Dystrophinglycoproteins associated in congenital muscular dystrophy immunohistochemical analysis of 59 brazilian cases lucio gobbo ferreira2, suely kazue marie1, enna cristina liu3, maria bernadete dutra resende2, mary souza carvalho2, milberto scaff4, umbertina conti reed1 abstract the congenital muscular dystrophies cmd are heterogeneous. Role of dystrophin isoforms and associated proteins in. The dystrophinassociated protein complex journal of cell. Regulation of the dystrophin associated glycoprotein complex composition by the. This large multicomponent complex has both mechanical stabilizing and signaling roles in mediating interactions between the cytoskeleton, membrane, and extracellular matrix. Regulation of the dystrophinassociated glycoprotein. Mutations of different components of the dystrophinglycoprotein complex dgc cause muscular dystrophies that vary in terms of severity, age of onset, and selective involvement of muscle groups. Discovery of the gene encoding the protein dystrophin delineated not only the cause of duchenne dystrophy but also an expanding family of at least eight different dystrophinassociated muscle proteins. Now that most of the genes responsible for these conditions have been identified, it is possible to accurately diagnose them and implement subtypespecific anticipatory care, as complications such as cardiac and respiratory muscle involvement vary. Knowledge of diseasespecific complications, implementation of anticipatory care, and medical advances. The reduction of dystrophin expression constitutes the structural basis in the hearts of patients with becker muscular dystrophy and the absence of dystrophin is associated with duchenne muscular.
The coohterminus of dystrophin mediates binding of adapter and signaling proteins, which in turn mediates associations with membranebound ion channels 96, 98. Duchenne muscular dystrophy and dystrophin youtube. It shares its localization at astrocytic endfeet with the dystrophinassociated glycoprotein complex dgc. Although the primary pathogenetic processes in the muscular dystrophies have clearly been identified as apoptotic and necrotic muscle cell death. Xlinked recessive as in duchenne or becker muscular dystrophy dmdbmd, autosomal dominant as in limbgirdle. Efforts to understand the function of dystrophin, the protein product for the duchenne muscular dystrophy. Duchenne muscular dystrophy dmd is a common xlinked, fatal genetic disorder characterized by progressive muscle wasting 1. Primary genetic abnormalities in dystrophin, and dystrophin. The muscular dystrophies affecting the dystrophin glycoprotein complex are associated with a dilated cardiomyopathy. Mlc1 is associated with the dystrophinglycoprotein complex. Muscular dystrophies are primary diseases of muscle due to mutations in more than 40 genes, which result in dystrophic changes on muscle biopsy. Some muscular dystrophies are caused by mutations of dgc components, such as dystrophin, sarcoglycan or laminin2, or also of dgcassociated molecules, such as caveolin3. Dystroglycan and muscolar dystrophies related to the.
The dystrophin glycoprotein complex dgc is a specialization of cardiac and skeletal muscle membrane. Congenital muscular dystrophies cmd 14 muscular dystrophies term coined by erb in 1891 unrelated hereditary, degenerative disorders of dystrophin dystrophinopathies or dystrophinassociated proteins. The duchenne muscular dystrophy dmd gene is the largest human gene 79 exons and 2. It encodes the protein dystrophin and is subject to a high number of mutations, with the majority. The results emphasize the close association between dystrophin and the glycoprotein complex and their role in the pathogenesis of muscle damage. Increased knowledge of the function of dystrophin and its role in muscle has led to a greater understanding of the pathogenesis of dmd. Dec 22, 2016 duchenne muscular dystrophy dmd is an genetic musclewasting disease that leads to disability and early death. Pdf dystroglycan and muscular dystrophies related to the. The dystrophin glycoprotein complex circulation research. In the late 1980s, major advances in molecular genetics led to the discovery of the dystrophin gene and its. Components of dystrophinglycoprotein complex dgc, or dgcassociated, involved in muscular dystrophies subcellular localization protein disease cytoskeleton dystrophin duchenne muscular dystrophy sarcolemma sarcoglycans limbgirdle muscular dystrophy 2cf caveolin3 limbgirdle muscular dystrophy 1c. Some types are also associated with problems in other organs. Defects in several members of the dystrophinglycoprotein complex dgc have been shown to lead to different forms of limbgirdle muscular dystrophy lgmd and congenital muscular dystrophy 7,8. Thus, dystrophin and utrophin are coexpressed in several fibres in carriers.
