In:
Cell Research, Springer Science and Business Media LLC, Vol. 30, No. 2 ( 2020-02), p. 133-145
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1001-0602
,
1748-7838
DOI:
10.1038/s41422-019-0264-2
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2020
detail.hit.zdb_id:
2082402-6
SSG:
12
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