Golden retrievers with the Duchenne mutation show that disease-modifying genes may provide routes to treat a genetic disorder; possible parallels to facioscapulohumeral muscular dystrophy.
Research led by Louis M. Kunkel, PhD, a member of the FSH Society’s board of directors and scientific advisory board, demonstrates that a disease might be treated by finding a gene that modifies the devastating impact of the mutant gene causing the disease.
Kunkel, a member of the Division of Genetics and Genomics at Boston Children’s Hospital; and Professor of Pediatrics and Genetics, Harvard Medical School, along with the study’s first author Natassia M. Vieira and colleagues, made the discovery in a strain of golden retriever that lacks dystrophin. In people, mutations of the dystrophin gene cause Duchenne muscular dystrophy, which Kunkel discovered in 1986 in a landmark study. This retriever strain (called GRMD) resembles human Duchenne MD closely, with early progressive muscle degeneration, pulmonary failure and heart damage leading to death by early adulthood (around 1 year in dogs and age 20-30 in humans).
However, Mayanna Zatz’s group in Brazil found two “exceptional” dogs, which, despite lacking dystrophin, remained able to walk and lived a normal lifespan. How did these dogs evade their fate? Finding the genetic escape route could point toward novel treatment strategies.
In a study published in this week’s issue of the journal Cell, the Kunkel team, working with Kerstin Lindblad-Toh of the Broad Institute in Cambridge, Massachusetts, analyzed the whole genome sequences and transcriptomes (the genes that are actually expressed) of these “escaper” dogs. When they compared them to affected GRMD dogs, one gene jumped out as being different. Called Jagged1, this gene is much more active in the escaper dogs. “The dogs are not normal but function normally and live a full life span,” said Kunkel. “We’re still trying to figure out how it works.” Preliminary data suggests that Jagged1 might promote faster muscle regeneration.
“Disease modifier genes” such as Jagged1 can point to new strategies for treatments. A drug that boosts Jagged1 activity, for example, might be a reasonable approach to treating Duchenne MD, which affects an estimated 1 in 3,000 boys.
This finding is an exciting proof-of-principle for diseases such as facioscapulohumeral muscular dystrophy (FSHD), a genetic condition that affects around 1 in 8,000 men, women and children and is among the most common forms of muscular dystrophy. From studies funded by the FSH Society, researchers discovered that some individuals who have the FSHD genetic mechanism do not develop symptoms. Like the GRDM retrievers who evaded developing disease, these non-manifesting FSHD individuals are “escaper” humans.
In FSHD, the genetic mechanism leads to expression of a gene called DUX4, which is toxic to muscle. Kunkel, whose lab is also working on FSHD, said “I look at the non-manifesting FSHD carriers as also having modifying genetics which change sensitivity to DUX4 expression.”
“We’re excited that Dr. Kunkel’s team is investigating the common theme of disease-modifying genes in both Duchenne MD and FSHD,” said FSH Society President and CEO Daniel Perez. “We have invested in this strategy because we believe this is a most promising approach to finding effective treatments.”
Reference: Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype. Natassia M. Vieira, Ingegerd Elvers, Matthew S. Alexander, Yuri B. Moreira, Alal Eran, Juliana P. Gomes, Jamie L. Marshall, Elinor K. Karlsson, Sergio Verjovski-Almeida, Kerstin Lindblad-Toh, Louis M. Kunkel, Mayana Zatz. Cell, published online November 12, 2015. DOI: http://dx.doi.org/10.1016/j.cell.2015.10.049
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Dr. Raymond Huml says
Great news! I remember Dr. Joe Kornegay’s dogs with muscular dystrophy when he worked at NCSU’s College of Veterinary Medicine in North Carolina. I hope that dogs provide a key to FSHD as we have been woefully short on good animal models.