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Biochimica Et Biophysica Acta Sep 2010Dystrophin is one of a number of large cytoskeleton associated proteins that connect between various cytoskeletal elements and often are tethered to the membrane through... (Review)
Review
Dystrophin is one of a number of large cytoskeleton associated proteins that connect between various cytoskeletal elements and often are tethered to the membrane through other transmembrane protein complexes. These cytolinker proteins often provide structure and support to the cells where they are expressed, and mutations in genes encoding these proteins frequently gives rise to disease. Dystrophin is no exception in any of these respects, providing connections between a transmembrane complex known as the dystrophin-glycoprotein complex and the underlying cytoskeleton. The most established connection and possibly the most important is that to F-actin, but more recently evidence has been forthcoming of connections to membrane phospholipids, intermediate filaments and microtubules. Moreover it is becoming increasingly clear that the multiple spectrin-like repeats in the centre of the molecule, that had hitherto been thought to be largely redundant, harbour binding activities that have a significant impact on dystrophin functionality. This functionality is particularly apparent when assessed by the ability to rescue the dystrophic phenotype in mdx mice. This review will focus on the relatively neglected but functionally vital coiled-coil region of dystrophin, highlighting the structural relationships and interactions of the coiled-coil region and providing new insights into the functional role of this region.
Topics: Animals; Dystrophin; Humans; Mice; Protein Interaction Domains and Motifs
PubMed: 20472103
DOI: 10.1016/j.bbapap.2010.05.001 -
Biochimica Et Biophysica Acta Feb 2014Dystrophin is a 427kDa sub-membrane cytoskeletal protein, associated with the inner surface membrane and incorporated in a large macromolecular complex of proteins, the... (Review)
Review
Dystrophin is a 427kDa sub-membrane cytoskeletal protein, associated with the inner surface membrane and incorporated in a large macromolecular complex of proteins, the dystrophin-associated protein complex (DAPC). In addition to dystrophin the DAPC is composed of dystroglycans, sarcoglycans, sarcospan, dystrobrevins and syntrophin. This complex is thought to play a structural role in ensuring membrane stability and force transduction during muscle contraction. The multiple binding sites and domains present in the DAPC confer the scaffold of various signalling and channel proteins, which may implicate the DAPC in regulation of signalling processes. The DAPC is thought for instance to anchor a variety of signalling molecules near their sites of action. The dystroglycan complex may participate in the transduction of extracellular-mediated signals to the muscle cytoskeleton, and β-dystroglycan was shown to be involved in MAPK and Rac1 small GTPase signalling. More generally, dystroglycan is view as a cell surface receptor for extracellular matrix proteins. The adaptor proteins syntrophin contribute to recruit and regulate various signalling proteins such as ion channels, into a macromolecular complex. Although dystrophin and dystroglycan can be directly involved in signalling pathways, syntrophins play a central role in organizing signalplex anchored to the dystrophin scaffold. The dystrophin associated complex, can bind up to four syntrophin through binding domains of dystrophin and dystrobrevin, allowing the scaffold of multiple signalling proteins in close proximity. Multiple interactions mediated by PH and PDZ domains of syntrophin also contribute to build a complete signalplex which may include ion channels, such as voltage-gated sodium channels or TRPC cation channels, together with, trimeric G protein, G protein-coupled receptor, plasma membrane calcium pump, and NOS, to enable efficient and regulated signal transduction and ion transport. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Hervé.
Topics: Animals; Dystrophin; Humans; Multiprotein Complexes; Muscle Contraction; Signal Transduction
PubMed: 24021238
DOI: 10.1016/j.bbamem.2013.08.023 -
Medical Hypotheses Sep 2008Dystrophin and its associated proteins form a scaffold underneath the cardiomyocyte membrane and connect the intracellular cytoskeleton to the extracellular matrix.... (Review)
Review
Dystrophin and its associated proteins form a scaffold underneath the cardiomyocyte membrane and connect the intracellular cytoskeleton to the extracellular matrix. Dystrophin localizes at the X chromosome, whose mutations might result in Duchenne muscular dystrophy, Becker muscular dystrophy and X-linked dilated cardiomyopathy. In addition to these genetic dilated cardiomyopathies, some acquired dilated cardiomyopathy like viral dilated cardiomyopathy is also related to dystrophin disruption or aberrant cleavage. In this review, we summarize the structure and distribution of dystrophin and researches of dystrophin in genetic and viral dilated cardiomyopathy. Moreover, we hypothesize that dystrophin play a critical role in ventricular remodeling in ischemic myocardium and treatment targeting restoration of dystrophin onto membrane could benefit for ischemic cardiomyopathy.
