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The Lancet. Neurology Sep 2022Duchenne muscular dystrophy is an X-linked disease caused by the absence of functional dystrophin in the muscle cells. Major advances have led to the development of gene... (Review)
Review
Duchenne muscular dystrophy is an X-linked disease caused by the absence of functional dystrophin in the muscle cells. Major advances have led to the development of gene therapies, tools that induce exon skipping, and other therapeutic approaches, including treatments targeting molecular pathways downstream of the absence of functional dystrophin. However, glucocorticoids remain the only treatment unequivocally shown to slow disease progression, despite the adverse effects associated with their long-term use. Besides glucocorticoids, which are standard care, five compounds have received regulatory approval in some but not all jurisdictions, with further efficacy results being awaited. Several compounds with promising results in early-phase clinical trials have not met their efficacy endpoints in late-phase trials, but the clinical development of many other compounds is ongoing. The current landscape is complicated by the number of compounds in various stages of development, their various mechanisms of action, and their genotype-specific applicability. The difficulties of clinical development that arise from both the rarity and variability of Duchenne muscular dystrophy might be overcome in the future by use of sensitive biomarkers, natural history data, and ameliorated trial designs.
Topics: Dystrophin; Exons; Genetic Therapy; Genotype; Humans; Muscular Dystrophy, Duchenne
PubMed: 35850122
DOI: 10.1016/S1474-4422(22)00125-9 -
Mass Spectrometry Reviews 2024The dystrophin-associated protein complex (DAPC) is a highly organized multiprotein complex that plays a pivotal role in muscle fiber structure integrity and cell... (Review)
Review
The dystrophin-associated protein complex (DAPC) is a highly organized multiprotein complex that plays a pivotal role in muscle fiber structure integrity and cell signaling. The complex is composed of three distinct interacting subgroups, intracellular peripheral proteins, transmembrane glycoproteins, and extracellular glycoproteins subcomplexes. Dystrophin protein nucleates the DAPC and is important for connecting the intracellular actin cytoskeletal filaments to the sarcolemma glycoprotein complex that is connected to the extracellular matrix via laminin, thus stabilizing the sarcolemma during muscle fiber contraction and relaxation. Genetic mutations that lead to lack of expression or altered expression of any of the DAPC proteins are associated with different types of muscle diseases. Hence characterization of this complex in healthy and dystrophic muscle might bring insights into its role in muscle pathogenesis. This review highlights the role of mass spectrometry in characterizing the DAPC interactome as well as post-translational glycan modifications of some of its components such as α-dystroglycan. Detection and quantification of dystrophin using targeted mass spectrometry are also discussed in the context of healthy versus dystrophic skeletal muscle.
Topics: Dystrophin; Dystrophin-Associated Protein Complex; Laminin; Sarcolemma; Muscle, Skeletal; Glycoproteins
PubMed: 36420714
DOI: 10.1002/mas.21823 -
Molecular Neurobiology Feb 2012Dystrophin Dp71 is expressed in all tissues, with the exception of skeletal muscle, and is the main Duchenne muscular dystrophy (DMD) gene product in brain. As... (Review)
Review
Dystrophin Dp71 is expressed in all tissues, with the exception of skeletal muscle, and is the main Duchenne muscular dystrophy (DMD) gene product in brain. As full-length dystrophin does in skeletal muscle, Dp71 associates with dystroglycans, sarcoglycans, dystrobrevins, syntrophins, and accessory proteins to form the dystrophin-associated protein complex (DAPC) in non-muscle tissues. Although it has been nearly 20 years since the discovery of Dp71, its study has become relevant only recently due to its direct involvement with the two main DMD non-muscular phenotypes: cognitive impairment and abnormal retinal physiology. In this review, we describe the historical background of Dp71 and the experimental models developed for its study. Additionally, we present and discuss the experimental evidence supporting the participation of Dp71 in different cellular processes, including cell adhesion, water homeostasis, cell division, and nuclear architecture. The functional diversity of Dp71 is attributed to the formation of Dp71-containing DAPC in numerous cell types and different subcellular compartments, including in plasma membrane and nucleus, as well as to the capability of Dp71-containing DAPC to work as the scaffold for proper clustering and anchoring of structural and signaling proteins to the plasma membrane and of nuclear envelope proteins to the inner nuclear membrane.
