Duchenne muscular dystrophy (DMD) is caused by the absence of functional dystrophin protein. This protein has an important binding role; it binds the proteins in the skeleton of muscle fibers to connective tissue that surrounds the muscle fibers. Dystrophin works as a shock absorber and protects the muscle fibers against damage during muscle movements (contraction and relaxation of the muscle fibers). Dystrophin can be seen as the rope between the anchor and the boat (Figure 1). The anchor can only function if the rope (dystrophin) is connected to both the anchor and the boat.
The blueprint of the dystrophin gene is found in the DMD gene. The parts of the DMD gene containing genetic information that the cells needs for generating proteins are called “exons”. The DMD gene has 79 exons (Figure 2). These exons fits like a jigsaw puzzle and together form the genetic code for the dystrophin gene.
Duchenne patients has mistakes (mutations) in their DMD gene. The most occurring mistake is 1 or more missing exons in the gene: a “deletion”. The example of Figure 3 shows a deletion of exon 48, 49 and 50 (48-50).
When we zoom in to the part where the mutation is found, we see that exon 47 does not fit to exon 51 (Figure 4).
Since exon 47 and exon 51 does not fit, the genetic code is broken. This results in an unreadable blueprint after exon 47 and a premature stop in the translation to dystrophin in exon 51. Since dystrophin has to bind to two different components (skeleton and connective tissue), this dystrophin protein is not functional anymore (Figure 5).
Due to the lack of functional dystrophin, the muscle fibers of Duchenne patients are extremely sensitive for muscle damage. You are most likely familiar with the consequences.
It is possible that the mutation not the genetic code of the DMD gene disrupts, as seen in the example in Figure 6 and Figure 7.
Due to the mutation exon 48, 49, 50 and 51 are missing. Exon 52 fits to exon 47 so the genetic code remains. Despite the mutation, the blueprint remains readable and the protein synthesis can proceed after the mutation. Since the beginning and the ending of the dystrophin protein is available, the connection is not lost. The protein is quite shorter (the part that used to be translated in exon 48-51 is missing). This dystrophin protein is mostly functional (Figure 8).
Mistakes which not disrupt the genetic code are found in Becker muscular dystrophy (BMD) patients. Since the dystrophin protein of these patients is partly functional, the muscle fibers are less sensitive for damage than the muscle fibers of Duchenne patients. Generally, the progress of the disease is less serious.
Scientific background of the exon skip therapy
The main goal of the exon skip therapy is to repair the genetic code of Duchenne patients. This results in the synthesis of a partly functional dystrophin protein instead of a non-functional protein. Hopefully, the progress of the disease will be slowed down or even stopped.
Exons can be skipped with the use of so-called antisense oligonucleotides (AONs). These are small parts of synthetic modified DNA that can cover up a specific exon (Figure 9). Because of this, the exon will be skipped when the genetic code is made up.
In the example of Figure 9 the skipping of exon 51 repairs the genetic code.
Due to the deletion exon 47 is connected to exon 51 when the genetic code is made up. These exons does not fit and the genetic code is disrupted (protein synthesis is prematurely stopped). With the use of an AON specific for exon 51, this exon is hidden during the composition of the genetic code. Now exon 47 is connected to exon 52: the genetic code is repaired and protein synthesis can be completed.