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Comprehensive Physiology Jul 2015The dystrophin complex stabilizes the plasma membrane of striated muscle cells. Loss of function mutations in the genes encoding dystrophin, or the associated proteins,... (Review)
Review
The dystrophin complex stabilizes the plasma membrane of striated muscle cells. Loss of function mutations in the genes encoding dystrophin, or the associated proteins, trigger instability of the plasma membrane, and myofiber loss. Mutations in dystrophin have been extensively cataloged, providing remarkable structure-function correlation between predicted protein structure and clinical outcomes. These data have highlighted dystrophin regions necessary for in vivo function and fueled the design of viral vectors and now, exon skipping approaches for use in dystrophin restoration therapies. However, dystrophin restoration is likely more complex, owing to the role of the dystrophin complex as a broad cytoskeletal integrator. This review will focus on dystrophin restoration, with emphasis on the regions of dystrophin essential for interacting with its associated proteins and discuss the structural implications of these approaches.
Topics: Animals; Dystrophin; Dystrophin-Associated Proteins; Genetic Therapy; Humans; Muscular Dystrophies
PubMed: 26140716
DOI: 10.1002/cphy.c140048 -
The Lancet. Neurology Dec 2003A large and complex gene on the X chromosome encodes dystrophin. Many mutations have been described in this gene, most of which affect the expression of the muscle... (Review)
Review
A large and complex gene on the X chromosome encodes dystrophin. Many mutations have been described in this gene, most of which affect the expression of the muscle isoform, the best-known protein product of this locus. These mutations result in the Duchenne and Becker muscular dystrophies (DMD and BMD). However, there are several other tissue specific isoforms of dystrophin, some exclusively or predominantly expressed in the brain or the retina. Mutations affecting the correct expression of these tissue-specific isoforms have been associated with the CNS involvement common in DMD. Rare mutations also account for the allelic disorder X-linked dilated cardiomyopathy, in which dystrophin expression or function is affected mostly or exclusively in the heart. Genotype definition of the dystrophin gene in patients with dystrophinopathies has taught us much about functionally important domains of the protein itself and has provided insights into several regulatory mechanisms governing the gene expression profile. Here, we focus on current understanding of the genotype-phenotype relation for mutations in the dystrophin gene and their implications for gene functions.
Topics: Animals; Dystrophin; Humans; Muscular Dystrophies; Mutation; Phenotype; Protein Isoforms
PubMed: 14636778
DOI: 10.1016/s1474-4422(03)00585-4 -
Physiological Reviews Apr 2002The 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... (Review)
Review
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.
Topics: Animals; Dystrophin; Humans; Muscle Proteins; Muscle, Skeletal; Muscular Dystrophies
PubMed: 11917091
DOI: 10.1152/physrev.00028.2001 -
Science (New York, N.Y.) Oct 2018Mutations in the gene encoding dystrophin, a protein that maintains muscle integrity and function, cause Duchenne muscular dystrophy (DMD). The deltaE50-MD dog model of...
Mutations in the gene encoding dystrophin, a protein that maintains muscle integrity and function, cause Duchenne muscular dystrophy (DMD). The deltaE50-MD dog model of DMD harbors a mutation corresponding to a mutational "hotspot" in the human gene. We used adeno-associated viruses to deliver CRISPR gene editing components to four dogs and examined dystrophin protein expression 6 weeks after intramuscular delivery ( = 2) or 8 weeks after systemic delivery ( = 2). After systemic delivery in skeletal muscle, dystrophin was restored to levels ranging from 3 to 90% of normal, depending on muscle type. In cardiac muscle, dystrophin levels in the dog receiving the highest dose reached 92% of normal. The treated dogs also showed improved muscle histology. These large-animal data support the concept that, with further development, gene editing approaches may prove clinically useful for the treatment of DMD.