Topics: Animals; Cell Adhesion; Cell Division; Cell Nucleus; Disease Models, Animal; Dystrophin; Homeostasis; Humans; Muscular Dystrophy, Duchenne
PubMed: 22105192
DOI: 10.1007/s12035-011-8218-9 -
Nature Cell Biology Nov 2020
Topics: Dystrophin; Humans; Muscular Dystrophies; RNA, Long Noncoding
PubMed: 33106655
DOI: 10.1038/s41556-020-00598-2 -
Advances in Genetics 1995
Review
Topics: Adolescent; Animals; Child; Child, Preschool; Chromosome Mapping; Dystrophin; Exons; Female; Gene Expression Regulation; Humans; Infant; Intellectual Disability; Introns; Male; Muscle, Skeletal; Muscular Dystrophies; Recombination, Genetic; X Chromosome
PubMed: 7484453
DOI: 10.1016/s0065-2660(08)60334-x -
Advances in Protein Chemistry 2005Spectrin family proteins represent an important group of actin-bundling and membrane-anchoring proteins found in diverse structures from yeast to man. Arising from a... (Review)
Review
Spectrin family proteins represent an important group of actin-bundling and membrane-anchoring proteins found in diverse structures from yeast to man. Arising from a common ancestral alpha-actinin gene through duplications and rearrangements, the family has increased to include the spectrins and dystrophin/utrophin. The spectrin family is characterized by the presence of spectrin repeats, actin binding domains, and EF hands. With increasing divergence, new domains and functions have been added such that spectrin and dystrophin also contain specialized protein-protein interaction motifs and regions for interaction with membranes and phospholipids. The acquisition of new domains also increased the functional complexity of the family such that the proteins perform a range of tasks way beyond the simple bundling of actin filaments by alpha-actinin in S. pombe. We discuss the evolutionary, structural, functional, and regulatory roles of the spectrin family of proteins and describe some of the disease traits associated with loss of spectrin family protein function.
Topics: Actinin; Amino Acid Sequence; Animals; Dystrophin; Genetic Diseases, Inborn; Humans; Protein Binding; Spectrin
PubMed: 15837517
DOI: 10.1016/S0065-3233(05)70007-3 -
ACS Nano Dec 2018Dystrophin is the largest protein isoform (427 kDa) expressed from the gene defective in Duchenne muscular dystrophy, a lethal muscle-wasting and genetically inherited...
Dystrophin is the largest protein isoform (427 kDa) expressed from the gene defective in Duchenne muscular dystrophy, a lethal muscle-wasting and genetically inherited disease. Dystrophin, localized within a cytoplasmic lattice termed costameres, connects the intracellular cytoskeleton of a myofiber through the cell membrane (sarcolemma) to the surrounding extracellular matrix. In spite of its mechanical regulation roles in stabilizing the sarcolemma during muscle contraction, the underlying molecular mechanism is still elusive. Here, we systematically investigated the mechanical stability and kinetics of the force-bearing central domain of human dystrophin that contains 24 spectrin repeats using magnetic tweezers. We show that the stochastic unfolding and refolding of central domain of dystrophin is able to keep the forces below 25 pN over a significant length change up to ∼800 nm in physiological level of pulling speeds. These results suggest that dystrophin may serve as a molecular shock absorber that defines the physiological level of force in the dystrophin-mediated force-transmission pathway during muscle contraction/stretch, thereby stabilizing the sarcolemma.
Topics: Absorption, Physicochemical; Dystrophin; Humans; Kinetics; Protein Folding
PubMed: 30457830
DOI: 10.1021/acsnano.8b05721 -
PloS One 2023Duchenne muscular dystrophy (DMD) is caused by genetic mutations leading to lack of dystrophin in skeletal muscle. A better understanding of how objective biomarkers for...
