A muscle protein localized in surface membranes which is the product of the Duchenne/Becker muscular dystrophy gene. Individuals with Duchenne muscular dystrophy usually lack dystrophin completely while those with Becker muscular dystrophy have dystrophin of an altered size. It shares features with other cytoskeletal proteins such as SPECTRIN and alpha-actinin but the precise function of dystrophin is not clear. One possible role might be to preserve the integrity and alignment of the plasma membrane to the myofibrils during muscle contraction and relaxation. MW 400 kDa.
An X-linked recessive muscle disease caused by an inability to synthesize DYSTROPHIN, which is involved with maintaining the integrity of the sarcolemma. Muscle fibers undergo a process that features degeneration and regeneration. Clinical manifestations include proximal weakness in the first few years of life, pseudohypertrophy, cardiomyopathy (see MYOCARDIAL DISEASES), and an increased incidence of impaired mentation. Becker muscular dystrophy is a closely related condition featuring a later onset of disease (usually adolescence) and a slowly progressive course. (Adams et al., Principles of Neurology, 6th ed, p1415)
An autosomally-encoded 376-kDa cytoskeletal protein that is similar in structure and function to DYSTROPHIN. It is a ubiquitously-expressed protein that plays a role in anchoring the CYTOSKELETON to the PLASMA MEMBRANE.
A strain of mice arising from a spontaneous MUTATION (mdx) in inbred C57BL mice. This mutation is X chromosome-linked and produces viable homozygous animals that lack the muscle protein DYSTROPHIN, have high serum levels of muscle ENZYMES, and possess histological lesions similar to human MUSCULAR DYSTROPHY. The histological features, linkage, and map position of mdx make these mice a worthy animal model of DUCHENNE MUSCULAR DYSTROPHY.
A heterogeneous group of inherited MYOPATHIES, characterized by wasting and weakness of the SKELETAL MUSCLE. They are categorized by the sites of MUSCLE WEAKNESS; AGE OF ONSET; and INHERITANCE PATTERNS.
A group of proteins that associate with DYSTROPHIN at the CELL MEMBRANE to form the DYSTROPHIN-ASSOCIATED PROTEIN COMPLEX.
Dystrophin-associated proteins that play role in the formation of a transmembrane link between laminin-2 and DYSTROPHIN. Both the alpha and the beta subtypes of dystroglycan originate via POST-TRANSLATIONAL PROTEIN PROCESSING of a single precursor protein.
The excitable plasma membrane of a muscle cell. (Glick, Glossary of Biochemistry and Molecular Biology, 1990)
A family of transmembrane dystrophin-associated proteins that play a role in the membrane association of the DYSTROPHIN-ASSOCIATED PROTEIN COMPLEX.
A subtype of striated muscle, attached by TENDONS to the SKELETON. Skeletal muscles are innervated and their movement can be consciously controlled. They are also called voluntary muscles.
The parts of a transcript of a split GENE remaining after the INTRONS are removed. They are spliced together to become a MESSENGER RNA or other functional RNA.
Major constituent of the cytoskeleton found in the cytoplasm of eukaryotic cells. They form a flexible framework for the cell, provide attachment points for organelles and formed bodies, and make communication between parts of the cell possible.
A macromolecular complex of proteins that includes DYSTROPHIN and DYSTROPHIN-ASSOCIATED PROTEINS. It plays a structural role in the linking the CYTOSKELETON to the EXTRACELLULAR MATRIX.
Contractile tissue that produces movement in animals.
Synthetic analogs of NUCLEIC ACIDS composed of morpholine ring derivatives (MORPHOLINES) linked by phosphorodimidates. One standard DNA nucleic acid base (ADENINE; GUANINE; CYTOSINE; OR THYMINE) is bound to each morpholine ring.
The protein constituents of muscle, the major ones being ACTINS and MYOSINS. More than a dozen accessory proteins exist including TROPONIN; TROPOMYOSIN; and DYSTROPHIN.
Large, multinucleate single cells, either cylindrical or prismatic in shape, that form the basic unit of SKELETAL MUSCLE. They consist of MYOFIBRILS enclosed within and attached to the SARCOLEMMA. They are derived from the fusion of skeletal myoblasts (MYOBLASTS, SKELETAL) into a syncytium, followed by differentiation.
Short fragments of RNA that are used to alter the function of target RNAs or DNAs to which they hybridize.
Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.
A high molecular weight (220-250 kDa) water-soluble protein which can be extracted from erythrocyte ghosts in low ionic strength buffers. The protein contains no lipids or carbohydrates, is the predominant species of peripheral erythrocyte membrane proteins, and exists as a fibrous coating on the inner, cytoplasmic surface of the membrane.
Techniques and strategies which include the use of coding sequences and other conventional or radical means to transform or modify cells for the purpose of treating or reversing disease conditions.
A caveolin that is expressed exclusively in MUSCLE CELLS and is sufficient to form CAVEOLAE in SARCOLEMMA. Mutations in caveolin 3 are associated with multiple muscle diseases including DISTAL MYOPATHY and LIMB-GIRDLE MUSCULAR DYSTROPHY.
Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors.
A protein factor that regulates the length of R-actin. It is chemically similar, but immunochemically distinguishable from actin.
A form of CARDIAC MUSCLE disease that is characterized by ventricular dilation, VENTRICULAR DYSFUNCTION, and HEART FAILURE. Risk factors include SMOKING; ALCOHOL DRINKING; HYPERTENSION; INFECTION; PREGNANCY; and mutations in the LMNA gene encoding LAMIN TYPE A, a NUCLEAR LAMINA protein.
The three possible sequences of CODONS by which GENETIC TRANSLATION may occur from one nucleotide sequence. A segment of mRNA 5'AUCCGA3' could be translated as 5'AUC.. or 5'UCC.. or 5'CCG.., depending on the location of the START CODON.
Test for tissue antigen using either a direct method, by conjugation of antibody with fluorescent dye (FLUORESCENT ANTIBODY TECHNIQUE, DIRECT) or an indirect method, by formation of antigen-antibody complex which is then labeled with fluorescein-conjugated anti-immunoglobulin antibody (FLUORESCENT ANTIBODY TECHNIQUE, INDIRECT). The tissue is then examined by fluorescence microscopy.
Histochemical localization of immunoreactive substances using labeled antibodies as reagents.
Short fragments of DNA or RNA that are used to alter the function of target RNAs or DNAs to which they hybridize.

Processing of endogenous pre-mRNAs in association with SC-35 domains is gene specific. (1/1292)

Analysis of six endogenous pre-mRNAs demonstrates that localization at the periphery or within splicing factor-rich (SC-35) domains is not restricted to a few unusually abundant pre-mRNAs, but is apparently a more common paradigm of many protein-coding genes. Different genes are preferentially transcribed and their RNAs processed in different compartments relative to SC-35 domains. These differences do not simply correlate with the complexity, nuclear abundance, or position within overall nuclear space. The distribution of spliceosome assembly factor SC-35 did not simply mirror the distribution of individual pre-mRNAs, but rather suggested that individual domains contain both specific pre-mRNA(s) as well as excess splicing factors. This is consistent with a multifunctional compartment, to which some gene loci and their RNAs have access and others do not. Despite similar molar abundance in muscle fiber nuclei, nascent transcript "trees" of highly complex dystrophin RNA are cotranscriptionally spliced outside of SC-35 domains, whereas posttranscriptional "tracks" of more mature myosin heavy chain transcripts overlap domains. Further analyses supported that endogenous pre-mRNAs exhibit distinct structural organization that may reflect not only the expression and complexity of the gene, but also constraints of its chromosomal context and kinetics of its RNA metabolism.  (+info)

Hindlimb immobilization applied to 21-day-old mdx mice prevents the occurrence of muscle degeneration. (2/1292)

Dystrophin-deficient skeletal muscles of mdx mice undergo their first rounds of degeneration-regeneration at the age of 14-28 days. This feature is thought to result from an increase in motor activity at weaning. In this study, we hypothesize that if the muscle is prevented from contracting, it will avoid the degenerative changes that normally occur. For this purpose, we developed a procedure of mechanical hindlimb immobilization in 3-wk-old mice to restrain soleus (Sol) and extensor digitorum longus (EDL) muscles in the stretched or shortened position. After a 14-day period of immobilization, the striking feature was the low percentage of regenerated (centronucleated) myofibers in Sol and EDL muscles, regardless of the length at which they were fixed, compared with those on the contralateral side (stretched Sol: 8.4 +/- 6.5 vs. 46.6 +/- 10.3%, P = 0.0008; shortened Sol: 1.2 +/- 1.6 vs. 50.4 +/- 16.4%, P = 0.0008; stretched EDL: 05 +/- 0.5 vs. 32.9 +/- 17.5%, P = 0. 002; shortened EDL: 3.3 +/- 3.1 vs. 34.7 +/- 11.1%, P = 0.002). Total numbers of myofibers did not change with immobilization. This study shows that limb immobilization prevents the occurrence of the first round of myofiber necrosis in mdx mice and suggests that muscle contractions play a role in the skeletal muscle degeneration of dystrophin-deficient mdx mouse muscles.  (+info)

Increased calcium entry into dystrophin-deficient muscle fibres of MDX and ADR-MDX mice is reduced by ion channel blockers. (3/1292)

1. Single fibres were enzymatically isolated from interosseus muscles of dystrophic MDX mice, myotonic-dystrophic double mutant ADR-MDX mice and C57BL/10 controls. The fibres were kept in cell culture for up to 2 weeks for the study of Ca2+ homeostasis and sarcolemmal Ca2+ permeability. 2. Resting levels of intracellular free Ca2+, determined with the fluorescent Ca2+ indicator fura-2, were slightly higher in MDX (63 +/- 20 nM; means +/- s.d.; n = 454 analysed fibres) and ADR-MDX (65 +/- 12 nM; n = 87) fibres than in controls (51 +/- 20 nM; n = 265). 3. The amplitudes of electrically induced Ca2+ transients did not differ between MDX fibres and controls. Decay time constants of Ca2+ transients ranged between 10 and 55 ms in both genotypes. In 50 % of MDX fibres (n = 68), but in only 20 % of controls (n = 54), the decay time constants were > 35 ms. 4. Bath application of Mn2+ resulted in a progressive quench of fura-2 fluorescence emitted from the fibres. The quench rate was about 2 times higher in MDX fibres (3.98 +/- 1.9 % min-1; n = 275) than in controls (2.03 +/- 1.4 % min-1; n = 204). The quench rate in ADR-MDX fibres (2.49 +/- 1.4 % min-1; n = 87) was closer to that of controls. 5. The Mn2+ influx into MDX fibres was reduced to 10 % by Gd3+, to 19 % by La3+ and to 47 % by Ni2+ (all at 50 microM). Bath application of 50 microM amiloride inhibited the Mn2+ influx to 37 %. 6. We conclude that in isolated, resting MDX muscle fibres the membrane permeability for divalent cations is increased. The presumed additional influx of Ca2+ occurs through ion channels, but is well compensated for by effective cellular Ca2+ transport systems. The milder dystrophic phenotype of ADR-MDX mice is correlated with a smaller increase of their sarcolemmal Ca2+ permeability.  (+info)

Characterization of dystrophin and utrophin diversity in the mouse. (4/1292)

Utrophin is a 400 kDa autosomal homolog of dystrophin and a component of the submembranous cytoskeleton. While multiple dystrophin isoforms have been identified along with alternatively spliced products, to date only two different mRNA species of utrophin have been identified. To determine the degree of evolutionary conservation between dystrophin and utrophin isoforms, we have compared their expression patterns in adult mice. Northern blot analysis of multiple adult tissues confirmed that only two major sizes of transcripts are produced from each gene: 13 and 5.5 kb from utrophin and 14 and 4.8 kb from dystrophin. However, western blot analysis detected several putative short utrophin isoforms that may be homologs of the dystrophin isoforms Dp140, Dp116 and Dp71. We also identified an alternatively spliced utrophin transcript that lacks the equivalent of the alternatively spliced dystrophin exon 71. Finally, we demonstrated that the C-terminal domain of utrophin targeted to neuromuscular junctions in normal mice, but localized to the sarcolemma efficiently only in the absence of dystrophin. Our results provide further evidence for a common evolutionary origin of the utrophin and dystrophin genes.  (+info)

Ecto-ATPase activity of alpha-sarcoglycan (adhalin). (5/1292)

alpha-Sarcoglycan is a component of the sarcoglycan complex of dystrophin-associated proteins. Mutations of any of the sarcoglycan genes cause specific forms of muscular dystrophies, collectively termed sarcoglycanopathies. Importantly, a deficiency of any specific sarcoglycan affects the expression of the others. Thus, it appears that the lack of sarcoglycans deprives the muscle cell of an essential, yet unknown function. In the present study, we provide evidence for an ecto-ATPase activity of alpha-sarcoglycan. alpha-Sarcoglycan binds ATP in a Mg2+-dependent and Ca2+-independent manner. The binding is inhibited by 3'-O-(4-benzoyl)benzoyl ATP and ADP. Sequence analysis reveals the existence of a consensus site for nucleotide binding in the extracellular domain of the protein. An antibody against this sequence inhibits the binding of ATP. A dystrophin.dystrophin-associated protein preparation demonstrates a Mg-ATPase activity that is inhibited by the antibody but not by inhibitors of endo-ATPases. In addition, we demonstrate the presence in the sarcolemmal membrane of a P2X-type purinergic receptor. These data suggest that alpha-sarcoglycan may modulate the activity of P2X receptors by buffering the extracellular ATP concentration. The absence of alpha-sarcoglycan in sarcoglycanopathies leaves elevated the concentration of extracellular ATP and the persistent activation of P2X receptors, leading to intracellular Ca2+ overload and muscle fiber death.  (+info)

Characterization of the transmembrane molecular architecture of the dystroglycan complex in schwann cells. (6/1292)

We have demonstrated previously 1) that the dystroglycan complex, but not the sarcoglycan complex, is expressed in peripheral nerve, and 2) that alpha-dystroglycan is an extracellular laminin-2-binding protein anchored to beta-dystroglycan in the Schwann cell membrane. In the present study, we investigated the transmembrane molecular architecture of the dystroglycan complex in Schwann cells. The cytoplasmic domain of beta-dystroglycan was co-localized with Dp116, the Schwann cell-specific isoform of dystrophin, in the abaxonal Schwann cell cytoplasm adjacent to the outer membrane. beta-dystroglycan bound to Dp116 mainly via the 15 C-terminal amino acids of its cytoplasmic domain, but these amino acids were not solely responsible for the interaction of these two proteins. Interestingly, the beta-dystroglycan-precipitating antibody precipitated only a small fraction of alpha-dystroglycan and did not precipitate laminin and Dp116 from the peripheral nerve extracts. Our results indicate 1) that Dp116 is a component of the submembranous cytoskeletal system that anchors the dystroglycan complex in Schwann cells, and 2) that the dystroglycan complex in Schwann cells is fragile compared with that in striated muscle cells. We propose that this fragility may be attributable to the absence of the sarcoglycan complex in Schwann cells.  (+info)

Extensive but coordinated reorganization of the membrane skeleton in myofibers of dystrophic (mdx) mice. (7/1292)

We used immunofluorescence techniques and confocal imaging to study the organization of the membrane skeleton of skeletal muscle fibers of mdx mice, which lack dystrophin. beta-Spectrin is normally found at the sarcolemma in costameres, a rectilinear array of longitudinal strands and elements overlying Z and M lines. However, in the skeletal muscle of mdx mice, beta-spectrin tends to be absent from the sarcolemma over M lines and the longitudinal strands may be disrupted or missing. Other proteins of the membrane and associated cytoskeleton, including syntrophin, beta-dystroglycan, vinculin, and Na,K-ATPase are also concentrated in costameres, in control myofibers, and mdx muscle. They also distribute into the same altered sarcolemmal arrays that contain beta-spectrin. Utrophin, which is expressed in mdx muscle, also codistributes with beta-spectrin at the mutant sarcolemma. By contrast, the distribution of structural and intracellular membrane proteins, including alpha-actinin, the Ca-ATPase and dihydropyridine receptors, is not affected, even at sites close to the sarcolemma. Our results suggest that in myofibers of the mdx mouse, the membrane- associated cytoskeleton, but not the nearby myoplasm, undergoes widespread coordinated changes in organization. These changes may contribute to the fragility of the sarcolemma of dystrophic muscle.  (+info)

Membrane targeting and stabilization of sarcospan is mediated by the sarcoglycan subcomplex. (8/1292)

The dystrophin-glycoprotein complex (DGC) is a multisubunit complex that spans the muscle plasma membrane and forms a link between the F-actin cytoskeleton and the extracellular matrix. The proteins of the DGC are structurally organized into distinct subcomplexes, and genetic mutations in many individual components are manifested as muscular dystrophy. We recently identified a unique tetraspan-like dystrophin-associated protein, which we have named sarcospan (SPN) for its multiple sarcolemma spanning domains (Crosbie, R.H., J. Heighway, D.P. Venzke, J.C. Lee, and K.P. Campbell. 1997. J. Biol. Chem. 272:31221-31224). To probe molecular associations of SPN within the DGC, we investigated SPN expression in normal muscle as a baseline for comparison to SPN's expression in animal models of muscular dystrophy. We show that, in addition to its sarcolemma localization, SPN is enriched at the myotendinous junction (MTJ) and neuromuscular junction (NMJ), where it is a component of both the dystrophin- and utrophin-glycoprotein complexes. We demonstrate that SPN is preferentially associated with the sarcoglycan (SG) subcomplex, and this interaction is critical for stable localization of SPN to the sarcolemma, NMJ, and MTJ. Our experiments indicate that assembly of the SG subcomplex is a prerequisite for targeting SPN to the sarcolemma. In addition, the SG- SPN subcomplex functions to stabilize alpha-dystroglycan to the muscle plasma membrane. Taken together, our data provide important information about assembly and function of the SG-SPN subcomplex.  (+info)

