Target gene identified to combat muscular dystrophy

Research from Brazil and the United States suggests by inducing overexpression of the gene — Jagged1 — development of muscular dystrophy can be prevented.

Researchers at the University of São Paulo's Bioscience Institute (IB-USP) in Brazil have shown that a gene called Jagged1, or JAG1 for short, could be a target for the development of new approaches to treat Duchenne muscular dystrophy (DMD), a genetic disorder characterized by progressive muscle degeneration.

The research was carried out at the Human Genome & Stem Cell Research Center (HUG-CELL), one of the Research, Innovation and Dissemination Centers (RIDCs) supported by São Paulo Research Foundation (FAPESP).

The findings appear in the journal Cell.

"All the genetic therapies tested so far, with little success, have targeted the gene that codes for the protein dystrophin. We're presenting a different approach, which opens up a range of new possibilities," said Mayana Zatz, Full Professor of Genetics at IB-USP and Head of HUG-CELL.

Duchenne muscular dystrophy primarily affects male children and is the most common and most rapidly progressing type of muscular dystrophy.

It is caused by a mutation, usually inherited, in the gene that encodes dystrophin — a protein essential for muscle health — that is entirely absent in DMD patients.

Zatz: "Dystrophin maintains the integrity of the membrane surrounding muscle cells. When this protein is absent, the membrane becomes flaccid, so important proteins leak out of the muscle tissue and enter the bloodstream. Conversely, substances that should remain outside, such as calcium, are able to get in. Without special care, patients don't reach the age of 20. Nowadays, with assisted breathing, they may survive until they're 40 or beyond."

The heart, diaphragm and skeletal muscles are affected. Difficulty with walking and running first appear in boys aged between 3 and 5. Patients are usually confined to a wheelchair by age 10 - 12.

Over the past 15 years, researchers at HUG-CELL have performed experiments to extend our knowledge of DMD. They found an animal model in Golden Retrievers, born with a dystrophin gene mutation, that develop a clinical condition similar to human DMD. Most dystrophic dogs live for only two years or less.

"Some time ago, we identified a dog that totally lacked dystrophin yet presented with a much milder form of the disease. It survived for 11 years, considered normal for this breed, and left a descendant that inherited the mutation and is now nine years old."

Mayana Zatz PhD, Professor of Genetics, IB-USP, and head of HUG-CELL.

Ringo and Suflair, as the dogs were called, became the center of attention for research. Scientists compared gene expression in healthy dogs, dogs with severe muscular dystrophy, and in Ringo and Suflair with the milder form of the disease.

The researchers identified some likely gene candidates in partnership with Professor Louis Kunkel and team, Harvard Medical School, and Professor Kerstin Lindblad-Toh, the Broad Institute of MIT and Harvard.

The combined results from these three groups of scientists identified a region of the genome associated with the benign clinical muscle condition found in Ringo and Suflair. Your genome is your complete set of DNA, including all genes. Each genome contains all of the information needed to build and maintain an organism. In humans, a copy of the entire genome—more than 3 billion DNA base pairs—is contained in every cell that has a nucleus.

A region of Ringo and Suflairs' genome contained increased amounts of the gene JAG1— which would explain why they had a benign form of the disease.

To confirm that alterations in JAG1 expression affected the severity of their DMD disease, the scientists conducted experiments on zebrafish, which shares approximately 70% of its genome with humans. Over expression of the JAG1 gene was induced in the zebrafish by injecting their embryos with JAG1 messenger RNA.

"The zebrafish model also has a dystrophin gene mutation. As a result, its muscles are weak and it can't move. But, when we increased JAG1 expression in zebrafish without dystrophin, we found that 75% failed to develop observable traits of muscular dystrophy."

Mayana Zatz PhD

Abstract Highlights
•Escaper GRMD dogs show that a normal lifespan is possible without muscle dystrophin
•Jagged1, a Notch ligand, is upregulated in mildly affected dystrophin deficient dogs
•Jagged1 overexpression can rescue the phenotype of dystrophin deficient zebrafish

Summary
Duchenne muscular dystrophy (DMD), caused by mutations at the dystrophin gene, is the most common form of muscular dystrophy. There is no cure for DMD and current therapeutic approaches to restore dystrophin expression are only partially effective. The absence of dystrophin in muscle results in dysregulation of signaling pathways, which could be targets for disease therapy and drug discovery. Previously, we identified two exceptional Golden Retriever muscular dystrophy (GRMD) dogs that are mildly affected, have functional muscle, and normal lifespan despite the complete absence of dystrophin. Now, our data on linkage, whole-genome sequencing, and transcriptome analyses of these dogs compared to severely affected GRMD and control animals reveals that increased expression of Jagged1 gene, a known regulator of the Notch signaling pathway, is a hallmark of the mild phenotype. Functional analyses demonstrate that Jagged1 overexpression ameliorates the dystrophic phenotype, suggesting that Jagged1 may represent a target for DMD therapy in a dystrophin-independent manner.

Related research:

Dystrophic phenotype of canine X-linked muscular dystrophy is mitigated by adenovirus-mediated utrophin gene transfer

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Nov 25, 2015   Fetal Timeline   Maternal Timeline   News   News Archive   

Suflair is a 9 year old golden retreiver with a mild form of Duchenne muscular dystrophy
(DMD). He inherited the gene from his father, Ringo, who lived to 11 years old.
Image Credit: Human Genome and Stem-Cell Research Center



Image Credit: Cell