TPI缺乏症斑马鱼模型的构建及分析

孙飘, 李颖, 刘帆, 王璐

doi:10.16288/j.yczz.23-316

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2024 , Vol. 46 >Issue 3: 232 - 241

DOI: https://doi.org/10.16288/j.yczz.23-316

研究报告

TPI缺乏症斑马鱼模型的构建及分析

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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

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。

王璐，博士，研究员，研究方向：发育生物学，干细胞与再生医学。E-mail: wanglu1@ihcams.ac.cn

收稿日期: 2023-12-22

修回日期: 2024-02-05

网络出版日期: 2024-02-22

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)

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Generation and analysis of TPI deficiency zebrafish model

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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 date: 2023-12-22

Revised date: 2024-02-05

Online published: 2024-02-22

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)

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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

本文引用格式

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 . DOI: 10.16288/j.yczz.23-316

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

参考文献

[1]	Schneider AS. Triosephosphate isomerase deficiency: historical perspectives and molecular aspects. Baillieres Best Pract Res Clin Haematol, 2000, 13(1): 119-140.
[2]	Rieder SV, Rose IA. The mechanism of the triosephosphate isomerase reaction. J Biol Chem, 1959, 234(5): 1007-1010.
[3]	Wierenga RK, Kapetaniou EG, Venkatesan R. Triosephosphate isomerase: a highly evolved biocatalyst. Cell Mol Life Sci, 2010, 67(23): 3961-3982.
[4]	Schneider AS, Valentine WN, Hattori M, Heins HL. Hereditary hemolytic anemia with triosephosphate isomerase deficiency. N Engl J Med, 1965, 272: 229-235.
[5]	Orosz F, Oláh J, Ovádi J. Triosephosphate isomerase deficiency: new insights into an enigmatic disease. Biochim Biophys Acta, 2009, 1792(12): 1168-1174.
[6]	Orosz F, Oláh J, Ovádi J. Triosephosphate isomerase deficiency: facts and doubts. IUBMB Life, 2006, 58(12): 703-715.
[7]	Daar IO, Artymiuk PJ, Phillips DC, Maquat LE. Human triose-phosphate isomerase deficiency: a single amino acid substitution results in a thermolabile enzyme. Proc Natl Acad Sci USA, 1986, 83(20): 7903-7907.
[8]	Schneider A, Cohen-Solal M. Hematologically important mutations: triosephosphate isomerase. Blood Cells Mol Dis, 1996, 22(1): 82-84.
[9]	Oliver C, Timson DJ. In silico prediction of the effects of mutations in the human triose phosphate isomerase gene: towards a predictive framework for TPI deficiency. Eur J Med Genet, 2017, 60(6): 289-298.
[10]	Ralser M, Heeren G, Breitenbach M, Lehrach H, Krobitsch S. Triose phosphate isomerase deficiency is caused by altered dimerization--not catalytic inactivity-- of the mutant enzymes. PLoS One, 2006, 1(1): e30.
[11]	Zhang CX, Liu F. A brief protocol for high-resolution whole mount in situ hybridization in zebrafish. Hereditas(Beijing), 2013, 35(4): 522-528.
	张春霞, 刘峰. 斑马鱼高分辨率整胚原位杂交实验方法与流程. 遗传, 2013, 35(4): 522-528.
[12]	Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez JY, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A. Fiji: an open-source platform for biological-image analysis. Nat Methods, 2012, 9(7): 676-682.
[13]	Roland BP, Zeccola AM, Larsen SB, Amrich CG, Talsma AD, Stuchul KA, Heroux A, Levitan ES, Vandemark AP, Palladino MJ. Structural and genetic studies demonstrate neurologic dysfunction in triosephosphate isomerase deficiency is associated with impaired synaptic vesicle dynamics. PLoS Genet, 2016, 12(3): e1005941.
[14]	Selamio?lu A, Karaca M, Balc? MC, K?rbeyli HK, Durmu? A, Y?ld?z EP, Karaman S, G?k?ay GF. Triosephosphate isomerase deficiency: E105D mutation in unrelated patients and review of the literature. Mol Syndromol, 2023, 14(3): 231-238.
[15]	Li XX, Li Y, Zhao X, Peng GX, Li JP, Ye L, Yang WR, Zhou K, Fan HH, Yang Y, Xiong YZ, Li Y, Song L, Jing LP, Zhang L, Zhang FK. Characteristics of bone marrow compensatory erythropoiesis in hereditary spherocytosis. Chin J Hematol, 2022, 43(2): 115-119.
	李小霞, 李园, 赵馨, 彭广新, 李建平, 叶蕾, 杨文睿, 周康, 樊慧慧, 杨洋, 熊佑祯, 李洋, 宋琳, 井丽萍, 张莉, 张凤奎. 遗传性球形红细胞增多症骨髓红系造血代偿特征. 中华血液学杂志, 2022, 43(2): 115-119.
[16]	Beguin Y, Clemons GK, Pootrakul P, Fillet G. Quantitative assessment of erythropoiesis and functional classification of anemia based on measurements of serum transferrin receptor and erythropoietin. Blood, 1993, 81(4): 1067-1076.
[17]	Horwood NJ. Macrophage polarization and bone formation: a review. Clin Rev Allergy Immunol, 2016, 51(1): 79-86.
[18]	Segal AW. How neutrophils kill microbes. Annu Rev Immunol, 2005, 23: 197-223.
[19]	Segal J, Mülleder M, Krüger A, Adler T, Scholze-Wittler M, Becker L, Calzada-Wack J, Garrett L, H?lter SM, Rathkolb B, Rozman J, Racz I, Fischer R, Busch DH, Neff F, Klingenspor M, Klopstock T, Grüning NM, Michel S, Lukaszewska-Mcgreal B, Voigt I, Hartmann L, Timmermann B, Lehrach H, Wolf E, Wurst W, Gailus-Durner V, Fuchs H, de Angelis MH, Schrewe H, Yuneva M, Ralser M. Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase deficiency. J Inherit Metab Dis, 2019, 42(5): 839-849.
[20]	Myers TD, Ferguson C, Gliniak E, Homanics GE, Palladino MJ. Murine model of triosephosphate isomerase deficiency with anemia and severe neuromuscular dysfunction. Curr Res Neurobiol, 2022, 3: 100062.
[21]	Hrizo SL, Eicher SL, Myers TD, Mcgrath I, Wodrich APK, Venkatesh H, Manjooran D, Swoger S, Gagnon K, Bruskin M, Lebedev MV, Zheng S, Vitantonio A, Kim S, Lamb ZJ, Vogt A, Ruzhnikov MRZ, Palladino MJ. Identification of protein quality control regulators using a Drosophila model of TPI deficiency. Neurobiol Dis, 2021, 152: 105299.
[22]	Mainfroid V, Terpstra P, Beauregard M, Frère JM, Mande SC, Hol WG, Martial JA, Goraj K. Three hTIM mutants that provide new insights on why TIM is a dimer. J Mol Biol, 1996, 257(2): 441-456.
[23]	Orosz F, Wágner G, Liliom K, Kovács J, Baróti K, Horányi M, Farkas T, Hollán S, Ovádi J. Enhanced association of mutant triosephosphate isomerase to red cell membranes and to brain microtubules. Proc Natl Acad Sci USA, 2000, 97(3): 1026-1031.

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