title: Neuromuscular disease. DOK7 gene therapy benefits mouse models of diseases characterized by defects in the neuromuscular junction.
abstract: 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.
authors.affiliation: Division of Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Sumimasa
authors.initials: S
authors.lastname: Arimura
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Okada
authors.affiliation: Division of Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Tezuka
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Chiyo
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kasahara
authors.affiliation: Department of Occupational Therapy, Nagasaki University School of Health Sciences, Nagasaki, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Yoshimura
authors.affiliation: Department of Electrical and Electronics Engineering, Faculty of Engineering, Nagasaki Institute of Applied Science, Nagasaki, Japan.
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Motomura
authors.affiliation: Laboratory of Developmental Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Yoshida
authors.affiliation: Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: David
authors.initials: D
authors.lastname: Beeson
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Division of Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. yyamanas@ims.u-tokyo.ac.jp.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamanashi
mesh_terms: D000818:Animals; D000229:Dependovirus; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000294:innervation* / Q000503:physiopathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D009469:Neuromuscular Junction / Q000473:pathology*
chemical_list: C511692:DOK7 protein, human; C511694:Dok-7 protein, mouse; D009124:Muscle Proteins