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Objective 7

Explain the Role of Dystrophin

What is Dystrophin

It is a rod shaped cytoplasmic protein located between the


sarcolemma and the outermost layer of myofilaments in muscle
fibers.

The dystrophin gene is the largest in the human genome,


encompassing 2.6 million base pairs of DNA and containing 79 exons.

It forms a protein complex called Dystrophin Associated Protein


Complex (DAPC) which contains other proteins such as
dystrobrevin,syncoilin,synemin,sarcoglycan,dystroglycan
andsarcospan, colocalize with dystrophin at the costamere.

Mutations in any of these components causes autosomally inherited


muscular dystrophies

It is located primarily in muscles used for movement (skeletal


muscles) and in heart (cardiac) muscle. Small amounts of dystrophin
are present in nerve cells in the brain.

The Role of Dystrophin

The dystrophin complex acts as an anchor, connecting each


muscle cell's structural framework (cytoskeleton) with the
lattice of proteins and other molecules outside the cell
(extracellular matrix).

Dystrophin complex may also play a role in cell signaling by


interacting with proteins that send and receive chemical
signals.

In skeletal and cardiac muscles, dystrophin is part of a


group of proteins (a protein complex) that work together to
strengthen muscle fibers and protect them from injury as
muscles contract and relax.

Pathogenesis
DNA encodes for RNA. The RNA is then transferred to the cytosol
where it is then coded by the ribosome for the protein Dystrophin.

It is a cohesive protein so it links actin filaments to another support


protein that resides on the inside surface of each muscle fibers
sarcolemma
This support protein 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
endomysiumof the entire muscle fiber.
The DAPC is destabilized when dystrophin is absent, which results in
diminished levels of the member proteins
This in turn leads to progressive fibre damage and membrane leakage.
The DAPC has a signalling role, the loss of which also contributes to
pathogenesis

Pathogensis

As a result of membrane leakage free flow of Calcium ions


into the cell occurs which causes necrosis of the cell.

Dystrophin plays a major role in supporting and anchoring the


muscle fibers and the cell membrane. Its absence or
deformity causes the following:

Reduced muscle stiffness


Increases sarcolemmal deformability
Comprises the stability of the costameres (protein complex
in which dystrophin is a part of)
Interferes with proper cell signalling pathways
Progressive muscle weakness and fatigability (Duchennes
Muscular Dystrophy)
Influx of Calcium ions into the cell which causes necrosis
or death of the cell.