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Dystrophin Essay

Medicine Notes > Embryology, Histology & Anatomy Notes

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How do we know that dystrophin is a critical protein in muscle cells and what do we understand of its function in these cells?
Dystrophin is a cytoskeletal protein which links the intracellular F-actin network of muscle cells to the extracellular matrix, and is thus critical to the correct functioning of muscle fibres. It is found at the sarcolemma as part of the dystrophin-associated protein complex (DAPC), and is present in many parts of the body including the brain, retina, kidney, liver, lung and Schwann cells, but plays its most important role in muscle cells. There are seven isoforms of the dystrophin protein which differ slightly towards their amino terminals; each is expressed in different tissues at different stages of development with the exception of the ubiquitous Dp71. These isoforms contribute to the complexity of the dystrophin gene, which is located on the X-chromosome and is the largest in the human genome at around

2.5Mb; differential splicing results in isoform expression1. Mutations in this gene such as duplicate exons, deleted exons, disrupted splice sites and premature stop codons are the cause of Duchenne Muscular Dystrophy (DMD), a progressive muscle wasting condition. Dystrophin and the dystrophin gene have been the subject of much research since their first cDNA cloning in 19872, through which many insights into the causes of DMD have been made. Studies of the mdx mouse give explanations for the DMD pathology as this mouse also possesses dystrophin gene mutations resulting in muscle wastage. As elucidated from these and other experiments, dystrophin has varied functions in muscle fibres. Firstly, it provides mechanical support for the cell as the macromolecules it attaches to may be under high mechanical stress and dystrophin provides a firm link between cytoskeleton, sarcolemma and extracellular matrix. Secondly, dystrophin enables muscle tissue to contract as the cortical actin is linked to the ECM, so taking part in force transduction. Thirdly, dystrophin, as an element of the DPAC, plays a role in regulating and organising the sarcolemmal components and maintaining selective membrane permeability. It has been show that sodium and calcium ion channels have different gating properties in the absence of dystrophin. When dystrophin is absent from myotubes, the membranes weaken, rupture and lose their ability to control ion fluxes. Lastly, dystrophin is thought to have a role in control of the myotendinous junction where it normally associates the thin filaments and the muscle membrane. Dystrophin is a critical component of muscle fibres. The initial and most evident proof of this is the fact that muscular dystrophies occur in genotypes with mutations on the dystrophin gene. These mutations can be duplicate exons, deleted exons, disrupted splice sites and premature stop codons, all of which will lead to abnormal or truncated dystrophin expression, or non-expression due to instability of the mRNA transcript or the resultant protein. Subsequently, muscle fibres lack dystrophin and become cumulatively weakened as regenerative satellite cells are unable to keep pace with the level of damage. The sarcolemma membranes rupture and the muscle fibres eventually undergo mass cell necrosis, resulting in severe muscle degeneration. The most frequent of these myopathies is Duchenne Muscular Dystrophy (DMD), where dystrophin is either absent or non-functional. This is a devastating progressive disease which results in loss of ambulation generally before the age of 12 and leads to premature death by respiratory or cardiac muscle failure, often in the late teens. A milder allelic form of dystrophy is Becker Muscular Dystrophy (BMD); here dystrophin is expressed at lower than normal levels or is smaller than usual due to in-frame deletions, but is still partially functional. An animal model for DMD exists in the form of the mdx mouse, which is phenotypically similar to DMD as it has a point mutation of a single base substitution, resulting in a prematurely terminated dystrophin translation 3. Experiments in mdx muscle have shown that the DAPC can be normally localised and expressed by the Dp71 isoform of dystrophin, but the muscle pathology is not improved. 4 Dp71 does not possess an actin-

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