Topics: Adenoviridae; Animals; CRISPR-Cas Systems; Disease Models, Animal; Dogs; Dystrophin; Female; Gene Editing; Gene Transfer Techniques; Male; Muscular Dystrophy, Duchenne
PubMed: 30166439
DOI: 10.1126/science.aau1549 -
Progress in Neurobiology Dec 1997Dystrophin is a plasma membrane-associated cytoskeletal protein of the spectrin superfamily. The dystrophin cytoskeleton has been first characterized in muscle. Muscular... (Review)
Review
Dystrophin is a plasma membrane-associated cytoskeletal protein of the spectrin superfamily. The dystrophin cytoskeleton has been first characterized in muscle. Muscular 427 kDa dystrophin binds to subplasmalemmal actin filaments via its amino-terminal domain. The carboxy-terminus of dystrophin binds to a plasma membrane anchor, beta-dystroglycan, which is associated on the external side with the extracellular matrix receptor, alpha-dystroglycan, that binds to the basal lamina proteins laminin-1, laminin-2, and agrin. In the muscle, the dystroglycan complex is associated with the sarcoglycan complex that consists of several glycosylated, integral membrane proteins. The absence or functional deficiency of the dystrophin cytoskeleton is the cause of several types of muscular dystrophies including the lethal Duchenne muscular dystrophy (DMD), one of the most severe and most common genetic disorders of man. The dystrophin complex is believed to stabilize the plasma membrane during cycles of contraction and relaxation. Muscular dystrophin and several types of dystrophin variants are also present in extramuscular tissues, e.g. in distinct regions of the central nervous systems including the retina. Absence of dystrophin from these sites is believed to be responsible for some extramuscular symptoms of DMD, e.g. mental retardation and disturbances in retinal electrophysiology (reduced b-wave in electroretinograms). The reduced b-wave in electroretinograms indicated a disturbance of neurotransmission between photoreceptors and ON-bipolar cells. At least two different dystrophin variants are present in photoreceptor synaptic complexes. One of these dystrophins (Dp260) is virtually exclusively expressed in the retina. In the neuroretina, dystrophin is found in significant amounts in the invaginated photoreceptor synaptic complexes. At this location dystrophin colocalizes with dystroglycan. Agrin, an extracellular ligand of alpha-dystroglycan, is also present at this location whereas the proteins of the sarcoglycan complex appear to be absent in photoreceptor synaptic complexes. Dystrophin and dystroglycan are located distal from the ribbon-containing active synaptic zones where both proteins are restricted to the photoreceptor plasma membrane bordering on the lateral sides of the synaptic invagination. In addition, some neuronal profiles of the postsynaptic complex also contain dystrophin and beta-dystroglycan. These profiles appear to belong at least in part to projections of the photoreceptor terminals into the postsynaptic dendritic complex. In view of the abnormal neurotransmission between photoreceptors and ON-bipolar cells in DMD patients the dystrophin/beta-dystroglycan-containing projections of photoreceptor presynaptic terminals into the postsynaptic dendritic plexus might somehow modify the ON-bipolar pathway. Another retinal site associated with dystrophin/beta-dystropglycan is the plasma membrane of Müller cells where dystrophin/beta-dystroglycan appear to be present at particular high concentrations. At this location the dystrophin/dystroglycan complex may play a role in the attachment of the retina to the vitreous, and, under pathological conditions, in traction-induced retinal detachment.
Topics: Animals; Cytoskeletal Proteins; Dystrophin; Humans; Membrane Glycoproteins; Membrane Proteins; Nerve Tissue Proteins; Nervous System; Retina; Synaptic Transmission; Utrophin
PubMed: 9421835
DOI: 10.1016/s0301-0082(97)00047-6 -
BioDrugs : Clinical Immunotherapeutics,... Jan 2024Duchenne muscular dystrophy is a devastating disease that leads to progressive muscle loss and premature death. While medical management focuses mostly on symptomatic... (Comparative Study)
Comparative Study Review
Duchenne muscular dystrophy is a devastating disease that leads to progressive muscle loss and premature death. While medical management focuses mostly on symptomatic treatment, decades of research have resulted in first therapeutics able to restore the affected reading frame of dystrophin transcripts or induce synthesis of a truncated dystrophin protein from a vector, with other strategies based on gene therapy and cell signaling in preclinical or clinical development. Nevertheless, recent reports show that potentially therapeutic dystrophins can be immunogenic in patients. This raises the question of whether a dystrophin paralog, utrophin, could be a more suitable therapeutic protein. Here, we compare dystrophin and utrophin amino acid sequences and structures, combining published data with our extended in silico analyses. We then discuss these results in the context of therapeutic approaches for Duchenne muscular dystrophy. Specifically, we focus on strategies based on delivery of micro-dystrophin and micro-utrophin genes with recombinant adeno-associated viral vectors, exon skipping of the mutated dystrophin pre-mRNAs, reading through termination codons with small molecules that mask premature stop codons, dystrophin gene repair by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated genetic engineering, and increasing utrophin levels. Our analyses highlight the importance of various dystrophin and utrophin domains in Duchenne muscular dystrophy treatment, providing insights into designing novel therapeutic compounds with improved efficacy and decreased immunoreactivity. While the necessary actin and β-dystroglycan binding sites are present in both proteins, important functional distinctions can be identified in these domains and some other parts of truncated dystrophins might need redesigning due to their potentially immunogenic qualities. Alternatively, therapies based on utrophins might provide a safer and more effective approach.
Topics: Humans; Dystrophin; Genetic Therapy; Muscular Dystrophy, Duchenne; Utrophin
PubMed: 37917377
DOI: 10.1007/s40259-023-00632-3 -
Molecular Aspects of Medicine 1991Recent advances concerning the genetic and biochemical basis of Duchenne and Becker muscular dystrophies have resulted in a good understanding of the etiology of these... (Review)
Review
Recent advances concerning the genetic and biochemical basis of Duchenne and Becker muscular dystrophies have resulted in a good understanding of the etiology of these common dystrophies. An important secondary consequence of the genetic and biochemical research has been the generation of gene-based and protein-based diagnostic tools which enable a 'molecular diagnosis' for patients and their families. This review summarizes our current understanding of the genetics, biochemistry, and pathophysiology of Duchenne dystrophy, and gives an overview of the molecular diagnostic tools and their applications. Recent correlations of clinical, genetic and biochemical data have indicated that dystrophinopathies can present with a wide range of neuromuscular symptoms, and that neither male sex nor proximal weakness are diagnostic prerequisites for consideration of an underlying dystrophin abnormality.
