Exploring genotype-phenotype correlations in Sox10 mutations

SOX10 is a crucial developmental transcription factor, with roles in neural crest derivatives including melanocytes, Schwann cells and glia, as well as some non-crest derivatives such as oligodendrocytes and cells of the inner ear.
Over 100 SOX10 mutations have been reported in humans, which can cause a wide range of syndromes, including Waardenburg syndrome, characterised by pigment loss and sensorineural deafness, and Hirschsprung's disease, caused by a lack of enteric nerves in the gut. SOX10 mutant phenotypes can overlap, and patients can present with various combinations of symptoms. At present, the correlations between genotype and phenotype are unclear for SOX10. It is possible that the variations in phenotypes are caused by gain of function effects of mutations, or by the combinations of these mutations with additional modifier loci. The aim of the project is to create a series of zebrafish mutant sox10 alleles, selected from those seen in humans.
The mutations will be engineered using a precise-genome-editing (PGE) CRISPR/Cas9 protocol, that employs a single-stranded DNA donor along with chemical modulations to create the edit. Zebrafish sox10 mutant lines that are successfully established will be phenotypically analysed on a cellular level, to understand the impact that different mutations have on individual cell types.
The project will aid understanding of the function of sox10, as well as the relationship between structure and function.
The project is funded by BBSRC and falls within its research theme "Advancing the Frontiers of Biosciences Discovery" and its sub-theme "Understanding the rules of life", as the overall goal of the PhD project is to better understand the function of Sox10. The use, development, and improvement of the PGE CRISPR/Cas9 protocol throughout the project also fits in with the BBSRC's support of "tools and technology underpinning biological research".