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene that abolish the synthesis of dystrophin protein. Antisense oligonucleotides (AOs) targeted to trigger excision of an exon bearing a mutant premature stop codon in the DMD transcript have been shown to skip the mutated exon and partially restore functional dystrophin protein in dystrophin-deficient mdx mice. To fully exploit the therapeutic potential of this method requires highly efficient systemic AO delivery to multiple muscle groups, to modify the disease process and restore muscle function. While systemic delivery of naked AOs in DMD animal models requires high doses and is of relatively poor efficiency, we and others have recently shown that short arginine-rich peptide-AO conjugates can dramatically improve in vivo DMD splice correction. Here we report for the first time that a chimeric fusion peptide (B-MSP-PMO) consisting of a muscle-targeting heptapeptide (MSP) fused to an arginine-rich cell-penetrating peptide (B-peptide)
Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene locus, is expressed on the muscle fiber surface. One key to further understanding of the cellular function of dystrophin would be extended knowledge about its subcellular organization. We have shown that dystrophin molecules are not uniformly distributed over the humen, rat, and mouse skeletal muscle fiber surface using three independent methods. Incubation of single-teased muscle fibers with antibodies to dystrophin revealed a network of denser transversal rings (costameres) and finer longitudinal interconnections. Double staining of longitudinal semithin cryosections for dystrophin and alpha-actinin showed spatial juxtaposition of the costameres to the Z bands. Where peripheral myonuclei precluded direct contact of dystrophin to the Z bands the organization of dystrophin was altered into lacunae harboring the myonucleus. These lacunae were surrounded by a dystrophin ring and covered by a more uniform dystrophin veil. ...
As a target for gene therapy, Duchenne muscular dystrophy (DMD) presents many obstacles but also an unparalleled prospect for correction by alternative splicing. The majority of mutations in the dystrophin gene occur in the region encoding the spectrin-like central rod domain, which is largely dispensable. Thus, splicing around mutations can generate a shortened but in-frame transcript, permitting translation of a partially functional dystrophin protein. We have tested this idea in vivo in the mdx dystrophic mouse (carrying a mutation in exon 23 of the dystrophin gene) by combining a potent transfection protocol with a 2-O-methylated phosphorothioated antisense oligoribonucleotide (2OMeAO) designed to promote skipping of the mutated exon*. The treated mice show persistent production of dystrophin at normal levels in large numbers of muscle fibers and show functional improvement of the treated muscle. Repeated administration enhances dystrophin expression without eliciting immune responses. Our ...
SingleCut CRISPR efficiently restored up to 90% of dystrophin expression in skeletal and heart muscles. Study published in the journal Science Translational Medicine. CAMBRIDGE, Mass. - November 29, 2017 - Exonics Therapeutics, Inc., a biotechnology company focused on developing SingleCut CRISPR technology to repair mutations causing Duchenne muscular dystrophy and other neuromuscular diseases, today announced the publication of a preclinical study demonstrating the Companys SingleCut CRISPR technology efficiently corrected in vivo dystrophin expression in a mouse model of Duchenne.. Duchenne is a devastating muscle disease in children for which there is no cure. It is caused by mutations of the dystrophin protein gene responsible for stabilizing and protecting muscle fibers, which results in progressive muscle weakness and leads to life-threatening and ultimately fatal medical issues. Data suggest that deletions of exon 50 of the dystrophin gene are among the most common single exon deletions ...
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
Mutations in the genes coding for either dystrophin or dysferlin cause distinct forms of muscular dystrophy. Dystrophin links the cytoskeleton to the sarcolemma through direct interaction with β-dystroglycan. This link extends to the extracellular matrix by β-dystroglycans interaction with α-dystroglycan, which binds extracellular matrix proteins, including laminin α2, agrin and perlecan, that possess laminin globular domains. The absence of dystrophin disrupts this link, leading to compromised muscle sarcolemmal integrity. Dysferlin, on the other hand, plays an important role in the Ca2+-dependent membrane repair of damaged sarcolemma in skeletal muscle. Because dysferlin and dystrophin play different roles in maintaining muscle cell integrity, we hypothesized that disrupting sarcolemmal integrity with dystrophin deficiency would exacerbate the pathology in dysferlin-null mice and allow further characterization of the role of dysferlin in skeletal muscle. To test our hypothesis, we generated
Objective Duchenne and Becker muscular dystrophy (DMD/BMD) are both caused by mutations in the DMD gene. Out-of-frame mutations in DMD lead to absence of the dystrophin protein, while in-frame BMD mutations cause production of internally deleted dystrophin. Clinically, patients with DMD loose ambulance around the age of 12, need ventilatory support at their late teens and die in their third or fourth decade due to pulmonary or cardiac failure. BMD has a more variable disease course. The disease course of patients with BMD with specific mutations could be very informative to predict the outcome of the exon-skipping therapy, aiming to restore the reading-frame in patients with DMD.. ...
Tay, S.K.H.,Khng, H.H.,Low, P.S.,Lai, P.S. (2006). Diagnostic strategy for the detection of dystrophin gene mutations in Asian patients and carriers using immortalized cell lines. Journal of Child Neurology 21 (2) : 150-155. [email protected] Repository. https://doi.org/10.1177/08830738060210021101 ...
Patterns of dystrophin and β-galactosidase expression were examined in mdx mice after i.m. injections of synthetic microspheres (MF-2) loaded with full-length (pHSADy) or mini-dystrophin gene (pSG5dys) cDNA plasmid constructs or with LacZ marker gene (pCMV-LacZ). A single injection of 25 μg pHSADy into quadriceps femoris muscle resulted in 6.8% of dystrophin positive myofibers (DPM) in a given muscle; 8.4% of DPM in glutaeus muscle and 4.3% of DPM in quadriceps femoris muscle of contralateral limb on day 21 after exposure compared with only 0.6% DPM in intact (non-injected) mdx mice. A high proportion of DPM (17.6% and 10.8%, respectively) was registered in both injected and contralateral muscles after mini- gene cDNA administration. MF-2/dystrophin cDNA par- ticles were detected by FISH analysis in about 60-70% of myofiber nuclei in muscles of injected and contralateral limbs 7 days after application. The presence of human dystrophin cDNA and its products in all skeletal muscles and in different
Medical Center Public Relations U-M scientists have developed a viral vector that delivers the gene for dystrophin, a protein critical for normal maintenance of muscle tissue, to the muscles of adult mice with muscular dystrophy. The secret: an ordinary virus with all its natural genetic material removed to make room for the dystrophin gene which triggers production of the protein. The result: dystrophic mice with muscles producing high levels of normal dystrophin protein for several months. We have induced long-term expression of the full-sized dystrophin protein for at least three months in the muscles of adult mice with Duchenne muscular dystrophy, says Jeffrey S. Chamberlain, associate professor of human genetics. We have shown that mice can incorporate the gene from our viral vector into their muscle tissue. It is an encouraging result, but it is not a cure. Chamberlain presented recent results from ongoing U-M research to develop an effective gene therapy for muscular dystrophy at the ...
A subsynaptic protein of Mr approximately 300 kD is a major component of Torpedo electric organ postsynaptic membranes and copurifies with the AChR and the 43-kD subsynaptic protein. mAbs against this protein react with neuromuscular synapses in higher vertebrates, but not at synapses in dystrophic muscle. The Torpedo 300-kD protein comigrates in SDS-PAGE with murine dystrophin and reacts with antibodies against murine dystrophin. The sequence of a partial cDNA isolated by screening an expression library with mAbs against the Torpedo 300-kD protein shows striking homology to mammalian dystrophin, and in particular to the b isoform of dystrophin. These results indicate that dystrophin is a component of the postsynaptic membrane at neuromuscular synapses and raise the possibility that loss of dystrophin from synapses in dystrophic muscle may have consequences that contribute to muscular dystrophy. ...
Duchenne muscular dystrophy is a neuromuscular disease caused by the lack of dystrophin that affects skeletal muscles, causing degeneration of muscle fibers and replacing them with fibrous and adipose tissue, events that gradually lead to functional loss. Patients with Duchenne muscular dystrophy have shown that bones become more fragile with age and with advancement of the disease. Muscle weakness and reduced mobility have been suggested to be the factors that promote bone deterioration. However, it seems that this does not occur in mdx mice. It has been identified in mdx mice the existence of a factor related or not to the lack of dystrophin that also participates in the impairment of bone quality. Mdx mice also exhibit muscle degeneration, but unlike human, it is compensated by muscle regeneration. In consequence, there is an increase in the muscle mass, but not necessarily of muscle contractile strength. The accommodation of this increased muscle mass promotes bone formation at specific ...
Induced splice modulation of pre-mRNAs shows promise to correct aberrant disease transcripts and restore functional protein and thus has therapeutic potential. Duchenne muscular dystrophy (DMD) results from mutations that disrupt the DMD gene open reading frame causing an absence of dystrophin protein. Antisense oligonucleotide (AO)-mediated exon skipping has been shown to restore functional dystrophin in mdx mice and DMD patients treated intramuscularly in two recent phase 1 clinical trials. Critical to the therapeutic success of AO-based treatment will be the ability to deliver AOs systemically to all affected tissues including the heart. Here, we report identification of a series of transduction peptides (Pip5) as AO conjugates for enhanced systemic and particularly cardiac delivery. One of the lead peptide-AO conjugates, Pip5e-AO, showed highly efficient exon skipping and dystrophin production in mdx mice with complete correction of the aberrant DMD transcript in heart, leading to |50% of the normal
Duchenne muscular dystrophy (DMD) is a fatal genetic disease caused by mutations in the dystrophin gene. Lack of dystrophin causes muscle wasting that eventually leads to premature death from respiratory and/or heart failure. Heart disease can be detected as early as six years of age in DMD patients. As heart disease progresses, patients begin to show overt signs of severe dilated cardiomyopathy and up to 40% of patients die from heart disease. Adeno-associated virus (AAV) mediated micro-dystrophin gene therapy brings the hope of ameliorating DMD. Dystrophin-deficient mdx mice exhibit a cardiac phenotype similar to human DMD patients albeit at a delayed progression (Bostick et al 2008 Cir Res102:121-130). Delineating the potential of gene therapy at different stages of dystrophic cardiomyopathy is critical to developing a successful gene therapy strategy. Investigators, including ourselves, have previously shown that AAV-9 can efficiently transduce the adult mouse heart. In this study, we ...
We report an unusual and complex dystrophin gene re-arrangement that causes Duchenne muscular dystrophy, and an antisense oligonucleotide (AO) exon skipping strategy that restores the reading frame. All dystrophin exons were present, as determined by MLPA and multiplex PCR studies, while RNA analysis indicated an anomaly involving exons 49 and 50. An inversion of 28 kb was identified that lead to the omission of these exons from the mature gene transcript. In addition, multiple mRNAs arising from the variable inclusion of at least six pseudo-exons were identified. The inversion arose from an unequal recombination event, and upon characterization of the precise breakpoints in introns 48 and 50, a small duplication was identified at the proximal intron 48 breakpoint and an 11 kb deletion was found at the distal intron 50 breakpoint. Several AOs were evaluated against the two most commonly incorporated pseudo-exons (PE1 and PE2) which, when used in conjunction with an AO targeting exon 51 for ...
Chromosome 6-encoded dystrophin-related-protein (DRP) shows significant structural similarities to dystrophin at the carboxyl terminus, though the two proteins are encoded on different chromosomes. Both DRP and dystrophin are expressed in muscle and brain and show some similarity in their subcellular localization. For example, in skeletal muscle both are expressed at neuromuscular and myotendinous junctions. However, while dystrophin is absent or severely reduced in Duchenne/Becker muscular dystrophy, DRP continues to be expressed. Within the brain, dystrophin is enriched at the postsynaptic regions of specific subsets of neurons, while the distribution of DRP is yet to be described. In this study we demonstrate a distinct though highly specific pattern of distribution of DRP in the brain. DRP is enriched in the choroid plexus, pia mater, intracerebral vasculature, and ependymal lining. Within the parenchyma proper, DRP is located at the inner plasma face of astrocytic foot processes at the ...
TY - JOUR. T1 - Brain dystrophin, neurogenetics and mental retardation. AU - Mehler, Mark F.. PY - 2000/3/24. Y1 - 2000/3/24. N2 - Duchenne muscular dystrophy (DMD) and the allelic disorder Becker muscular dystrophy (BMD) are common X-linked recessive neuromuscular disorders that are associated with a spectrum of genetically based developmental cognitive and behavioral disabilities. Seven promoters scattered throughout the huge DMD/BMD gene locus normally code for distinct isoforms of the gene product, dystrophin, that exhibit nervous system developmental, regional and cell-type specificity. Dystrophin is a complex plasmalemmal-cytoskeletal linker protein that possesses multiple functional domains, autosomal and X-linked homologs and associated binding proteins that form multiunit signaling complexes whose composition is unique to each cellular and developmental context. Through additional interactions with a variety of proteins of the extracellular matrix, plasma membrane, cytoskeleton and ...
Duchenne muscular dystrophy (DMD), a recessive X-linked disorder and the most common of a class of progressive muscle-wasting diseases, is characterized by the lack of dystrophin at the muscle cell membrane (1). Replacement of absent dystrophin in mdx mice by transgenic expression leads to complete restoration of normal muscle cell membrane function (2). Muscle is known to be a regenerative tissue, and this regeneration is accomplished via a heterogeneous population of cells called satellite cells or myoblasts. These cells divide upon damage to muscle, fuse to one another and with existing myofibers, and create new muscle fibers. One approach to therapy for DMD was the intramuscular injection of normal myoblasts into the skeletal muscle of DMD patients or mdx mice, which lack full-length functional dystrophin. Although early results in mdx mice were promising, the human clinical trials proved safe but ineffective, with little or no new expression of dystrophin documented (3, 4). Originally, it ...
UK researchers have successfully trialled a new drug to help patients with a severe form of muscular dystrophy. The new drug helps cells skip past sections of a gene damaged in Duchenne Muscular Dystrophy (DMD) so they can make smaller - but better functioning - dystrophin proteins. Dystrophin protects and connects muscle fibres. DMD affects about one in 3,500 boys who normally die in their teens or early twenties and has no cure or real treatment. Ive worked with patients with DMD for many years and this is the first time we can say with confidence that weve made a significant breakthrough towards finding a targeted treatment, said lead researcher Professor Francesco Muntoni from the Institute of Child Health, London.. Three boys, on the highest drug doses, had levels of normal dystrophin protein 18 percent (%) that of those of unaffected boys. One boys functional dystrophin level rose from near zero to 50% of normal.. The test was a phase two clinical trial, assessing which of six drug ...
Duchenne Muscular Dystrophy (DMD) is a progressive lethal disease caused by X-linked mutations of the dystrophin gene. Dystrophin deficiency clinically man
A type of polymerase chain reaction (q.v.) that is used to sample various regions of a large gene from one end to the other. For example, to analyze the human dystrophin gene, which occupies over 2 million base pairs on the X chromosome, multiplex PCR might involve simultaneous amplification from nine different sets of primers, all within the same reaction test tube. Each set of primers is chosen to produce a different-sized amplification product from a different region of the dystrophin gene. Normal males will display nine characteristic bands after the amplification products are separated by gel electrophoresis. Males with deletions in the dystrophin gene will be missing one or more of these bands. See muscular dystrophy. ...
In the high-dose cohort (n=3) for whom 12-month data are available, the mean percent normal dystrophin at 12 months was 51.6% mean normal dystrophin level. Significant and Sustained Distribution of Dystrophin in muscle biopsy were observed by immunofluorescence. All clinical subject (both low does and high dose patient) showed a significant functional improvement from baseline NSAA scores after one year, compared with the scores in an independent, external control group ...
Monoclonal clone# G2 antibody for DYSTROPHIN/DMD detection. Host: Mouse.Size: 100μg/vial. Tested applications: IHC-P. Reactive species: Human. DYSTROPHIN/DMD information: Molecular Weight: 425828 MW; Subcellular Localization: Cell membrane, sarcolemma ;
BACKGROUND: Targeted splice modulation of pre-mRNA transcripts by antisense oligonucleotides (AOs) can correct the function of aberrant disease-related genes. Duchenne muscular dystrophy (DMD) arises as a result of mutations that interrupt the open-reading frame in the DMD gene encoding dystrophin such that dystrophin protein is absent, leading to fatal muscle degeneration. AOs have been shown to correct this dystrophin defect via exon skipping to yield functional dystrophin protein in animal models of DMD and also in DMD patients via intramuscular administration. To advance this therapeutic method requires increased exon skipping efficiency via an optimized AO sequence, backbone chemistry and additional modifications, and the improvement of methods for evaluating AO efficacy. METHODS: In the present study, we establish the conditions for rapid in vitro AO screening in H(2)K muscle cells, in which we evaluate the exon skipping properties of a number of known and novel AO chemistries [2-O-methyl,
Different strategies involving stem cells for muscular dystrophy may be on the horizon, research suggests. Scientists have been using stem cells isolated from muscle tissue, bone marrow and blood vessels in lab animals to regenerate muscle fibers that are deficient in dystrophin[3] and results are encouraging.. In 2006, researchers managed to restore mobility in two afflicted dogs using stem cells isolated from muscle blood vessels [4], and in 2007 scientists managed to treat Duchenne MD in research mice using a combination of genetic correction and stem cells [3]. The latter study showed that it is possible to correct the genetic error in the cells that no longer produce dystrophin protein, and inject corrected cells stimulating the regeneration of muscles.. Researchers at the Harvard Stem Cell Institute obtained similar results, demonstrating that transplanted muscle stem cells can improve function in mice with MD, while replenishing the stem cell population in muscle fibers [5].. Although ...
For Duchenne muscular dystrophy-the most severe and common form of a heterogeneous group of inheritable muscle wasting disorders-a solution might lie in reframing the problem. All muscular dystrophies are caused by mutations in the DMD gene, which encodes dystrophin, a large cytoplasmic protein that plays a critical role in muscle-fiber integrity. Duchenne muscular dystrophy occurs only when the DMD mutations cause reading-frame disruptions that result in nonfunctional forms of dystrophin. In contrast, in-frame deletions in the DMD gene yield internally truncated but functional dystrophins that cause a less severe form of the disease called Becker muscular dystrophy.. In a new study, Maggio and colleagues employed CRISPR/Cas9 gene editing technology to delete internal portions of the DMD gene in muscle progenitor cells from patients. By moving the DMD reading frame back on track, the authors facilitated the expression of Becker-like dystrophin proteins, which have been shown to confer ...
The requirement of muscle damage for effective delivery and AON induced dystro-phin expression is further supported by the result obtained in the cardiac muscle in the mdx mice after systemic treatment of both 2OMePS AON and PMO. Cardiac muscles in mdx mice are less affected by the dystrophic process and no significant pathology and functional impairment can be obviously demonstrated until late age. Consistently, only minimum amount of dystrophin expression can be detected in the cardiac muscle even after repeated injections of both 2OMePS AON and PMO in all mdx mice aged 6 months or younger (Lu et al. 2005; Alter et al. 2006), whereas the same treatment can induce high levels of dystrophin in skeletal muscles. There is a possibility that the special tissue structure (vasculature and membrane) and pattern of metabolism or gene expression regulation could be responsible for lower efficiency of AON delivery or exon skipping inside myonuclei. However, direct injection of AON into cardiac muscles ...