Topics: Amino Acid Sequence; Base Sequence; Chromosome Deletion; DNA; Dystrophin; Female; Heterozygote; Humans; Male; Models, Genetic; Molecular Sequence Data; Muscular Dystrophies; Mutation
PubMed: 1770836
DOI: 10.1016/0098-2997(91)90001-3 -
Current Opinion in Genetics &... Jun 1993During the past year significant progress has been made in understanding how dystrophin deficiency leads to muscle cell necrosis in Duchenne muscular dystrophy and... (Review)
Review
During the past year significant progress has been made in understanding how dystrophin deficiency leads to muscle cell necrosis in Duchenne muscular dystrophy and Becker muscular dystrophy. Dystrophin interacts with a glycoprotein complex spanning the muscle sarcolemma, effectively linking the actin cytoskeleton to the extracellular matrix. The carboxyl terminus of dystrophin is required for glycoprotein binding. Interestingly, at least three mRNAs transcribed from the distal end of the DMD gene in tissues other than muscle have been shown to encode this domain. Deficiency of a second component of the dystrophin-associated glycoprotein complex has been shown to occur in another muscle-wasting disorder, severe childhood autosomal recessive muscular dystrophy. Sequence analysis of the entire cDNA for the autosomal dystrophin-related protein utrophin has shown that dystrophin and utrophin are closely related. Furthermore, both of these proteins have been shown to bind to the same or a similar glycoprotein complex in muscle.
Topics: Animals; Cytoskeletal Proteins; Dystrophin; Humans; Membrane Proteins; Muscular Dystrophies; Utrophin
PubMed: 8353425
DOI: 10.1016/0959-437x(93)90124-8 -
Sub-cellular Biochemistry 2017Dystrophin and Spectrin are two proteins essential for the organization of the cytoskeleton and for the stabilization of membrane cells. The comparison of these two... (Review)
Review
Dystrophin and Spectrin are two proteins essential for the organization of the cytoskeleton and for the stabilization of membrane cells. The comparison of these two sister proteins, and with the dystrophin homologue utrophin, enables us to emphasise that, despite a similar topology with common subdomains and a common structural basis of a three-helix coiled-coil, they show a large range of dissimilarities in terms of genetics, cell expression and higher level structural organisation. Interactions with cellular partners, including proteins and membrane phospholipids, also show both strikingly similar and very different behaviours. The differences between dystrophin and spectrin are also illustrated by the large variety of pathological anomalies emerging from the dysfunction or the absence of these proteins, showing that they are keystones in their function of providing a scaffold that sustains cell structure.
Topics: Amino Acid Sequence; Animals; Cytoskeleton; Dystrophin; Humans; Protein Conformation; Spectrin
PubMed: 28101868
DOI: 10.1007/978-3-319-49674-0_12 -
Drugs Sep 2023Delandistrogene moxeparvovec (delandistrogene moxeparvovec-rokl; ELEVIDYS) is an adeno-associated virus (AAV) vector-based gene therapy designed to deliver a gene... (Review)
Review
Delandistrogene moxeparvovec (delandistrogene moxeparvovec-rokl; ELEVIDYS) is an adeno-associated virus (AAV) vector-based gene therapy designed to deliver a gene encoding a micro-dystrophin protein [i.e. a shortened (138 kDa) version of the dystrophin protein expressed in normal muscle cells (427 kDa)] to all muscles involved in the pathology of Duchenne muscular dystrophy (DMD). Developed by Sarepta Therapeutics, it is the first gene therapy to be approved (in June 2023 under the Accelerated Approval pathway) for the treatment of DMD in the USA, where it is indicated for ambulatory paediatric patients aged 4 through 5 years with DMD and a confirmed mutation in the dystrophin (DMD) gene. The recommended dose of delandistrogene moxeparvovec is 1.33 × 10 vector genomes per kg of body weight or 10 mL/kg body weight, administered as a single intravenous infusion. Delandistrogene moxeparvovec is undergoing clinical development in several countries/regions, including the EU and Japan. This article summarizes the milestones in the development of delandistrogene moxeparvovec leading to this first approval in the USA for the treatment of ambulatory paediatric patients aged 4 through 5 years with DMD and a confirmed mutation in the DMD gene.
Topics: Humans; Child; Dystrophin; Muscular Dystrophy, Duchenne; Genetic Therapy; Mutation; Muscles; Muscle, Skeletal
PubMed: 37566211
DOI: 10.1007/s40265-023-01929-x