Topics: Cardiomyopathies; Dystrophin; Glycoproteins; Humans; Myocardial Ischemia; Ventricular Remodeling
PubMed: 18562127
DOI: 10.1016/j.mehy.2008.04.004 -
BioEssays : News and Reviews in... Jun 1993This review is primarily concerned with two key issues in research on dystrophin: (1) how the protein interacts with the plasma membrane of skeletal muscle fibres and... (Comparative Study)
Comparative Study Review
This review is primarily concerned with two key issues in research on dystrophin: (1) how the protein interacts with the plasma membrane of skeletal muscle fibres and (2) how an absence of dystrophin gives rise to Duchenne muscular dystrophy. In relation to the first point, we suggest that the post-translational acylation of dystrophin may contribute to its interaction with the plasma membrane. Regarding the second point, it is generally considered that an absence of dystrophin makes the plasma membrane susceptible to damage by contraction/relaxation cycles. In this connection, we propose that the progressive nature of Duchenne dystrophy, and the phenotypic characteristics of mdx mice, are more consistent with dystrophin functioning as a mechanical transducer that transmits growth stimuli from the enlarging skeleton to the muscle. On the basis of this hypothesis, dystrophin-deficient muscles would be unable to grow at the same rate as the skeleton.
Topics: Amino Acid Sequence; Animals; Cell Membrane; Dystrophin; Humans; Models, Structural; Molecular Sequence Data; Muscle Development; Muscles; Sequence Homology, Amino Acid; Signal Transduction
PubMed: 8357344
DOI: 10.1002/bies.950150608 -
Brain Pathology (Zurich, Switzerland) Jan 1996
Review
Topics: Animals; Cognition; Dystrophin; Heterozygote; Humans; Isomerism; Muscular Dystrophies; Nerve Tissue Proteins; Nervous System; Tissue Distribution
PubMed: 8866748
DOI: 10.1111/j.1750-3639.1996.tb00783.x -
Glia Mar 2022In addition to progressive muscular degeneration due to dystrophin mutations, 1/3 of Duchenne muscular dystrophy (DMD) patients present cognitive deficits. However,...
In addition to progressive muscular degeneration due to dystrophin mutations, 1/3 of Duchenne muscular dystrophy (DMD) patients present cognitive deficits. However, there is currently an incomplete understanding about the function of the multiple dystrophin isoforms in human brains. Here, we tested the hypothesis that dystrophin deficiency affects glial function in DMD and could therefore contribute to neural impairment. We investigated human dystrophin isoform expression with development and differentiation and response to damage in human astrocytes from control and induced pluripotent stem cells from DMD patients. In control cells, short dystrophin isoforms were up-regulated with development and their expression levels changed differently upon neuronal and astrocytic differentiation, as well as in 2-dimensional versus 3-dimensional astrocyte cultures. All DMD-astrocytes tested displayed altered morphology, proliferative activity and AQP4 expression. Furthermore, they did not show any morphological change in response to inflammatory stimuli and their number was significantly lower as compared to stimulated healthy astrocytes. Finally, DMD-astrocytes appeared to be more sensitive than controls to oxidative damage as shown by their increased cell death. Behavioral and metabolic defects in DMD-astrocytes were consistent with gene pathway dysregulation shared by lines with different mutations as demonstrated by bulk RNA-seq analysis. Together, our DMD model provides evidence for altered astrocyte function in DMD suggesting that defective astrocyte responses may contribute to neural impairment and might provide additional potential therapeutic targets.