This protocol represent an open randomized and prospective trial, designed to answer the specific question regarding the role of the cardioprotective therapy in Duchenne Muscular Dystrophy and Becker Muscular Dystrophy patients. In this light, CMR could provide relevant data, reinforcing the scientific background, to start early (particularly in BMD patients in whom this is still a debated question) a cardioprotective treatment with carvedilol or ramipril.Finally,this clinical trial will clarify whether a preventive therapy may be helpful on the clinical outcome, both in reducing myocardial fibrosis and preventing the progression towards the cardiomyopathy ...
Authors: Sura, Thanyachai , Eu-ahsunthornwattana, Jakris , Pingsuthiwong, Sarinee , Busabaratana, Manisa Article Type: Research Article Abstract: Background: Duchenne muscular dystrophy (DMD), a lethal X-linked disease affecting 1 in 3500 male births, and its more benign variant, Becker muscular dystrophy (BMD), are caused by mutations in the dystrophin gene. Because of its large size, analysing the whole gene is impractical. Methods have been developed to detect the commonest mutations i.e. the deletions of the exons. Although these tests are highly specific, their sensitivity is inherently limited by the prevalence of deletions, which differs …among different populations. Methods: We reviewed our database for the detection of Dystrophin gene mutation by means of 31-exon multiplex PCR in Thai males, diagnosed clinically and biochemically with DMD or BMD from July 1994 to November 2006. One index patient was chosen from each family for statistical analysis. The overall sensitivity of the test, ...
Monoclonal antibodies for dystrophin analysis: epitope mapping and improved binding to SDS treated muscle sections is an eagle-i resource of type Journal article at eagle-i Network Shared Resource Repository.
Large deletions in the dystrophin gene account for | 60% of mutations responsible for Duchenne muscular dystrophy (DMD). We have developed a genetic test that can be used directly for the preimplantation genetic diagnosis (PGD) of a majority of coupl
Sarepta is preparing to file a follow-up to its Duchenne muscular dystrophy (DMD) treatment Exondys 51 that seems to have greater efficacy.. Shares in the company were on the rise after it reported positive data from a phase I/II trial of the follow-up - called golodirsen - which showed the exon-skipping drug met its primary objective of raising levels of functional dystrophin, a protein that is mutated in DMD leading to the characteristic muscle wasting symptoms.. The European trial in 25 boys with deletions in the dystrophin gene amenable to treatment with golodirsen - an exon 53-skipping drug - showed that dystrophin levels increased to 1.019% of normal from an average baseline level of 0.095% of normal, which is a 10-fold increase and superior to that seen with exon 51-targeting Exondys 51 (eteplirsen). Some clinicians have suggested however that restoring dystrophin levels to 10% may be needed to have a real clinical benefit.. Nevertheless, Sarepta is hoping that data may be enough for it ...
Duchenne/Becker muscular dystrophy (DBMD) is a genetic disorder that develops in boys. It is caused by a mutation in the gene for dystrophin, a protein that is important for maintaining normal muscle structure and function. Loss of dystrophin causes muscle fragility that leads to weakness and loss of walking ability during childhood and teenage years. A specific type of mutation, called a nonsense (premature stop codon) mutation, is the cause of DBMD in approximately 10-15% of boys with the disease. Ataluren is an orally delivered, investigational drug that has the potential to overcome the effects of the nonsense mutation. This study is an open-label trial for patients with nonsense mutation dystrophinopathy who received ataluren in a prior PTC-sponsored study at a US clinical trial site. This trial will be conducted at sites in the US and will evaluate the long-term safety of ataluren, as determined by adverse events and laboratory abnormalities ...
Although muscular dystrophies are among the most common human genetic disorders, there are few treatment options available. Animal models have become increasingly important for testing new therapies prior to entering human clinical trials. The DMDmdx mouse is the most widely used animal model for Duchenne muscular dystrophy (DMD), presenting the same molecular and protein defect as seen in humans with the disease. However, this mouse is not useful for clinical trials, because of its very mild phenotype. The mouse model for congenital myodystrophy type 1D, Largemyd, harbors a mutation in the glycosyltransferase Large gene and displays a severe phenotype. To help elucidate the role of the proteins dystrophin and LARGE in the organization of the dystrophin-glycoprotein complex in muscle sarcolemma, we generated double-mutant mice for the dystrophin and LARGE proteins. The new DMDmdx/Largemyd mouse model is viable and shows a severe phenotype that is associated with the lack of dystrophin in muscle. ...
The human dystrophin gene extends almost 2.5 million bases, and includes a large number of exons separated by larger intron regions. Depending on the tissue type and developmental stage, any of seven different promoters (start signals) may be used to transcribe all or a part of the gene region and produce variants of the gene product. ...
Duchenne muscular dystrophy (DMD) is a genetic disease affecting 1 out of every 3500 boys [1] . This X-linked pathology is characterized by the absence of dystrophin in muscle fibers [2] . Dystrophin is linked to several proteins in a complex named dystrophin-associated glycoprotein complex (DGC) [3] . This complex is needed for the mechanical stability of muscle fibers and its absence weakens the sarcolemma and thus makes muscle fibers less resistant to physical and mechanical stress leading to a progressive muscle degeneration [4] . DMD patients die generally between 17 and 30 years of age. There are currently no curative treatments for this disease.. When a muscle is damaged, satellite cells surrounding the damage area are activated and migrate through the basement membrane to be incorporated into the wounded muscle fiber. They need to degrade the extracellular matrix (ECM) present between fibers to reach the damaged fibers [5] . Muscle precursor cells (MPCs) transplanted in muscle either ...
Antisense-mediated exon skipping aims to reframe dystrophin transcripts to allow generation of partly functional proteins and conversion of a severe Duchenne into a milder Becker phenotype. The first proof-of-concept in patient-derived cells was obtained in 2001 (van Deutekom et al. 2001), and the first clinical trial in DMD patients was conducted in 2006 (van Deutekom et al. 2007). This is relatively fast, especially given that AONs are a new type of drug. There are several reasons why AONs are now closer to clinical application than some of the more traditional therapeutic approached like gene and cell therapy. The exon skipping approach modulates endogenous pre-mRNA transcripts using synthetic DNA/RNA analogs. This eliminates the risks of an immune response towards viral vectors, donor-derived or autologous ex vivo modified cells and/or insertional mutagenesis. In addition, delivery of small AONs is very efficient, especially in dystrophic muscle, while efficient delivery of genes without a ...
Dystrophin, the protein defective in Duchenne muscular dystrophy (DMD), plays a critical role in the formation and maintenance of the neuromuscular junction. In addition to dystrophin, activation of internal promoters of the DMD gene leads to the production of several short products. Among these, Dp71, which consists of the C-terminal domain of dystrophin, is the most abundant product of the gene in non-muscle tissues and brain. In this report, we compare the temporal and regional expression patterns of dystrophin and Dp71 at different stages of embryonic development and during retinal differentiation in zebrafish. The Dp71 transcripts are the earliest to be expressed at 9-10 h post-fertilization (hpf) in the axial mesoderm. As development proceeds, intense Dp71 staining is observed in the notochord, the developing brain, the marginal regions of the somites and the eye primordium. At the completion of retinal differentiation, Dp71 is expressed in the ganglion and inner nuclear layers. ...
Duchenne muscular dystrophy (DMD) is an inherited X-linked disease that leads to severe muscular weakness. It is caused by mutations in the gene encoding dystrophin, which is responsible for connecting the cytoskeleton of muscle fibers to the extracellular matrix. The only disease-modifying therapy currently on the market is Sarepta Therapeutics Eteplirsen (Exondys 51), which targets an out-of-frame mutation implicated in 13% of DMD cases. Eteplirsen is a morpholino antisense oligomer that triggers the excision of the out-of-frame exon 51 during the pre-mRNA splicing of the dystrophin RNA transcript, leading to the production of truncated, yet functional dystrophin. Despite its approval by the FDA in 2016, Eteplirsens relatively poor efficacy has sparked a highly controversial debate. However, sales for 2017 are expected to reach approximately $125 million.. The field of DMD has seen increased gene supplementation therapy activities (e.g., Solid Biosciences is preparing an initial clinical ...
Real progress is being made in supplying functional dystrophin genes to treat Duchenne muscular dystrophy (DMD), a disease in which mutated dystrophin genes keep this critical protein from being produced in muscle fibers. ...
Dystrophin maintains the integrity of striated muscles by linking the actin cytoskeleton with the cell membrane. Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD) that result in progressive, debilitating muscle weakness, cardiomyopathy, and a shortened lifespan. Mutations of dystrophin that disrupt the amino-terminal actin-binding domain 1 (ABD-1), encoded by exons 2-8, represent the second-most common cause of DMD. In the present study, we compared three different strategies for CRISPR/Cas9 genome editing to correct mutations in the ABD-1 region of the DMD gene by deleting exons 3-9, 6-9, or 7-11 in human induced pluripotent stem cells (iPSCs) and by assessing the function of iPSC-derived cardiomyocytes ...
This study is the first to demonstrate the critical role of a dystrophin isoform for the targeting and subcellular distribution of a potassium channel in glial cells. Our immunocytochemical and electrophysiological results demonstrate that functional expression of the dystrophin isoform Dp71 is necessary for the highly asymmetric expression of the inwardly rectifying potassium channel Kir4.1 in the main glial cell type in retina, the Müller cells.. Genetic inactivation of the weakly inwardly rectifying potassium channel Kir4.1 in mice demonstrated that this particular Kir subunit sets the membrane potential in Müller cells and underlies the main potassium conductance in these cells (Kofuji et al., 2000). Such marked asymmetric and clustered distribution of Kir4.1 subunits in these specialized glial cells has presumably the important physiological function of promoting the efficient buffering of extracellular potassium concentration in the retina (Newman et al., 1984). Although the cellular ...
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In the 1860s French physician Guillaume Duchenne (1806-1875) noticed that the muscles in some young boys were weakening as he believed that dystrophy progressed as muscles continued to develop without the nutrients they needed. In 1987 a protein was identified that named dystrophin because of its abnormal form causes muscular dystrophy ...
Epitopes in the interacting regions of beta dystroglycan (PPxY motif) and dystrophin (WW domain) is an eagle-i resource of type Journal article at eagle-i Network Shared Resource Repository.
A ready source of autologous myogenic cells is of vital importance for drug screening and functional genetic studies in Duchenne Muscular Dystrophy (DMD), a rare disease caused by a variety of dystrophin gene mutations. As stem cells (SCs) can be easily and non-invasively obtained from urine specimens, we set out to determine whether they could be myogenic-induced and useful in DMD research. To this end, we isolated stem cells from the urine of two healthy donors and one patient with DMD, and performed surface-marker characterization, myogenic differentiation (MyoD), and then transfection with antisense oligoribonucletoides to test for exon skipping and protein restoration. We demonstrated that native urine-derived stem cells express the full-length dystrophin transcript, and that the dystrophin mutation was retained in DMD patient cells, although the dystrophin protein was detected solely in control cells following myogenic transformation according to the phenotype. Notably, we also showed that ...
TY - JOUR. T1 - Transcription factors YY1, Sp1 and Sp3 modulate dystrophin Dp71 gene expression in hepatic cells. AU - Peñuelas-Urquides, Katia. AU - Becerril-Esquivel, Carolina. AU - Mendoza-de-León, Laura C.. AU - Silva-Ramírez, Beatriz. AU - Dávila-Velderrain, José. AU - Cisneros, Bulmaro. AU - Bermúdez De León, Mario. N1 - Publisher Copyright: © 2016 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.. PY - 2016/1/1. Y1 - 2016/1/1. N2 - Dystrophin Dp71, the smallest product encoded by the Duchenne muscular dystrophy gene, is ubiquitously expressed in all nonmuscle cells. Although Dp71 is involved in various cellular processes, the mechanisms underlying its expression have been little studied. In hepatic cells, Dp71 expression is down-regulated by the xenobiotic β-naphthoflavone. However, the effectors of this regulation remain unknown. In the present study we aimed at identifying DNA ...
Duchenne and Becker muscular dystrophies are muscle-wasting disorders caused by mutations in the X-linked dystrophin gene. Dystrophin is a large cytoskeletal protein belonging to the spectrin superfamily, that links intracellular F-actin to the extracellular matrix via a membrane-associated glyco-protein complex thus maintaining structural rigidity and flexibility. Utrophin is a widely expressed protein that has been shown to functionally compensate for dystrophin in cultured muscle cells as well as in the muscular dystrophy mice model. Both utrophin and dystrophin share a similar domain architecture with N-terminal actin-binding domains and C-terminal variable domains separated by 22 or 24 spectrin-like repeats respectively. Therapeutic strategies to replace individuals having defective dystrophin with utrophin require full characterisation of these proteins. In this thesis, high-resolution structures of the N-terminal first spectrin repeat domains from utrophin and dystrophin have been ...
TY - JOUR. T1 - Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: An open-label, phase 2, dose-escalation study. AU - Cirak, Sebahattin. AU - Arechavala-Gomeza, Virginia. AU - Guglieri, Michela. AU - Feng, Lucy. AU - Torelli, Silvia. AU - Anthony, Karen. AU - Abbs, Stephen. AU - Garralda, Maria Elena. AU - Bourke, John. AU - Wells, Dominic J.. AU - Dickson, George. AU - Wood, Matthew Ja. AU - Wilton, Steve D.. AU - Straub, Volker. AU - Kole, Ryszard. AU - Shrewsbury, Stephen B.. AU - Sewry, Caroline. AU - Morgan, Jennifer E.. AU - Bushby, Kate. AU - Muntoni, Francesco. PY - 2011/8/13. Y1 - 2011/8/13. N2 - We report clinical safety and biochemical efficacy from a dose-ranging study of intravenously administered AVI-4658 phosphorodiamidate morpholino oligomer (PMO) in patients with Duchenne muscular dystrophy. We undertook an open-label, phase 2, dose-escalation study (0·5, 1·0, 2·0, 4·0, ...
Sarcoglycan is a multimeric, integral membrane glycoprotein complex that associates with dystrophin. Mutations in individual sarcoglycan subunits have been identified in inherited forms of muscular dystrophy. To evaluate the contributions of sarcoglycan and dystrophin to muscle membrane stability and muscular dystrophy, we compared muscle lacking specific sarcoglycans or dystrophin. Here we report that mice lacking (delta)-sarcoglycan developed muscular dystrophy and cardiomyopathy similar to mice lacking (gamma)-sarcoglycan. However, unlike muscle lacking (gamma)-sarcoglycan, (delta)-sarcoglycan-deficient muscle was sensitive to eccentric contraction-induced disruption of the plasma membrane. In the absence of (delta)-sarcoglycan, (alpha)-, (beta)- and (gamma)-sarcoglycan were undetectable, while dystrophin was expressed at normal levels. In contrast, without (gamma)-sarcoglycan, reduced levels of (alpha)-, (beta)- and (delta)-sarcoglycan were expressed, glycosylated and formed a complex with ...
β-Dystrobrevin is a dystrophin-related and -associated protein that is highly expressed in brain, kidney, and liver. Recent studies with the kidneys of the mdx3Cv mouse, which lacks all dystrophin isoforms, suggest that β-dystrobrevin, and not the dystrophin isoforms, may be the key component in the assembly of complexes similar to the muscle dystrophin-associated protein complexes (DPC) in nonmuscle tissues. To understand the role of β-dystrobrevin in the function of nonmuscle tissues, we generated β-dystrobrevin-deficient (dtnb −/−) mice by gene targeting. dtnb −/− mice are healthy, fertile, and normal in appearance. No β-dystrobrevin was detected in these mice by Western blotting or immunocytochemistry. In addition, the levels of several β-dystrobrevin-interacting proteins, namely Dp71 isoforms and the syntrophins, were greatly reduced from the basal membranes of kidney tubules and liver sinusoids and on Western blots of crude kidney and liver microsomes of ...
Duchenne muscular dystrophy is a highly complex multi-system disorder caused by primary abnormalities in the Dmd gene encoding the membrane cytoskeletal protein dystrophin. The resulting loss of the dystrophin protein triggers a concomitant disintegration of the dystrophin-associated glycoprotein complex at the sarcolemma. This complex links intracellular actin to components of the extracellular matrix and serves as a stabilising support network during normal muscle excitation-contraction-relaxation cycles. In Duchenne muscular dystrophy, the loss of dystrophin and its associated protein complex leads to membrane instability and micro-rupturing, the influx of excessive levels of calcium ions, the activation of proteases, sterile inflammation and eventually muscle degeneration and infiltration of adipose and connective tissue. Affected children suffer from severe and progressive skeletal muscle wasting with a loss of independent ambulation occurring during the early teenage years. In addition to ...
Mutations in the DMD gene encoding dystrophin-a critical structural element in muscle cells-cause Duchenne muscular dystrophy (DMD), which is the most common fatal genetic disease. Clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene editing is a promising strategy for permanently curing DMD. In this study, we developed a novel strategy for reframing DMD mutations via CRISPR-mediated large-scale excision of exons 46-54. We compared this approach with other DMD rescue strategies by using DMD patient-derived primary muscle-derived stem cells (DMD-MDSCs). Furthermore, a patient-derived xenograft (PDX) DMD mouse model was established by transplanting DMD-MDSCs into immunodeficient mice. CRISPR gene editing components were intramuscularly delivered into the mouse model by adeno-associated virus vectors. Results demonstrated that the large-scale excision of mutant DMD exons showed high efficiency in restoring dystrophin protein expression. We also confirmed that CRISPR from
Dystrophin deficiency sensitizes skeletal muscle of mice to eccentric contraction (ECC)-induced strength loss. ECC protocols distinguish dystrophin-deficient from healthy, wild type muscle, and test the efficacy of therapeutics for Duchenne muscular dystrophy (DMD). However, given the large lab-to-lab variability in ECC-induced strength loss of dystrophin-deficient mouse skeletal muscle (10-95%), mechanical factors of the contraction likely impact the degree of loss. Therefore, the purpose of this study was to evaluate the extent to which mechanical variables impact sensitivity of dystrophin-deficient mouse skeletal muscle to ECC. We completed ex vivo and in vivo muscle preparations of the dystrophin-deficient mdx mouse and designed ECC protocols within physiological ranges of contractile parameters (length change, velocity, contraction duration, and stimulation frequencies). To determine whether these contractile parameters affected known factors associated with ECC-induced strength loss, we measured
Antisense-mediated exon skipping in Duchenne Muscular Dystrophy aims to restore the expression of dystrophin protein. However, accurate quantification of dystrophin expression is challenging and, therefore, it is difficult to evaluate the outcome of the exon skipping treatment.. I have just joined COST member Dr Virginia Arechavala-Gomezas group in Spain, to collaborate in the project Quantification of dystrophin restoration by exon skipping, which aims to develop a reliable RT-qPCR method for dystrophin expression analysis and link dystrophin RNA and protein quantification methods.. Although I have extensive experience in the development custom PCR and RT-PCR assays, as well as in gene expression analysis, I havent worked in neuromuscular disorders before. Thus, my week-long visit (13-17 April 2015) to the DMD Genetic Therapy Group in the Human Genetics Department at the Leiden University Medical Centre, led by COST member Annemieke Aartsma-Rus, has been extremely beneficial for my future ...
This report documents the formation of stable fetal cardiomyocyte grafts in the myocardium of dystrophic dogs. Preliminary experiments established that the dystrophin gene product could be used to follow the fate of engrafted cardiomyocytes in dystrophic mdx mice. Importantly, ultrastructural analyses revealed the presence of intercalated discs consisting of fascia adherens, desmosomes, and gap junctions at the donor-host cardiomyocyte border. To determine if isolated cardiomyocytes could form stable intracardiac grafts in a larger species, preparations of dissociated fetal canine cardiomyocytes were delivered into the hearts of adult CXMD (canine X-linked muscular dystrophy) dogs. CXMD dogs, like Duchenne muscular dystrophy patients and mdx mice, fail to express dystrophin in both cardiac and skeletal muscle. Engrafted fetal cardiomyocytes, identified by virtue of dystrophin immunoreactivity, were observed to be tightly juxtaposed with host cardiomyocytes as long as 10 wk after engraftment, the ...
