CRISPR/Cas9-generated mouse model of Duchenne muscular dystrophy recapitulating a newly identified large 430 kb deletion in the human DMD gene
| Autor: | Svetlana G. Vassilieva, Dmitry V. Vlodavets, A. V. Polikarpova, Alexey A. Gavrilov, Denis A. Reshetov, Sergey V. Ulianov, Vladimir L. Buchman, Evgenia D. Zotova, Alexei V. Deykin, Tatiana V. Egorova |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Duchenne muscular dystrophy Medicine (miscellaneous) lcsh:Medicine medicine.disease_cause New deletion Dystrophin Exon 0302 clinical medicine Muscle degeneration Immunology and Microbiology (miscellaneous) CRISPR Muscular dystrophy Child Base Pairing Sequence Deletion Mutation Muscles Exons Chromatin Biomechanical Phenomena Phenotype Female Exon skipping RNA Guide Kinetoplastida Genome editing lcsh:RB1-214 musculoskeletal diseases congenital hereditary and neonatal diseases and abnormalities Neuroscience (miscellaneous) Computational biology Biology General Biochemistry Genetics and Molecular Biology Frameshift mutation Cell Line Mouse model 03 medical and health sciences DMD medicine lcsh:Pathology Animals Humans Resource Article lcsh:R medicine.disease Mice Inbred C57BL Muscular Dystrophy Duchenne Disease Models Animal 030104 developmental biology biology.protein CRISPR-Cas Systems 030217 neurology & neurosurgery |
| Zdroj: | Disease Models & Mechanisms, Vol 12, Iss 4 (2019) Disease Models & Mechanisms |
| ISSN: | 1754-8411 1754-8403 |
| Popis: | 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. Summary: The authors describe the creation of a mouse strain that reproduces a newly identified deletion mutation in a DMD patient in Russia, and present the characteristics of this new model. |
| Databáze: | OpenAIRE |
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