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Understanding a human disease gene using zebrafish genetic models

How zebrafish have been used in our research to better understand a human disease gene associated with skin and pigment diseases.

5 day old zebrafish embryo
A 5 day old normal (wild-type) Zebrafish embryo

In humans, diseases affecting pigment cells are rather common, for example: albinism, melanoma and vitiligo. One such important class of diseases are the Waardenburg syndromes in which patients have large areas of skin devoid of pigment cells, while the rest of the skin is normal.

One gene associated with Waardenburg syndrome is called SOX10, and it can readily be recognised as encoding a protein that drives the expression of many target genes. The question that remained unanswered, however, was what is the main purpose of those target genes i.e. what biological process does SOX10 perform?

We identified the first zebrafish models for the type of Waardenburg syndrome associated with SOX10, and showed that they were in fact caused by mutations in the zebrafish sox10 gene. In subsequent work we have identified the common theme in the role of Sox10 in pigment cells, but also in other cell types that share a common stem cell origin.

Our work, confirmed in mammalian models, shows that SOX10 seems to function primarily to direct stem cells to develop into specific individual cell types, including pigment cells and neurons.

We are now extending this work, in collaboration with a consortium of human and mouse geneticists, trying to understand why the human conditions associated with SOX10 mutations have very variable disease effects, sometimes mild, sometimes very severe.

We have developed a zebrafish embryo-based phenotypic rescue assay to assess the activities of the mutant forms of the human SOX10 protein, and are now attempting to engineer humanised’ zebrafish mutants to assess more precisely their effects in vivo.

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