Sg have been identified as additional members of the sg family. Further delineation of the sarcoglycan sg complex as a member of the daps formed the basis for the. Sep, 2006 the dystrophinglycoprotein complex, cellular signaling, and the regulation of cell survival in the muscular dystrophies. In becker muscular dystrophy, dystrophin is reduced to a lesser degree and a more variable, typically later, presentation is observed.
The sg complex has four subunits and is part of the dystrophinassociated protein complex. It encodes the protein dystrophin and is subject to a high number of mutations, with the majority. Worton discusses three new papers, one in this issue of science noguchi et al. 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. Mlc1 is associated with the dystrophinglycoprotein complex. 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. The muscular dystrophies affecting the dystrophin glycoprotein complex are associated with a dilated cardiomyopathy. Two forms of dystrophindeficient muscular dystrophies are dmd and becker muscular dystrophy bmd. 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. 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. This complex is variously known as the costamere or the dystrophinassociated protein complex dapc. Dec 16, 2019 for sarcolemmal stability, dystrophin and the dystrophin associated glycoproteins dags are important elements.
Genes associated with muscular dystrophies encode proteins of the plasma membrane and extracellular matrix, and the sarcomere and z band. Dystrophin immunohistochemistry in muscular dystrophies 243 and eosin, pas and gomoris trichrome stains. Some types are also associated with problems in other organs. Nonmechanical roles of dystrophin and associated proteins. 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. Deficiencies in other components of the dgc, such as laminin2, can elicit md with similarly devastating symptoms fig. Muscular dystrophies involving the dystrophinglycoprotein. An improved understanding of their molecular bases has led to more accurate definitions of the clinical features associated with known subtypes. Muscular dystrophy, dystrophin, signaling, neuronal nitric oxide synthase. Duchennebecker muscular dystrophy, congenital muscular dystrophy and various forms of limbgirdle muscular dystrophy.
In the late 1980s, major advances in molecular genetics led to the discovery of the dystrophin gene and its. Muscular dystrophy has five essential characteristics. In muscular dystrophy, almost all dystrophinassociated proteins are greatly reduced in their relative density 26, 90, 91. Aggregation of acetylcholine receptors achrs on skeletal muscle fibers is thought to be mediated by the basal lamina protein agrin.
Dmd is associated with mutations that disrupt the proteins reading frame. Mutations in components of the dgc are responsible for muscular dystrophies and congenital myopathies. Singlecut genome editing restores dystrophin expression. 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 dystrophin glycoprotein complex circulation research. Cardiac muscle is commonly affected in muscular dystrophies. Mutations in the dystrophin gene are associated with sporadic dilated cardiomyopathy. Mutations in different dgc components lead to various muscular dystrophies. Dystrophinglycoprotein complex and laminin colocalize to the sarcolemma and transverse tubules of cardiac muscle.
A complete loss of dystrophin due to outofframe mutations leads to dmd, a severe and rapidly progressive muscular disease. This complex is variously known as the costamere or the dystrophin associated protein complex dapc. Various muscular dystrophies md result from defects in the muscle dgc. Structural similarities shared by agrin and laminin suggested that the laminin receptor dystroglycan. The role of the dystrophinglycoprotein complex in the molecular. Muscular dystrophies and the dystrophinglycoprotein complex. Restoration of the dystrophinassociated glycoprotein complex after exon skipping therapy in duchenne muscular dystrophy. 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. Dissecting the signaling and mechanical functions of the dystrophin. 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. Duchenne muscular dystrophy dmd is a common xlinked, fatal genetic disorder characterized by progressive muscle wasting 1. Muscular dystrophies are a heterogeneous group of inherited disorders that share similar clinical features and dystrophic changes on muscle biopsy.
Dystrophin is missing in duchenne muscular dystrophy dmd patients or reduced in amount in becker muscular dystrophy bmd patients. Regulation of the dystrophinassociated glycoprotein complex. Muscular dystrophies involving the dystrophinglycoprotein complex durbeej and campbell 351 figure 1 the dgc in skeletal muscle is composed of dystrophin, the dystroglycans. Although the primary pathogenetic processes in the muscular dystrophies have clearly been identified as apoptotic and necrotic muscle cell death.
Efforts to understand the function of dystrophin, the protein product for the duchenne muscular dystrophy. 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. Membrane organization of the dystrophinglycoprotein complex mit. Regulation of the dystrophin associated glycoprotein complex composition by the.
Increased knowledge of the function of dystrophin and its role in muscle has led to a greater understanding of the pathogenesis of dmd. Deficiency in laminin leads to congenital muscular dystrophy and defective glycosylation of the dystroglycan leads to limbgirdle. In skeletal and cardiac muscle, dystrophin is associated with a large oligomeric complex of sarcolemmal glycoproteins. Pdf muscular dystrophies are genetically diverse but share common. The dystrophinglycoprotein complex, cellular signaling, and the regulation of cell survival in the muscular dystrophies. Duchenne muscular dystrophy and dystrophin youtube. 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. Muscular dystrophies and the dystrophin glycoprotein complex. 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. Dystrophin immunohistochemistry in muscular dystrophies on. Muscular dystrophies arising from dgc defects are recessively inherited, suggesting that gene replacement could be an effective treatment that. Regulation of the dystrophinassociated glycoprotein. Becker muscular dystrophy severity is linked to the.
