CRISPR/Cas9-generated mouse model of Duchenne muscular dystrophy recapitulating a newly identified large 430 kb deletion in the human DMD gene

Egorova, T.; Zotova, E.; Reshetov, D.; Polikarpova, A.; Vassilieva, S.; Vlodavets, D.; Gavrilov, A.; Ulianov, S.; Buchman, V.; Deykin, A.

Авторы: Egorova TV, Zotova ED, Reshetov DA, Polikarpova AV, Vassilieva SG, Vlodavets DV, Gavrilov AA, Ulianov SV, Buchman VL, Deykin AV
Журнал: DMM Disease Models and Mechanisms
Том: 12
Номер: 4
Год издания: 2019
Издательство: The Company of Biologists Ltd.
Местоположение издательства: United Kingdom
DOI: 10.1242/dmm.037655
Аннотация: Exon skipping is a promising strategy for Duchenne muscular dystrophy (DMD) disease-modifying therapy. To make this approach safe, ensuring that excluding one or more exons will restore the reading frame and that the resulting protein will retain critical functions of the full-length dystrophin protein is necessary. However, in vivo testing of the consequences of skipping exons that encode the N-terminal actin-binding domain (ABD) has been confounded by the absence of a relevant animal model. We created a mouse model of the disease recapitulating a novel human mutation, a large de novo deletion of exons 8-34 of the DMD gene, found in a Russian DMD patient. This mutation was achieved by deleting exons 8-34 of the X-linked mouse Dmd gene using CRISPR/Cas9 genome editing, which led to a reading frame shift and the absence of functional dystrophin production. Male mice carrying this deletion display several important signs of muscular dystrophy, including a gradual age-dependent decrease in muscle strength, increased creatine kinase, muscle fibrosis and central nucleation. The degrees of these changes are comparable to those observed in mdx mice, a standard laboratory model of DMD. This new model of DMD will be useful for validating therapies based on skipping exons that encode the N-terminal ABD and for improving our understanding of the role of the N-terminal domain and central rod domain in the biological function of dystrophin. Simultaneous skipping of exons 6 and 7 should restore the gene reading frame and lead to the production of a protein that might retain functionality despite the partial deletion of the ABD.
Добавил в систему: Ульянов Сергей Владимирович

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CRISPR/Cas9-generated mouse model of Duchenne muscular dystrophy recapitulating a newly identified large 430 kb deletion in the human DMD geneстатья

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