Personal+Genomics+of+Duchenne+Muscular+Dystrophy

Abigail Goen Abby.Goen@gmail.com

Abstract:

Duchenne Muscular Dystrophy (DMD) is the most common form of muscular dystrophy. It is an x-linked disorder that is most commonly observed in males, though female carriers may exhibit some relatively mild symptoms. Approximately, 2/3 of cases are caused by hereditable conditions while 1/3 are caused by spontaneous mutation. In males it is a fatal disease that has no cure and limited treatment options. DMD occurrence is roughly 1 of 3,300-5,000 males at birth and is caused by the lack of production of the dystrophin protein due to a mutation in the gene that codes for dystrophin which is critical for maintaining muscle mass. Life expectancy is roughly 20 years with progressive ambulatory failure, eventually leading to muscle wasting of the diaphragm and pulmonary failure. DMD patients typically present with increased levels of creatine kinase, voluntary muscle weakness (initially in upper legs and pelvic region), disproportionate calf development, and overall muscle fatigue. Muscle biopsy and genetic testing can give a definitive diagnosis.

Research has been aimed at identifying the contributing genetic factors that prevent the production of dystrophin and developing technological advancements in genomics to trigger the production of dystrophin. Understanding the specific mutation that is causing DMD in each patient is critical to design targeted treatment. As of now, treatment is maintenance based and typically includes significant corticosteroid treatment to prevent the onset of secondary symptoms such as loss of ambulatory ability and increased risk of cardiomyopathy.

Another therapeutic strategy being investigated is exon-skipping. For example, with some forms of DMD, within the gene that gives rise to exon 51, one of the 79 exons that makes up the dystrophin gene, there is deletion. Due to the structure of the neighboring exons, the cannot join together allowing for the production of dystrophin, albeit a lesser functioning version. This also causes a break in the open reading frame (ORF), which all together results in a completely non-functional protein. Exon skipping uses antisense oligonucleotides to act as patches that allow exons to be skipped during splicing and a truncated functional protein produced.

There is promising research for the treatment of DMD in the area of exon skipping. This study sought to understand the methodology behind this treatment option and to understand the limitations and potential impact of such a method. Several primary articles were used to compile this study which defined and discussed the procedural and effectual aspects of exon skipping. This method, while showing potential success for many suffering from DMD, is limited by which exons are affected by the mutation, and here we discuss the skipping of Exon 51 which is applicable for approximately 14% of all DMD patients.

Background:

•DMD is the most common form of muscular dystrophy, it is fatal. It is an X-linked recessive disorder. Occurs mostly in males, 1:3500-5000 births.



•Effects production of dystrophin which is coded for by the largest known gene in human genome.

•Exons are the material that get translated into amino acids which become proteins. They fit together like a linear puzzle. If a deletion occurs that prevents the mRNA from being translated into a protein- no dystrophin is produced.

•If deletion occurs within certain exons, those exons can be “skipped’ allowing for a smaller but functional protein to be produced, minimizing symptoms and downgrading the disease from fatal to chronic.

Materials and Methods Results Discussion Broader Impact Works Cited