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

Author:

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

Abstract

AbstractMultisystem 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.

Publisher

Cold Spring Harbor Laboratory

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