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
Derek Blake was, until 2007, the Isobel Laing Post-Doctoral Fellow in Biomedical Sciences, and the Wellcome Trust Senior Fellow in Basic Biomedical Science, Oriel College, Oxford.
Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major constituents of the basement membrane, namely the basal lamina. Laminins are vital to biological activity, influencing cell differentiation, migration, and adhesion.
The sarcoglycans are a family of transmembrane proteins involved in the protein complex responsible for connecting the muscle fibre cytoskeleton to the extracellular matrix, preventing damage to the muscle fibre sarcolemma through shearing forces.
Dystroglycan is a protein that in humans is encoded by the DAG1 gene.
Utrophin is a protein that in humans is encoded by the UTRN gene. The name is a short form for ubiquitous dystrophin.
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.
The syntrophins are a family of five 60-kiloDalton proteins that are associated with dystrophin, the protein associated with Duchenne muscular dystrophy and Becker muscular dystrophy. The name comes from the Greek word syntrophos, meaning "companion." The five syntrophins are encoded by separate genes and are termed α, β1, β2, γ1, and γ2. Syntrophin was first identified as a dystrophin-associated protein present in the Torpedo electric organ. Subsequently, α-syntrophin was shown to be the predominant isoform in skeletal muscle where it is localized on the sarcolemma and enriched at the neuromuscular junction. The β-syntrophins and γ2-syntrophin are also present in skeletal muscle but also are in most other tissues. The expression of γ1-syntrophin is mostly confined to brain. The syntrophins are adaptor proteins that use their multiple protein interaction domains to localize a variety of signaling proteins to specific intracellular locations. α-Syntrophin binds to nNOS in the dystrophin-associated glycoprotein complex in skeletal muscle cells. There it produces NO upon muscle contraction leading to dilation of the arteries in the local area.
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.
Dystrobrevin alpha is a protein that in humans is encoded by the DTNA gene.
Laminin–111 is a protein of the type known as laminin isoforms. It was among the first of the laminin isoforms to be discovered. The "111" identifies the isoform's chain composition of α1β1γ1. This protein plays an important role in embryonic development. Injections of this substance are used in treatment for Duchenne muscular dystrophy, and its cellular action may potentially become a focus of study in cancer research.
Ezutromid is an orally administered small molecule utrophin modulator 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.
