Dosage effect of multiple genes accounts for multisystem disorder of myotonic dystrophy type 1

查看全文 作　　者：Qi [1]Yin;Hongye [1,2]Wang;Na [1,3]Li;Yifu [1]Ding;Zhenfei [1]Xie;Lifang [1,4]Jin;Yan [2]Li;Qiong [2]Wang;Xinyi [5]Liu;Liuqing [5]Xu;Qing [1]Li;Yongjian [1]Ma;Yanbo [1]Cheng;Kai [1]Wang;Cuiqing [1]Zhong;Qian [6]Yu;Wei [6]Tang;Wanjin [5]Chen;Wenjun [1]Yang;Fan [7]Zhang;Chen [7]Ding;Lan [2]Bao;Bin [2]Zhou;Ping [2,8]Hu;Jinsong [1,9]Li

机构地区：[1]State Key Laboratory of Cell Biology,Shanghai Key Laboratory of Molecular Andrology,CAS Center for Excellence in Molecular Cell Science,Shanghai Institute of Biochemistry and Cell Biology,Chinese Academy of Sciences,University of Chinese Academy of Sciences,Shanghai 200031,China;[2]State Key Laboratory of Cell Biology,CAS Center for Excellence in Molecular Cell Science,Shanghai Institute of Biochemistry and Cell Biology,Chinese Academy of Sciences,University of Chinese Academy of Sciences,Shanghai 200031,China;[3]Shanghai University of Medicine and Health Sciences affiliated Jiading District Central Hospital,Shanghai Key Laboratory of Molecular Imaging,School of Medical Technology,Shanghai University of Medicine and Health Sciences,Shanghai 201318,China;[4]College of Life Science of Shaoxing University,Shaoxing,Zhejiang 312000,China;[5]Department of Neurology and Institute of Neurology,First Affiliated Hospital,Fujian Medical University,Fuzhou,Fujian 350005,China;[6]Animal Core Facility,CAS Center for Excellence in Molecular Cell Science,Shanghai Institute of Biochemistry and Cell Biology,Chinese Academy of Sciences,University of Chinese Academy of Sciences,Shanghai 200031,China;[7]State Key Laboratory of Genetic Engineering,Human Phenome Institute,Institutes of Biomedical Sciences,School of Life Sciences,Zhongshan Hospital,Fudan University,Shanghai 200032,China;[8]Institute for Stem Cell and Regeneration,Chinese Academy of Sciences,Beijing 100101,China;[9]School of Life Science and Technology,Shanghai Tech University,Shanghai 201210,China

出　　处：《Cell Research》索引2020年第30卷第2期,共13页

基　　金：Supported by Genome Tagging Project,Fountain-Valley Life Sciences Fund of University of Chinese Academy of Sciences Education Foundation,and grants from the Ministry of Science and Technology of China(2019YFA0109900,2017YFA0102700);Chinese Academy of Sciences(XDB19010204,XDA16020400,QYZDJ-SSW-SMC023);the National Natural Science Foundation of China(31530048,31821004,81672117,31900541,91649104,31671536);Shanghai Municipal Commission for Science and Technology(17411954900,17JC1400900,18ZR1446300 and 19ZR1423900);CAS-CSIRO Cooperative Research Program(GJHZ1504)and Innovation Promotion Association of the Chinese Academy of Sciences(to W.Y.). 摘　　要：Multisystem manifestations in myotonic dystrophy type 1(DM1)may be due to dosage reduction in multiple genes induced by aberrant expansion of CTG repeats in DMPK,including DMPK,its neighboring genes(SIX5 or DMWD)and downstream MBNLh However,direct evidence is lacking.Here,we develop a new strategy to generate mice carrying multigene heterozygous mutations to mimic dosage reduction in one step by injection of haploid embryonic stem cells with mutant Dmpk,Six5 and Mbnll into oocytes.The triple heterozygous mutant mice exhibit adult-onset DM1 phenotypes.With the additional mutation in Dmwd,the quadruple heterozygous mutant mice recapitulate many major manifestations in congenital DM1.Moreover,muscle stem cells in both models display reduced sternness,providing a unique model for screening small molecules for treatment of DM1.Our results suggest that the complex symptoms of DM1 result from the reduced dosage of multiple genes. 关键词：DOSAGE DYSTROPHY effect

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Dosage effect of multiple genes accounts for multisystem disorder of myotonic dystrophy type 1

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