1. HoffmanEP. BrownRHJr. KunkelLM. 1987 Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51 919 928. 2. KoenigM. HoffmanEP. BertelsonCJ. MonacoAP. FeenerC. 1987 Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 50 509 517. 3. EmeryAE. Muntoni. 2003 Duchenne Muscular Dystrophy., 3rd edn. Oxford University Press, Oxford. 4. BanksGB. FuhrerC. AdamsME. FroehnerSC. 2003 The postsynaptic submembrane machinery at the neuromuscular junction: requirement for rapsyn and the utrophin/dystrophin-associated complex. J Neurocytol 32 709 726. 5. BhasinN. LawR. LiaoG. SaferD. EllmerJ. 2005 Molecular extensibility of mini-dystrophins and a dystrophin rod construct. J Mol Biol 352 795 806. 6. ErvastiJM. 2007 Dystrophin, its interactions with other proteins, and implications for muscular dystrophy. Biochim Biophys Acta 1772 108 117. 7. ...
Duchenne muscular dystrophy (DMD) (OMIM #310200) is an X-linked recessive inherited muscle-wasting disease characterised primarily by progressive weakness and atrophy of the skeletal and cardiac muscle. DMD patients are typically wheelchair-bound by 12 years of age and die in their late teens or early twenties of respiratory failure. It is one of the most common Mendelian disorders, occurring in all population groups with a birth prevalence of approximately 1/3 500 males. The disease gene, DMD, linked to chromosome Xp21.2, was one of the first genes to be isolated by positional cloning,[1] and the deficient product in affected boys was then identified as the protein dystrophin.[2] Dystrophin localises to the cell membrane in muscle cells and binds the protein actin, in this way forming part of the protein complex which links the cytoskeleton with the cell membrane. The gene is extremely large, spanning 2 400 kb of genomic DNA and comprising 79 exons which encode a 14 kb transcript. Causative ...
Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disorder caused by mutations in the dystrophin gene. Antisense-mediated exon skipping is one of the most promising approaches for the treatment of DMD but still faces personalized medicine challenges as different mutations found in DMD patients require skipping of different exons. However, 70% of DMD patients harbor dystrophin gene deletions in a mutation-rich area or hot-spot in the central genomic region. In this study, we have developed 11 different U7 small-nuclear RNA, to shuttle antisense sequences designed to mask key elements involved in the splicing of exons 45 to 55. We demonstrate that these constructs induce efficient exon skipping both in vitro in DMD patients myoblasts and in vivo in human DMD (hDMD) mice and that they can be combined into a single vector to achieve a multi skipping of at least 3 exons. These very encouraging results provide proof of principle that efficient multiexon-skipping can be achieved using adeno
Although the cause of Duchenne muscular dystrophy (DMD) is known, the specific factors that initiate and perpetuate disease progression are not well understood. We hypothesized that leaky dystrophin-deficient skeletal muscle releases endogenous danger signals (TLR ligands), which bind to Toll-like receptors (TLRs) on muscle and immune cells and activate downstream processes that facilitate degeneration and regeneration in dystrophic skeletal muscle. Here, we demonstrate that dystrophin-deficient mouse muscle cells show increased expression of several cell-surface and endosomal TLRs. In vitro screening identified ssRNA as a relevant endogenous TLR7 ligand. TLR7 activation led to myd88-dependent production of pro-inflammatory cytokines in dystrophin-deficient muscle cells, and cause significant degeneration/regeneration in vivo in mdx mouse muscle. Also, knockout of the central TLR adaptor protein, myd88 in mdx mice significantly improved skeletal and cardiac muscle function. Likewise, ...
In Duchenne muscular dystrophy (DMD), a disease with a prevalence of 1 in 3500 boys, an X-linked mutation of the dystrophin gene causes absence of the dystrophin protein in the muscle cell membrane. This leads to progressive loss of muscular tissue resulting in weakness and ultimately failure of skeletal, respiratory and heart musculature. The expected lifespan of DMD boys is about 27 years. In addition, about 30% of DMD patients show cognitive impairment with an unknown etiology and prognosis. Recently, the Leiden Duchenne research group showed the first successful restoration of dystrophin expression in skeletal muscle in humans. For the further development of therapies, two advances are imperative:. ...
Evidence-based recommendations on ataluren (Translarna) for treating Duchenne muscular dystrophy with a nonsense mutation in the dystrophin gene..
Knowledge about the parental origin of new mutations and the occurrence of germline mosaicism is important for estimating recurrence risks in Duchenne (DMD) and Becker muscular dystrophy (BMD). However, there are problems in resolving these issues partly because not all mutations can as yet be directly detected, and additionally because genetic ratios are very sensitive to ascertainment bias. In the present study, therefore, analysis was restricted to currently detectable mutations (deletions and duplications) in particular types of families which tend to be rare. In order to obtain sufficient data we pooled results from 25 European centers. In mothers of affected patients who were the first in their family with a dystrophin gene deletion or duplication, the ratio between the paternal and the maternal origin of this new mutation was 32:49 (binomial test P = 0.075) for DMD. In five BMD families the ratio between paternal and maternal origin of new mutations was 3∶2. Recurrence risk because of maternal
Animals have frequently been used as models for human disorders and mutations. Following advances in genetic testing and treatment options, and the decreasing cost of these technologies in the clinic, mutations in both companion and commercial animals are now being investigated. A recent review highlighted the genes associated with both human and non-human dilated cardiomyopathy. Cardiac troponin T and dystrophin were observed to be associated with both human and turkey (troponin T) and canine (dystrophin) dilated cardiomyopathies. This review gives an overview of the work carried out in cardiac troponin T and dystrophin to date in both human and animal dilated cardiomyopathy.. ...
Clinical trials are underway to demonstrate that antisense oligomers (AOs) can redirect dystrophin gene transcript splicing to excise selected exons, and thereby remove protein truncating mutations that would otherwise lead to Duchenne muscular dystrophy (DMD). Due to the widespread and complex nature of dystrophin gene expression, DMD is a great challenge to any therapy. However, characterization of the gene structure in Becker MD patients presenting with mild phenotypes, indicate that substantial portions of the dystrophin gene can be lost with relatively minor consequences, and some in-frame deletions may only be identified late in life. It as been confirmed that over half of the 79 exons are redundant, when lost in particular combinations. While 10-12 AOs should restore the reading- frame in the more common genomic deletion hotspots, scores of AOs will be needed to by-pass the many different protein-truncating mutations spread across the gene. The immediate challenges are (i) to establish ...
Utrophin is a homologue of dystrophin, the protein whose absence is responsible for Duchenne muscular dystrophy (DMD). As a first step toward clarifying if adenovirus (AV)-mediated utrophin transfer is a possible option to treat DMD, we have constructed an AV expressing utrophin (AdCMV-Utr) and studied utrophin expression after intramuscular injection of mdx mice, the mouse DMD model. Overexpression of utrophin by AdCMV-Utr was marked and nontoxic. The recombinant utrophin was distributed homogeneously at the surface of the muscle fibers. Its expression was sufficient to restore the normal histochemical pattern of alpha-sarcoglycan and beta-dystroglycan at this site. These two proteins are members of the dystrophin associated protein complex whose distribution is greatly reduced at the surface of the DMD muscle. These data indicate that AV-mediated utrophin transfer is an efficient way of utrophin upregulation in muscle and has the potential of becoming a treatment for DMD.
Muscular dystrophies are a group of diseases that primarily affect striated muscle and are characterized by the progressive loss of muscle strength and integrity. Major forms of muscular dystrophies are caused by the abnormalities of the dystrophin glycoprotein complex (DGC) that plays crucial roles as a structural unit and scaffolds for signaling molecules at the sarcolemma. α-Dystrobrevin is a component of the DGC and directly associates with dystrophin. α-Dystrobrevin also binds to intermediate filaments as well as syntrophin, a modular adaptor protein thought to be involved in signaling. Although no muscular dystrophy has been associated within mutations of the α-dystrobrevin gene, emerging findings suggest potential significance of α-dystrobrevin in striated muscle. This review addresses the functional role of α-dystrobrevin in muscle as well as its possible implication for muscular dystrophy.
Dystrophin acts as a glue, which holds muscles together and maintains the structure of cells. It is also known to carry signals inside and outside of muscle fibers. Since dystrophin is carried on the X-chromosome, and boys only carry one X-chromosome, they are more susceptible to damage. Boys is considered diagnosed with Duchenne when they are unable to produce dystrophin at all. Duchenne is normally passed from parent to child but mainly occurs spontaneously.. ...
This exciting work offers another gene-editing reagent that could potentially be used in clinical settings in the future, said Renzhi Han, who studies the molecular mechanisms of muscular dystrophies at the Ohio State University Medical Center and also was not involved in the study.. DMD, a fatal X-linked disease that results in progressively weakened skeletal and heart muscles, is caused by one of thousands of different mutations, including large deletions that disrupt the open reading of the dystrophin gene, resulting in in nonsense-mediated decay of associated messenger RNAs (mRNAs). In 2014, UT Southwesterns Eric Olson and colleagues demonstrated the ability of CRISPR-Cas9 to correct a dystrophin gene mutation in the germline of the DMD mouse model. In the present study, Olson and colleagues applied a similar strategy, but used the Cpf1 endonuclease, which differs somewhat from the widely used Streptococcus pyogenes-derived Cas9, including that it requires only a single-and shorter-guide ...
Here, we show that the newly discovered CRISPR-Cpf1 nuclease can efficiently correct DMD mutations in patient-derived iPSCs and mdx mice, allowing for restoration of dystrophin expression. Lack of dystrophin in DMD has been shown to disrupt the integrity of the sarcolemma, causing mitochondrial dysfunction and oxidative stress (28, 29). We found increased mtDNA and higher OCRs in LbCpf1-corrected iPSC-derived cardiomyocytes compared to uncorrected DMD iPSC-derived cardiomyocytes. Metabolic abnormalities of human DMD iPSC-derived cardiomyocytes were also rescued by Cpf1-mediated genomic editing. Our findings also demonstrated the robustness and efficiency of Cpf1 in mouse genome editing. By using HDR-mediated correction, the ORF of the mouse Dmd gene was completely restored, and pathophysiological hallmarks of the dystrophic phenotype, such as fibrosis and inflammatory infiltration, were also rescued.. Two different strategies-reframing and exon skipping-were applied to restore the ORF of the DMD ...
Ablation of DG in primary hippocampal culture has revealed that DG is not necessary for GABAergic synapse formation and for clustering of main GABAergic PSD proteins, including GABAARs (Lévi et al., 2002). Yet, involvement of the DGC in clustering of GABAergic postsynaptic proteins was supported by several lines of evidence. Mdx mice, used as a DMD model because of their lack of full-length dystrophin, were shown to have reduced GABAAR (but not gephyrin) clustering in the hippocampus CA1 region (Knuesel et al., 1999). Overexpression of a shorter dystrophin construct in vivo rescued the decrease of GABAAR cluster density and size, adding to the notion that dystrophin loss directly caused GABAAR clustering defects (Vaillend et al., 2010). NL2 was shown to biochemically interact with dystrophin over the intracellular synaptic scaffolding molecule S-SCAM (Sumita et al., 2007). Furthermore, a functional connection between the DGC and NL2 is suggested by the observation that, in GABAAR α2 subunit KO ...
The change in the gene that causes Duchenne/Becker muscular dystrophy (DBMD) happens on the X chromosome. A boy gets an X chromosome from his mother and a Y chromosome from his father. Only the X chromosome can have the changed gene that causes DBMD. Females almost never have DBMD because they have two X chromosomes. Even if a female has one X chromosome with the DBMD gene, her second X chromosome usually will make enough dystrophin to keep her muscles strong.. Because a female can carry (or have) one DBMD mutation and not be affected, she is referred to as a carrier. As a carrier, a female does have a risk of passing the same mutation on to her children. Each son born to a carrier female has a 50% chance of inheriting the DBMD mutation and having MD. Each daughter born to a carrier female instead has a 50% chance of inheriting the DBMD mutation and becoming a carrier like her mother.. Although most males diagnosed with DBMD are known to have inherited the mutation from their mothers, about ...
The hippocampal form of an essential muscle protein called dystrophin is found in higher levels in people with temporal lobe epilepsy (TLE), according to a new study published in the scientific journal Frontiers in Cellular Neuroscience.This could be the result of a compensatory mechanism - in r ...
Skeletal muscle has tissue-specific stem cells named satellite cells. Satellite cells exist in a quiescent state between myofibers and the basal lamina. When skeletal muscle is injured, satellite cells are activated, proliferate, and differentiate into myofibers. It is reported that isolated satellite cells/myoblasts from healthy donors are able to fuse with host dystrophin-deficient myofibers after transplantation via intramuscular injection, and expression of dystrophin at the sarcolemma was observed. Therefore, myoblast transfer is expected to be a promising therapy for DMD. However, the numbers of cells prepared from donors are not adequate for clinical use. To obtain a large number of satellite cells/ myoblasts of good quality, we are developing a method to induce muscle stem cells from human iPS cells. Although autologous cell transplantation needs no immunosuppression, the genes require editing to express dystrophin. In addition, the time and expense required for the process impose a ...
Dystrophin gene (DYS) defects cause three major clinical phenotypes: Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) and X-linked dilated cardiomyopathy (DCM). In the cardiology setting patients come to the clinical attention for DCM with/without increased serum creatine phosphokinase (sCPK) and/or myopathy. Purpose To determine the prevalence of DYS defects in a consecutive series of 408 DCM patients and to describe their phenotypes.. Methods DCM was diagnosed according to WHO criteria. The criterion for first level DYS screening was male sex: we included males with both normal and increased sCPK. The criterion for second level DYS screening was the presence of defects of myocyte immunostaining by 5′, rod, midrod and C-terminal domain using anti-DYS antibodies at endomyocardial biopsy. This latter analysis consisted of the direct automated sequencing of the 75 exons and flanking regions of the gene.. Results We identified DYS defects in 31 of the 408 probands (7.6%); the ...
Background: One of the most common and efficient methods for detecting mutations in genes is PCR amplification followed by direct sequencing. Until recently, the process of designing PCR assays has been to focus on individual assay parameters rather than concentrating on matching conditions for a set of assays. Primers for each individual assay were selected based on location and sequence concerns. The two primer sequences were then iteratively adjusted to make the individual assays work properly. This generally resulted in groups of assays with different annealing temperatures that required the use of multiple thermal cyclers or multiple passes in a single thermal cycler making diagnostic testing time-consuming, laborious and expensive. These factors have severely hampered diagnostic testing services, leaving many families without an answer for the exact cause of a familial genetic disease. A search of GeneTests for sequencing analysis of the entire coding sequence for genes that are known to ...
Duchenne muscular dystrophy (DMD) is a severe and fatal muscle wasting disease characterized by a high mutation rate in the gene that encodes the membrane-associated protein dystrophin that results in absence of expressed protein. Although the primary genetic defect for DMD is known, the mechanisms that initiate the onset of DMD are not currently understood. This study tested the hypothesis that pathophysiological processes involved in DMD could be identified by the global expression of mRNA in maturing dystrophin- and utrophin-deficient mouse (mdx:utrn-/-) muscles. Two potential dystrophic onset mechanisms targeted for analysis were (1) disrupted expression of calcium handling proteins; and, (2) increased expression of immune response markers. An mRNA expression profile was developed following isolation of total RNA from control and mdx:utrn-/- triceps surae (TS) muscles at ages 9-10 and 20-21 days using Affymetrix® Mu74Av2 GeneChips®. Compared to control, the mRNA expression profile in ...
Current Research and Scholarly InterestsDuchenne muscular dystrophy (DMD) is an X-chromosome-linked genetic disease that is caused by a mutation in the dystrophin gene and affects 1 in every 3500 boys. DMD patients suffer progressive muscle wasting and eventual cardiorespiratory failure that results in an early death in the second or third decade of life. Although extensive research effort has been invested, lack of a good mouse model that mimics the cardiac failure hinders research. We have developed a novel mouse model that exhibit all the symptoms found in DMD patients and our research is aimed at understanding the cardiac failure in DMD for future therapeutic interventions. Our mouse model fully recapitulates the DMD symptoms because we also took into account of the size of human protection DNA on chromosomal ends (telomere) compared to mouse. We would like to study the cause of cardiac failure in our mouse model by 1) determine if telomere shortening is specific to cardiomyocytes, 2) ...
This gene encodes a protein belonging to the syntrophin family. Syntrophins are cytoplasmic peripheral membrane proteins that bind to components of mechanosenstive sodium channels and the extreme carboxy-terminal domain of dystrophin and dystrophin-related proteins. The PDZ domain of this protein product interacts with a protein component of a mechanosensitive sodium channel that affects channel gating. Absence or reduction of this protein product has been associated with Duchenne muscular dystrophy. There is evidence of alternative splicing yet the full-length nature of these variants has not been described. [provided by RefSeq, Jul 2008 ...
Soudon reported results for 20+ DMD patients who used CTMV (DMD3). The patients had an average survival of 3.6 years.. Eagle et al. reported results for 200 DMD patients who were either untreated or used TMV/CTMV (DMD4). The untreated patients had an average survival of 19.5 years (cardiomyopathy was the cause of death for 7.4%). The patients who used TMV/CTMV had an average survival of 24.8 years (cardiomyopathy was the cause of death for 36.8%).. Bach et al. reported results for seven DMD patients who used CTMV for a mean of 7.1 years starting from the average age of 21.1±3.8 to 28.1±4.5 years (JBCV7). Two of the seven patients were still alive at time of publication. Complications were not reported.. The DMD patients of Baydur and Bach, who survived long enough after episodes of acute respiratory failure to be referred to rehabilitation centers and who used TMV/CTMV, had an improved average survival of 6.2 and 7.1 years, respectively.. Ishikawa et al. reported that (YICV7):. ...
A promising minidystrophin gene that restores normal muscle force to skeletal and diaphragm muscles in mice with a disease resembling Duchenne muscular dystrophy (DMD) seems to be only partially effective at restoring strength and function to heart muscles. ...
The primary endpoint of the Phase 1b study is to assess the safety and tolerability of this investigational gene therapy in ambulatory boys with Duchenne muscular dystrophy through 12 months following treatment. Based on the data to date, the most common adverse events (AEs) suspected to be related to PF-06939926 (occurring in ,40% of patients) were vomiting, nausea, decreased appetite, and pyrexia. There was no evidence of clinically relevant anti-dystrophin responses or hepatic dysfunction with the protocol-defined daily glucocorticoid regimen.. Among the 9 patients, 3 serious adverse events (SAEs) were reported in the first 14 days following administration, one more SAE than at Pfizers previous update. Importantly, each of these SAEs was fully resolved and at their last clinic visits, all patients were doing well. The first SAE involved persistent vomiting resulting in dehydration, which required admission for IV anti-emetics and fluids. The second SAE involved acute kidney injury with ...
Abstract: Cultured muscle cells from DMD patients carrying duplications were transfected with AONs targeting the duplicated exons, and the dystrophin RNA and protein were analyzed.For two brothers with an exon 44 duplication, skipping was, even at suboptimal transfection conditions, so efficient that both exons 44 were skipped, thus generating, once more, an out-of-frame transcript. In such cases, one may resort to multi-exon skipping to restore the reading frame, as is shown here by inducing skipping of exon 43 and both exons 44. By contrast, in cells from a patient with an exon 45 duplication we were able to induce single exon 45 skipping, which allowed restoration of wild type dystrophin. The correction of a larger duplication (involving exons 52 to 62), by combinations of AONs targeting the outer exons, appeared problematic due to inefficient skipping and mistargeting of original instead of duplicated exons.The correction of DMD duplications by exon skipping depends on the specific exons ...

