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Mol Ther Nucleic Acids. 2018 Dec 7;13:198-207. doi: 10.1016/j.omtn.2018.08.013. Epub 2018 Aug 22.

Exon Skipping in a Dysf-Missense Mutant Mouse Model.

Author information

1
Muscle Research Unit, Experimental and Clinical Research Center (ECRC), a cooperation between the Charité, Universitätsmedizin Berlin and the Max- Delbrück- Center for Molecular Medicine, 13125 Berlin, Germany; Université de Versailles St-Quentin, INSERM U1179, 78180 Montigny-le-Bretonneux, France.
2
Muscle Research Unit, Experimental and Clinical Research Center (ECRC), a cooperation between the Charité, Universitätsmedizin Berlin and the Max- Delbrück- Center for Molecular Medicine, 13125 Berlin, Germany; Charité, Universitätsmedizin Berlin, 10117 Berlin, Germany.
3
Université de Versailles St-Quentin, INSERM U1179, 78180 Montigny-le-Bretonneux, France.
4
Muscle Research Unit, Experimental and Clinical Research Center (ECRC), a cooperation between the Charité, Universitätsmedizin Berlin and the Max- Delbrück- Center for Molecular Medicine, 13125 Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany.
5
Muscle Research Unit, Experimental and Clinical Research Center (ECRC), a cooperation between the Charité, Universitätsmedizin Berlin and the Max- Delbrück- Center for Molecular Medicine, 13125 Berlin, Germany; Charité, Universitätsmedizin Berlin, 10117 Berlin, Germany; Berlin Institute of Health, 10178 Berlin, Germany.
6
Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany; Charité, Universitätsmedizin Berlin, 10117 Berlin, Germany; Berlin Institute of Health, 10178 Berlin, Germany; DZHK (German Centre for Cardiovascular Research), partner site, 13347 Berlin, Germany.
7
Muscle Research Unit, Experimental and Clinical Research Center (ECRC), a cooperation between the Charité, Universitätsmedizin Berlin and the Max- Delbrück- Center for Molecular Medicine, 13125 Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany; Charité, Universitätsmedizin Berlin, 10117 Berlin, Germany; Berlin Institute of Health, 10178 Berlin, Germany. Electronic address: simone.spuler@charite.de.
8
Muscle Research Unit, Experimental and Clinical Research Center (ECRC), a cooperation between the Charité, Universitätsmedizin Berlin and the Max- Delbrück- Center for Molecular Medicine, 13125 Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany; Berlin Institute of Health, 10178 Berlin, Germany.

Abstract

Limb girdle muscular dystrophy 2B (LGMD2B) is without treatment and caused by mutations in the dysferlin gene (DYSF). One-third is missense mutations leading to dysferlin aggregation and amyloid formation, in addition to defects in sarcolemmal repair and progressive muscle wasting. Dysferlin-null mouse models do not allow study of the consequences of missense mutations. We generated a new mouse model (MMex38) carrying a missense mutation in exon 38 in analogy to a clinically relevant human DYSF variant (DYSF p.Leu1341Pro). The targeted mutation induces all characteristics of missense mutant dysferlinopathy, including a progressive dystrophic pattern, amyloid formation, and defects in membrane repair. We chose U7 small nuclear RNA (snRNA)-based splice switching to demonstrate a possible exon-skipping strategy in this new animal model. We show that Dysf exons 37 and 38 can successfully be skipped in vivo. Overall, the MMex38 mouse model provides an ideal tool for preclinical development of treatment strategies for dysferlinopathy.

KEYWORDS:

AAV; MMex38; U7 snRNA; dysferlin; dysferlinopathy; exon skipping; mouse model

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