Duchenne Muscular Dystrophy and Dystrophin

Duchenne Muscular Dystrophy and Dystrophin


As children, they have difficulty walking. As teenagers, most require wheelchairs. Their average lifespan is less than 30 years
old. What devastating disease do these people have? Join me in this episode of Medicurio where
we will discuss one of the most debilitating muscular diseases: Duchenne muscular dystrophy. All movement is controlled by contracting
various muscles in our body. If we zoom into muscle, we see that it is
made up of many long, tubular cells called myocytes that can contract to cause flexing. An important structural protein called dystrophin
is located near the membrane of myocytes. Dystrophin acts like a chain that links the
skeleton of the myocyte, made of actin, to the extracellular matrix, which is a mesh-like
structure outside the myocyte. This linkage prevents membrane damage when
the muscle contracts. Dystrophin has three important areas: the
actin-binding end, which attaches to the cellular skeleton, the central rod, and the dystroglycan-binding
end which attaches to the dystroglycan complex within the membrane that is anchored to the
extracellular matrix. In Duchenne muscular dystrophy, a genetic
mutation causes dystrophin to be extremely short, often lacking the dystroglycan-binding
end, making it dysfunctional. Because of this, every time the muscle contracts,
small rips appear in the membrane. These small rips allow diffusion of various
molecules into and out of the myocyte. The most important substance involved in damaging
muscle is calcium. Calcium ions, found plentifully outside of
the myocyte, flow in through these small rips and activate calcium dependent cellular enzymes
that break down proteins, called proteases. Normally, by carefully regulating cellular
calcium levels, these proteases only break down old and damaged proteins. However, in DMD, extremely high calcium levels
activate too many of these proteases, which begin to break down important, functional
proteins as well. This kills the myocyte. Another important molecule that diffuses through
the rips is creatine kinase, which leaks out of the cell and eventually into the blood. This elevated level of creatine kinase in
blood is often used to diagnose DMD. Creatine kinase is an enzyme that stores energy
for myocytes to use during contraction. With less creatine kinase, less energy storage
occurs, which also weakens muscles. Muscle repair and regeneration can occur at
younger ages. As patients get older though, muscles no longer
regenerate fast enough to keep up with the constant death of myocytes. Instead, fat and scar tissue begin to fill
in the gaps. Since fat and scar tissue are unable to contract,
muscles get weaker over time. This weakening leads to a distinct pattern
of symptoms, such as Gower’s sign, where a child must use his or her arms to stand
up because the leg muscles are too weak. As well, other physical symptoms appear, such
as a curved posture to account for weaker chest and leg muscles, and calves that are
swollen due to buildup of fat and scar tissue. Since the heart and diaphragm are also muscles,
they gradually weaken over time as well. Eventually, they stop working, leading to
death often before age 30. Currently, there is no cure for DMD, but there
are many ways to control its symptoms to prolong lifespan. Physical therapy, steroids, and surgery can
all help slow down muscle weakening. What is most interesting is current research
being done to cure DMD by directly manipulating the dysfunctional dystrophin gene. In order to understand how these techniques
work, we must first understand the characteristics of the dystrophin gene. The dystrophin gene is located on the X-chromosome,
making DMD an X-linked recessive disease affecting mostly males. This is because females have two X chromosomes,
while males only have one X and one Y chromosome. Therefore, if a female has a mutation in one
of her X chromosomes, the other X chromosome acts as a backup. This is not the case for males, who only have
one X chromosome and no backup, since the Y chromosome does not have the dystrophin gene, therefore
making this disease more common in boys. Approximately 1/3500 boys have this disease. Females who have a copy of a defective dystrophin
gene are known as carriers, since despite not being affected by the disease, they have
a 50% chance of passing down the defective gene to their children. Interestingly, inheritance only explains two-thirds
of DMD cases. The remaining one-third of patients have parents
who do not have the disease and are not carriers. This is because everybody has random, often
harmless mutations in their genes. Unluckily, their random mutation in the dystrophin gene
is harmful. Genes consist of a sequence of nucleotides:
adenine, guanine, thymine, and cytosine, which are abbreviated as letters. Whenever a cell wants to make a certain protein,
cellular machinery “reads” genetic material three nucleotides at a time. These triplets are called codons. Each codon corresponds to a certain amino
acid, which make up proteins, and the final codon is a stop codon which tells the cell
that the protein is finished, such as the codon TGA. Much like how a sentence is made up of three-letter
words ending with a period, a protein is made up of amino acids corresponding to three-nucleotide
codons ending with a stop codon. The most common mutation in the dystrophin
gene that causes DMD is known as a “frameshift” mutation. If a nucleotide gets removed due to DNA damage
or errors in DNA replication, the reading frame changes. Now, cellular machinery reads different codons
which code for different amino acids, usually resulting in a non-functional protein, much
like how if a letter is deleted, the sentence makes no sense. In this example and in DMD, the frameshift
mutation causes a stop codon to appear in the middle of the protein, which results in
an incomplete, non-functional dystrophin protein. Gene therapy aims at fixing the mutated dystrophin
gene. One way is by making the cell skip a segment
of the gene containing an early stop codon, a technique known as exon-skipping. This results in a functional dystrophin protein
with a slightly shorter central rod. Going back to the sentence analogy, by skipping
part of the sentence, it makes sense again, although missing some trivial information. Another fascinating treatment method is by
using viral vectors. Some viruses are known to incorporate their
own DNA into human cells. Scientists have been able to take advantage
of this skill to make viruses carry a modified dystrophin gene instead of viral genes, which
gets incorporated into DMD myocytes, allowing these myocytes to produce the modified functional
dystrophin protein. The main limitation to these two techniques
is ensuring that the technique can affect myocytes but not other cells. Gene therapy is still in its early stages
with mixed success in human patients. However, with further research on these treatments,
a cure to DMD seems to be near in the future. Check out the links in the description below
to learn more about DMD or to support the ongoing research about this debilitating muscular
disease. Thanks for watching, and see you next time
for another explanation of a disease on Medicurio.

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