Bryson-Richardson Research Group

Research impact

Zebrafish and DNA representing functional validation of a disease gene

Validating novel disease genes to enable diagnosis and treatment

 Damaged muscle fibres transitioning to restored muscle structure

Identifying a potential treatment for BAG3 myofibrillar myopathy

Diagnosis and future therapies

Validating novel disease genes to enable diagnosis and treatment

One of our goals is to understand the genetic basis of disease. For many individuals and families, the cause of their condition remains unknown even after comprehensive genetic testing.

One example began when our collaborators identified changes in HMGCS1 in five people from four unrelated families with rigid spine syndrome but no known genetic cause. Rigid spine syndrome is a rare childhood-onset muscle disorder that can cause weakness, stiffness of the spine, scoliosis, and serious breathing difficulties.

Unaffected hmgcs1 zebrafish sibling compared with an hmgcs1 mutant zebrafish
Loss of hmgcs1 causes severe early abnormalities in zebrafish compared with unaffected siblings.

We carried out the zebrafish studies needed to test whether these genetic changes disrupted gene function. Zebrafish lacking hmgcs1 developed severe early abnormalities, including greatly reduced movement and early death. Introducing normal human HMGCS1 restored these defects. In contrast, the HMGCS1 variants identified in affected individuals were much less effective at restoring normal development and movement.

This functional evidence was essential to confirm that the variants were disease-causing. It established HMGCS1 as a new disease gene, providing a genetic explanation for these families and a basis for diagnosis in future families with similar symptoms.

HMGCS1 is part of the mevalonate pathway, which produces molecules required for normal cell function. We then tested whether supplying mevalonic acid, a downstream product of this pathway, could improve the zebrafish phenotype. Treatment increased survival, reduced the severity of abnormalities, and improved swimming ability in the disease model.

Together, these results provide a new genetic diagnosis, a model for understanding the disease, and early evidence that a targeted therapeutic approach may be worth investigating further.

Publication: HMGCS1 variants cause rigid spine syndrome amenable to mevalonic acid treatment in an animal model, Brain.

Disease biology and drug repurposing

Identifying a potential treatment for BAG3 myofibrillar myopathy

BAG3 myofibrillar myopathy is a severe childhood-onset muscle condition caused by changes in the BAG3 gene. It leads to progressive muscle weakness and the breakdown of muscle fibres. There is currently no established treatment.

We created zebrafish models of BAG3 myofibrillar myopathy to understand how these genetic changes cause disease. Our studies showed that the altered BAG3 protein forms aggregates within muscle cells. These aggregates trap normal BAG3 protein, leaving too little functional BAG3 available for the cell.

BAG3 normally helps cells clear damaged proteins through a process called autophagy. Using our zebrafish models, we found that this process is impaired as functional BAG3 is lost, leading to muscle fibre breakdown and weakness.

Muscle fibres in an untreated bag3 mutant zebrafish and a metformin-treated bag3 mutant zebrafish
Metformin treatment improves muscle fibre structure in bag3 mutant zebrafish.

This discovery suggested a potential treatment strategy: improving autophagy to clear protein aggregates and support muscle health. We screened a panel of compounds that promote autophagy in our zebrafish models and identified metformin as particularly effective. Metformin reduced protein aggregates, preserved muscle fibre structure, and improved swimming ability in affected fish.

To test whether these findings were relevant beyond the zebrafish model, we worked with an international team of clinicians and researchers. Together, we confirmed impaired autophagy in muscle samples from people with BAG3 myofibrillar myopathy and showed that metformin reduced protein aggregation in human muscle cells. Evidence of altered autophagy in other forms of myofibrillar myopathy also suggests that this approach may have relevance beyond BAG3-related disease.

These results identify a biological process that contributes to muscle weakness in BAG3 myofibrillar myopathy and provide early evidence that an existing medicine may offer a path towards future treatment. Because metformin is already widely used in clinical care, repurposing it could provide a faster route to clinical translation than developing an entirely new medicine.

Publications: Zebrafish models of BAG3 myofibrillar myopathy suggest a toxic gain of function leading to BAG3 insufficiency, Acta Neuropathologica; Metformin rescues muscle function in BAG3 myofibrillar myopathy models, Autophagy.