文献类型：期刊文献

英文题名：Dosage effect of multiple genes accounts for multisystem disorder of myotonic dystrophy type 1

作者：Yin, Qi[1];Wang, Hongye[2];Li, Na[1,3];Ding, Yifu[1];Xie, Zhenfei[1];Jin, Lifang[1,4];Li, Yan[2];Wang, Qiong[2];Liu, Xinyi[5,6];Xu, Liuqing[5,6];Li, Qing[1];Ma, Yongjian[1];Cheng, Yanbo[1];Wang, Kai[1];Zhong, Cuiqing[1];Yu, Qian[7];Tang, Wei[7];Chen, Wanjin[5,6];Yang, Wenjun[1];Zhang, Fan[8];Ding, Chen[8];Bao, Lan[2];Zhou, Bin[2];Hu, Ping[2,9];Li, Jinsong[1,10]

机构：[1]Univ Chinese Acad Sci, Chinese Acad Sci, CAS Ctr Excellence Mol Cell Sci,Shanghai Inst Bio, State Key Lab Cell Biol,Shanghai Key Lab Mol Andr, Shanghai 200031, Peoples R China;[2]Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, State Key Lab Cell Biol,CAS Ctr Excellence Mol Ce, Shanghai 200031, Peoples R China;[3]Shanghai Univ Med & Hlth Sci, Affiliated Jiading Dist Cent Hosp, Sch Med Technol, Shanghai Key Lab Mol Imaging, Shanghai 201318, Peoples R China;[4]Shaoxing Univ, Coll Life Sci, Shaoxing 312000, Zhejiang, Peoples R China;[5]Fujian Med Univ, Affiliated Hosp 1, Dept Neurol, Fuzhou 350005, Fujian, Peoples R China;[6]Fujian Med Univ, Affiliated Hosp 1, Inst Neurol, Fuzhou 350005, Fujian, Peoples R China;[7]Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Anim Core Facil,CAS Ctr Excellence Mol Cell Sci, Shanghai 200031, Peoples R China;[8]Fudan Univ, Zhongshan Hosp, State Key Lab Genet Engn, Human Phenome Inst,Inst Biomed Sci,Sch Life Sci, Shanghai 200032, Peoples R China;[9]Chinese Acad Sci, Inst Stem Cell & Regenerat, Beijing 100101, Peoples R China;[10]Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China

年份：2020

卷号：30

期号：2

起止页码：133

外文期刊名：CELL RESEARCH

收录：SCI-EXPANDED(收录号：WOS:000510783300006)、、Scopus(收录号：2-s2.0-85077041927)、WOS

基金：HSALR mice were obtained from Dr. Charles Thornton in the Wellstone Center at the University of Rochester. We thank Y. Chen and X. Ding from the Core Facility for Stem Cell Research at SIBCB for support with cell cultures and M. Chen from Core Facility for Chemical Biology for support with small-molecule screen. This study was 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,

语种：英文

外文摘要：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 MBNL1. 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 Mbnl1 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 stemness, 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.