Winder summary muscular dystrophies are associated with mutations in. The dystrophinglycoprotein complex, cellular signaling, and the regulation of cell survival in the muscular dystrophies. Dystrophinglycoprotein complex, muscular dystrophy, muscle magnetic resonance imaging, differential diagnosis background the dystrophinglycoprotein complex dgc or the dystrophinassociated protein complex composed of the cytoplasmic dystrophin, syntrophin. Dystrophin immunohistochemistry in muscular dystrophies 243 and eosin, pas and gomoris trichrome stains. Deficiency in laminin leads to congenital muscular dystrophy and defective glycosylation of the dystroglycan leads to limbgirdle.
The lethal musclewasting disorder, duchenne muscular dystrophy, is caused by mutations or deletions in the dystrophin gene. Muscular dystrophies arising from dgc defects are recessively inherited, suggesting that gene replacement could be an effective treatment that. We find that wasting in cancer is linked to a dysfunctional dystrophin glycoprotein complex dgc, a membrane structure associated with muscular dystrophy. Muscular dystrophy has five essential characteristics.
Nov 12, 2019 dystrophin glycoprotein complex dgcrelated muscular dystrophies may present similar clinical and pathological features as well as undetectable mutations thus being sometimes difficult to distinguish. When dystrophin is solubilized from the sarcolemmal fraction it is associated with a large oligomeric complex of sarcolemmal proteins and glycoproteins, the dystrophinglycoprotein complex dgc. We investigated the value of muscle magnetic resonance imaging mri in the differential diagnosis of dgcrelated muscular dystrophies and reported the largest series of chinese patients. Further delineation of the sarcoglycan sg complex as a member of the daps formed the basis for the. Components of dystrophin glycoprotein complex dgc, or dgc associated, involved in muscular dystrophies subcellular localization protein disease cytoskeleton dystrophin duchenne muscular dystrophy sarcolemma sarcoglycans limbgirdle muscular dystrophy 2cf caveolin3 limbgirdle muscular dystrophy 1c. The dgc is expressed in various tissues and has been characterized best in skeletal muscle where it connects the cytoskeleton of muscle fibers to the extracellular matrix. This complex is variously known as the costamere or the dystrophinassociated protein complex dapc. Restoration of the dystrophinassociated glycoprotein complex after exon skipping therapy in duchenne muscular dystrophy. Dmd is associated with mutations that disrupt the proteins reading frame. A complete loss of dystrophin due to outofframe mutations leads to dmd, a severe and rapidly progressive muscular disease. To optimize the correction of dmd mutations by crisprcas9 gene editing, amoasii et al. Aggregation of acetylcholine receptors achrs on skeletal muscle fibers is thought to be mediated by the basal lamina protein agrin. Muscular dystrophy md is a group of muscle diseases that results in increasing weakening and breakdown of skeletal muscles over time.
It showed membrane staining of skeletal muscle fibers in all the 32 100% specimens. Mutations in the dgc disrupt the complex and lead to muscular dystrophy. Regulation of the dystrophinassociated glycoprotein complex. Pdf muscular dystrophies are genetically diverse but share common. Sites of disruption of the dystrophinglycoprotein com plex in various diseases are illustrated by sin gleheaded arrows. Deficiencies in other components of the dgc, such as laminin2, can elicit md with similarly devastating symptoms fig. Becker muscular dystrophy bmd is also caused by mutations in the dmd gene that.
