Dystrophin
From Proteopedia
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== Introduction == | == Introduction == | ||
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Dystrophin is a 427 kDa protein with 4 major domains involved in the dystrophin-associated glycoprotein complex which lies between the sarcolemma and myofilaments in muscle fibers. By action of linking various support proteins to actin filaments through it’s amino-terminal domain, dystrophin is classified as a cohesive protein. It connects the elements of the sarcomere to the sarcolemma. The sarcolemma, or the cell membrane of striated muscle fibers, is <scene name='81/815388/Actin-binding_site/1'>linked</scene> to these actin filaments through the dystrophin-associated glycoprotein complex, or also known as the costamere. <ref name="Garcia">(García-Pelagio KP, Bloch RJ, Ortega A, González-Serratos H (March 2011) "Biomechanics of the sarcolemma and costameres in single skeletal muscle fibers from normal and dystrophin-null mice".) www.ncbi.nlm.nih.gov./pmc/articles/PMC4326082/</ref> Skeletal muscle tissue contains a surprisingly small amount of dystrophin, about 0.002% of total muscle protein. However, the absence of this protein amounts to disruption of the stability of the myofibril as well as the linkage to nearby myofibrils, vastly reduces the stiffness of muscle cells, and compromises the mechanical stability of costameres. <ref name="Garcia"/> Disruption or loss of dystrophin through mutations leads to muscular dystrophy, a condition in which the patient experiences progressive weakness and loss of muscle mass. The most common of the nine types of muscular dystrophy is Duchenne’s, where the patient completely lacks the protein. Duchenne’s is a more severe form of Becker’s dystrophy, where the patient only has a decreased number (or a weakening) of dystrophin. | Dystrophin is a 427 kDa protein with 4 major domains involved in the dystrophin-associated glycoprotein complex which lies between the sarcolemma and myofilaments in muscle fibers. By action of linking various support proteins to actin filaments through it’s amino-terminal domain, dystrophin is classified as a cohesive protein. It connects the elements of the sarcomere to the sarcolemma. The sarcolemma, or the cell membrane of striated muscle fibers, is <scene name='81/815388/Actin-binding_site/1'>linked</scene> to these actin filaments through the dystrophin-associated glycoprotein complex, or also known as the costamere. <ref name="Garcia">(García-Pelagio KP, Bloch RJ, Ortega A, González-Serratos H (March 2011) "Biomechanics of the sarcolemma and costameres in single skeletal muscle fibers from normal and dystrophin-null mice".) www.ncbi.nlm.nih.gov./pmc/articles/PMC4326082/</ref> Skeletal muscle tissue contains a surprisingly small amount of dystrophin, about 0.002% of total muscle protein. However, the absence of this protein amounts to disruption of the stability of the myofibril as well as the linkage to nearby myofibrils, vastly reduces the stiffness of muscle cells, and compromises the mechanical stability of costameres. <ref name="Garcia"/> Disruption or loss of dystrophin through mutations leads to muscular dystrophy, a condition in which the patient experiences progressive weakness and loss of muscle mass. The most common of the nine types of muscular dystrophy is Duchenne’s, where the patient completely lacks the protein. Duchenne’s is a more severe form of Becker’s dystrophy, where the patient only has a decreased number (or a weakening) of dystrophin. | ||
== Genetics and Expression of the Protein == | == Genetics and Expression of the Protein == | ||
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Dystrophin is a member of the β-spectrin/α-actinin protein family and is expressed from one of the largest genes in the human genome, DMD (Duchenne Muscular Dystrophy Gene) spanning 2.3 megabases at locus Xp21 . The tissue distribution of the protein’s expression is indicated by the three separate promoters for dystrophin expression present in the brain, muscle, and purkinji’s, although the protein is most abundant in striated muscle fibers found in skeletal muscles and cardiac muscle <ref name="Fourth">“Dystrophin, Its Interactions with Other Proteins, and Implications for Muscular Dystrophy.” Biochimica Et Biophysica Acta (BBA) - Molecular Basis of Disease, Elsevier, 7 June 2006, www.sciencedirect.com/science/article/pii/S0925443906001037.</ref>. Additionally, internal promoters that lie within the transcript allow for genesis of shortened expressions of COOH-terminal isoforms; these isoforms contain binding sites for association with multiple dystrophin-associated proteins (DAPs) <ref name="Second">“Dystrophin Complex Functions as a Scaffold for Signalling Proteins.” Biochimica Et Biophysica Acta (BBA) - Biomembranes, Elsevier, 7 Sept. 2013, www.sciencedirect.com/science/article/pii/S0005273613003027?via%3Dihub.</ref>. These truncated forms expressed by alternative promoters can be used in non-muscle tissues with unique amino-terminus sites. <ref name="Fourth">. | Dystrophin is a member of the β-spectrin/α-actinin protein family and is expressed from one of the largest genes in the human genome, DMD (Duchenne Muscular Dystrophy Gene) spanning 2.3 megabases at locus Xp21 . The tissue distribution of the protein’s expression is indicated by the three separate promoters for dystrophin expression present in the brain, muscle, and purkinji’s, although the protein is most abundant in striated muscle fibers found in skeletal muscles and cardiac muscle <ref name="Fourth">“Dystrophin, Its Interactions with Other Proteins, and Implications for Muscular Dystrophy.” Biochimica Et Biophysica Acta (BBA) - Molecular Basis of Disease, Elsevier, 7 June 2006, www.sciencedirect.com/science/article/pii/S0925443906001037.</ref>. Additionally, internal promoters that lie within the transcript allow for genesis of shortened expressions of COOH-terminal isoforms; these isoforms contain binding sites for association with multiple dystrophin-associated proteins (DAPs) <ref name="Second">“Dystrophin Complex Functions as a Scaffold for Signalling Proteins.” Biochimica Et Biophysica Acta (BBA) - Biomembranes, Elsevier, 7 Sept. 2013, www.sciencedirect.com/science/article/pii/S0005273613003027?via%3Dihub.</ref>. These truncated forms expressed by alternative promoters can be used in non-muscle tissues with unique amino-terminus sites. <ref name="Fourth">. | ||