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  • Dystrophin and mutations: one gene, several proteins, multiple phenotypes. (nih.gov)
  • 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. (nih.gov)
  • Here, we focus on current understanding of the genotype-phenotype relation for mutations in the dystrophin gene and their implications for gene functions. (nih.gov)
  • Deletions in the dystrophin gene represent 65% of mutations in DMD/BMD patients. (hindawi.com)
  • Dystrophin localizes at the X chromosome, whose mutations might result in Duchenne muscular dystrophy, Becker muscular dystrophy and X-linked dilated cardiomyopathy. (biomedsearch.com)
  • Duchenne muscular dystrophy is caused by mutations in the DMD gene that disrupt the open reading frame and prevent the full translation of its protein product, dystrophin. (nih.gov)
  • Duchenne muscular dystrophy, or DMD, is caused by mutations in the gene that encodes dystrophin, which plays a role in stabilizing the membrane of muscle fibers. (eurekalert.org)
  • Many different types of mutations can lead to DMD, some of which block dystrophin production altogether and others that result in a protein that doesn't function normally. (eurekalert.org)
  • Muscle biopsies revealed that, despite the genetic mutations, the patients were producing significant amounts of a slight smaller yet functioning dystrophin. (eurekalert.org)
  • In explaining the mild symptoms seen in many patients with mutations in the first exons of the dystrophin gene -- including the group of patients they first described in 2009 -- the researchers have now demonstrated that dystrophin can be produced by an alternate cellular mechanism in which capping of the messenger RNA is not required. (eurekalert.org)
  • Although clinical trials are currently investigating drugs to treat the more common gene mutations found in the middle of the dystrophin gene, no current therapies are specifically directed toward the approximately 6 percent of patients with mutations affecting the first four exons. (eurekalert.org)
  • Mutations in the DMD gene result in absent/non-functional muscle dystrophin protein in DMD and shortened/partially functional protein in BMD. (nature.com)
  • It results from mutations in an exceptionally large gene which encodes the sarcolemma-bound protein dystrophin. (nature.com)
  • Duchenne muscular dystrophy (DMD) is a fatal genetic disease caused by mutations in the dystrophin gene. (ahajournals.org)
  • Among them, dystrophin strengthens the sarcolemma through protein-lipid interactions, and its absence due to gene mutations leads to the severe Duchenne muscular dystrophy. (cea.fr)
  • Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and structural defects in the neuromuscular synapse that are caused by mutations in dystrophin. (pubmedcentralcanada.ca)
  • Due to the large size of the dystrophin gene (79 exons), finding point mutations (substitutions, deletions or insertions of one or several nucleotides) has been prohibitively expensive and laborious. (harvard.edu)
  • The aim of this project was to develop an effective and convenient method of finding all, or most, mutations in the dystrophin gene with only a moderate increase in cost. (harvard.edu)
  • Results: Using denaturing high performance liquid chromatography (DHPLC) screening and direct sequencing, 86 PCR amplicons of genomic DNA from the dystrophin gene were screened for mutations in eight patients diagnosed with DMD who had tested negative for large DNA rearragements. (harvard.edu)
  • Conclusions: We have shown that it is now feasible for clinical laboratories to begin testing for both point mutations and large deletions/duplications in the dystrophin gene. (harvard.edu)
  • Muscular dystrophy is caused by mutations in a large, complex gene that produces dystrophin. (umich.edu)
  • Monaco et al found that frame shift mutations in the DMD gene will lead to a truncated and non-functional form of dystrophin [ 1 ], which become the primary cause of the disease. (springer.com)
  • Dystrophin-glycoprotein complex (DGC)-related muscular dystrophies may present similar clinical and pathological features as well as undetectable mutations thus being sometimes difficult to distinguish. (springer.com)
  • Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD) that result in progressive, debilitating muscle weakness, cardiomyopathy, and a shortened lifespan. (jci.org)
  • Mutations of dystrophin that disrupt the amino-terminal actin-binding domain 1 (ABD-1), encoded by exons 2-8, represent the second-most common cause of DMD. (jci.org)
  • These findings represent an important step toward eventual correction of common DMD mutations and provide a means of rapidly assessing the expression and function of internally truncated forms of dystrophin-lacking portions of ABD-1. (jci.org)
  • Primary mutations in the dystrophin gene result in the absence of the protein in DMD, and mutations in any one of four sarcoglycan (á, â, ä, ã) genes results in a loss of the entire sarcoglycan complex in LGMD. (pitt.edu)
  • Duchenne muscular dystrophy (DMD) results from mutations that disrupt the DMD gene open reading frame causing an absence of dystrophin protein. (surrey.ac.uk)
  • Genetic mutations resulting in the absence of dystrophin cause Duchenne muscular dystrophy, and those resulting in insufficient or abnormal dystrophin cause Becker muscular dystrophy. (thefreedictionary.com)
  • Duchenne's muscular dystrophy (DMD) is a fatal disease caused by mutations in the DMD gene that lead to quantitative and qualitative disturbances in dystrophin expression. (ox.ac.uk)
  • These mutations have remained undetected in most patients, both male and female, because available techniques are relatively expensive and laborious given the size of the dystrophin gene. (biomedcentral.com)
  • Duchenne muscular dystrophy (DMD) is the most common, serious form of muscular dystrophy and is caused by mutations in the large dystrophin gene. (edu.au)
  • In DMD/BMD, the individual profiles of cognitive and behavioral deficits, mental retardation and other phenotypic variations appear to depend on complex profiles of transcriptional regulation associated with individual dystrophin mutations that result in the corresponding presence or absence of individual brain dystrophin isoforms that normally exhibit developmental, regional and cell-type-specific expression and functional regulation. (elsevier.com)
  • Dystrophinopathies are a group of distinct neuromuscular diseases that result from mutations in the structural cytoskeletal Dystrophin gene. (umn.edu)
  • The dystrophin-associated protein complex is a multiprotein complex that includes dystrophin and the dystrophin-associated proteins. (wikipedia.org)
  • Dystrophin binds to actin of the cytoskeleton, and also to proteins in the extracellular matrix. (wikipedia.org)
  • The dystrophin-associated protein complex also contains dystrophin-associated proteins. (wikipedia.org)
  • The importance of dystrophin and its associated proteins in normal muscle function is now well established. (pnas.org)
  • Dystrophin and its associated proteins form a scaffold underneath the cardiomyocyte membrane and connect the intracellular cytoskeleton to the extracellular matrix. (biomedsearch.com)
  • It shares features with other cytoskeletal proteins such as SPECTRIN and alpha-actinin but the precise function of dystrophin is not clear. (curehunter.com)
  • Videos accompanying the online publication show visual evidence of pronounced curving of the spine and dramatically reduced mobility as a result of deficiency of both dystrophin and utrophin proteins (Hyperlink to: Mouse Pretreatment/Supplementary Video S1, http://www.avibio.com/videos03.php ). (scienceblog.com)
  • A macromolecular complex of proteins that includes DYSTROPHIN and DYSTROPHIN-ASSOCIATED PROTEINS. (curehunter.com)
  • Dystrophin and its partially redundant homolog Utrophin are associated with a number of other proteins, members of the Dystrophin-glycoprotein complex (DGC) ( Ervasti and Campbell, 1991 ). (jneurosci.org)
  • PURPOSE: To test the hypothesis that exercise training (ET) would alleviate age-related disruption of localization in DGC proteins (dystrophin, α-syntrophin, and β-sarcoglycan), and ET will upregulate decorin. (wku.edu)
  • Dystrophin localizes to the sarcolemma and stabilizes a complex of proteins (dystrophin-associated proteins, DAPs) that link the extracellular matrix to the actin cytoskeleton ( Ohlendieck, 1996 ). (biologists.org)
  • Several studies have shown that α-dystrobrevin can bind many of the same proteins that associate with dystrophin. (biologists.org)
  • an adapter protein that links signaling proteins to the dystrophin-dystrobrevin scaffold. (biologists.org)
  • Therefore, both dystrophin and dystrobrevin serve as scaffolds for a variety of signaling proteins. (biologists.org)
  • Dystrophin-less DMD and MDX myotubes were more susceptible to hypoosmotic shock than controls, as monitored by the uptake of external horseradish peroxidase and release of the soluble enzymes creatinine kinase or pyruvate kinase and of radiolabelled proteins. (biologists.org)
  • The present study was intended to identify all known members of the dystrophin superfamily and their associated proteins expressed in Müller glial cells (MGC). (arvojournals.org)
  • In morphologically preserved differentiated Müller cells, Dp71f was localized in clusters, utrophin was diffusely distributed in the cytoplasm, and dystrophin-associated proteins (DAPs) were membrane-bound. (arvojournals.org)
  • 1 In the muscle, dystrophin is a submembranous cytoskeletal protein 2 that links actin 3 to a complex of dystrophin-associated proteins (DAPs) composed of transmembranous and submembranous proteins, such as dystroglycans, sarcoglycans, and syntrophins. (arvojournals.org)
  • Our results provide evidence for the role of the dystrophin central rod domain as a scaffold platform with a wide range of surface features and biophysical properties allowing it to interact with its various known partners such as proteins and membrane lipids. (inserm.fr)
  • Utrophin and dystrophins are minor actin-binding proteins present in muscle and non-muscle cytoskeleton. (inserm.fr)
  • Two new dystrophin isoforms were found, Dp71f and Dp71 d, as well as the Up71 isoform and the dystrophin-associated proteins, alpha and beta -dystrobrevins. (inserm.fr)
  • Distribution of Dp71d/Dp71delta110m, Up400/Up71 and dystrophin-associated proteins in relation to the actin cytoskeleton was evaluated by confocal microscopy in both resting and platelets adhered on glass. (inserm.fr)
  • Therefore, connection of defined areas of plasma membrane or its constituents such as ion channels to single sarcomeres might be a potential function exerted by dystrophin alone or in conjunction with other submembrane cytoskeletal proteins. (rupress.org)
  • Of the numerous elements necessary for proper functioning of this synaptic contact, dystrophin proteins in the eye play an important role. (arvojournals.org)
  • Harnessing the potential of dystrophin-related proteins for ameliorating Duchenne's muscular dystrophy. (ox.ac.uk)
  • Dystrophin is a member of the spectrin superfamily of proteins. (ox.ac.uk)
  • Dystrophin itself is closely related to three proteins that constitute a family of dystrophin-related proteins (DRPs): the chromosome 6-encoded DRP or utrophin, the chromosome-X encoded, DRP2 and the chromosome-18 encoded, dystrobrevin. (ox.ac.uk)
  • These proteins share sequence similarity and functional motifs with dystrophin. (ox.ac.uk)
  • Dystrophin is a complex plasmalemmal-cytoskeletal linker protein that possesses multiple functional domains, autosomal and X-linked homologs and associated binding proteins that form multiunit signaling complexes whose composition is unique to each cellular and developmental context. (elsevier.com)
  • Through additional interactions with a variety of proteins of the extracellular matrix, plasma membrane, cytoskeleton and distinct intracellular compartments, brain dystrophin acquires the capability to participate in the modulatory actions of a large number of cellular signaling pathways. (elsevier.com)
  • Members of the dystrophin family of proteins perform a critical role in the maintenance of membrane-associated complexes at points of intercellular contact in vertebrate cells. (nih.gov)
  • Association of syncollin and desmin: Linking intermediate filament proteins to the dystrophin-associated protein complex. (ox.ac.uk)
  • Dystrophin is a sub-sarcolemmal component of skeletal muscle fibres and is enriched at the postsynaptic membrane of the neuromuscular junction (NMJ). (mendeley.com)
  • While dystrophin in skeletal muscle has been extensively studied, the function of dystrophin in vascular smooth muscle is less clear. (sigmaaldrich.com)
  • Collectively, these data suggest dystrophin directly organizes and/or stabilizes costameric MTs and classifies dystrophin as a cytolinker in skeletal muscle. (rupress.org)
  • Collectively, these data support the hypothesis that dystrophin may function as a cytolinker in skeletal muscle. (rupress.org)
  • The presence of human dystrophin cDNA and its products in all skeletal muscles and in different internal organs was proven by PCR and RT-PCR analysis. (nature.com)
  • The absence of any efficient pharmaceutical or biological (myoblast transplantation) methods for the treatment of DMD makes the development of gene therapy approaches for widespread systemic delivery of dystrophin gene to skeletal muscles very urgent for the correction and management of this primary lethal genetic disorder. (nature.com)
  • The levels of dystrophin gene expression in different skeletal muscles as a function of time was examined in mdx mice after a single i.m. administration of microspheres loaded with 25 μg of full-length dystrophin cDNA (MF2/pHSADy). (nature.com)
  • DMD with a nonsense mutation is caused by a single base variation in a person's DNA, which leads to incomplete dystrophin production in the skeletal, smooth and cardiac muscle fibres. (nice.org.uk)
  • Immunoblots of affected heart and skeletal muscle showed a dramatic reduction of dystrophin protein and histopathology of affected hearts indicated muscle fiber degeneration. (biomedcentral.com)
  • 2006), whereas the same treatment can induce high levels of dystrophin in skeletal muscles. (fitness-vip.com)
  • While these treatments hold great promise for improving skeletal muscle, Bronson explains that their impact may not be as robust in the heart: "Refining the selection of which DMD gene sequences are included in the mini-dystrophin gene may allow for improved cardiac function. (pharmiweb.com)
  • The CT domain was not included in the mini- or micro-dystrophin genes in current clinical trials as it had no contribution to skeletal muscle. (pharmiweb.com)
  • While the focus of this research is on improving cardiac function through modified mini-dystrophin genes, skeletal muscle function will be evaluated. (pharmiweb.com)
  • The hope is not to protect the heart at the expense of skeletal muscle, but to generate mini-dystrophin genes that can fulfill both roles. (pharmiweb.com)
  • The current versions of the minimized dystrophin gene are designed based on the knowledge of dystrophin structure-function relationship in skeletal muscle. (pharmiweb.com)
  • Role of Toll-like receptors in the pathogenesis of dystrophin-deficient skeletal and heart muscle. (kennedykrieger.org)
  • We hypothesized that leaky dystrophin-deficient skeletal muscle releases endogenous danger signals (TLR ligands), which bind to Toll-like receptors (TLRs) on muscle and immune cells and activate downstream processes that facilitate degeneration and regeneration in dystrophic skeletal muscle. (kennedykrieger.org)
  • 4 The mechanism(s) by which the absence of dystrophin causes the myodegenerative disorder is still unclear, although it has been suggested that dystrophin may be responsible for maintaining the cell shape in skeletal fibers and for the clustering of acetylcholine receptor molecules at the neuromuscular junction. (arvojournals.org)
  • In striated muscle, dystrophin transcripts are detectable from about 9 d in the heart and slightly later in skeletal muscle. (rupress.org)
  • However, there is an important difference between the two types of muscle: the heart is already functional as a contractile organ before the appearance of dystrophin transcripts, whereas this is not the case in skeletal muscle, where dystrophin and myosin heavy chain transcripts are first detectable at the same time. (rupress.org)
  • Direct visualization of the dystrophin network on skeletal muscle fiber membrane. (rupress.org)
  • We have shown that dystrophin molecules are not uniformly distributed over the humen, rat, and mouse skeletal muscle fiber surface using three independent methods. (rupress.org)
  • These data suggest that dystrophin defects are not a common cause of idiopathic DCM in this age group in the absence of skeletal muscle cramps or weakness. (elsevier.com)