Duchenne muscular dystrophy dmd is an genetic musclewasting disease that leads to disability and early death. Sites of disruption of the dystrophin glycoprotein com plex in various diseases are illustrated by sin gleheaded arrows. The histopathological features of muscular dystrophies. In duchenne muscular dystrophy, dystrophin is nearly absent, leading to an early presentation. Various muscular dystrophies md result from defects in the muscle dgc. Xlinked duchennes muscular dystrophy and beckers muscular dystrophy are caused by mutations in the gene encoding dystrophin, a membrane cytoskeletal protein. Duchennebecker muscular dystrophy, congenital muscular dystrophy and various forms of limbgirdle muscular dystrophy.
Muscular dystrophy an overview sciencedirect topics. In skeletal and cardiac muscle, dystrophin associates with various proteins to form the dystrophinassociated protein complex dapc. Discovery of the gene encoding the protein dystrophin delineated not only the cause of duchenne dystrophy but also an expanding family of at least eight different dystrophin associated muscle proteins. Other proteins localized at astrocytic endfeet are those of a multisubunit complex called dystrophinassociated glycoprotein complex dgc 12, 20. Jul, 2007 mlc1 is a protein with unknown function that is mainly expressed in the brain in astrocytic endfeet at the bloodbrain and cerebrospinal fluidbrain barriers. The dystrophin glycoprotein complex dgc is a multisubunit complex that connects the cytoskeleton of a muscle fiber to its surrounding extracellular matrix. Dystrophin is missing in duchenne muscular dystrophy dmd patients or reduced in amount in becker muscular dystrophy bmd patients. The role of the dystrophinglycoprotein complex in the molecular. Two forms of dystrophindeficient muscular dystrophies are dmd and becker muscular dystrophy bmd. Dystrophin is a rodshaped cytoplasmic protein, and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. Pdf the dystrophinglycoprotein complex in the prevention of. Muscular dystrophies and the dystrophinglycoprotein complex. Muscular dystrophies constitute a clinically and genetically heterogeneous group of skeletal musclewasting diseases.
Zebrafish models flex their muscles to shed light on. The gene is the largest in the human genome, encompassing 2. Muscular dystrophy, dystrophin, signaling, neuronal nitric oxide synthase. Mutations in the dystrophin gene cause duchenne muscular dystrophy dmd, a fatal childhood muscle disease. Mlc1 is associated with the dystrophinglycoprotein. Arrhythmias in the muscular dystrophies heart rhythm. Singlecut genome editing restores dystrophin expression. Young patients have motor delays and gait disturbances.
The membrane cytoskeletal component dystrophin and its associated glycoproteins play a central role in the molecular pathogenesis of several muscular dystrophies, i. These mutations are generally located in genes encoding proteins of the dystrophin associated glycoprotein. Dystrophinglycoprotein complex dgcrelated muscular dystrophies may present similar clinical and pathological features as well as undetectable mutations thus being sometimes difficult to distinguish. When dystrophin is solubilized from the sarcolemmal fraction it is associated with a large oligomeric complex of sarcolemmal proteins and glycoproteins, the dystrophin glycoprotein complex dgc. In muscular dystrophy, almost all dystrophinassociated proteins are greatly reduced in their relative density 26, 90, 91. The dystrophinglycoprotein complex, cellular signaling. Sep, 2006 the dystrophinglycoprotein complex, cellular signaling, and the regulation of cell survival in the muscular dystrophies. The sg complex has four subunits and is part of the dystrophinassociated protein complex. Following the identification of dystrophin mutations as the underlying genetic cause of duchenne and becker muscular dystrophies hoffman et al. Defects in the gene for the muscle protein dystrophin cause many cases of muscular dystrophy. The roles of the dystrophinassociated glycoprotein complex at.
