How is the dystrophin gene altered in Duchenne? The dystrophin gene contains 79 exons. In Duchenne some exons are missing or deleted, meaning the dystrophin protein is not produced correctly. This can be explained much like a paragraph in a book made up of 79 letters, with exons being the letters of each individual word in each sentence. If some of these words or letters are missing the sentence will not make sense. Exons or groups of exons from the dystrophin gene (in groups of three/triplets) can be disrupted to produce a partially readable sentence or genetic code. This is known as an in-frame error, where shorter but functional dystrophin can be made, this occurs in Becker's muscular dystrophy (BMD). Figure 1 - In Becker muscular dystrophy (BMD) a dystrophin deletion takes out three letter ‘chunks’ (2) producing a shorter but readable sentence (3), this is known as an in-frame error. In Duchenne muscular dystrophy, deletion of an exon or group of exons from the dystrophin gene disrupts the three letter ‘chunks’ of the sentence. This leads to letters of the sentence shifting, producing a non-readable sentence or genetic code, known as an out-of frame error. Dystrophin cannot be translated into a functioning product as the sentence does not make sense. Figure 2- In Duchenne muscular dystrophy (DMD) an out-of frame error occurs as a result of deletion of an exon or group of exons in the dystrophin gene (2), this leads to disruption of the three letter reading pattern. As a result a non-readable sentence or genetic code is produced, this cannot be translated into a functioning dystrophin protein (3). In some forms of Duchenne caused by nonsense mutations, the sentence or genetic code for making dystrophin is cut short. Nonsense mutations result in a shorter (truncated) dystrophin protein being produced, this occurs due to incomplete translation of dystrophin. Figure 3 - Duchenne muscular dystrophy can be caused by a nonsense mutation producing a sentence or genetic code that is shorter than normal (2), as a result incomplete translation of dystrophin protein occurs (3). Exon skipping Exon skipping technology is a promising potential treatment for Duchenne. Exon skipping is based on antisense chemistries, this can be used to skip over faulty or deleted parts of the genetic code, restoring the reading frame to produce a smaller yet functioning protein. Action Duchenne supports research that will further optimise the efficiency of this technique, with the potential of Exon skipping working alongside other potential therapies. More can be found out about research that Action Duchenne funds in research basics and in our research strategy. Figure 4 - Exon skipping works by changing an out-of frame error into an in-frame error, skipping over deleted exons as well as neighbouring exons (2), leading to the restoration of the reading frame. Production of a shorter but readable sentence produces a smaller functioning dystrophin protein (3). This causes Duchenne muscular dystrophy to become more like Becker’s muscular dystrophy, the milder form of Duchenne.