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== Disease Pathology Associated with Dystrophin == | == Disease Pathology Associated with Dystrophin == | ||
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Duchenne’s muscular dystrophy is an x-linked recessive disease characterized by a general loss of dystrophins throughout the patient’s body. The lack of this important multifaceted protein diminished the levels of DAPC associated elements including dystroglycans, sarcoglycans, integrins and caveolin, resulting in cellular content leakage, destabilization of the myofibrils, ion leakage, calcium-dependent protease overactivation, and a major loss of signaling elements, as well as other functions of this complicated structure and constituents. It is hypothesized that these alterations allow calcium ions to enter the mitochondria and cause it to burst. This in turn leads to amplification of stress-induced cytosolic calcium signals and in an amplification of stress-induced reactive oxygen species production [7]. This complicate cascade of events results ultimately in the death of the muscle cell and a replacement with adipose or connective tissue. Patient’s diagnosed with DMD experience muscle loss around age 4 and are generally wheelchair-bound by age 12 and pass away from respiratory failure in their early twenties. Becker muscular dystrophy, a milder form of the disease, is characterized by a reduction in the amount or the actual size of the dystrophin proteins, rather than widespread loss. Large insertions or deletions with consequent downstream frameshift errors account for approximately 60% of cases of DMD, and 40% involve point mutations or small rearrangements [6]. Dystrophin or dystrophin-associated glycoprotein elements may also undergo spontaneous mutations that lead to muscular degrative pathologies [8]. DMD is currently uncurable, but several treatments do exist including gene therapy, where either viruses or plasmids are used to deliver dystrophin sequences to the patient, myoblast transplantation, therapy involving stem-cells which have been shown to proliferate longer than myoblasts, and proteasome inhibitors. Advancements in studying the function of dystrophin and its interaction with other molecular subunits and signaling roles will aid in the search for more effective treatments for Duchenne’s muscular dystrophy [6]. | Duchenne’s muscular dystrophy is an x-linked recessive disease characterized by a general loss of dystrophins throughout the patient’s body. The lack of this important multifaceted protein diminished the levels of DAPC associated elements including dystroglycans, sarcoglycans, integrins and caveolin, resulting in cellular content leakage, destabilization of the myofibrils, ion leakage, calcium-dependent protease overactivation, and a major loss of signaling elements, as well as other functions of this complicated structure and constituents. It is hypothesized that these alterations allow calcium ions to enter the mitochondria and cause it to burst. This in turn leads to amplification of stress-induced cytosolic calcium signals and in an amplification of stress-induced reactive oxygen species production [7]. This complicate cascade of events results ultimately in the death of the muscle cell and a replacement with adipose or connective tissue. Patient’s diagnosed with DMD experience muscle loss around age 4 and are generally wheelchair-bound by age 12 and pass away from respiratory failure in their early twenties. Becker muscular dystrophy, a milder form of the disease, is characterized by a reduction in the amount or the actual size of the dystrophin proteins, rather than widespread loss. Large insertions or deletions with consequent downstream frameshift errors account for approximately 60% of cases of DMD, and 40% involve point mutations or small rearrangements [6]. Dystrophin or dystrophin-associated glycoprotein elements may also undergo spontaneous mutations that lead to muscular degrative pathologies [8]. DMD is currently uncurable, but several treatments do exist including gene therapy, where either viruses or plasmids are used to deliver dystrophin sequences to the patient, myoblast transplantation, therapy involving stem-cells which have been shown to proliferate longer than myoblasts, and proteasome inhibitors. Advancements in studying the function of dystrophin and its interaction with other molecular subunits and signaling roles will aid in the search for more effective treatments for Duchenne’s muscular dystrophy [6]. | ||
Revision as of 18:07, 4 May 2019
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References
- ↑ 1.0 1.1 (García-Pelagio KP, Bloch RJ, Ortega A, González-Serratos H (March 2011) "Biomechanics of the sarcolemma and costameres in single skeletal muscle fibers from normal and dystrophin-null mice".) www.ncbi.nlm.nih.gov./pmc/articles/PMC4326082/
- ↑ 2.0 2.1 2.2 “Dystrophin, Its Interactions with Other Proteins, and Implications for Muscular Dystrophy.” Biochimica Et Biophysica Acta (BBA) - Molecular Basis of Disease, Elsevier, 7 June 2006, www.sciencedirect.com/science/article/pii/S0925443906001037.
- ↑ 3.0 3.1 3.2 “Dystrophin Complex Functions as a Scaffold for Signalling Proteins.” Biochimica Et Biophysica Acta (BBA) - Biomembranes, Elsevier, 7 Sept. 2013, www.sciencedirect.com/science/article/pii/S0005273613003027?via%3Dihub.
