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Dystrophin is a rod-shaped cytoplasmic protein, and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. This complex is variously known as the costamere or the dystrophin-associated protein complex (DAPC). Many muscle proteins, such as α-dystrobrevin, syncoilin, synemin, sarcoglycan, dystroglycan, and sarcospan, colocalize with dystrophin at the costamere. It has a molecular weight of 427 kDa
Dystrophin is coded for by the DMD gene – the largest known human gene, covering 2.4 megabases (0.08% of the human genome) at locus Xp21. The primary transcript in muscle measures about 2,100 kilobases and takes 16 hours to transcribe;the mature mRNA measures 14.0 kilobases. The 79-exon muscle transcript codes for a protein of 3685 amino acid residues.
Spontaneous or inherited mutations in the dystrophin gene can cause different forms of muscular dystrophy, a disease characterized by progressive muscular wasting. The most common of these disorders caused by genetic defects in dystrophin is Duchenne muscular dystrophy.
Dystrophin is a protein located between the sarcolemma and the outermost layer of myofilaments in the muscle fiber (myofiber). It is a cohesive protein, linking actin filaments to other support proteins that reside on the inside surface of each muscle fiber's plasma membrane (sarcolemma). These support proteins on the inside surface of the sarcolemma in turn links to two other consecutive proteins for a total of three linking proteins. The final linking protein is attached to the fibrous endomysium of the entire muscle fiber. Dystrophin supports muscle fiber strength, and the absence of dystrophin reduces muscle stiffness, increases sarcolemmal deformability, and compromises the mechanical stability of costameres and their connections to nearby myofibrils. This has been shown in recent studies where biomechanical properties of the sarcolemma and its links through costameres to the contractile apparatus were measured,and helps to prevent muscle fiber injury. Movement of thin filaments (actin) creates a pulling force on the extracellular connective tissue that eventually becomes the tendon of the muscle. The dystrophin associated protein complex also helps scaffold various signalling and channel proteins, implicating the DAPC in regulation of signalling processes.
Dystrophin deficiency has been definitively established as one of the root causes of the general class of myopathies collectively referred to as muscular dystrophy. The deletions of one or several exons of the dystrophin DMD gene cause Duchenne and Becker muscular dystrophies.The large cytosolic protein was first identified in 1987 by Louis M. Kunkel, after concurrent works by Kunkel and Robert G. Worton to characterize the mutated gene that causes Duchenne muscular dystrophy (DMD). At least 9 disease-causing mutations in this gene have been discovered.
Normal skeletal muscle tissue contains only small amounts of dystrophin (about 0.002% of total muscle protein), —a result of severe myocardial fibrosis—typically results in premature death in the first two or three decades of life. Variants (mutations) in the DMD gene that lead to the production of too little or a defective, internally shortened but partially functional dystrophin protein, result in a display of a much milder dystrophic phenotype in affected patients, resulting in the disease known as Becker's muscular dystrophy (BMD). In some cases, the patient's phenotype is such that experts may decide differently on whether a patient should be diagnosed with DMD or BMD. The theory currently most commonly used to predict whether a variant will result in a DMD or BMD phenotype, is the reading frame rule.but its absence (or abnormal expression) leads to the development of a severe and currently incurable constellation of symptoms most readily characterized by several aberrant intracellular signaling pathways that ultimately yield pronounced myofiber necrosis as well as progressive muscle weakness and fatigability. Most DMD patients become wheelchair-dependent early in life, and the gradual development of cardiac hypertrophy
Though its role in airway smooth muscle is not well established, recent research indicates that dystrophin along with other subunits of dystrophin glycoprotein complex is associated with phenotype maturation.
A number of models are used to facilitate research on DMD gene defects. These include the mdx mouse, GRMD (golden retriever muscular dystrophy) dog, and HFMD (hypertrophic feline muscular dystrophy) cat.
The mdx mouse contains a nonsense mutation in exon 23, leading to a shortened dystrophin protein.Levels of dystrophin in this model is not zero: a variety of mutation alleles exist with measurable levels certain of dystrophin isoforms. Muscle degeneration pathology is most easily visible in the diaphragm. Generally, clinically relevant pathology is observed with older mdx mice.
The GRMD dog is one of several existing dystrophin-deficient dogs identified where substantial characterization has been performed.Clinically relevant pathology can be observed at 8 weeks after birth, with continued gradual deterioration of muscle function. Muscle histology is most analogous to clinical presentation of DMD in humans with necrosis, fibrosis and regeneration.
The HFMD cat has a deletion in the promoter region of the DMD gene.Muscle histology shows necrosis but no fibrosis. Extensive hypertrophy has been observed which is thought to be responsible for shorter lifespans. Due to the hypertrophy, this model may have limited uses for DMD studies.
Dystrophin has been shown to interact with:
A variant of the DMD gene, which is on the X chromosome, named B006, appears to be an introgression from a Neanderthal-modern human mating.
Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy that primarily affects boys. Muscle weakness usually begins around the age of four, and worsens quickly. Muscle loss typically occurs first in the thighs and pelvis followed by the arms. This can result in trouble standing up. Most are unable to walk by the age of 12. Affected muscles may look larger due to increased fat content. Scoliosis is also common. Some may have intellectual disability. Females with a single copy of the defective gene may show mild symptoms.
