Dystrophin: the Dysfunctional Gene
Devan Osegueda, Hannah Kuhl, Marcellla Muysson
Muscular Dystrophy
Dystrophin In Focus
Functions of Dystrophin
Treatments
Muscular dystrophies are hereditary diseases that
progressively weaken the musculoskeletal system until it
becomes dysfunctional.11 They are typically caused by
defects in proteins, which lead to the death of muscle cells
and tissue. The most common form of muscular dystrophy
(MD) is Duchenne (DMD), but other forms include Becker,
limb-girdle, congenital, facioscapulohumeral, myotonic,
oculopharyngeal, distal and Emery-Dreifuss.
Structure
Protein Complex
Current Treatments/Research
The Dystrophin protein consists of 4 domains: N-terminal
actin-binding domain with 2 actin binding sites; central
rod domain; then 24 spectrin-like repeat units
interspersed by 4 hinge regions followed by the cysteinerich domain; C-terminal domain. Contains 79 exons and
spreads out over 2.4 million base pairs of DNA.4
The primary function of dystrophin is its role in a very
important protein complex known as the dystrophinassociated protein complex.1 In this complex, a group of
proteins work together to strengthen muscle fibers and
protect them from injury as they contract and relax.12
This dystrophin complex works like an anchor, linking the
cell’s structural framework to the proteins and other
molecules outside the cell. The absence of dystrophin
results in destabilization of the complex and fleeting
disruptions of sarcolemma integrity, and the combination
of these two things leads to myofiber necrosis.13 The
exact mechanisms leading to necrosis are poorly
understood.
There is no cure for Muscular Dystrophy, but treatment
focuses on delaying the onset and minimizing the effects of
symptoms. Corticosteroids are taken to increase energy and
strength to counteract the two main symptoms of fatigue
and muscle weakness. Prednisolone is an example of a
glucocorticoid which inhibits inflammatory responses by
binding to receptors that results in the inhibition of
cytokine production and transcription of many other
proteins. This works to greatly reduce severity of some
symptoms with a prolongation of the ability to walk by two
years. Treatment includes physical therapy and mild
activity to prevent further muscle loss. Ankle braces are
worn at night to prevent contractures, the shortening of
muscles.
DMD is caused by
mutations in the protein
dystrophin, and is a
severe form of MD that
usually leads to death
between 20 and 35
years.2
a.
Figure 4a: Structure of Dystrophin gene showing domains and additional key elements. Ref 3.
Figure 1: Histopathology of muscle from a patient who died of DMD. This
cross section shows extensive replacement of muscle fibers by adipose
cells. Ref. 8.
b.
Dystrophin
Figure 4b: PDB rendering of Dystrophin. Ref 1.
Located on the X chromosome, one of the longest known
human genes. Rod-shaped cytoplasmic protein. Vital part
of protein complex that connects cytoskeleton of a muscle
fiber to the surrounding extracellular matrix through the
cell membrane. Supports muscle fiber strength, reduces
stiffness, etc. Deficiency results in muscular dystrophy.1
Figure 2: Dystrophin bound at DAPC
through its C terminus. DAPC
consists of sarcoplasmic,
transmembrane and extracellular
proteins. N terminus of Dystrophin
binds to the cytoskeleton. DAPC
provides strong, mechanical link
between intracellular cytoskeleton
and extracellular matrix. Ref. 2.
Mutations
a.
Large size of this gene makes it susceptible to mutations.
Different mutations in one of the 4 domains will result in
different forms of disease and in particular various types
of muscular dystrophy. Mutations are usually deletions.
Differences in locations of deletions may result in more
severe phenotypes than deletions in other locations.
Mutations that disrupt the open reading frame usually
cause DMD while in-frame mutations will result in BMD–
reading-frame rule.4,5
Figure 7 shows two forms of treatment of Duchenne Muscular
dystrophy. (a) is the glucocorticoid, Prednisolone, that is the main
drug given to patients. (b) shows a common physical therapy
precaution used by patients during sleep. Ref. 7.
The future of Duchenne Muscular Dystrophy looks heavily to
stem cell treatment.9 Research often involves using some
types of cell with the defective dystrophin gene. For
example, At UMLHI skin cells from mice with DMD were
transformed into iPSC (induced pluripotent stem cells). This
allowed the researchers to introduce a gene called microutropin which promotes new muscle growth. Finally the cell
were converted to mesenchymal stem cells (Fig. 10) which
can develop into muscle tissue. When the cells were
inserted back into the originating mice, the cells were not
rejected and generated properly functioning muscle tissue.
Figure 6: This figure shows dystrophin in comparison to an entire muscle. You can see that the muscle is
broken down into fascicles (bundles), which are further broken down into individual muscle fibers. Dystrophin
is found in the muscle fiber membrane of a muscle fiber, along with the other proteins in the dystrophinassociated protein complex. Ref. 14.
Figure 5a: Overview of relation between in-frame deletions and severity of the phenotype. Ref. 4.
Other Functions
It is believed that dystrophin may also play an important
role in cell signaling, through its interaction with other
proteins that send and receive chemical signals.12
Further research concerning the signaling cascades of
certain components of the dystrophin-associated protein
complex could help us understand why exactly myofiber
necrosis occurs when dystrophin disfunctions.13 More
information about dystrophin’s indirect role in localizing
these signaling molecules could provide insight
concerning the potential treatments for muscular
dystrophy.
b.
Figure 5b: Most common deletions in
Dystrophin that result in DMD and BMD. Ref. 5.
Little is known about the function of dystrophin in nerve
cells, but research suggests that it is vital for the normal
structure and function of synapses.12
References
1.
2.
3.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
RESEARCH POSTER PRESENTATION DESIGN © 2011
www.PosterPresentations.com
Figure 8 shows the
process that
combines stem cell
technology with new
genetic therapy to
be a possible
treatment for DMD.
Ref. 8.
.
4.
Figure 3: Shows the approximate
ages at which symptoms of DMD
begin to occur.
Ref. 6.
b.
Future Treatments
a.
Case Study
John Gugie was diagnosed with Duchenne Muscular
Dystrophy at the age of 6.10 He began walking at 7 months
and lived a seemingly normal life, but once he entered
elementary school he quickly realized he was much slower
than the other children. Once his mother noticed he
sprained his ankle twice over the next two years, walked
slightly on his toes, his back curved inward, and he fell
frequently, she took him to get a biopsy and other tests
that proved he had DMD. At 8 years old, John had to use a
wheelchair. The progression of muscle deterioration is still
occurring, and John Gugie knows he does not have many
years ahead of him.
b.
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