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Duchenne Muscular Dystrophy is caused by a malfunction in translation known exon skipping. Translation is a three step process that begins with an mRNA template and finishes with a protein, when all steps go correctly. As an mRNA template is being fed through the ribosome, the mRNA is binding with nucleotides and producing a full length functional protein that will be released into the cell for the job it is meant for. These nucleotides are matched with the mRNA based off of the special three code letters known as codons, which tells what specific amino acid or stop signal during the production of a protein. During Duchenne Muscular Dystrophy what happens is instead of a regular codons being fed through then a stop codon coming and clipping off a full length protein, instead, a nonsense mutation occurs.  This premature termination of codon mutations, occur in an estimated 10-15% of genetically based disorders such as Duchenne Muscular Dystrophy. A nonsense mutation is an incident that occurs when a correct codon is change to a chain terminating codon, which in-turn causes for the protein to be prematurely released and therefore becomes a non-functional protein. Skipping an exon is like skipping a segment of a DNA or RNA containing information coding for a protein or peptide sequence. By skipping this critical information needed to produce a full, functional protein, this results in an unfinished protein that lacks in length causing defective and non-functional protein. Exon skipping normally occurs in the step where elongation of the protein should be occurring.

    A metaphor that may help this malfunction make sense, could be the idea of driving from your house to a restaurant three miles away. You have never been to this reasurgnt therefore, you use a GPS to get there. As you are driving on your way to the reasutrant, the GPS says to continue straight, but the road that is under construction says to detour to the right. You choose to detour to the right and end up at a dead end. This metaphor is similar to the nonsense mutation occurring in the muscular dystrophy gene. The car being driven can be thought of as the ribosome, and the directions could be thought of the code being followed to produce a full-length protein, and finally, the detour can be thought of as the premature stop codon that causes the release of the premature protein.

    A treatment by the name of Nonsense Suppression Therapy is method known to prevent exon skipping by promoting read through mutations, allowing for a full length protein to be produced. Aminoglycosides and Ataluren [PTC124] are the two, developed, primary drugs that are currently under clinical testing for nonsense suppression therapy. Ataluren aims to facilitate the production of a functional protein in patients who cannot produce it normally. The drug forces the cell to ignore the abnormal premature stop signal, enabling the production of full-length, functional protein. Aminoglycosides on the other hand allows for an amino acid to be inserted at the stop codon, rather than cutting off and releasing a premature protein. This is similar to ignoring the detour sign, and continuing to drive on the GPS route.

References

Finkel, R. S. (2010). Read-Through Strategies for Suppression of Nonsense Mutations in Duchenne/ Becker Muscular Dystrophy: Aminoglycosides and Ataluren (PTC124). Journal of Child Neurology, 25(9), 1158-1164. doi:10.1177/0883073810371129

Hoffman, E. P., & Giron, J. (n.d.). Molecular Diagnosis and Genetic Counseling of the Manifesting Carrier of Duchenne Muscular Dystrophy. Muscular Dystrophy, 173-188. doi:10.1385/1-59259-138-8:173

Russell, P. J. (2002). Genetics. San Francisco: Benjamin Cummings.

Menezes, M. (2017). Faculty of 1000 evaluation for Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. F1000 - Post-publication Peer Review of the Biomedical Literature. doi:10.3410/f.727824728.793536094

Narang, M. (2011). Chapter-29 Duchenne Muscular Dystrophy (DMD). Approach to Practical Pediatrics, 373-381. doi:10.5005/jp/books/11201_29