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Whether it’s a new gene in which mutations cause a rare disease, or a novel gene pathway involved in a complex trait, we are interested in identifying the potential biological mechanisms that link the genotype to the disease phenotype. We are using both in vitro (cell) and in vivo (zebrafish) models to characterise our genetic findings functionally, towards unraveling the biological bases of genetic disease.

Modelling genetic diseases in zebrafish 

Zebrafish provide an excellent laboratory model to understand the aetiology of many human genetic diseases.Zebrafish have a high number (over 80%) of disease-causing genes in common with humans, allowing many diseases to be modelled in the fish. Thus, zebrafish serve as an excellent replacement to study developmental biology compared to higher vertebrates. Zebrafish produce hundreds of eggs per adult female are easy to genetically manipulate providing large datasets for genetic and statistical analyses. Zebrafish eggs are transparent, allowing development to be carefully studied under the microscope.

Dr Dan Osborn and his team have been modelling muscle and nerve diseases in zebrafish. They have recently shown that mutations in INPP5K, a gene that encodes inositol polyphosphate-5-phosphatase K, are responsible for a rare inherited form of congenital muscular dystrophy. Through modelling the disease in zebrafish they have been able to prove that genetic changes in inpp5k lead to a diseased muscle pathology. They are currently using the zebrafish to tease out the mechanism of inpp5k action. Furthermore, they are using the zebrafish model to screen for molecules that can rescue the observed muscle phenotypes, offering potential future therapeutics for patients.

Molecular mechanisms of mitochondrial gene expression disorders

Defects in mitochondrial protein synthesis are a common cause of mitochondrial disease. Dr Chris Carroll and his team identified a mutation in the gene MRPL44, a component of the mitochondrial ribosome, to be novel genetic cause of infantile cardiomyopathy (Carroll et al JMG 2013). The precise function of MRPL44 and many other mitochondrial ribosomal units have not been well characterised. They are using the cutting edge technique of CRISPR/Cas9 genome editing in human cell lines to gain a more complete understanding of how defects in mitochondrial ribosomal subunits lead to human mitochondrial disorders.

 

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