Gene Upregulation Found To “Rescue” Detrimental Phenotype of Duchenne Muscular Dystrophy

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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In a new study entitled Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype,” a team of researchers identified a single gene – Jagged1 – as the potential critical player capable of “rescuing” Duchenne muscular dystrophy phenotype in dogs that exhibit a complete absence of dystrophin. The study was published in the journal Cell.

Duchenne muscular dystrophy (DMD) is a genetic disorder caused by mutations in the dystrophin gene leading to myofiber degeneration and muscle wasting. The disease mainly affects boys, with symptoms usually arising between 3 to 5 years of age. By the time patients reach 9 to 12 years of age, they have lost ambulation and ultimately succumb to the disease in the second or third decade of life due to respiratory or cardiac failure.

Currently lacking a cure, ongoing therapeutic strategies for DMD aim to rescue dystrophin expression in the muscle. The efficiency of these treatments, however, needs to be first tested in animal models that mimic human features of the disease. From the existing models, including fish and mouse, the golden retriever muscular dystrophy (GRMD) model is the most similar to the human disease.

In a previous study, an international team of researchers at Boston Children’s Hospital and at the Biosciences Institute, athte University of São Paulo in Brazil identified two exceptional GRMD dogs that, despite a complete absence of dystrophin, presented functional muscle and normal lifespan. The two dogs, which researchers called “escapers,” reveal that a functional muscle is possible in a dystrophin-deficient animal. In this study, researchers investigated as to how this is possible.

To answer this question, the team combined a triple strategy with linkage, whole-genome sequencing, and transcriptome analysis and discovered a unique region on chromosome 24 associated with the escaper phenotype. Within this region, a single gene called Jagged1 exhibited a differential expression between escaper and affected dogs. Although the role of Jagged1 in skeletal muscle development and disease is far from completely understood, the team showed that Jagged1 is upregulated in mildly affected dystrophin deficient dogs. When the team performed functional studies and overexpressed Jagged1, the dystrophic phenotype was improved.

Jagged1 is what is called a “Notch ligand,” part of the Notch signaling pathway that is a key regulator of gene expression responsible for cellular proliferation, differentiation, and cell death throughout embryonic muscle development.

These findings suggest Jagged1 is a potential new target for DMD therapies in a dystrophin-independent manner. Understanding Jagged1 role in muscle development will allow researchers to better understand the molecular mechanisms behind DMD along with disease pathogenesis.