  • We examined aspects of collagen cross-linking in dystrophin-deficient murine, canine, and human skeletal muscle. (elsevier.com)
  • Dystrophin is a high molecular weight protein localized under the sarcolemma of normal extrafusal muscle fibers but absent in skeletal muscles of Duchenne muscular dystrophy patients and in the mdx mouse. (ubc.ca)
  • In the brain, β-dystrobrevin coimmunoprecipitates with the dystrophin isoforms Dp71 and Dp140. (pnas.org)
  • However, there are several other tissue specific isoforms of dystrophin, some exclusively or predominantly expressed in the brain or the retina. (nih.gov)
  • To gain more insights into the role of dystrophin in this cognitive phenotype, we performed a comprehensive analysis of the expression patterns of dystrophin isoforms across human brain development, using unique transcriptomic data from Allen Human Brain and BrainSpan atlases. (nature.com)
  • Dystrophin isoforms show large changes in expression through life with pronounced differences between the foetal and adult human brain. (nature.com)
  • The expression of dystrophin isoforms was significantly associated with genes implicated in neurodevelopmental disorders, like autism spectrum disorders or attention-deficit hyper-activity disorders, which are known to be associated to DMD. (nature.com)
  • Our results point to the crucial role of several dystrophin isoforms in the development and function of the human brain. (nature.com)
  • To further our understanding of this aspect of the function of dystrophin , we have generated Drosophila mutants that lack the large dystrophin isoforms and analyzed their role in synapse function at the neuromuscular junction. (jneurosci.org)
  • In expression and rescue studies, we show that lack of the large dystrophin isoforms in the postsynaptic muscle cell leads to elevated evoked neurotransmitter release from the presynaptic apparatus. (jneurosci.org)
  • Absence of the large dystrophin isoforms does not lead to changes in muscle cell morphology or alterations in the postsynaptic electrical response to spontaneously released neurotransmitter. (jneurosci.org)
  • Expression of the shorter dystrophin-EGFP isoforms Dp71 in the brain, Dp260 in the retina, and Dp116 in the peripheral nerve remained unabated by the mdx-23 mutation. (unboundmedicine.com)
  • The huge size of the dystrophin gene, its complex expression patterns and expression of the predominant isoforms in non-dividing cells, have hindered gene replacement therapies for DMD, but render the dystrophin gene product an ideal candidate to evaluate AO therapies directed at splicing intervention. (edu.au)
  • Seven promoters scattered throughout the huge DMD/BMD gene locus normally code for distinct isoforms of the gene product, dystrophin, that exhibit nervous system developmental, regional and cell-type specificity. (elsevier.com)
  • The protein encoded by this gene is predicted to resemble certain short C-terminal isoforms of dystrophin and dystrophin-related protein 1 (DRP1 or utrophin). (nih.gov)
  • Synthetic peptide within Human Dystrophin aa 3650 to the C-terminus (C terminal). (abcam.com)
  • Recombinant adeno-associated virus (AAV) carrying a truncated human dystrophin gene (mini-dystrophin) expressed from a cytomegalovirus (CMV) promoter. (clinicaltrials.gov)
  • Computational study of the human dystrophin repeats: interaction properties and molecular dynamics. (inserm.fr)
  • We investigated NMJs of a series of mdx-XistΔhs mice, which expressed dystrophin between ~2% and 19% of normal. (mendeley.com)
  • On the other hand, mdx+/- mice (expressing ~50% dystrophin) showed normal NMJ features. (mendeley.com)
  • When they used 10 times more guide RNA than Cas9, they found that mice were able to reach roughly 90 percent of the normal dystrophin protein expression in their muscles and hearts four weeks after gene editing. (the-scientist.com)
  • Increased neointimal thickening in dystrophin-deficient mdx mice. (sigmaaldrich.com)
  • In contrast, dystrophin-deficient mdx mice appear physically normal despite their underlying muscle pathology. (nih.gov)
  • We describe mice deficient for both dystrophin and the dystrophin-related protein utrophin. (nih.gov)
  • Using tissue-based cosedimentation assays on mice expressing endogenous dystrophin or truncated transgene products, we find that constructs harboring spectrinlike repeat 24 through the first third of the WW domain cosediment with MTs. (rupress.org)
  • Furthermore, FKRP sedimentation shifts with dystroglycan in disease models involving the dystrophin-glycoprotein complex, and sarcolemmal FKRP immunofluorescence mirrors that of dystroglycan in muscular dystrophy mice, suggesting that FKRP localization may be mediated by dystroglycan. (biomedsearch.com)
  • Oxford, United Kingdom & Bothell, WA, USA - October 20, 2009 - An exon skipping PPMO has demonstrated dramatic effects in the prevention and treatment of severely affected, dystrophin and utrophin-deficient mice, preventing severe deterioration of the treated animals and extending their lifespan. (scienceblog.com)
  • The paper "Prevention of Dystrophic Pathology in Severely Affected Dystrophin/Utrophin-deficient Mice by Morpholino-oligomer-mediated Exon-skipping" details the successful exon skipping and treatment of utrophin/dystrophin double knockout (dKO) mice with a cell-penetrating peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) targeting exon 23 in dystrophin pre-mRNA. (scienceblog.com)
  • Patterns of dystrophin and β-galactosidase expression were examined in mdx mice after i.m. injections of synthetic microspheres (MF-2) loaded with full-length (pHSADy) or mini-dystrophin gene (pSG5dys) cDNA plasmid constructs or with LacZ marker gene (pCMV-LacZ). (nature.com)
  • We report here for the first time efficient transfection of mdx mice myofibers with dystrophin gene constructs delivered in vivo by the microsphere particles MF-2. (nature.com)
  • Dystrophin-deficient mdx mice exhibit a cardiac phenotype similar to human DMD patients albeit at a delayed progression (Bostick et al 2008 Cir Res102:121-130). (ahajournals.org)
  • In this study, we delivered an AAV-9 micro-dystrophin vector to mdx mice at both the pre-clinical and symptomatic stages of disease (1-5 x 10 12 viral particles per mouse). (ahajournals.org)
  • U-M scientists have developed a viral vector that delivers the gene for dystrophin, a protein critical for normal maintenance of muscle tissue, to the muscles of adult mice with muscular dystrophy. (umich.edu)
  • The result: dystrophic mice with muscles producing high levels of normal dystrophin protein for several months. (umich.edu)
  • We have induced long-term expression of the full-sized dystrophin protein for at least three months in the muscles of adult mice with Duchenne muscular dystrophy," says Jeffrey S. Chamberlain, associate professor of human genetics. (umich.edu)
  • Now that we have succeeded at pr oducing long-term expression of dystrophin in adult mice without a working immune system, the next step is to test the virus in mice with a normal immune response. (umich.edu)
  • If our adenoviral vector is able to produce this same level of dystrophin expression in immunologically normal mice, then we may be in a position to begin limited clinical trials for safety in humans. (umich.edu)
  • Intravital microscopy in anaesthetized mice allowed live-imaging of sarcolemmal dystrophin-EGFP fusion protein of revertant fibres as well as following therapeutic restoration. (unboundmedicine.com)
  • Consistently, only minimum amount of dystrophin expression can be detected in the cardiac muscle even after repeated injections of both 2OMePS AON and PMO in all mdx mice aged 6 months or younger (Lu et al. (fitness-vip.com)
  • We used a transgenic approach to restore α-dystrobrevin to the sarcolemma in mice that lack dystrophin (mdx mice) to study two interrelated functions: (1) the ability of α-dystrobrevin to rescue components of the dystrophin complex in the absence of dystrophin and (2) the ability of sarcolemmal α-dystrobrevin to ameliorate the dystrophic phenotype. (biologists.org)
  • The mdx5cv mouse is a model of DMD in which a point mutation in exon 10 of the dystrophin gene creates an artificial splice site.Using primary myoblasts from mdx5cv mice, single-stranded DNA oligonucleotides were designed to correct this DNA mutation.Exogenous manipulations, such as RNAi, are certainly feasible and possibly required to increase the successful application of gene repair in some primary or progenitor muscle cells. (nih.gov)
  • The donor splice site in the DMD gene in mdx5cv mice causes a frameshift which results in a translation of truncated dystrophin protein (10 of the 79 exons). (nih.gov)
  • Cy3) correct the dystrophin gene in cultures containing an enriched population of myoblasts isolated from dystrophic mice. (nih.gov)
  • Pip5 transduction peptides direct high efficiency oligonucleotide-mediated dystrophin exon skipping in heart and phenotypic correction in mdx mice. (surrey.ac.uk)
  • Antisense oligonucleotide (AO)-mediated exon skipping has been shown to restore functional dystrophin in mdx mice and DMD patients treated intramuscularly in two recent phase 1 clinical trials. (surrey.ac.uk)
  • Intramuscular administration of the morpholino to juvenile mice reduced central nucleation and resulted in near-normal dystrophin expression and muscle architecture. (edu.au)
  • We show that EDL muscles from dystrophin-deficient mdx mice recover 65% of lost force within 120 min of eccentric contraction and exhibit minimal force loss when the interval between contractions is increased from 3 to 30 min. (umn.edu)
  • We have recently reported that cell-penetrating peptides (CPPs) and novel chimeric peptides containing CPP (referred as B peptide) and muscle-targeting peptide (referred as MSP) motifs significantly improve the systemic exon-skipping activity of morpholino phosphorodiamidate oligomers (PMOs) in dystrophin-deficient mdx mice. (ox.ac.uk)
  • Muscle spindles in the soleus of 32-week-old normal and age-matched mdx mice were examined by immunocytochemical methods to determine the localization of dystrophin in polar and equatorial regions of the intrafusal fibers. (ubc.ca)
  • By fluorescence microscopy, intrafusal fibers in the soleus of mdx mice were deficient in dystrophin throughout their lengths, whereas their sensory nerve-terminals stained intensely with the nerve-specific antibody and appeared unaltered in dystrophy. (ubc.ca)
  • Additionally, it was found that chronic denervation of muscle spindles in normal mice did not affect the expression of dystrophin either at these sites or at the non-sensory regions of the sarcolemma. (ubc.ca)
  • Robust statistical models were built for extracts and intact cardiac tissue, distinguishing mice according to expression of dystrophin. (ox.ac.uk)
  • Whether aberrant neuromuscular synapse structure is an indirect consequence of muscle degeneration or a direct result of loss of dystrophin function is not known. (pubmedcentralcanada.ca)
  • Homology and protein-binding similarities have led to the idea that dystrobrevin partially compensates for the loss of dystrophin in dystrophic muscle. (biologists.org)
  • The exact function of dystrophin remains to be determined. (pnas.org)
  • However, no overt disease symptoms are observed in dystrophin-less cultured myotubes, and the biological function of dystrophin in normal muscle cells is still unknown. (biologists.org)
  • One key to further understanding of the cellular function of dystrophin would be extended knowledge about its subcellular organization. (rupress.org)
  • These results show that dystrophin deficiency stimulates neointima formation and suggest that expression of dystrophin in vascular smooth muscle cells may protect the artery wall against injury-induced intimal thickening. (sigmaaldrich.com)
  • Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder, which is caused by dystrophin deficiency in muscle fibers. (springer.com)
  • Deficiency of muscle dystrophin causes Duchenne muscular dystrophy (DMD), an X-linked disease that affects muscle function and leads to decreased life expectancy. (arvojournals.org)
  • Dystrophin deficiency in DMD/BMD patients and in the mdx mouse model appears to impair intracellular calcium homeostasis and to disrupt multiple protein-protein interactions that normally promote information transfer and signal integration from the extracellular environment to the nucleus within regulated microdomains. (elsevier.com)
  • Component of the dystrophin-associated glycoprotein complex which accumulates at the neuromuscular junction (NMJ) and at a variety of synapses in the peripheral and central nervous systems and has a structural function in stabilizing the sarcolemma. (abcam.com)
  • Your search returned 13 sarcoglycan, alpha (50kDa dystrophin-associated glycoprotein) ELISA ELISA Kit across 1 supplier. (biocompare.com)
  • Fukutin-related protein associates with the sarcolemmal dystrophin-glycoprotein complex. (biomedsearch.com)
  • Biochemical analyses revealed that mouse muscle FKRP and dystroglycan co-enrich and co-fractionate, indicating that FKRP coexists with dystroglycan in the native dystrophin-glycoprotein complex. (biomedsearch.com)
  • These data offer the first evidence of an FKRP complex in muscle and suggest that FKRP may influence the glycosylation status of dystroglycan from within the sarcolemmal dystrophin-glycoprotein complex. (biomedsearch.com)
  • It is a crucial component of the dystrophin-glycoprotein complex (DGC), which bridges the inner cytoskeleton and the extracellular matrix providing structural stability to muscle fibers 12 , 13 . (nature.com)
  • Dystrophin and beta-dystroglycan are components of the dystrophin-glycoprotein complex (DGC), a multimolecular assembly that spans the cell membrane and links the actin cytoskeleton to the extracellular basal lamina. (rcsb.org)
  • Without dystrophin, the dystrophin-glycoprotein complex (DGC) is unstable, leading to an increase in muscle damage. (mdpi.com)
  • Auf www.antikoerper-online.de finden Sie aktuell 59 Sarcoglycan, beta (43kDa Dystrophin-Associated Glycoprotein) (SGCB) Antikörper von 19 unterschiedlichen Herstellern. (antikoerper-online.de)
  • Insgesamt sind aktuell 77 Sarcoglycan, beta (43kDa Dystrophin-Associated Glycoprotein) Produkte verfügbar. (antikoerper-online.de)
  • Muscle analysis, performed at the age of 4 and 9-months, showed the presence of the mutated beta-sarcoglycan protein and of the other components of the dystrophin-associated glycoprotein complex at the muscle membrane. (antikoerper-online.de)
  • Zusätzlich bieten wir Ihnen Sarcoglycan, gamma (35kDa Dystrophin-Associated Glycoprotein) Proteine (10) und viele weitere Produktgruppen zu diesem Protein an. (antikoerper-online.de)
  • Sarcoglycans are transmembrane components in the dystrophin-glycoprotein complex which help stabilize the muscle fiber membranes and link the muscle cytoskeleton to the extracellular matrix. (creative-biogene.com)
  • The dystrophin-glycoprotein complex (DGC) is localized and integrated into the cell membrane. (wku.edu)
  • Three promoters express full-length dystrophin, while two promoters near the C terminus express the last domains in a mutually exclusive manner. (nih.gov)
  • Hippocampal full-length dystrophin (Dp427) levels are upregulated in human TLE, but not in AK rats, possibly indicating a compensatory mechanism in the chronic epileptic human brain. (frontiersin.org)
  • Lentiviral vectors can be used for full-length dystrophin gene therapy. (physiciansweekly.com)
  • Viral gene transfer of full-length dystrophin could restore wild-type functionality, although this approach is restricted by the limited capacity of recombinant viral vectors. (physiciansweekly.com)
  • Lentiviral vectors can package larger transgenes than adeno-associated viruses, yet lentiviral vectors remain largely unexplored for full-length dystrophin delivery. (physiciansweekly.com)
  • During this work, we discovered that a standard, unmodified lentiviral vector was efficient in delivering full-length dystrophin to target cells, within a total genomic load of more than 15,000 base pairs. (physiciansweekly.com)
  • Ultimately, our work demonstrates proof-of-concept that lentiviruses can be used for permanent full-length dystrophin gene therapy, which presents a significant advancement in developing an effective treatment for DMD. (physiciansweekly.com)
  • 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. (nih.gov)
  • Current experimental therapeutic approaches in Duchenne muscular dystrophy aim to restore dystrophin expression. (mendeley.com)
  • Thus, the minimal dystrophin level required for normal NMJ function and morphology lies between 19% and 50% of normal when expression of dystrophin is not uniform. (mendeley.com)
