Understanding the Scientific Basis of Duchenne & Becker Muscular Dystrophy

Faced with a diagnosis of muscular dystrophy, patients and families invariably ask - "What causes muscular dystrophy?" One of the first things they need to understand is that there are so many different forms of muscular dystrophies and that each has its own cause. Over the years, we've improved our understanding of what causes many forms of the disease. The muscular dystrophy for which we have the most answers is Duchenne muscular dystrophy. Indeed, it is the first muscular dystrophy of which the scientific basis of the disease has, more or less, been worked out. In this article I will attempt to explain step by step what actually happens in the muscle to cause DMD. Scientists are studying the process in a similar vein to try to unravel the causes of most -- if not all -- the muscular dystrophies!!

It has long been known that the gene responsible for Duchenne muscular dystrophy (DMD) resides somewhere in the X chromosome. The chromosomes that determine sex are the X and Y chromosomes. Boys have a Y chromosome paired with an X chromosome, while girls have a pair of X chromosomes. This would explain why the disease is sex-linked, occurring in boys and not girls. When boys inherit an X chromosome with an abnormal DMD gene, they develop the disease because they do not have a normal DMD gene on the Y chromosome to compensate for this abnormality. If a girl inherits an X chromosome with an abnormal DMD gene, her other X chromosome has a normal DMD gene to compensate for the abnormal gene, so she will not develop the disease.

16 years ago, the gene involved in DMD was precisely located on the X chromosome and its structure identified. The discovery was a major breakthrough in our understanding of the disease. It also heralded the tremendous burst of discoveries that were to follow and that continues to this day in the field of muscular dystrophy. Like pieces of a jigsaw puzzle falling into place, this discovery led to a sequence of discoveries that revealed the basis of the disease, not just in DMD, but also in Becker muscular dystrophy and several forms of limb girdle muscular dystrophy.

First of all, when the gene for DMD was identified, it was quickly revealed that this was the same gene responsible for Becker muscular dystrophy (BMD). This association was already suspected at the time, because BMD shows many common features with DMD, except it was a much milder disease. Like DMD, it was X-linked, and showed the same pattern of muscle involvement. However, only with the identification of the DMD gene was it possible to prove this beyond doubt. At the same time, it was shown that though DMD and BMD were caused by abnormalities in the same gene (known as mutations), the mutations causing DMD were not the same as those causing BMD.

Identifying the DMD gene allowed scientists to go one critical step forward. It allowed scientists to determine the protein made from the DMD gene. Genes can be likened to specific codes for proteins that are used by cells in the body to manufacture these proteins. Each and every protein in the body is coded by a specific gene. Thus, when the structure of the DMD gene was discovered, the protein coded by this gene could be reconstructed. The reconstructed protein was given the name dystrophin.

Normal muscle with dystrophin stained brown in membrane outlining cell

Normal muscle with dystrophin stained brown in membrane outlining cell

DMD muscle: Absence of dystrophin stain except in one fibre in middle

DMD muscle: Absence of dystrophin stain except in one fibre in middle

A host of questions emerged. Is this protein present in muscle cells? If so, where does this protein reside in the muscle cell? And, what does it do? What happens to the dystrophin in DMD and in BMD? These questions amounted to one central question, "What is happening in the muscle cell that causes DMD?"

Scientists quickly developed special stains to stain the dystrophin protein, so that we could see if dystrophin was present in muscle cells and where it was present. They proved that dystrophin was, indeed, present in muscle cells. Not only that, they showed that dystrophin was present in the membrane lining the surface of muscle cells. This discovery was in tune with unverified observations made by scientists in the past. Scientists had previously observed that cracks were sometimes present on the muscle membrane in DMD, leading to damage of part of the muscle underneath these cracks. Discovering that dystrophin actually resided in the surface membrane immediately gave us a plausible explanation for these early observations. This was further affirmed when it was shown that in DMD, dystrophin was completely absent from the muscle surface membrane, while in BMD, the dystrophin present was reduced in amount or abnormal in structure.

Therefore, it is now believed that in DMD and in BMD, the absence or lack of normal dystrophin causes the muscle surface membrane to be structurally weak. Dystrophin helps protect the muscle surface membrane from breakage, particularly as the muscle cells are regularly subjected to the mechanical forces of contraction. In DMD and BMD, this susceptibility to breakage of the muscle surface membrane eventually leads to damage and death of the muscle cell. This is the underlying basis of what happens in the muscles of patients with DMD and BMD.

Our story does not end here. In science, one discovery leads to another and another. Once dystrophin was discovered, other proteins associated with dystrophin in the muscle membrane were identified. These "dystrophin associated glycoproteins" could also be important for the structural integrity of the muscle surface membrane. Immediately, you may also realise that these proteins could, like dystrophin, play a role in causing muscular dystrophy - not DMD or BMD, but another form of muscular dystrophy. That story next time!

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