Duchenne muscular dystrophy (DMD) is caused by genetic mutations leading to lack of dystrophin in skeletal muscle. A better understanding of how objective biomarkers for DMD vary across subjects and over time is needed to model disease progression and response to therapy more effectively, both in pre-clinical and clinical research. We present an in-depth characterization of disease progression in 3 murine models of DMD by multiomic analysis of longitudinal trajectories between 6 and 30 weeks of age. Integration of RNA-seq, mass spectrometry-based metabolomic and lipidomic data obtained in muscle and blood samples by Multi-Omics Factor Analysis (MOFA) led to the identification of 8 latent factors that explained 78.8% of the variance in the multiomic dataset. Latent factors could discriminate dystrophic and healthy mice, as well as different time-points. MOFA enabled to connect the gene expression signature in dystrophic muscles, characterized by pro-fibrotic and energy metabolism alterations, to inflammation and lipid signatures in blood. Our results show that omic observations in blood can be directly related to skeletal muscle pathology in dystrophic muscle.
Topics: Mice; Animals; Dystrophin; Mice, Inbred mdx; Multiomics; Muscular Dystrophy, Duchenne; Muscle, Skeletal; Disease Progression; Disease Models, Animal
PubMed: 37000843
DOI: 10.1371/journal.pone.0283869 -
International Journal of Molecular... Mar 2023Several clinical trials are working on drug development for Duchenne and Becker muscular dystrophy (DMD and BMD) treatment, and, since the expected increase in...
Several clinical trials are working on drug development for Duchenne and Becker muscular dystrophy (DMD and BMD) treatment, and, since the expected increase in dystrophin is relatively subtle, high-sensitivity quantification methods are necessary. There is also a need to quantify dystrophin to reach a definitive diagnosis in individuals with mild BMD, and in female carriers. We developed a method for the quantification of dystrophin in DMD and BMD patients using spectral confocal microscopy. It offers the possibility to capture the whole emission spectrum for any antibody, ensuring the selection of the emission peak and allowing the detection of fluorescent emissions of very low intensities. Fluorescence was evaluated first on manually selected regions of interest (ROIs), proving the usefulness of the methodology. Later, ROI selection was automated to make it operator-independent. The proposed methodology correctly classified patients according to their diagnosis, detected even minimal traces of dystrophin, and the results obtained automatically were statistically comparable to the manual ones. Thus, spectral imaging could be implemented to measure dystrophin expression and it could pave the way for detailed analysis of how its expression relates to the clinical course. Studies could be further expanded to better understand the expression of dystrophin-associated protein complexes (DAPCs).
Topics: Humans; Female; Dystrophin; Muscular Dystrophy, Duchenne
PubMed: 37047330
DOI: 10.3390/ijms24076358 -
International Journal of Biological... Apr 2024Duchenne Muscular Dystrophy (DMD) is an X-linked recessive genetic disorder characterized by progressive and severe muscle weakening and degeneration. Among the various... (Review)
Review
Duchenne Muscular Dystrophy (DMD) is an X-linked recessive genetic disorder characterized by progressive and severe muscle weakening and degeneration. Among the various forms of muscular dystrophy, it stands out as one of the most common and impactful, predominantly affecting boys. The condition arises due to mutations in the dystrophin gene, a key player in maintaining the structure and function of muscle fibers. The manuscript explores the structural features of dystrophin protein and their pivotal roles in DMD. We present an in-depth analysis of promising therapeutic approaches targeting dystrophin and their implications for the therapeutic management of DMD. Several therapies aiming to restore dystrophin protein or address secondary pathology have obtained regulatory approval, and many others are ongoing clinical development. Notably, recent advancements in genetic approaches have demonstrated the potential to restore partially functional dystrophin forms. The review also provides a comprehensive overview of the status of clinical trials for major therapeutic genetic approaches for DMD. In addition, we have summarized the ongoing therapeutic approaches and advanced mechanisms of action for dystrophin restoration and the challenges associated with DMD therapeutics.
Topics: Male; Humans; Muscular Dystrophy, Duchenne; Dystrophin; Muscle Fibers, Skeletal; Genetic Diseases, X-Linked
PubMed: 38428778
DOI: 10.1016/j.ijbiomac.2024.130544