Research areas
Myopathy
From diagnosis to treatment
We investigate the genetic causes, mechanisms of disease, and potential therapies for a range of muscle diseases (myopathies), using the advantages of the zebrafish model system for in vivo imaging, genetic manipulation, and screening to accomplish these goals. The process of muscle development, and the genes involved, are highly conserved between zebrafish and humans, therefore the zebrafish provides an excellent model system in which to study myopathies. When candidate novel disease genes are identified it is necessary to confirm their role in disease, and we achieve this through the use of advanced genome editing tools to introduce similar genetic changes into the zebrafish and then examine muscle structure and function.
Identifying disease mechanisms
Whilst the genetic causes are known in many cases the mechanisms by which mutations in these genes result in disease are poorly understood. We use the advantages of the zebrafish model system, allowing genetic manipulation and in vivo imaging to investigate the onset and progression of disease and determine the processes that are disrupted resulting in muscle weakness.
Identifying potential therapies
Using our understanding of the disease mechanisms we can then explore potential therapies. For example, we have used our models to identify that autophagy is disrupted in many forms of myofibrillar myopathy, a finding we have confirmed in patient samples. As a result we conducted a drug screen with autophagy promoting drugs and identified metformin as a potential therapy.
Neuropathy
In addition to our work on muscle disease we investigate neuropathies, cerebellar ataxias, and atrophies, testing candidate genes to identify the genetic basis of disease and explore the role of these genes in the function of the nervous system.
Genes required for neurogenesis and the function of the nervous system are very highly conserved between zebrafish and human, allowing us to study these disorders in the zebrafish model. We can examine a wide range of pathologies and phenotypes in the fish including the formation of the nervous system, the innervation of the muscle by motor neurons (above), and the neuromuscular junction (right).
Variant testing
Currently less than 50% of individuals with inherited disease receive a genetic diagnosis, even after multigene panel/exome analysis. While some of the missing diagnoses may be due to genes not yet associated with the disease, in more than 40% of individuals tested one or more variants of unknown significance (VUS) are reported.
High-throughput in vivo analysis
We are developing zebrafish-based approaches to test the functional impact of these variants in vivo. These methods allow rapid assessment of gene function, and phenotypic consequences in a vertebrate system, enabling genetic diagnosis.