  • We detected a down-regulation of dystrophin, dystroglycan and β-sarcoglycan mRNA expression when vascular smooth muscle cells de-differentiate in vitro. (sigmaaldrich.com)
  • To this end, we have characterized the clinical phenotype of 17 patients with Becker muscular dystrophy harbouring in-frame deletions relevant to on-going or planned exon skipping clinical trials for Duchenne muscular dystrophy and correlated it to the levels of dystrophin, and dystrophin-associated protein expression. (nih.gov)
  • 40% of control and significantly higher dystrophin (P = 0.013), β-dystroglycan (P = 0.025) and neuronal nitric oxide synthase (P = 0.034) expression was observed in asymptomatic individuals versus symptomatic patients with Becker muscular dystrophy. (nih.gov)
  • This is the first quantitative study on both dystrophin and dystrophin-associated protein expression in patients with Becker muscular dystrophy with deletions relevant for on-going exon skipping trials in Duchenne muscular dystrophy. (nih.gov)
  • Comparative immunohistochemical analysis of dystrophin expression in 17 patients with Becker muscular dystrophy with in-frame deletions. (nih.gov)
  • Western blotting and immunohistochemistry are the two established methods for the detection of abnormalities of dystrophin expression in muscle biopsies. (thermofisher.com)
  • We are very pleased to report successful delivery of the micro-dystrophin transgene to the nuclei - corresponding to robust gene expression and proper localization of micro-dystrophin," said Jerry Mendell, MD, the study's co-author and principal investigator with the Center for Gene Therapy in the Abigail Wexner Research Institute at Nationwide Children's Hospital. (eurekalert.org)
  • Antisense-mediated exon-skipping represents one of the most promising approaches for the treatment of DMD because of its capacity to correct the reading frame and restore dystrophin expression," said Steve Wilton, Ph.D. Professor at the Center for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, Western Australia, Australia and co-author of the study. (scienceblog.com)
  • High levels of dystrophin cDNA expression, and an efficient distant transfection effect with preferential intranuclei inclusion of MF-2 vehicle, are very encouraging for the development of a new constructive strategy in gene therapy trials of DMD. (nature.com)
  • These exciting results will support more effective clinical trials for examining myofibers dystrophin expression by driving a greater level of consistency and detail," says Trevor D. Johnson, Flagship Biosciences CEO. (prweb.com)
  • Here, we aimed to study brain dystrophin distribution and expression in both, human and experimental temporal lobe epilepsy (TLE). (frontiersin.org)
  • Herein we investigated whether the distribution and functional properties of Kir4.1 channels are dependent on expression of the Dp71, a dystrophin isoform expressed in Müller cells. (jneurosci.org)
  • Micro-dystrophin expression and cardiac function were analyzed six weeks to four months post gene transfer. (ahajournals.org)
  • Immunofluorescence staining revealed widespread micro-dystrophin expression in the heart. (ahajournals.org)
  • Rational design of truncated dystrophins has enabled the design of expression cassettes highly effective at preventing muscle degeneration in mouse models of DMD using gene therapy. (pubmedcentralcanada.ca)
  • The se verity of symptoms correlates with the degree to which expression of dystrophin is impaired. (umich.edu)
  • We assessed the exon skipping level, transcriptional expression of myostatin and its target genes, and combined myostatin and several dystrophin AONs. (springer.com)
  • Current translational research is methodologically hampered by the lack of a reporter mouse model, which would allow direct visualization of dystrophin expression as well as longitudinal in vivo studies. (unboundmedicine.com)
  • All three exon deletion strategies enabled the expression of truncated dystrophin protein and restoration of cardiomyocyte contractility and calcium transients to varying degrees. (jci.org)
  • In patients with some expression of dystrophin, the absence of a particular region of the DMD gene was associated with higher incidence of cardiac disease. (pharmiweb.com)
  • 3%) or no expression of dystrophin in muscle. (portlandpress.com)
  • Duchenne Muscular Dystrophy (DMD) is caused by a lack of dystrophin expression in patient muscle fibres. (physiciansweekly.com)
  • Current DMD gene therapy strategies rely on the expression of internally deleted forms of dystrophin, missing important functional domains. (physiciansweekly.com)
  • We have demonstrated gene therapy with this vector by restoring dystrophin expression in DMD myoblasts, where dystrophin was expressed at the sarcolemma of myotubes after myogenic differentiation. (physiciansweekly.com)
  • Here, we demonstrate that dystrophin-deficient mouse muscle cells show increased expression of several cell-surface and endosomal TLRs. (kennedykrieger.org)
  • The abnormal retinal electrophysiology observed in patients with Duchenne muscular dystrophy (DMD) has been attributed to an altered expression of C-terminal products of the dystrophin gene. (arvojournals.org)
  • Single-stranded DNA oligonucleotides that were designed to repair this splice site mutation corrected the mutation in the gene and restored expression of wild-type dystrophin. (nih.gov)
  • The spatial and temporal expression of the dystrophin gene has been examined during mouse embryogenesis, using in situ hybridization on tissue sections with a probe from the 5' end of the dystrophin coding sequence. (rupress.org)
  • Currently, a promising avenue of research consists of identifying molecules that would increase the expression of utrophin and the delivery of these molecules to dystrophin-deficient tissues as a means of DMD therapy. (ox.ac.uk)
  • The 2OMeAO was able to restore dystrophin expression in vitro and in vivo when complexed with delivery agents. (edu.au)
  • Metabolic profiles of dystrophin and utrophin expression in mouse models of Duchenne muscular dystrophy. (ox.ac.uk)
  • Using metabolic profiles of diaphragm, models were built describing dystrophin and utrophin, a dystrophin related protein, expression. (ox.ac.uk)
  • In the epithelia of the kidney, dystrophin may be replaced with utrophin. (wikipedia.org)
  • The data suggest that utrophin and dystrophin have complementing roles in normal functional or developmental pathways in muscle. (nih.gov)
  • An alternative strategy for DMD therapy, that circumvents many of these problems, has arisen from the demonstration that the DRP utrophin can functionally substitute for the missing dystrophin and its overexpression can rescue dystrophin-deficient muscle. (ox.ac.uk)
  • In the mdx mouse, dystrophin absence not only causes muscle damage but also mild synaptic dysfunctions and clear morphological aberrations at NMJs. (mendeley.com)
  • The absence of dystrophin at the muscle membrane leads to Duchenne muscular dystrophy (DMD), a severe muscle-wasting disease that is inevitably fatal in early adulthood. (nih.gov)
  • The absence of dystrophin leads to myofiber membrane fragility that results in the progressive muscular degeneration that characterizes DMD ( Sussman, 2002 ). (frontiersin.org)
  • The absence of dystrophin at the sarcolemma also delocalizes and downregulates nitric oxide synthase (nNOS) and alters enzymatic antioxidant responses, leading to an increase in oxidative stress. (mdpi.com)
  • Short-term synaptic facilitation of evoked transmitter release is decreased in the mutants, suggesting that the absence of dystrophin results in increased probability of release. (jneurosci.org)
  • The absence of dystrophin in the heart contributes to a progressive deterioration of cardiac muscle and eventual cardiomyopathy. (pharmiweb.com)
  • Duchenne muscular dystrophy (DMD) is a severe and lethal X-linked myodegenerative disease caused by the absence of the DMD gene product called dystrophin. (arvojournals.org)
  • However, in the absence of any high-resolution structure of these repeats, the molecular basis of dystrophin central domain's functions has not yet been deciphered. (inserm.fr)
  • Immunoblotting of dystrophin in DMD muscles reveals the total absence of dystrophin except in some revertant fibers. (thefreedictionary.com)
  • (Click on image to enlarge) Considerable efforts are underway to develop drugs and biologics (cell and gene therapy) to address the primary problem in Duchenne-the absence of dystrophin. (stemcellsgroup.com)
  • In addition to these genetic dilated cardiomyopathies, some acquired dilated cardiomyopathy like viral dilated cardiomyopathy is also related to dystrophin disruption or aberrant cleavage. (biomedsearch.com)
  • In this review, we summarize the structure and distribution of dystrophin and researches of dystrophin in genetic and viral dilated cardiomyopathy. (biomedsearch.com)
  • This review gives an overview of the work carried out in cardiac troponin T and dystrophin to date in both human and animal dilated cardiomyopathy. (nottingham.ac.uk)
  • A dilated cardiomyopathy is common in patients with symptomatic Duchenne/Becker muscular dystrophy, a disease caused by dystrophin gene defects. (elsevier.com)
  • Despite restoration of sarcolemmal α-syntrophin, neuronal nitric oxide synthase (nNOS) was not localized to the sarcolemma, suggesting that nNOS requires both dystrophin and α-syntrophin for correct localization. (biologists.org)
  • Little is known about the localization of α-dystrobrevin-3, a short isoform that lacks the dystrophin and syntrophin interaction sites. (biologists.org)
  • Localization of dystrophin gene transcripts during mouse embryogenesis. (rupress.org)
  • This approach aims to transform the Duchenne muscular dystrophy phenotype to that of the milder disorder, Becker muscular dystrophy, typically caused by in-frame dystrophin deletions that allow the production of an internally deleted but partially functional dystrophin. (nih.gov)
  • Taken together, our results indicate that all varieties of internally deleted dystrophin assessed in this study have the functional capability to provide a substantial clinical benefit to patients with Duchenne muscular dystrophy. (nih.gov)
  • shows structural and functional similarities to cytolinkers, which suggests the hypothesis that dystrophin performs a cytolinker role in muscle. (rupress.org)
  • Researchers from Nationwide Children's Hospital have published in JAMA Neurology results from the first four patients treated in the first clinical trial of systemic delivery of micro-dystrophin gene therapy in children with Duchenne muscular dystrophy (DMD) - and initial findings suggest that the therapy can provide functional improvement that is greater than that observed under the standard of care. (eurekalert.org)
  • Genetic information important for production of a functional dystrophin protein is deleted from the DMD gene of many patients. (nationwidechildrens.org)
  • Platelet adhesion: structural and functional diversity of short dystrophin and utrophins in the formation of dystrophin-associated-protein complexes related to actin dynamics. (inserm.fr)
  • 5-8] In this clinically suspected BMD case, we found exceptional deletion exons 3-44 of both actin-binding and the rod domain, which is approximately 50% deletion for targeted dystrophin gene containing 79 exons for translation fully functional dystrophin protein. (thefreedictionary.com)
  • We are evaluating the potential of antisense oligonucleotides (AOs) to bypass defects in the dystrophin gene that preclude the synthesis of a functional protein. (edu.au)
  • A dystrophin-associated protein is a protein that helps to form the connection between intracellular dystrophin and the extracellular basal lamina. (wikipedia.org)
  • Dystrophin is part of a protein complex that connects the cytoskeleton to the extracellular matrix. (frontiersin.org)
  • The Dystrophin protein provides a structural link between the muscle cytoskeleton and extracellular matrix to maintain muscle integrity. (jneurosci.org)
  • A gene on chromosome Xp21.2 that encodes dystrophin, a protein that anchors the extracellular matrix to the cytoskeleton via F-actin. (thefreedictionary.com)
  • sarcoglycan, gamma (35kDa dystrophin. (wikigenes.org)
  • SGCG encodes gamma-sarcoglycan, one of several sarcolemmal transmembrane glycoproteins that interact with dystrophin. (antikoerper-online.de)
  • RESULTS: Dystrophin, α-syntrophin, and β-sarcoglycan in LV were delocalized from the membrane with aging, particularly in fibrotic areas, which was normalized by ET. (wku.edu)
  • This phase I randomized double blind dose escalation study investigates the safety and efficacy of the mini-dystrophin gene transferred to the biceps muscle for Duchenne muscular dystrophy patients, ages 5 to 12 years of age, using a recombinant adeno-associated virus. (clinicaltrials.gov)
  • The mini-dystrophin gene or a placebo agent (normal saline or empty viral capsids) are injected directly into both biceps muscles while under conscious sedation. (clinicaltrials.gov)
  • This region, termed the heart domain, will be incorporated into a modified mini-dystrophin gene. (pharmiweb.com)
  • This CT domain will be combined with a mini-dystrophin gene and evaluated for its ability to protect cardiac function in a pre-clinical model. (pharmiweb.com)
  • Parts of the corrected dystrophin protein are clearly foreign because of the patient's DMD gene deletion, and so unwanted T cell immunity targeting the repaired muscle cells was a possibility. (nationwidechildrens.org)
  • The researchers did detect T cell immunity was against foreign segments of the corrected dystrophin protein in one patient with a large DMD gene deletion. (nationwidechildrens.org)
  • The amount of corrected dystrophin protein that is foreign should also be small, and possibly ignored altogether by the T cells. (nationwidechildrens.org)
  • Duchenne and Becker muscular dystrophies are caused by defects of the dystrophin gene. (nih.gov)
  • Duchenne and Becker muscular dystrophy (DMD and BMD) are X-linked diseases resulting from a defect in the dystrophin gene located on Xp21. (hindawi.com)
  • Dystrophin quantification and clinical correlations in Becker muscular dystrophy: implications for clinical trials. (nih.gov)
  • Furthermore, grouping the patients by deletion, patients with Becker muscular dystrophy with deletions with an end-point of exon 51 (the skipping of which could rescue the largest group of Duchenne muscular dystrophy deletions) showed significantly higher dystrophin levels (P = 0.034) than those with deletions ending with exon 53. (nih.gov)
  • Control, Duchenne muscular dystrophy and Becker muscular dystrophy transverse muscle sections were immunolabelled for β-spectrin and with MANDYS106 (exon 43) and Dys2 (C-terminal, last 17 amino acids) antibodies against dystrophin. (nih.gov)
  • Individuals with Duchenne muscular dystrophy usually lack dystrophin completely while those with Becker muscular dystrophy have dystrophin of an altered size. (curehunter.com)
  • Defects in the dystrophin gene are the cause of Duchenne and Becker muscular dystrophies. (rcsb.org)
  • 1. Duchenne and Becker muscular dystrophies are X-linked disorders caused by defects in muscle dystrophin. (portlandpress.com)
  • α-Dystrobrevin associates with and is a homologue of dystrophin, the protein linked to Duchenne and Becker muscular dystrophies. (biologists.org)
  • A lack of the cytoskeletal protein dystrophin causes muscle fiber necrosis in Duchenne/Becker muscular dystrophies (DMD/BMD) and in murine X-linked muscular dystrophy (MDX). (biologists.org)
  • Also, I don't get why, if there was an immune response seen in two of the boys BEFORE treatment - possibly due to revertant fibres producing some dystrophin - why doesn't that happen in Becker cases where individuals produce even more dystrophin? (parentprojectmd.org)
  • This new integrative view is strongly supported by the previous experimental works that investigated the isolated domains and the observed heterogeneity of the severity of dystrophin related pathologies, especially Becker muscular dystrophy. (inserm.fr)
  • a mutation that codes for a smaller amount of dystrophin or a modified molecule causes Becker dystrophy. (thefreedictionary.com)
  • In-frame dystrophin gene rearrangements typically result in the milder allelic disorder, Becker muscular dystrophy, clearly demonstrating that some regions of the dystrophin protein can be lost with relatively minor consequences. (edu.au)
  • Analysis of Scottish Duchenne and Becker muscular dystrophy families with dystrophin cDNA probes. (semanticscholar.org)
  • Purified Dp260, a truncated isoform of dystrophin, bound MTs with a K d of 0.66 µM, a stoichiometry of 1 Dp260/1.4 tubulin heterodimer at saturation, and stabilizes MTs from cold-induced depolymerization. (rupress.org)
  • In this study, we investigate the role of the postsynaptically localized dystrophin-like protein 2 (DLP2) Dystrophin isoform at the Drosophila NMJ. (jneurosci.org)
