Identification of a chromosome 6-encoded dystrophin-related protein.

The X-linked muscle-wasting disease Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin. There is currently no effective treatment for the disease; however, the complex molecular pathology of this disorder is now being unravelled. Dystrophin is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Mutations in many components of the dystrophin protein complex cause other forms of autosomally inherited muscular dystrophy, indicating the importance of this complex in normal muscle function. Although the precise function of dystrophin is unknown, the lack of protein causes membrane destabilization and the activation of multiple pathophysiological processes, many of which converge on alterations in intracellular calcium handling. Dystrophin is also the prototype of a family of dystrophin-related proteins, many of which are found in muscle. This family includes utrophin and alpha-dystrobrevin, which are involved in the maintenance of the neuromuscular junction architecture and in muscle homeostasis. New insights into the pathophysiology of dystrophic muscle, the identification of compensating proteins, and the discovery of new binding partners are paving the way for novel therapeutic strategies to treat this fatal muscle disease. This review discusses the role of the dystrophin complex and protein family in muscle and describes the physiological processes that are affected in Duchenne muscular dystrophy.

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“…1). Because of its structural kinship with dystrophin and its ubiquitous tissue distribution, this protein was called utrophin (43,270,307).…”

Section: A the Utrophin Genementioning

confidence: 99%

Function and Genetics of Dystrophin and Dystrophin-Related Proteins in Muscle

Blake

Weir

Newey

et al. 2002

Physiological Reviews

1,046

879

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“…The antibodies used in this study were well characterized in previous studies (Hoffman et al 1987;Sealock et al 1991). They only recognize dystrophin and do not cross-react with the recently discovered relative of dystrophin, the dystrophin-related protein (Love et al 1991;Khurana et al 1990;Thi Man et al 1991;Ohlendieck et al 1991) in mammalian muscle. Since one of the antibodies used in this study (mAb 1958) was prepared against Torpedo postsynaptic membrane, we compared the dystrophin band in this tissue with the Xenopus sample in the same experiments.…”

Section: Detection Of Xenopus Dystrophin By Western Blotsmentioning

confidence: 99%

Induction of dystrophin localization in cultured Xenopus muscle cells by latex beads

Peng

Chen

1992

Journal of Cell Science

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The distribution of dystrophin in Xenopus myotomal muscle cells was examined in conventional and confocal immunofluorescence microscopy. By labeling dissociated single muscle fibers with a monoclonal or a polyclonal antibody against dystrophin, we found that dystrophin is ten times more concentrated at the myotendinous junction (MTJ) than at the extrajunctional sarcolemma. At the MTJ, dystrophin lines the membrane invaginations where myofibrils attach to the membrane. It is colocalized with talin, but is not related to the distribution of acetylcholine receptors (AChRs) which are clustered at the postsynaptic membrane in the vicinity of the MTJ in these fibers. We found that the localization of dystrophin can be induced in cultured Xenopus myotomal muscle cells by treating them with polystyrene latex beads. Dystrophin is discretely localized at the bead-muscle contacts. With electron microscopy, a sarcolemma specialization with all the salient features of the MTJ, including basal lamina-lined membrane invaginations along which myofibrils make attachment. Although these beads also induce clustering of AChRs, the patterns of dystrophin and AChR localization are distinct. The appearance of dystrophin at the bead-contacted sarcolemma is coincident with the development of the membrane invaginations. This, together with its concentration along membrane invaginations at the MTJ in vivo, suggests a role for dystrophin in the formation of this junctional specialization. Since the signal for MTJ development can be presented to cultured muscle cells in a temporally and spatially controlled manner by beads, this system offers a simple model for analyzing the mechanism of this sarcolemma specialization.

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“…During foetal development utrophin is found over the entire surface of muscle fibres, but is replaced by dystrophin during development, when utrophin becomes localized to the neuromuscular junction in adult skeletal muscle (Hoffman et al 1989;Khurana et al 1990Khurana et al , 1991. The dystrophic phenotype normally observed in mdx mice is absent when muscles overexpress utrophin (Tinsley et al 1998).…”

Section: Defining the Action Of Dystrophin And Dystrophin-related Proteins Through Metabolitesmentioning

confidence: 99%

Metabolic profiles to define the genome: can we hear the phenotypes?

Griffin

2004

Phil. Trans. R. Soc. Lond. B

119

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There is an increased reliance on genetically modified organisms as a functional genomic tool to elucidate the role of genes and their protein products. Despite this, many models do not express the expected phenotype thought to be associated with the gene or protein. There is thus an increased need to further define the phenotype resultant from a genetic modification to understand how the transcriptional or proteomic network may conspire to alter the expected phenotype. This is best typified by the description of the silent phenotype in genetic manipulations of yeast. High-resolution proton nuclear magnetic resonance ((1)H NMR) spectroscopy provides an ideal mechanism for the profiling of metabolites within biofluids, tissue extracts or, with recent advances, intact tissues. These metabolic datasets can be readily mined using a range of pattern recognition techniques, including hierarchical cluster analysis, principal components analysis, partial least squares and neural networks, with the combined approach being termed metabolomics. This review describes the application of NMR-based metabolomics or metabonomics to genetic and chemical interventions in a number of different species, demonstrating the versatility of such an approach, as well as suggesting how it may be integrated with other "omic" technologies.

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Identification of a chromosome 6-encoded dystrophin-related protein.

Cited by 198 publications

References 26 publications

Function and Genetics of Dystrophin and Dystrophin-Related Proteins in Muscle

Function and Genetics of Dystrophin and Dystrophin-Related Proteins in Muscle

Induction of dystrophin localization in cultured Xenopus muscle cells by latex beads

Metabolic profiles to define the genome: can we hear the phenotypes?

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