Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

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

Egorova, Tatiana V., Zotova, Evgenia D., Reshetov, Denis A., Polikarpova, Anna V., Vassilieva, Svetlana G., Vlodavets, Dmitry V., Gavrilov, Alexey A., Ulianov, Sergey V., Buchman, Vladimir L. ORCID: https://orcid.org/0000-0002-7631-8352 and Deykin, Alexei V. 2019. CRISPR/Cas9-generated mouse model of Duchenne muscular dystrophy recapitulating a newly identified large 430 kb deletion in the human DMD gene. Disease Models and Mechanisms 12 (4) , -. 10.1242/dmm.037655

[thumbnail of CRISPR-Cas9-generated mouse model of Duchenne muscular dystrophy recapitulating a newly identified large 430 kb deletion.pdf]
Preview
PDF - Published Version
Available under License Creative Commons Attribution.

Download (9MB) | Preview

Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Company of Biologists: OAJ
ISSN: 1754-8403
Date of First Compliant Deposit: 21 May 2019
Date of Acceptance: 20 March 2019
Last Modified: 02 May 2023 22:15
URI: https://orca.cardiff.ac.uk/id/eprint/122752

Citation Data

Cited 20 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics