Generation and characterization of a novel mouse model of Becker Muscular Dystrophy with a deletion of exons 52 to 55

• Published in: Disease models & mechanisms
• Main Authors: Perillat, Lucie O M, Wong, Tatianna W Y, Maino, Eleonora, Ahmed, Abdalla, Scott, Ori, Hyatt, Elzbieta, Delgado-Olguin, Paul, Visuvanathan, Shagana, Ivakine, Evgueni A, Cohn, Ronald D
• Format: Journal Article
• Language: English
• Published: England 05-08-2024
• Subjects: BMD; DMD; Mouse model; CRISPR-Cas9; Muscular dystrophy; In-frame deletions
• ISSN: 1754-8403; 1754-8411; 1754-8411
• DOI: 10.1242/dmm.050595

Becker Muscular Dystrophy (BMD) is a rare X-linked recessive neuromuscular disorder frequently caused by in-frame deletions in the DMD gene that result in the production of a truncated, yet functional, dystrophin protein. The consequences of BMD-causing in-frame deletions on the organism are difficult to predict, especially in regard to long-term prognosis. Here, we employed CRISPR-Cas9 to generate a new Dmd del52-55 mouse model by deleting exons 52-55, resulting in a BMD-like in-frame deletion. To delineate the long-term effects of this deletion, we studied these mice over 52 weeks by performing histology and echocardiography analyses and assessing motor functions. Our results suggest that a truncated dystrophin is sufficient to maintain wildtype-like muscle and heart histology and functions in young mice. However, the truncated protein appears insufficient to maintain normal muscle homeostasis and protect against exercise-induced damage at 52 weeks. To further delineate the effects of this exon52-55 in-frame deletion, we performed RNA-Seq pre- and post-exercise and identified several differentially expressed pathways that reflect the abnormal muscle phenotype observed at 52 weeks in the BMD model.