Topics: Astrocytes; Cell Differentiation; Dystrophin; Humans; Induced Pluripotent Stem Cells; Muscular Dystrophy, Duchenne
PubMed: 34773297
DOI: 10.1002/glia.24116 -
Bosnian Journal of Basic Medical... Jul 2015Mutations of the dystrophin DMD gene, essentially deletions of one or several exons, are the cause of two devastating and to date incurable diseases, Duchenne (DMD) and... (Review)
Review
Mutations of the dystrophin DMD gene, essentially deletions of one or several exons, are the cause of two devastating and to date incurable diseases, Duchenne (DMD) and Becker (BMD) muscular dystrophies. Depending upon the preservation or not of the reading frame, dystrophin is completely absent in DMD, or present in either a mutated or a truncated form in BMD. DMD is a severe disease which leads to a premature death of the patients. Therapy approaches are evolving with the aim to transform the severe DMD in the BMD form of the disease by restoring the expression of a mutated or truncated dystrophin. These therapies are based on the assumption that BMD is a mild disease. However, this is not completely true as BMD patients are more or less severely affected and no molecular basis of this heterogeneity of the BMD form of the disease is yet understood. The aim of this review is to report for the correlation between dystrophin structures in BMD deletions in view of this heterogeneity and to emphasize that examining BMD patients in details is highly relevant to anticipate for DMD therapy effects.
Topics: Dystrophin; Humans; Muscular Dystrophy, Duchenne; Mutation
PubMed: 26295289
DOI: 10.17305/bjbms.2015.636 -
Biochimica Et Biophysica Acta Feb 2007Duchenne muscular dystrophy is the most prevalent and severe form of human muscular dystrophy. Investigations into the molecular basis for Duchenne muscular dystrophy... (Review)
Review
Duchenne muscular dystrophy is the most prevalent and severe form of human muscular dystrophy. Investigations into the molecular basis for Duchenne muscular dystrophy were greatly facilitated by seminal studies in the 1980s that identified the defective gene and its major protein product, dystrophin. Biochemical studies revealed its tight association with a multi-subunit complex, the so-named dystrophin-glycoprotein complex. Since its description, the dystrophin-glycoprotein complex has emerged as an important structural unit of muscle and also as a critical nexus for understanding a diverse array of muscular dystrophies arising from defects in several distinct genes. The dystrophin homologue utrophin can compensate at the cell/tissue level for dystrophin deficiency, but functions through distinct molecular mechanisms of protein-protein interaction.
Topics: Animals; Dystrophin; Glycoproteins; Humans; Muscular Dystrophy, Duchenne; Protein Interaction Mapping
PubMed: 16829057
DOI: 10.1016/j.bbadis.2006.05.010 -
Trends in Molecular Medicine Jul 2015Targeted dystrophin exon removal is a promising therapy for Duchenne muscular dystrophy (DMD); however, dystrophin expression in some reports is not supported by the... (Review)
Review
Targeted dystrophin exon removal is a promising therapy for Duchenne muscular dystrophy (DMD); however, dystrophin expression in some reports is not supported by the associated data. As in the account of 'The Emperor's New Clothes', the validity of such claims must be questioned, with critical re-evaluation of available data. Is it appropriate to report clinical benefit and induction of dystrophin as dose dependent when the baseline is unclear? The inability to induce meaningful levels of dystrophin does not mean that dystrophin expression as an end point is irrelevant, nor that induced exon skipping as a strategy is flawed, but demands that drug safety and efficacy, and study parameters be addressed, rather than questioning the strategy or the validity of dystrophin as a biomarker.
Topics: Animals; Dystrophin; Exons; Humans; Muscular Dystrophy, Duchenne
PubMed: 26051381
DOI: 10.1016/j.molmed.2015.04.006 -
International Journal of Molecular... Oct 2018Mutations in the gene encoding for the intracellular protein dystrophin cause severe forms of muscular dystrophy. These so-called dystrophinopathies are characterized by... (Review)
Review
Mutations in the gene encoding for the intracellular protein dystrophin cause severe forms of muscular dystrophy. These so-called dystrophinopathies are characterized by skeletal muscle weakness and degeneration. Dystrophin deficiency also gives rise to considerable complications in the heart, including cardiomyopathy development and arrhythmias. The current understanding of the pathomechanisms in the dystrophic heart is limited, but there is growing evidence that dysfunctional voltage-dependent ion channels in dystrophin-deficient cardiomyocytes play a significant role. Herein, we summarize the current knowledge about abnormalities in voltage-dependent sarcolemmal ion channel properties in the dystrophic heart, and discuss the potentially underlying mechanisms, as well as their pathophysiological relevance.
Topics: Animals; Arrhythmias, Cardiac; Cardiomyopathies; Dystrophin; Humans; Ion Channels; Potassium Channels; Sarcolemma; Sodium Channels
PubMed: 30360568
DOI: 10.3390/ijms19113296