Surprise mutation to JAG1 salvages Duchenne muscular dystrophy phenotype

Muscular dystrophies are a group of inherited genetic and progressive conditions that gradually cause the muscles to weaken, leading to an increasing level of disability. Duchenne muscular dystrophy (DMD) is one of the most common and severe forms of muscular dystrophy. It is a recessive X-linked disorder affecting boys in early childhood. It has an incidence of 1 in 3,600 male infants. The condition is due to a mutation in the gene dystrophin, which codes for the protein of the same name. The latter provides stability to the dystroglycan complex of the cell membrane and as such, is a critical structural component within the muscle tissue. In its absence, calcium enters the cell membrane of each muscle fiber causing alterations to signaling pathways and absorption of water by the mitochondria, which then burst. As a result of the decrease in the mitochondrial mass, stress-induced cytosolic calcium signals and reactive oxygen species production are enhanced. It eventually leads to death of the cells by necrosis causing the early and characteristic symptoms of muscle weakness of the legs and the pelvis. As the disease progresses, this weakness spreads to the arms, the neck and other areas such as the heart and the respiratory muscles. Muscle fibers are slowly substituted with adipose and connective tissue and an overall loss of muscle mass is observed. There is, unfortunately, no cure for DMD. Current treatments such as β2-agonists, corticosteroids and physical therapy are only palliative and men with the condition can expect to live into their 20s.

Natassia M. Vieira and colleagues from Harvard Medical School and the University of Sao Paulo noticed that Ringo, a golden retriever bred to have a severe form of muscular dystrophy, did not show any signs of the disease.

Interestingly, one of his puppies also seemed to be protected. Both dogs have inherited the dystrophin mutation and were rescued by a mutation in a gene called Jagged 1 (JAG1). The latter is the ligand for the receptor Notch 1, a type 1 transmembrane protein that controls cell fate decisions and therefore plays a key role in several developmental processes. Genome-wide analysis demonstrated that the mutation was absent from severely affected dogs from the same colony. Jagged 1 expression was also found to be significantly up-regulated both at the mRNA and protein levels in the muscles of Ringo and his son when compared with affected dogs. The authors demonstrated that overexpression of Jagged 1 not only rescued dogs with a dysfunctional dystrophin but also salvaged similar dystrophic muscle phenotype in other species. Using an affected dystrophic zebrafish model, they mimicked the over-expression of Jagged 1 and noticed a protection from muscle shredding and other abnormalities typically associated with muscular dystrophy in the zebrafish. Further work was conducted on mice where injury on the muscles of the anterior legs was induced with a cardiotoxin. As a result of this toxic insult, Jagged 1 was found to be up-regulated. Finally, muscle cells are expected to divide less recurrently in dystrophic dogs than in healthy dogs. They determined that muscle cells from escaper dogs do in fact divide significantly faster than those from affected dogs. Altogether, these results demonstrate that mutations have the potential to counteract the effects of a genetic disorder and that thanks to Ringo, Jagged 1 may be an interesting and potent ally against DMD. Both Ringo and his son went on to live a normal life.

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