Dysfunctional gene may hold key to muscular dystrophy breakthrough

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Discovery of the underlying mechanism of the Schmd1 gene, responsible for some cases of muscular dystrophy, is likely to advance research into potential treatments for this currently untreatable debilitating disease.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant degenerative disease characterized by muscle wasting and often asymmetrical muscle weakness. Skeletal muscle of the face, scapula and upper arms is involved.  The disease usually manifests in teens and becomes increasingly debilitating as the disease progresses.

Melbourne researchers based at the Walter and Eliza Hall Institute (Victoria, Australia) sought to investigate the gene Smchd1, which functions abnormally in FSHD2. The team duplicated the genetic mutations found in some patients to elucidate how these genetic changes lead to disease.

When asked about the findings of the study, co-author Kelan Chen explained, “We reproduced in the lab the genetic change to Smchd1 found in one of the families to better understand how this mutation alters Smchd1 and its ability to function in the cell. We discovered that just a single change to one molecule that makes up the DNA can affect the ability of Smchd1 to reach and bind to the DNA properly, and it is no longer able to do its job.”

Smchd1, colloquially known as ‘Smooch’ by the researchers encodes an epigenetic factor that suppresses gene expression by switching genes off. Although it was already known that Schmd1 was an epigenetic suppressor, Marnie Blewitt, Laboratory Head in Molecular Medicine at the Walter and Eliza Hall Institute, explained that they “were in the dark about where and how it was acting on the DNA.”

The results were not what the authors were expecting. “Smchd1 is enormous, I think of it as a massive ‘Goliath’ molecule,” Blewitt said. “So I had expected that this Goliath molecule would be greedy and crude, spreading out across the DNA to ‘exert its power’.

“In fact the opposite was true. Smchd1 is still a Goliath, but it very delicately squeezes itself into a tiny ‘seat’ on the DNA. It binds at just a few discrete sites on the DNA, then draws these pieces together to ‘shield’ them from being activated.”

The authors hope that understanding the fundamental functions of Smchd1 and how certain mutations affect its function will advance translational research into potential treatments for FSHD. At risk patients could be genetically tested and the gene manipulated to prevent muscles from degenerating. Blewitt is optimistic that, “…we could in the long term develop drugs that would substitute for its activity and prevent the debilitating muscle wasting which occurs in FSHD.”

Source: Gene discovery could lead to muscular dystrophy treatment: www.wehi.edu.au/news/gene-discovery-could-lead-muscular-dystrophy-treatment