Mlc1 is associated with the dystrophinglycoprotein. Xlinked recessive as in duchenne or becker muscular dystrophy dmdbmd, autosomal dominant as in limbgirdle. 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. In duchenne muscular dystrophy, dystrophin is nearly absent, leading to an early presentation. Pdf the dystrophinglycoprotein complex in the prevention of. Role of dystrophin isoforms and associated proteins in. Mutations in the dgc disrupt the complex and lead to muscular dystrophy. Following the identification of dystrophin mutations as the underlying genetic cause of duchenne and becker muscular dystrophies hoffman et al. Dystroglycan and muscolar dystrophies related to the. However, these genes do not cause muscular dystrophies and their exact function is under investigation. 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. Becker muscular dystrophy bmd is also caused by mutations in the dmd gene that. Primary genetic abnormalities in dystrophin, and dystrophin.
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 results emphasize the close association between dystrophin and the glycoprotein complex and their role in the pathogenesis of muscle damage. The coohterminus of dystrophin mediates binding of adapter and signaling proteins, which in turn mediates associations with membranebound ion channels 96, 98. The muscular dystrophies affecting the dystrophinglycoprotein complex are associated with a dilated cardiomyopathy. The dystrophinglycoprotein complex, cellular signaling. Arrhythmias in the muscular dystrophies heart rhythm. Sites of disruption of the dystrophin glycoprotein com plex in various diseases are illustrated by sin gleheaded arrows. In skeletal and cardiac muscle, dystrophin associates with various proteins to form the dystrophin associated protein complex dapc. 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. Xlinked duchennes muscular dystrophy and beckers muscular dystrophy are caused by mutations in the gene encoding dystrophin, a membrane cytoskeletal protein. The roles of the dystrophinassociated glycoprotein complex at.
Sites of disruption of the dystrophinglycoprotein com plex in various diseases are illustrated by sin gleheaded arrows. The duchenne muscular dystrophy dmd gene is the largest human gene 79 exons and 2. The lethal musclewasting disorder, duchenne muscular dystrophy, is caused by mutations or deletions in the dystrophin gene. Mutations in the dystrophin gene cause duchenne muscular dystrophy dmd, a fatal childhood muscle disease. Pdf dystroglycan and muscular dystrophies related to the. The dystrophin glycoprotein complex dgc is a multisubunit complex that connects the cytoskeleton of a muscle fiber to its surrounding extracellular matrix. Muscular dystrophies involving the dystrophinglycoprotein complex. Restoration of the dystrophinassociated glycoprotein complex. 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. Muscular dystrophies are primary diseases of muscle due to mutations in more than 40 genes, which result in dystrophic changes on muscle biopsy. Nonmechanical roles of dystrophin and associated proteins in. Dec 22, 2016 duchenne muscular dystrophy dmd is an genetic musclewasting disease that leads to disability and early death. The gene is the largest in the human genome, encompassing 2.
This large multicomponent complex has both mechanical stabilizing and signaling roles in mediating interactions between the cytoskeleton, membrane, and extracellular matrix. 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. The authors then reported a method in which a single cut in genomic. In skeletal and cardiac muscle, dystrophin associates with various proteins to form the dystrophinassociated protein complex dapc.
We find that wasting in cancer is linked to a dysfunctional dystrophin glycoprotein complex dgc, a membrane structure associated with muscular dystrophy. Dystrophinglycoprotein complex dgcrelated muscular dystrophies may present similar clinical and pathological features as well as undetectable mutations thus being sometimes difficult to distinguish. Muscular dystrophy an overview sciencedirect topics. 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. These mutations are generally located in genes encoding proteins of the dystrophin associated glycoprotein.
Some muscular dystrophies are caused by mutations of dgc components, such as dystrophin, sarcoglycan or laminin2, or also of dgcassociated molecules, such as caveolin3. Thus, dystrophin and utrophin are coexpressed in several fibres in carriers. Duchenne muscular dystrophy dmd is an genetic musclewasting disease that leads to disability and early death. 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. Efforts to understand the function of dystrophin, the protein product for the duchenne muscular dystrophy gene, resulted in the purification of the dystrophinglycoprotein complex. Duchenne muscular dystrophy dmd is caused by mutations in the gene that encodes the 427kda cytoskeletal protein dystrophin. Knowledge of diseasespecific complications, implementation of anticipatory care, and medical advances. Becker muscular dystrophy severity is linked to the structure. Winder summary muscular dystrophies are associated with mutations in. Congenital muscular dystrophies cmd 14 muscular dystrophies term coined by erb in 1891 unrelated hereditary, degenerative disorders of dystrophin dystrophinopathies or dystrophinassociated 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. The histopathological features of muscular dystrophies. The disorders differ in which muscles are primarily affected, the degree of weakness, how fast they worsen, and when symptoms begin. Muscular dystrophies, the cytoskeleton and cell adhesion heather j.
It shares its localization at astrocytic endfeet with the dystrophinassociated glycoprotein complex dgc. The phenotype of muscular dystrophy is an endpoint that arises from a diverse set of genetic pathways. The membrane cytoskeletal component dystrophin and its associated glycoproteins play a central role in the molecular pathogenesis of several muscular dystrophies, i. In all cases of this disease, the gene for a protein known as dystrophin is mutated. Young patients have motor delays and gait disturbances. To optimize the correction of dmd mutations by crisprcas9 gene editing, amoasii et al. Defects in the gene for the muscle protein dystrophin cause many cases of muscular dystrophy. The dystrophinglycoprotein complex, cellular signaling, and. 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. The dystrophinassociated protein complex journal of cell. These include two that span the membrane the dystroglycans, at least five within the membrane the sarcoglycans, and a submembrane protein utrophin. The dystrophin glycoprotein complex dgc is a specialization of cardiac and skeletal muscle membrane. Gene therapy of muscular dystrophy human molecular. Dmd results from a complete deficiency of dystrophin, whereas a partial deficiency leads to bd.
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