Dosage effect of multiple genes accounts for multisystem disorder of myotonic dystrophy type 1.,Cell Research

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Dosage effect of multiple genes accounts for multisystem disorder of myotonic dystrophy type 1.
Cell Research ( IF 28.1 ) Pub Date : 2019-12-18 , DOI: 10.1038/s41422-019-0264-2
Qi Yin ₁ , Hongye Wang ₂ , Na Li _{1,

3} , Yifu Ding ₁ , Zhenfei Xie ₁ , Lifang Jin _{1,

4} , Yan Li ₂ , Qiong Wang ₂ , Xinyi Liu ₅ , Liuqing Xu ₅ , Qing Li ₁ , Yongjian Ma ₁ , Yanbo Cheng ₁ , Kai Wang ₁ , Cuiqing Zhong ₁ , Qian Yu ₆ , Wei Tang ₆ , Wanjin Chen ₅ , Wenjun Yang ₁ , Fan Zhang ₇ , Chen Ding ₇ , Lan Bao ₂ , Bin Zhou ₂ , Ping Hu _{2,

8} , Jinsong Li _{1,

9}

Affiliation

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.
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.
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.
College of Life Science of Shaoxing University, Shaoxing, Zhejiang, 312000, China.
Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, 350005, China.
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.
State Key Laboratory of Genetic Engineering, Human Phenome Institute, Institutes of Biomedical Sciences, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
School of Life Science and Technology, Shanghai Tech University, Shanghai, 201210, China.

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.

中文翻译：

多种基因的剂量效应解释了1型肌强直性营养不良的多系统疾病。

1型强直性肌营养不良症（DM1）的多系统表现可能是由于DMPK中CTG重复异常扩增引起的多个基因剂量减少所致，包括DMPK，其邻近基因（SIX5或DMWD）和下游MBNL1。但是，缺乏直接的证据。在这里，我们开发了一种新策略，可通过将带有突变Dmpk，Six5和Mbnl1的单倍体胚胎干细胞注射到卵母细胞中来生成携带多基因杂合突变的小鼠，从而一步一步模拟剂量的降低。三重杂合突变小鼠表现出成年发作的DM1表型。随着Dmwd中的额外突变，四重杂合突变小鼠概括了先天性DM1中的许多主要表现。此外，两种模型中的肌肉干细胞均显示出降低的干性，从而为筛选用于治疗DM1的小分子提供了独特的模型。

更新日期：2019-12-19

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