  • Aquaporin 4 may be connected to the dystrophin-associated protein complex. (wikipedia.org)
  • The dystrophin-associated protein complex is important for cell structure and cell signalling. (wikipedia.org)
  • Many forms of muscular dystrophy are associated with disorders of the dystrophin-associated protein complex. (wikipedia.org)
  • Costamere Dystrophin-Associated+Protein+Complex at the US National Library of Medicine Medical Subject Headings (MeSH) Welling, Paul A. (2008-01-01), Alpern, ROBERT J. (wikipedia.org)
  • These data provide evidence that the composition of the dystrophin-associated protein complex in the brain differs from that in muscle. (pnas.org)
  • Here a model system has been developed to study dystrophin protein complex (DPC) assembly in living cells. (pitt.edu)
  • MF-2/dystrophin cDNA par- ticles were detected by FISH analysis in about 60-70% of myofiber nuclei in muscles of injected and contralateral limbs 7 days after application. (nature.com)
  • The capacity of AAV1, AAV6 or AAV8 to cross the vascular endothelial barrier carrying a micro-dystrophin cDNA was compared under identical conditions with delivery through a catheter placed in the femoral artery of the mdx mouse. (biomedcentral.com)
  • Dystrophin is functionally similar to cytolinkers, as it links the multiple components of the cellular cytoskeleton to the transmembrane dystroglycan complex. (rupress.org)
  • The C-terminal region of dystrophin binds the cytoplasmic tail of beta-dystroglycan, in part through the interaction of its WW domain with a proline-rich motif in the tail of beta-dystroglycan. (rcsb.org)
  • Here we report the crystal structure of this portion of dystrophin in complex with the proline-rich binding site in beta-dystroglycan. (rcsb.org)
  • Studies and research have shown that the ability to skip certain exons in dystrophin pre-mRNA could circumvent these dystrophin gene errors and provide a potential treatment for DMD patients. (scienceblog.com)
  • At 12 weeks post-infusion, gastrocnemius muscle biopsy specimens showed a mean of 81.2% of muscle fibers expressing micro-dystrophin, with a mean intensity of 96% at the sarcolemma. (eurekalert.org)
  • 1, 2 Myofibers lacking dystrophin are abnormally susceptible to contraction-induced sarcolemma damage with subsequent myofiber dysfunction, necrosis and regeneration leading ultimately to the replacement of the lost fibers by adipose and connective tissue and premature death often associated with cardiomyopathy. (nature.com)
  • These results position archvillin (zeige SVIL Antikörper ) as a mechanically sensitive component of the dystrophin (zeige DMD Antikörper ) complex and demonstrate that signaling defects caused by loss of gamma-SG occur both at the sarcolemma and in the nucleus. (antikoerper-online.de)
  • It is α-dystrobrevin-2a that is most abundant on the sarcolemma where it colocalizes with dystrophin. (biologists.org)
  • The entire dystrophin network remained preserved in its structure on isolated muscle sarcolemma and identical in appearance to the pattern observed on teased fibers. (rupress.org)
  • Dystrophin labelling in equatorial regions of normal intrafusal fibers, however, showed dystrophin-deficient segments alternating in a spiral fashion with positive-staining domains along the sarcolemma. (ubc.ca)
  • Dp71 is the most prominent dystrophin gene product in the adult brain. (biologists.org)
  • Here, we have analyzed the role of dystrophin in injury-induced arterial neointima formation. (sigmaaldrich.com)
  • These results lend further support to the suggested stabilizing role of dystrophin in the context of the membrane-cytoskeletal complex. (biologists.org)
  • Recent studies suggest that dystrophin may contain unique domains that can help the heart better cope with the stress generated during contraction. (pharmiweb.com)
  • The results of this study suggest that dystrophin is not an integral part of the subsynaptic sensory-membrane in equatorial regions of normal intrafusal fibers, and, that the neurotrophic effect of sensory innervation is not the principle cause of this unique arrangement of dystrophin in equatorial regions. (ubc.ca)
  • In this study, the researchers found that equal parts enzyme and guide RNA-targeted at a specific part of the DMD gene-didn't bump up the production of dystrophin very much. (the-scientist.com)
  • The researchers also used CRISPR gene-editing techniques to restore production of dystrophin in human heart cells affected by Duchenne muscular dystrophy. (the-scientist.com)
  • However, when the patients were evaluated three months later, long-term production of dystrophin protein from the corrected DMD gene was not detected. (nationwidechildrens.org)
  • The following antibody was used in this experiment: Dystrophin Polyclonal Antibody from Thermo Fisher Scientific, catalog # 12715-1-AP. (thermofisher.com)
  • Cultures containing dystrophic myoblasts were seeded in 8 well chambers and were targeted with a 72 hour recovery time after the addition of the either the nonspecific ODN (A) or mdx47NT (B). These cells were then allowed to differentiate for 96 hours at which point they were fixed and incubated with antibody specific for a rabbit polyclonal antibody that recognizes dystrophin and a secondary Alexa fluor labeled antibody (red). (nih.gov)
  • The entire assay was performed in microscope chambers so that the samples could be probed directly with an antibody specific for the dystrophin protein. (nih.gov)
  • Transduction efficiency was assessed by immuno-staining using an antibody (Manex1a) that recognizes the N-terminus of micro-dystrophin. (biomedcentral.com)
  • Spindles were serially-sectioned in transverse and longitudinal planes, and they were double-labelled with an antibody to dystrophin and with a 200 kD neurofilament protein antibody which revealed their sensory innervation. (ubc.ca)
  • We have analyzed DNA from 72 Moroccan patients with DMD/BMD using the multiplex polymerase chain reaction (PCR) to screen for exon deletions within the dystrophin gene, and to estimate the frequency of these abnormalities. (hindawi.com)
  • Dystrophin abnormalities are thought to occur in 100% of patients with DMD/BMD, although genetic abnormalities may only be detected in up to 65% of cases. (thermofisher.com)
  • A novel stress syndrome was characterized in pigs and the causative genetic factor most likely resides within DMD that results in less dystrophin protein and cardiac abnormalities that can lead to death under stressful conditions. (biomedcentral.com)
  • 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. (biomedsearch.com)
  • Restoration of the open reading frame and dystrophin production can be achieved by exon skipping using antisense oligonucleotides targeted to splicing elements. (nih.gov)
  • This first generation PMO drug candidate is designed to skip exon 51 of the dystrophin gene, allowing for restoration of the reading frame in the dystrophin mRNA sequence. (scienceblog.com)
  • T nonsense mutation in Dmd exon 23, is a mouse model for Duchenne muscular dystrophy (DMD), frequently used to test therapies aimed at dystrophin restoration. (unboundmedicine.com)
  • 2008). This is further supported by the restoration of dystrophin in cardiac muscles via AAV-mediated AON delivery (Denti et al. (fitness-vip.com)
  • As shown above, correction of the mutation at the DNA level resulted in the restoration of intact dystrophin message. (nih.gov)
  • Immunohistochemical staining, RT-PCR and western blot results indicated that B-9-PMO induced significantly higher level of exon skipping and dystrophin restoration than its counterpart (9-B-PMO), further corroborating the notion that the activity of chimeric peptide-PMO conjugates is dependent on relative position of the tissue-targeting peptide motif within the chimeric peptide with respect to PMOs. (ox.ac.uk)
  • In Duchene muscular dystrophy, the muscles lack dystrophin, the protein needed for maintaining the integrity of muscle fibers. (stemcellsgroup.com)
  • By contrast, in the mature brain, dystrophin is preferentially expressed by specific regional neuronal subpopulations within proximal somadendritic microdomains associated with synaptic terminal membranes. (elsevier.com)
  • A large and complex gene on the X chromosome encodes dystrophin. (nih.gov)
  • An immune reaction to dystrophin, the muscle protein that is defective in patients with Duchenne muscular dystrophy, may pose a new challenge to strengthening muscles of patients with this disease, suggests a new study appearing in the October 7, 2010, issue of The New England Journal of Medicine . (nationwidechildrens.org)
  • Most of the dystrophin protein consists of a central domain made of 24 spectrin-like coiled-coil repeats (R). Using small angle neutron scattering (SANS) and the contrast variation technique, we specifically probed the structure of the three first consecutive repeats 1-3 (R1-3), a part of dystrophin known to physiologically interact with membrane lipids. (cea.fr)
  • Dystrophin maintains the integrity of striated muscles by linking the actin cytoskeleton with the cell membrane. (jci.org)
  • Mechanical skinning of single-teased fibers revealed tighter mechanical connection of dystrophin to the plasma membrane than to the underlying internal domain of the muscle fiber. (rupress.org)
  • In smooth muscle dystrophin transcripts are first detectable from 11 d post coitum in blood vessels, and subsequently in lung bronchi and in the digestive tract. (rupress.org)
  • P eople with Duchenne muscular dystrophy carry a mutation in the DMD gene coding for dystrophin, a protein crucial for proper muscle function. (the-scientist.com)
  • It is caused by a mutation in the gene that encodes for dystrophin, and symptoms usually appear in infants and toddlers. (eurekalert.org)
  • This mutation should have made natural production of functioning dystrophin impossible, resulting in severe disease. (eurekalert.org)
  • Eligible participants must have a known dystrophin gene mutation and may be concurrently treated with corticoid steroids. (clinicaltrials.gov)
  • The mdx5cv mouse is a model of DMD in which a point mutation in exon 10 of the dystrophin gene creates an artificial splice site. (nih.gov)
  • Somatic mosaicism of a point mutation in the dystrophin gene in a patient presenting with an asymmetrical muscle weakness and contractures. (semanticscholar.org)
  • Duchenne muscular dystrophy is a severe X chromosome-linked, muscle-wasting disease caused by lack of the protein dystrophin. (pnas.org)
  • Dystrophin is the 427kDa protein product of the DMB/BMD gene located on the X chromosome at position Xp21. (thermofisher.com)
  • The DMD gene spans 2.4 million base pairs of genomic DNA on the X chromosome and its 14 kb transcript encodes a full-length protein (dystrophin) of 427 kiloDaltons. (biomedcentral.com)
  • Adeno-associated virus (AAV) mediated micro-dystrophin gene therapy brings the hope of ameliorating DMD. (ahajournals.org)
  • In summary, our results suggest that AAV-9 mediated micro-dystrophin gene therapy is a promising approach to treat DMD heart disease. (ahajournals.org)
  • However, direct injection of AON into cardiac muscles showed effective dystrophin induction, suggesting that lower delivery efficiency is perhaps the most critical factor (Vitiello et al. (fitness-vip.com)
  • HACKENSACK, N.J., Jan. 24, 2019 /PRNewswire/ -- Parent Project Muscular Dystrophy (PPMD), a nonprofit organization leading the fight to end Duchenne muscular dystrophy (Duchenne), awarded the University of Missouri School of Medicine a grant for $105,000 to continue development of a minimized dystrophin gene aimed at protecting cardiac function in people with Duchenne. (pharmiweb.com)
  • Cardiac troponin T and dystrophin were observed to be associated with both human and turkey (troponin T) and canine (dystrophin) dilated cardiomyopathies. (nottingham.ac.uk)
  • parallels the structural deficiencies observed in other cytolinker-deficient tissues, further demonstrating a close relationship between dystrophin and other cytolinkers. (rupress.org)
  • The dystrophin-deficient mdx mouse has historically been used as the primary model of DMD, although this mouse does not experience the severe, body-wide dystrophy that considerably shortens lifespan in humans. (scienceblog.com)
  • TLR7 activation led to myd88-dependent production of pro-inflammatory cytokines in dystrophin-deficient muscle cells, and cause significant degeneration/regeneration in vivo in mdx mouse muscle. (kennedykrieger.org)
  • Additionally, we will address the techniques used for anatomical, biochemical and physiological evaluation of the potential benefits of this and other forms of DMD therapy in dystrophin-deficient animal models. (ox.ac.uk)
  • Scientists have been using stem cells isolated from muscle tissue, bone marrow and blood vessels in lab animals to regenerate muscle fibers that are deficient in dystrophin[3] and results are encouraging. (stemcellsgroup.com)
  • Barton, Elisabeth R. / Increased collagen cross-linking is a signature of dystrophin-deficient muscle . (elsevier.com)
  • Double-labelling for dystrophin and neurofilament protein showed that these dystrophin-deficient sites were subjacent to the annulospiral sensory-nerve wrappings terminating on the intrafusal fibers. (ubc.ca)
  • Kamdar, F & Garry, DJ 2016, ' Dystrophin-Deficient Cardiomyopathy ', Journal of the American College of Cardiology , vol. 67, no. 21, pp. 2533-2546. (umn.edu)
  • Subsequent clinical trials have shown that two different AON chemistries, either 2'- O -methyl phosphorothioate (2'OMePS)[ 12 ] or phosphorodiamidate morpholino oligomer (PMO)[ 13 ] targeting DMD exon 51 can restore local dystrophin synthesis in DMD patients with no to minimum side effect. (springer.com)
  • Flagship Biosciences' MuscleMap algorithm that supports therapeutic development for DMD, a fatal neuromuscular disease, has been validated to be as effective as manual pathology in the study, "Validation of a Muscle-Specific Tissue Image-Analysis Tool for Quantitative Assessment of Dystrophin Staining in Frozen Muscle Biopsies," published Aug. 31, 2018. (prweb.com)
  • Duchenne muscular dystrophy (DMD) is a rare, progressive, and fatal neuromuscular disease caused by dystrophin protein loss in muscle. (prweb.com)
  • Our results indicate that the postsynaptically localized scaffolding protein Dystrophin is required for appropriate control of neuromuscular synaptic homeostasis. (jneurosci.org)
  • Together, these data suggest that maintenance of the neuromuscular synapse is governed through its lateral association with the muscle cytoskeleton, and that dystrophin has a direct role in promoting the maturation of synaptic folds to allow more sodium channels into the junction. (pubmedcentralcanada.ca)
  • The dystrophin gene, which is mutated in Duchenne muscular dystrophy (DMD), encodes a large cytoskeletal protein present in muscle fibers. (sigmaaldrich.com)
  • To determine whether dystrophin gene defects might account for a significant number of patients with apparently isolated idiopathic DCM, we performed dystrophin gene analysis in 27 DCM patients, who were ascertained as part of a prospective study on idiopathic DCM. (elsevier.com)
  • No dystrophin gene defects were found in our patients, whose average age was 50 years. (elsevier.com)
  • The latest report Dystrophin (DMD) - Pipeline Review, H1 2018, outlays comprehensive information on the Dystrophin (DMD) targeted therapeutics, complete with analysis by indications, stage of development, mechanism of action (MoA), route of administration (RoA) and molecule type. (marketresearch.com)
  • The study, "Validation of a Muscle-Specific Tissue Image-Analysis Tool for Quantitative Assessment of Dystrophin Staining in Frozen Muscle Biopsies," was published in the Archives of Pathology & Laboratory Medicine on August 31, 2018. (prweb.com)
  • Independently, we will also request a meeting with the Agency to discuss the micro-dystrophin program with the goal of commencing a pivotal trial by year-end 2018. (firstwordpharma.com)
  • Formation of two dystrophin-associated protein complexes (Dp71d/Dp71delta110m approximately DAPC and Up400/Up71 approximately DAPC) was demonstrated by co-immunoprecipitation and their distribution in relation to the actin cytoskeleton was characterised during platelet adhesion. (inserm.fr)
  • We report that a minidystrophin gene construct, currently the most promising avenue for adeno-associated virus mediated gene therapy, properly assembles and integrates into the DPC in vivo, utilizing similar mechanisms as wild type dystrophin. (pitt.edu)
  • In all, 75% of the dystrophin molecule consists of a large central rod domain made up of 24 repeat units that share high structural homology with spectrin-like repeats. (inserm.fr)
  • We found dystrophin gene deletions in 37 cases. (hindawi.com)

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