The “Weakness” in Single Gene Disorder Research: The Role of Signaling Pathways and Vasoregulation in the Dystrophin- Glycoprotein Complex (DGC) in Duchenne Muscular Dystrophy

Nicole Fogel

Abstract


Duchenne muscular dystrophy (DMD) is the severe form of a group of muscle degenerative diseases caused by mutations in the DMD gene on the X chromosome. The DMD gene is approximately 2.4 Mb in size and encodes the muscle structural support protein dystrophin. Dystrophin is a component of the dystrophin-glycoprotein complex (DGC), which assembles at the plasma membrane of muscle and non-muscle tissues. Although the role of dystrophin and the DGC has been the focus of therapeutic studies, there is currently very little knowledge about the cell signaling events that occur within the complex or about its role in vasoconstriction. Characteristics of DMD, such as muscle weakness and impaired cognition, are thought to arise from deletions and duplications in the DMD gene that result mainly in the loss of dystrophin. Loss of dystrophin and upsetting of the DGC induces a change in the downstream cascade of events: improper placement of SLO-1 channels, decrease in nitric oxide (NO), increase in phosphatidylinositol 3-kinase (PI3K/Akt) and nuclear factor-kappa B (NF-κB) signaling, increase in creatine kinase (CK) levels, and abnormal vasoconstriction. These events bring about symptoms of the disorder. This review will compare important studies that have contributed to the current understanding of the molecular basis of signaling mechanisms that occur within the DGC. Specifically, it will address the changes that occur in signaling pathways from the loss of dystrophin that lead to decreased regulation of vasoconstriction and muscle stability, thereby promoting disease. By providing a more integrated approach to analyzing cell signaling pathways, this review hopes to encourage the continuation of these types of studies and promote the understanding of single gene disorders. In this way, novel pharmacological and genetic counseling therapies can be established, and health policies can be revised for incapacitating diseases like DMD.

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