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

By Qi Yin, Hongye Wang, Zhenfei Xie, Lifang Jin, Yifu Ding, Na Li, Yan Li, Qiong Wang, Xinyi Liu, Liuqing Xu, Kai Wang, Yanbo Cheng, Boran Chang, Cuiqing Zhong, Qian Yu, Wei Tang, Wanjin Chen, Wenjun Yang, Fan Zhang, Chen Ding, Lan Bao, Bin Zhou, Ping Hu, Jinsong Li

Posted 03 Jun 2019
bioRxiv DOI: 10.1101/658526 (published DOI: 10.1038/s41422-019-0264-2)

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 and its neighboring genes (Six5 or Dmwd) and downstream Mbnl1. However, the direct evidences are lack. Here, we develop a new strategy to generate mice carrying multigene mutations 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, quadruple heterozygous mutant mice recapitulate many major manifestations in congenital DM1. Moreover, muscle stem cells in both models display reduced stemness. Our results suggest that the complex symptoms of DM1 result from the reduced gene dosage of multiple genes.

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