrafish model

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