Researchers Identify Initial Stages of Prevalent Muscular Dystrophy Type
In a groundbreaking discovery, a team of international researchers has identified the root cause of Facioscapulohumeral muscular dystrophy (FSHD), a common type of muscular dystrophy that affects approximately 1 in 20,000 people worldwide, including about 15,000 Americans.
The research, led by genetics researchers at the University of Leiden in the Netherlands, sheds light on the de-repression and aberrant expression of the toxic DUX4 gene in muscle cells, which is the primary molecular cause of FSHD.
Normally, DUX4 is epigenetically silenced. However, the deletion or contraction of certain repetitive elements (D4Z4 macrosatellite repeats) on chromosome 4 allows inappropriate activation of DUX4, resulting in muscle cell toxicity, inflammation, and progressive muscle degeneration characteristic of FSHD.
This mechanistic insight offers several potential therapeutic targets for FSHD:
- Direct suppression of DUX4 gene expression or its regulatory elements. CRISPR-mediated targeting of a distal regulatory element of DUX4 has been shown to repress the expression of DUX4 target genes involved in FSHD pathology, suggesting gene editing approaches to silence DUX4 as promising therapies.
- Modulating downstream effects or damage caused by DUX4 toxicity. For example, gene therapy using adeno-associated virus to deliver follistatin—a natural inhibitor of myostatin (a negative regulator of muscle growth)—has increased muscle mass and strength in DUX4-expressing mouse models. This approach does not modulate DUX4 itself but mitigates muscle weakness caused by its expression, representing a potential adjunct treatment.
- Targeting the epigenetic regulators that maintain repression of DUX4, such as factors involved in heterochromatin formation, might restore normal silencing and prevent DUX4 activation.
The findings, published online on August 19 in the journal Science, settle a longstanding question about the roots of FSHD. The genetic defect at the root of FSHD was first identified in 1992 by a team from the same laboratory in Leiden.
The latest research was funded by several organizations, including the Fields Center for FSHD and Neuromuscular Research, based at Rochester and at Leiden, the Netherlands Organization for Scientific Research, the Netherlands Genomic Initiative NOW, the U.S. National Institutes of Health, the Muscular Dystrophy Assn., the Shaw Family Foundation, a Marjorie Bronfman Fellowship grant from the FSH Society, the Pacific Northwest Friends of FSH Research, the Centro Investigación Biomédica en Red para Enfermedades Neurodegenerativas, the Basque Government, and the Instituto Carlos III.
The team plans to screen existing compounds in a search for one that inhibits DUX4. With this discovery, researchers now have a clear target to develop treatments or even potential cures for FSHD, either by eliminating the root cause (DUX4 expression) or counteracting its toxic effects on muscle tissue.
- This groundbreaking health research, published in Science, provides new insights into the science behind Facioscapulohumeral muscular dystrophy (FSHD), a medical-condition affecting thousands of people worldwide.
- The discovery sheds light on the role of the de-repression and aberrant expression of the toxic DUX4 gene in muscle cells, which is the primary cause of FSHD and falls under the umbrella of neurological-disorders.
- In light of these findings, strategies for health-and-wellness, fitness-and-exercise may not be the primary focus for FSHD management, as the research suggests potential therapies targeting the DUX4 gene and its regulatory elements.
