共查询到20条相似文献,搜索用时 0 毫秒
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An agrin minigene rescues dystrophic symptoms in a mouse model for congenital muscular dystrophy 总被引:21,自引:0,他引:21
Moll J Barzaghi P Lin S Bezakova G Lochmüller H Engvall E Müller U Ruegg MA 《Nature》2001,413(6853):302-307
Congenital muscular dystrophy is a heterogeneous and severe, progressive muscle-wasting disease that frequently leads to death in early childhood. Most cases of congenital muscular dystrophy are caused by mutations in LAMA2, the gene encoding the alpha2 chain of the main laminin isoforms expressed by muscle fibres. Muscle fibre deterioration in this disease is thought to be caused by the failure to form the primary laminin scaffold, which is necessary for basement membrane structure, and the missing interaction between muscle basement membrane and the dystrophin-glycoprotein complex (DGC) or the integrins. With the aim to restore muscle function in a mouse model for this disease, we have designed a minigene of agrin, a protein known for its role in the formation of the neuromuscular junction. Here we show that this mini-agrin-which binds to basement membrane and to alpha-dystroglycan, a member of the DGC-amends muscle pathology by a mechanism that includes agrin-mediated stabilization of alpha-dystroglycan and the laminin alpha5 chain. Our data provides in vivo evidence that a non-homologous protein in combination with rational protein design can be used to devise therapeutic tools that may restore muscle function in human muscular dystrophies. 相似文献
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P N Goodfellow 《Nature》1986,322(6074):12-13
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Failure to correct murine muscular dystrophy. 总被引:17,自引:0,他引:17
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Defective membrane repair in dysferlin-deficient muscular dystrophy 总被引:35,自引:0,他引:35
Bansal D Miyake K Vogel SS Groh S Chen CC Williamson R McNeil PL Campbell KP 《Nature》2003,423(6936):168-172
Muscular dystrophy includes a diverse group of inherited muscle diseases characterized by wasting and weakness of skeletal muscle. Mutations in dysferlin are linked to two clinically distinct muscle diseases, limb-girdle muscular dystrophy type 2B and Miyoshi myopathy, but the mechanism that leads to muscle degeneration is unknown. Dysferlin is a homologue of the Caenorhabditis elegans fer-1 gene, which mediates vesicle fusion to the plasma membrane in spermatids. Here we show that dysferlin-null mice maintain a functional dystrophin-glycoprotein complex but nevertheless develop a progressive muscular dystrophy. In normal muscle, membrane patches enriched in dysferlin can be detected in response to sarcolemma injuries. In contrast, there are sub-sarcolemmal accumulations of vesicles in dysferlin-null muscle. Membrane repair assays with a two-photon laser-scanning microscope demonstrated that wild-type muscle fibres efficiently reseal their sarcolemma in the presence of Ca2+. Interestingly, dysferlin-deficient muscle fibres are defective in Ca2+-dependent sarcolemma resealing. Membrane repair is therefore an active process in skeletal muscle fibres, and dysferlin has an essential role in this process. Our findings show that disruption of the muscle membrane repair machinery is responsible for dysferlin-deficient muscle degeneration, and highlight the importance of this basic cellular mechanism of membrane resealing in human disease. 相似文献
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Germline mosaicism and Duchenne muscular dystrophy mutations 总被引:12,自引:0,他引:12
E Bakker C Van Broeckhoven E J Bonten M J van de Vooren H Veenema W Van Hul G J Van Ommen A Vandenberghe P L Pearson 《Nature》1987,329(6139):554-556
Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disease with an incidence of approximately 1 in 3,500 newborn boys. The DMD locus has a high mutation frequency: one third of the cases is thought to result from a new mutation. Linkage studies using probes to detect restriction fragment length polymorphisms and DNA deletion studies have greatly improved DMD carrier detection and prenatal diagnosis. Here we report on two families in which a pERT87 (DXS164) deletion was transmitted to more than one offspring by women who showed no evidence for the mutation in their own somatic (white blood) cells. We also show that the deletion in both siblings in one of the families is identical, indicating that the deletion must have occurred during mitosis in early germline proliferation, leading to a germline mosaicism. This phenomenon may turn out to be a major factor contributing to the induction of DMD mutations, and has important implications for the counselling of DMD families. 相似文献
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J L Howland 《Nature》1974,251(5477):724-725
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Duchenne muscular dystrophy. Localizing the gene product 总被引:2,自引:0,他引:2
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Muscle membrane protein kinase in myotonic muscular dystrophy 总被引:7,自引:0,他引:7
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Long-range restriction map around the Duchenne muscular dystrophy gene 总被引:14,自引:0,他引:14
Duchenne muscular dystrophy is an X-linked recessive disease affecting about 1 in 4,000 newborn boys. As in many other inherited diseases, the biochemical basis of the condition is unknown, and as yet there is no effective treatment. Translocations, deletions and other mutations leading to the DMD phenotype are distributed over a chromosomal area of large, but unknown size. Using pulsed-field gradient gel electrophoresis, we have now determined restriction maps of a major fraction of this area, covering two regions of three million basepairs in total, and used it to determine the position of several probes linked to DMD. The maps establish physical distances between structural changes associated with the DMD phenotype and provide evidence for a CpG-rich island proximal to the area containing translocations and deletions associated with the DMD phenotype. 相似文献
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