Omim 310200 is an xlinked recessive disorder that affects 1 in 3,500 males and is caused by mutations in the dystrophin gene blake et al, 2002. Efforts to understand the function of dystrophin, the protein product for the duchenne muscular dystrophy gene, resulted in the purification of the dystrophinglycoprotein complex. In skeletal and cardiac muscle, dystrophin is associated with a large oligomeric complex of sarcolemmal glycoproteins. Dystrophin glycoproteins associated in congenital muscular dystrophy immunohistochemical analysis of 59 brazilian cases lucio gobbo ferreira2, suely kazue marie1, enna cristina liu3, maria bernadete dutra resende2, mary souza carvalho2, milberto scaff4, umbertina conti reed1 abstract the congenital muscular dystrophies cmd are heterogeneous. Worton discusses three new papers, one in this issue of science noguchi et al. Becker muscular dystrophy severity is linked to the. Structural similarities shared by agrin and laminin suggested that the laminin receptor dystroglycan. Muscular dystrophies and the dystrophin glycoprotein complex. In skeletal and cardiac muscle, dystrophin associates with various proteins to form the dystrophin associated protein complex dapc. Restoration of the dystrophinassociated glycoprotein complex. Nonmechanical roles of dystrophin and associated proteins in. However, these genes do not cause muscular dystrophies and their exact function is under investigation.
This complex is variously known as the costamere or the dystrophin associated protein complex dapc. Muscular dystrophies involving the dystrophinglycoprotein. Membrane organization of the dystrophinglycoprotein complex mit. In all cases of this disease, the gene for a protein known as dystrophin is mutated. Dystrophinglycoprotein complex and laminin colocalize to the sarcolemma and transverse tubules of cardiac muscle. Muscular dystrophies involving the dystrophinglycoprotein complex. Dissecting the signaling and mechanical functions of the dystrophin. An improved understanding of their molecular bases has led to more accurate definitions of the clinical features associated with known subtypes. Gene therapy of muscular dystrophy human molecular. The dystrophinglycoprotein complex, cellular signaling, and. These include two that span the membrane the dystroglycans, at least five within the membrane the sarcoglycans, and a submembrane protein utrophin. Cardiac muscle is commonly affected in muscular dystrophies.
The authors then reported a method in which a single cut in genomic. Sg have been identified as additional members of the sg family. The phenotype of muscular dystrophy is an endpoint that arises from a diverse set of genetic pathways. The dystrophinassociated protein complex journal of. Nonmechanical roles of dystrophin and associated proteins. Mutations in the dystrophin gene are associated with sporadic dilated cardiomyopathy. Muscular dystrophies involving the dystrophinglycoprotein complex durbeej and campbell 351 figure 1 the dgc in skeletal muscle is composed of dystrophin, the dystroglycans. The disorders differ in which muscles are primarily affected, the degree of weakness, how fast they worsen, and when symptoms begin. Becker muscular dystrophy severity is linked to the structure. Muscular dystrophies, the cytoskeleton and cell adhesion heather j. Duchenne muscular dystrophy dmd is caused by mutations in the gene that encodes the 427kda cytoskeletal protein dystrophin.
Duchenne muscular dystrophy dmd is a progressive, severely disabling, and incurable xlinked recessive inherited disorder that affects 1 in. Genes associated with muscular dystrophies encode proteins of the plasma membrane and extracellular matrix, and the sarcomere and z band. Mutations in components of the dgc are responsible for muscular dystrophies and congenital myopathies. Dec 16, 2019 for sarcolemmal stability, dystrophin and the dystrophin associated glycoproteins dags are important elements. In becker muscular dystrophy, dystrophin is reduced to a lesser degree and a more variable, typically later, presentation is observed. We investigated the value of muscle magnetic resonance imaging mri in the differential diagnosis of dgcrelated muscular dystrophies and reported the largest series of chinese patients with. The muscular dystrophies affecting the dystrophinglycoprotein complex are associated with a dilated cardiomyopathy. Duchenne muscular dystrophy is a muscle disease caused by mutation in the gene that encodes the cytoskeletal protein dystrophin.
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