Becker muscular dystrophy is an X-linked recessive inherited disorder characterized by slowly progressing muscle weakness of the legs and pelvis. It is a type of dystrophinopathy. This is caused by mutations in the dystrophin gene, which encodes the protein dystrophin. Becker muscular dystrophy is related to Duchenne muscular dystrophy in that both result from a mutation in the dystrophin gene, but has a milder course.
The dystrophin-associated protein complex, also known as the dystrophin-associated glycoprotein complex is a multiprotein complex that includes dystrophin and the dystrophin-associated proteins. It is one of the two protein complexes that make up the costamere in striated muscle cells. The other complex is the integrin-vinculin-talin complex.
Utrophin is a protein that in humans is encoded by the UTRN gene.
The costamere is a structural-functional component of striated muscle cells which connects the sarcomere of the muscle to the cell membrane.
Dystrobrevin is a protein that binds to dystrophin in the costamere of skeletal muscle cells. In humans, there are at least two isoforms of dystrobrevin, dystrobrevin alpha and dystrobrevin beta.
Alpha-1-syntrophin is a protein that in humans is encoded by the SNTA1 gene. Alpha-1 syntrophin is a signal transducing adaptor protein and serves as a scaffold for various signaling molecules. Alpha-1 syntrophin contains a PDZ domain, two Pleckstrin homology domain and a 'syntrophin unique' domain.
Alpha-7 integrin is a protein that in humans is encoded by the ITGA7 gene. Alpha-7 integrin is critical for modulating cell-matrix interactions. Alpha-7 integrin is highly expressed in cardiac muscle, skeletal muscle and smooth muscle cells, and localizes to Z-disc and costamere structures. Mutations in ITGA7 have been associated with congenital myopathies and noncompaction cardiomyopathy, and altered expression levels of alpha-7 integrin have been identified in various forms of muscular dystrophy.
Beta-sarcoglycan is a protein that in humans is encoded by the SGCB gene.
Delta-sarcoglycan is a protein that in humans is encoded by the SGCD gene.
Beta-2-syntrophin is a protein that in humans is encoded by the SNTB2 gene.
Alpha-sarcoglycan is a protein that in humans is encoded by the SGCA gene.
Gamma-sarcoglycan is a protein that in humans is encoded by the SGCG gene. The α to δ-sarcoglycans are expressed predominantly (β) or exclusively in striated muscle. A mutation in any of the sarcoglycan genes may lead to a secondary deficiency of the other sarcoglycan proteins, presumably due to destabilisation of the sarcoglycan complex. The disease-causing mutations in the α to δ genes cause disruptions within the dystrophin-associated protein (DAP) complex in the muscle cell membrane. The transmembrane components of the DAP complex link the cytoskeleton to the extracellular matrix in adult muscle fibres, and are essential for the preservation of the integrity of the muscle cell membrane.
Beta-1-syntrophin is a protein that in humans is encoded by the SNTB1 gene.
Dystrobrevin alpha is a protein that in humans is encoded by the DTNA gene.
In molecular biology, exon skipping is a form of RNA splicing used to cause cells to “skip” over faulty or misaligned sections (exons) of genetic code, leading to a truncated but still functional protein despite the genetic mutation.
Eteplirsen is a medication to treat, but not cure, some types of Duchenne muscular dystrophy (DMD), caused by a specific mutation. Eteplirsen only targets specific mutations and can be used to treat about 14% of DMD cases. Eteplirsen is a form of antisense therapy.
The mdx mouse is a popular model for studying Duchenne muscular dystrophy (DMD). The mdx mouse has a point mutation in its DMD gene, changing the amino acid coding for a glutamine to STOP codon. This causes the muscle cells to produce a small, nonfunctional dystrophin protein. As a result, the mouse has a mild form of DMD where there is increased muscle damage and weakness.
Ezutromid is an orally administered small molecule utrophin modulator currently involved in a Phase 2 clinical trial produced by Summit Therapeutics for the treatment of Duchenne muscular dystrophy (DMD). DMD is a fatal x-linked recessive disease affecting approximately 1 in 5000 males and is a designated orphan disease by the FDA and European Medicines Agency. Approximately 1/3 of the children obtain DMD as a result of spontaneous mutation in the dystrophin gene and have no family history of the disease. Dystrophin is a vital component of mature muscle function, and therefore DMD patients have multifarious forms of defunct or deficient dystrophin proteins that all manifest symptomatically as muscle necrosis and eventually organ failure. Ezutromid is theorized to maintain utrophin, a protein functionally and structurally similar to dystrophin that precedes and is replaced by dystrophin during development. Utrophin and dystrophin are reciprocally expressed, and are found in different locations in a mature muscle cell. However, in dystrophin-deficient patients, utrophin was found to be upregulated and is theorized to replace dystrophin in order to maintain muscle fibers. Ezutromid is projected to have the potential to treat all patients suffering with DMD as it maintains the production of utrophin to counteract the lack of dystrophin to retard muscle degeneration. Both the FDA and European Medicines Agency has given ezutromid an orphan drug designation. The FDA Office of Orphan Products and Development offers an Orphan Drug Designation program (ODD) that allows drugs aimed to treat diseases that affect less than 200,000 people in the U.S. monetary incentives such as a period of market exclusivity, tax incentives, and expedited approval processes.
Viltolarsen, sold under the brand name Viltepso, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). Viltolarsen is a Morpholino antisense oligonucleotide.
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