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First published online October 22, 2003
doi: 10.1242/10.1242/dev.00799

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Dystrophin is required for the formation of stable muscle attachments in the zebrafish embryo

¹ Comparative and Developmental Genetics Section, MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK
² Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK
³ Victor Chang Cardiac Research Institute, 384 Victoria Street, Darlinghurst, Sydney 2010, Australia
⁴ Department of Molecular and Cell Biology, University of California Berkeley, 555 Life Sciences Addition #3200, Berkeley, CA 94720-3200, USA

^* Author for correspondence (e-mail: dbassett{at}hgu.mrc.ac.uk)

Accepted 12 August 2003

A class of recessive lethal zebrafish mutations has been identified in which normal skeletal muscle differentiation is followed by a tissue-specific degeneration that is reminiscent of the human muscular dystrophies. Here, we show that one of these mutations, sapje, disrupts the zebrafish orthologue of the X-linked human Duchenne muscular dystrophy (DMD) gene. Mutations in this locus cause Duchenne or Becker muscular dystrophies in human patients and are thought to result in a dystrophic pathology through disconnecting the cytoskeleton from the extracellular matrix in skeletal muscle by reducing the level of dystrophin protein at the sarcolemma. This is thought to allow tearing of this membrane, which in turn leads to cell death. Surprisingly, we have found that the progressive muscle degeneration phenotype of sapje mutant zebrafish embryos is caused by the failure of embryonic muscle end attachments. Although a role for dystrophin in maintaining vertebrate myotendinous junctions (MTJs) has been postulated previously and MTJ structural abnormalities have been identified in the Dystrophin-deficient mdx mouse model, in vivo evidence of pathology based on muscle attachment failure has thus far been lacking. This zebrafish mutation may therefore provide a model for a novel pathological mechanism of Duchenne muscular dystrophy and other muscle diseases.

Key words: Myomuscular junctions, Myotendinous junctions, Dystrophin, sapje, Muscle attachments, Muscular dystrophy, Congenital myopathy

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