Muscular dystrophies are among the most common human genetic diseases and are characterized by progressive muscle degeneration. Muscular dystrophies result from genetic defects in components of the dystrophin–glycoprotein complex (DGC), a multimeric complex found in the muscle cell plasma membrane1. The DGC links the intracellular cytoskeleton to the extracellular matrix and is thought to be important for maintaining the mechanical integrity of muscles2 and organizing signalling molecules3. The exact role of the DGC in the pathogenesis of disease has, however, remained uncertain4. Mutations in Caenorhabditis elegans DGC genes lead to specific defects in coordinated movement and can also cause muscle degeneration5,6,7. Here we show that mutations in the gene snf-6 result in phenotypes indistinguishable from those of the DGC mutants, and that snf-6 encodes a novel acetylcholine/choline transporter. SNF-6 mediates the uptake of acetylcholine at neuromuscular junctions during periods of increased synaptic activity. SNF-6 also interacts with the DGC, and mutations in DGC genes cause a loss of SNF-6 at neuromuscular junctions. Improper clearing of acetylcholine and prolonged excitation of muscles might contribute to the pathogenesis of muscular dystrophies.
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We thank J. S. Kim, C. Yu and R. Ho for technical help, J. Rand and C. Bargmann for personal communication and helpful discussions, and all members of the McIntire laboratory for discussions and comments on the manuscript. Some strains were provided by the National Bioresource Project (Japan), the C. elegans Gene Knockout Consortium and the Caenorhabditis Genetics Center. This work was supported by funds provided by the State of California for medical research on alcohol and substance abuse through the University of California, San Francisco, by a grant to S.L.M. from the Department of the Army, by a grant to J.E.R. from NIH and by a development grant to H.K. from the Muscular Dystrophy Association.
This movie was taken immediately after animals were transferred to a new plate. Wild-type N2 animals.
This movie was taken immediately after animals were transferred to a new plate. dys-1 mutants.
This movie was taken immediately after animals were transferred to a new plate. snf-6 mutants.
This movie was taken immediately after animals were transferred to a new plate. snf-6; ace-1 mutants.
Wild-type N2 movie before and after touch.
snf-6 mutant movie before and after touch.
About this article
European Journal of Human Genetics (2005)