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The neuromuscular junction (NMJ) is the synapse between a motor neuron and skeletal muscle. Defects in NMJ transmission cause muscle weakness, termed myasthenia. The muscle protein Dok-7 is essential for activation of the receptor kinase MuSK, which governs NMJ formation, and DOK7 mutations underlie familial limb-girdle myasthenia (DOK7 myasthenia), a neuromuscular disease characterized by small NMJs. Here, we show in a mouse model of DOK7 myasthenia that therapeutic administration of an adeno-associated virus (AAV) vector encoding the human DOK7 gene resulted in an enlargement of NMJs and substantial increases in muscle strength and life span. When applied to model mice of another neuromuscular disorder, autosomal dominant Emery-Dreifuss muscular dystrophy, DOK7 gene therapy likewise resulted in enlargement of NMJs as well as positive effects on motor activity and life span. These results suggest that therapies aimed at enlarging the NMJ may be useful for a range of neuromuscular disorders.

Original publication

DOI

10.1126/science.1250744

Type

Journal article

Journal

Science

Publication Date

19/09/2014

Volume

345

Pages

1505 - 1508

Keywords

Animals, Dependovirus, Disease Models, Animal, Female, Genetic Therapy, Genetic Vectors, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle Proteins, Muscle, Skeletal, Muscular Dystrophies, Limb-Girdle, Neuromuscular Junction